WO2008079988A2 - Quinazolines for pdk1 inhibition - Google Patents

Quinazolines for pdk1 inhibition Download PDF

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Publication number
WO2008079988A2
WO2008079988A2 PCT/US2007/088392 US2007088392W WO2008079988A2 WO 2008079988 A2 WO2008079988 A2 WO 2008079988A2 US 2007088392 W US2007088392 W US 2007088392W WO 2008079988 A2 WO2008079988 A2 WO 2008079988A2
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Prior art keywords
substituted
phenyl
ylamino
methyl
ylammo
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Application number
PCT/US2007/088392
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French (fr)
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WO2008079988A9 (en
WO2008079988A3 (en
Inventor
Savithri Ramurthy
Xiaodong Lin
Sharada Subramanian
Alice C. Rico
Xiaojing M. Wang
Rama Jain
Jeremy M. Murray
Steven E. Basham
Robert L. Warne
Wei Shu
Yasheen Zhou
Jeffrey Dove
Mina Aikawa
Payman Amiri
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Novartis Ag
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Publication date
Priority to EA200900819A priority Critical patent/EA200900819A1/en
Priority to MX2009006627A priority patent/MX2009006627A/en
Priority to CA002673003A priority patent/CA2673003A1/en
Priority to BRPI0720563-5A priority patent/BRPI0720563A2/en
Application filed by Novartis Ag filed Critical Novartis Ag
Priority to JP2009543225A priority patent/JP2010514693A/en
Priority to EP07869660A priority patent/EP2125755A2/en
Priority to AU2007336893A priority patent/AU2007336893A1/en
Priority to US12/448,390 priority patent/US20100216767A1/en
Publication of WO2008079988A2 publication Critical patent/WO2008079988A2/en
Publication of WO2008079988A3 publication Critical patent/WO2008079988A3/en
Priority to IL198774A priority patent/IL198774A0/en
Priority to TNP2009000255A priority patent/TN2009000255A1/en
Priority to SM200900055T priority patent/SMP200900055B/en
Priority to NO20092725A priority patent/NO20092725L/en
Publication of WO2008079988A9 publication Critical patent/WO2008079988A9/en

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    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
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Definitions

  • the present invention generally relates to small molecule inhibitors of 3- phosphomositide-dependent kinase (PDK1/PDPK1)
  • the compounds can be used as therapeutics in the treatment of cellular proliferative diseases
  • BACKGROUND PDKl (3-Phosphoinositide-dependent kinase 1) is a se ⁇ ne/threomne kinase belonging to the AGC kinase super family PDKl was first identified as the upstream kinase responsible for activating protein kinase B/AKT in the presence of phosphomositide lipids (PIP 3 ) PDKl activates AKT by phosphorylatmg a specific residue (threonine 308) located in the activation loop of this kinase Subsequent research has shown that PDKl is responsible for phosphorylatmg the activation-loop of many AGC kinases including p90 ⁇ bosomal S6 kinase (RSK), protein kinase C family members (PKC), p70 ⁇ bosomal S6 kinase (70S6K), and the serum and glucocorticoid-induced protein kinas
  • the human PDKl gene encodes a 556 ammo acid protein with an ammo-terminal catalytic domain and a non-catalytic carboxy terminal containing a pleckst ⁇ n homology domain (PH)
  • PH pleckst ⁇ n homology domain
  • PDKl is a constitutively active kinase, and that PDKl regulation occurs through the localization or conformational state of PDKl target proteins
  • the PH domain of PDKl is required for the binding OfPIP 3 lipids produced by PBkinase (PI3K)
  • PI3K PBkinase
  • PDKl binding of PP 3 lipids results in membrane co- locahzation with AKT, another PH domain containing protein
  • PDKl activates AKT by phosphorylatmg threonine308
  • PDKl can activate other AGC kinases independent of PIP 3 lipids by bindmg directly to a conserved
  • PDKl is a central activator of several signaling pathways that are frequently altered in human cancers making it an attractive target for therapeutic intervention
  • the present invention provides PDKl inhibitors that are useful as therapeutic agents, for the treatment of diseases and disorders characterized by abnormal cellular proliferation, for example cancers of the prostate, lung, colon, breast, among others
  • the present invention provides, inter aha, compounds of Formula I
  • the present invention further provides compositions comprising a compound of Formula I and at least one pharmaceutically acceptable earner
  • the present invention further provides methods of inhibiting PDKl or a PDKl variant in a patient comprising administering to said patient, a therapeutically effective amount of a compound of the invention, or pharmaceutically acceptable salt, ester, or tautomer thereof
  • the present invention further provides methods of treating a disease characte ⁇ zed by abnormal cellular proliferation in a patient comprising administering to said patient a therapeutically effective amount of a compound of the invention, or pharmaceutically acceptable salt, ester, or tautomer thereof
  • the present mvention further provides methods of inhibiting the tumor growth in a patient, the method comprising admimste ⁇ ng to said patient a therapeutically effective amount of a compound of the invention, or pharmaceutically acceptable salt, ester, or tautomer thereof
  • the present invention further provides methods of treating cancer in a patient, the method comp ⁇ sing administering to said patient a therapeutically effective amount of a compound of the invention, or pharmaceutically acceptable salt, ester, or tautomer thereof
  • the present invention further provides a compound of the invention, or pharmaceutically acceptable salt, ester, or tautomer thereof for use in therapy
  • the present mvention further provides a compound of the mvention, or pharmaceutically acceptable salt, ester, or tautomer thereof for use in the preparation of a medicament for use in therapy
  • Figure 1 provides the chemical structures and activity data for Examples 177-681
  • Figure 2 provides the chemical structures and activity data for Examples 682-1185
  • the column marked "Activity” indicates the compound's activity in the PDKl Kinase Alpha Screen Assay
  • the symbol “*” indicates that IC 50 value is greater than 0 30 ⁇ M
  • the symbol “**” indicates that IC 50 value is less than or equal to 0 30 ⁇ M but greater than 0 10 ⁇ M
  • the symbol “***” indicates that IC 50 value is less than or equal to 0 10 ⁇ M but greater than 0 05 ⁇ M
  • the symbol "****” indicates that IC 50 value is less than or equal to 0 05 ⁇ M
  • the invention provides compounds that have the Formula I
  • Ar is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, including fused bicyclic systems,
  • R 1 is H, Ci 3 alkyl, halo, cyano, mtro, CF 3 , lmidazolyl, thiazolyl, oxazolyl, or amino
  • R 2 and R 3 are independently selected from the group consisting of H, alkoxy, substituted alkoxy, and halo
  • L is a covalent bond, carbonyl, carbonylammo, armnocarbonyl, -O-, -S-, -SO-, -SO 2 -, -NH-, Ci 3 alkyl, substituted Ci 3 alkyl, or an alkyl interrupted with -O-, -S-, -SO-, -SO 2 -, -NH-, carbonyl, carbonylammo, or ammocarbonyl, and A 1 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylammo, acyloxy, amino, substituted ammo, ammocarbonyl, aminothiocarbonyl, ammocarbonylamino, aminothiocarbonylamino, ammocarbonyloxy, aminosulfonyl, ammosulfonyloxy, ammosulfony
  • R 1 , R 2 , and R 3 are each H and L is a covalent bond
  • a 1 is other than aryl or substituted aryl
  • R 1 , R 2 , and R 3 are each H
  • L is a covalent bond
  • a 1 is Br, substituted phenyl, or substituted py ⁇ dinyl
  • Ar is other than phenyl, phenyl substituted with piperazmyl or heterocyclylalkyloxy, or pyndmyl
  • R 1 , R 2 , and R 3 are each H, L is a covalent bond, and A 1 is hydroxy or alkoxy, then Ar is other than phenyl substituted with one or more alkyl or halo
  • R 1 , R 2 , and R 3 are each H and L is O, then A 1 is other than pyndmyl or substituted pyndmyl
  • the invention provides compounds that have the Formula I
  • Ar is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, including fused bicyclic systems,
  • R 1 is H, Ci 3 alkyl, halo, cyano, mtro, CF 3 , lmidazolyl, thiazolyl, oxazolyl, or amino
  • R 2 is selected from the group consisting of H, alkoxy, substituted alkoxy, alkyl, substituted alkyl, CN, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, and halo
  • R 3 is selected from the group consisting of H, halo, CN, carboxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, cycloalkyloxy, substituted cycloalkyloxy, heterocyclylalkyloxy, substituted heterocyclylalkyloxy, heteroaryloxy, substituted heteroaryloxy, heteroaryl alkyloxy, substituted heteroarylalkyloxy, arylalkyloxy, substituted
  • L is a covalent bond, carbonyl, carbonylamino, aminocarbonyl, -O-, -S-, -SO-, -SO 2 -, -NH-, Ci 3 alkyl, substituted Ci 3 alkyl, C 2 3 alkenyl, C 2 3 alkynyl or an alkyl interrupted with -O-, -S-, -SO-, -SO 2 -, -NH-, carbonyl, carbonylamino, or aminocarbonyl, and A 1 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, ammocarbonylammo, aminothiocarbonylammo, aminocarbonyloxy, aminosulfonyl, ammosulfonyloxy,
  • R 1 , R 2 , and R 3 are each H and L is a covalent bond, then A 1 is other than aryl or substituted aryl
  • R 1 , R 2 , and R 3 are each H, L is a covalent bond, and A 1 is Br, substituted phenyl, or substituted py ⁇ dmyl, then Ar is other than phenyl, phenyl substituted with piperazinyl or heterocyclylalkyloxy, or pyndmyl
  • R 1 , R 2 , and R 3 are each H, L is a covalent bond, and A 1 is hydroxy or alkoxy, then Ar is other than phenyl substituted with one or more alkyl or halo
  • R 1 , R 2 , and R 3 are each H and L is O, then A 1 is other than pyndinyl or substituted py ⁇ dinyl
  • L is a covalent bond
  • a 1 is an optionally substituted alkyne or an optionally substituted heterocyclyl or heteroaryl
  • Preferred alkynes include ethyne, 1-propyne, 3-hydroxypropyne, and 3-methoxypropyne, as well as other 3-alkoxypropynes
  • Preferred heteroaryls for these embodiments include thiazole, pyridine, imidazole, furan, 1,2,3-t ⁇ azole, 1,2,4-t ⁇ azole, pyrazole, isothiazole, oxazole, and isoxazole, each of which can be substituted
  • Specific heteroaryls for these embodiments include 2-thiazolyl, 5-hydroxymethyl-2-thiazolyl, 3-py ⁇ dyl, 5-methoxy-3- py ⁇ dyl, 6-ammo-3-pyridyl, 4-thiazolyl, 3-pyrazolyl, and 4-pyrazolyl Preferred heterocyclyl groups include
  • Some specific embodiments include compounds wherein A 1 is selected from the following group
  • L is -O- According to some embodiments, L is -S-
  • L is -SO 2 -
  • L is NH
  • L is carbonyl
  • L is ammocarbonyl or carbonylammo According to some embodiments, L is carbonyl ammo According to some embodiments, L is aminocarbonyl
  • L is an alkyl interrupted with -O-, -S-, -SO-, -SO 2 -, -NH-, carbonyl, carbonylammo or aminocarbonyl
  • a 1 is alkyl Accordmg to some embodiments, A 1 is substituted alkyl According to some embodiments, A 1 is alkenyl Accordmg to some embodiments, A 1 is substituted alkenyl According to some embodiments, A 1 is alkynyl
  • a 1 is ethynyl, propynyl, phenylethynyl or py ⁇ dylethynyl
  • a 1 is substituted alkynyl According to some embodiments, A 1 is alkoxy Accordmg to some embodiments, A 1 IS substituted alkoxy
  • a 1 is acyl Accordmg to some embodiments, A 1 is cyano Accordmg to some embodiments, A 1 is aryl According to some embodiments, A is substituted aryl According to some embodiments, A 1 is substituted phenyl
  • a 1 is heteroaryl According to some embodiments, A 1 is substituted heteroaryl Accordmg to some embodiments, the heteroaryl or substituted heteroaryl is selected from the group consisting of py ⁇ dyl, pyrazolyl, thiazolyl, py ⁇ midyl, pyndazinyl, oxazolyl, isoxazolyl, substituted py ⁇ dyl, substituted pyrazolyl, substituted thiazolyl, substituted py ⁇ midyl, substituted py ⁇ dazinyl, substituted oxazolyl and substituted isoxazolyl According to some embodiments, A 1 is cycloalkyl According to some embodiments, A 1 is substituted cycloalkyl Accordmg to some embodiments, A 1 is heterocyclyl According to some embodiments, A 1 is substituted heterocyclyl
  • the heterocyclyl or substituted heterocyclyl is selected from the group consisting of pipendmyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, morpholmyl, thiomorpholino, substituted pipendmyl, substituted piperazinyl, substituted pyrrolidmyl, substituted tetrahydrofuranyl, substituted tetrahydrothiophenyl, substituted morpholinyl and substituted thiomorpholino
  • a 1 is hydroxy
  • a 1 is halo According to some embodiments, A is cyano
  • -L-A 1 is -Br, -C ⁇ CH, -C ⁇ N, 2-thiazolyl, or 1-methylimidazol- 2-yl
  • R 1 is H, Ci 3 alkyl, halo, cyano, mtro, CF 3 or amino
  • R 1 is H, Ci 3 alkyl, halo, cyano, mtro or amino According to some embodiments, R 1 is H, Ci 3 alkyl, halo, cyano, imidazolyl, thiazolyl, oxazolyl or ammo
  • R 1 is H, Ci 3 alkyl, halo or cyano
  • R 1 is H, Ci 3 alkyl, or halo
  • R 1 is H or halo According to some embodiments, R 1 is H
  • R 1 is halo
  • R 2 and R 3 are independently selected from the group consisting of H, alkoxy, substituted alkoxy, and halo,
  • R 2 and R 3 are independently selected from the group consisting of H, halo and alkoxy
  • R 2 and R 3 are independently selected from the group consisting of H, and halo
  • R 2 and R 3 are independently selected from the group consisting of H and alkoxy According to some embodiments, R 2 and R 3 are independently selected from the group consisting of H and Ci 6 alkoxy
  • R 2 and R 3 are independently selected from the group consisting of H and methoxy
  • At least one of R 2 and R 3 is H According to some embodiments, both R 2 and R 3 are H
  • R 2 is H
  • R 3 is H
  • one of R 2 and R 3 is H and the other of R 2 and R 3 is alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, cycloalkyloxy, substituted cycloalkyloxy, heterocyclylalkyloxy, substituted heterocyclylalkyloxy, heteroaryloxy, substituted heteroaryloxy, heteroarylalkyloxy, substituted heteroarylalkyloxy, arylalkyloxy, or substituted arylalkyloxy
  • one of R 2 and R 3 is H and the other is arylalkoxy, alkoxy or substituted alkoxy, or a substituted or unsubstituted heteroaryloxy, heteroarylalkyloxy, heterocyclyloxy, or heterocyclylalkyloxy
  • R 2 is often H and R 3 is substituted or unsubstituted alkoxy or heterocyclyloxy group
  • R 2 is selected from H, F, Cl, Br, CN, CF 3 , methoxy, ethoxy, isopropoxy, 4-pipendinyloxy, 3-azetidinyloxy, and 2-aminoethoxy
  • R 3 is selected from
  • R 3 can be one of the following heterocyclyloxy groups
  • Ar is substituted aryl or substituted heteroaryl According to some embodiments, Ar is substituted aryl
  • Ar is aryl, substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, amino, substituted ammo, armnocarbonyl, ammothiocarbonyl, ammocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, ammosulfonyloxy, aminosulfonylamino, amidino, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guamdino, substituted
  • Ar is aryl substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of aminosulfonyl, aminocarbonyl, aryl, heteroaryl, heterocyclyl, amino, substituted amino, alkyl, halo, and cyano, wherein the alkyl, aryl, and heteroaryl moieties contained within any of the listed substituted aryl groups are optionally substituted by 1, 2, 3, 4 or 5 substituents mdependently selected from the group consisting of alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, ammo, substituted amino, aminocarbonyl, aminothiocarbonyl, ammocarbonylamino, aminothiocarbonylamino, ammocarbonyloxy, aminosulfonyl, ammosulfonyloxy, aminosulfonylamino, amidino, aryl, aryloxy, arylthio, carb
  • phenyl is substituted by 1 , 2 or 3 groups that are not attached to said phenyl ortho to the NH of formula I
  • Ar is of the formula
  • Q' is alkyl, alkoxy, halo, aryl, heteroaryl, aryloxy, heteroaryloxy, heterocyclyloxy, arylalkyl, heteroaryl, or heterocyclyloxy, each of which can be substituted, or Q' can be H, halo, CN, COOR', CONR' 2 , NR' 2 , S(O) q R', or S(O) q NR' 2 , where each R' is H or Ci-C 4 alkyl
  • Q' is H or halo or alkoxy
  • Q in these fused systems can be, for example
  • Ar is phenyl having either 1 or 2 substituents, or it is a phenyl with an additional ring fused to it Frequently, Ar is phenyl with a non-hydrogen substituent at one or both of the 'meta' positions of the phenyl ⁇ ng, i e , it is a 3-substituted phenyl or a 3,5-disubstituted phenyl In other embodiments, Ar is phenyl with a non-hydrogen substituent at one or both of positions 3 and 4, e g , it is a 4-substituted phenyl or a 3,4- disubstituted phenyl
  • Ar is heteroaryl
  • Ar is heteroaryl selected from the group consisting of pyrrolyl, furanyl, thiophenyl (thienyl), imidazolyl, pyrazolyl, oxazolyl, lsoxazolyl, thiazolyl, lsothiazolyl, 1,2,3-tnazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, py ⁇ dinyl, pyrazinyl, py ⁇ midinyl, py ⁇ dazmyl, t ⁇ azmyl, rndolyl, isoindole, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzothiazolyl, quinolmyl, lsoqumolyl, qumazolyl, qumozalyl, cinnolyl, pt
  • Ar is a heteroaryl group selected from the group consisting of 2- py ⁇ dmyl, 3-py ⁇ dinyl, 4-py ⁇ dmyl, 2-py ⁇ rmdinyl, 4-py ⁇ midmyl, 5- pyranidniyl, 1-pyrazolyl, 3-pyrazolyl, 4- ⁇ yrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5- oxazolyl, and 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl
  • Ar is aryl or heteroaryl, substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylammo, acyloxy, ammo, substituted ammo, aminocarbonyl, aminothi
  • Ar is aryl or heteroaryl, substituted by 1 , 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, acyl, acylammo, acyloxy, ammo, substituted ammo, aminocarbonyl, aminothiocarbonyl, ammocarbonylammo, ammothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, ammosulfonyloxy, ammosulfonylammo, amidino, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, gu
  • Ar is heteroaryl, substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, acyl, acylammo, acyloxy, amino, substituted ammo, aminocarbonyl, ammothiocarbonyl, ammocarbonylammo, aminothiocarbonylammo, ammocarbonyloxy, ammosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guamdmo, substitutedmo, substitute
  • Ar is heteroaryl substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of aminosulfonyl, aminocarbonyl, aryl, heteroaryl, heterocyclyl, amino, substituted amino, alkyl, halo, and cyano, wherein the alkyl, aryl, and heteroaryl moieties contained withm any of the listed substituted aryl groups are optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkenyl, alkynyl, alkoxy, acyl, acylammo, acyloxy, amino, substituted ammo, aminocarbonyl, ammotmocarbonyl, ammocarbonylammo, aminothiocarbonylamino, ammocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, aryloxy, arylthio, carboxy
  • the invention provides compounds that have the Formula I
  • Ar is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, including fused bicyclic systems
  • R 1 is H, Ci 3 alkyl, halo, cyano, mtro, CF 3 , lmidazolyl, thiazolyl, oxazolyl, or amino
  • R 2 and R 3 are independently selected from the group consisting of H, alkoxy, substituted alkoxy, and halo
  • L is a covalent bond, carbonyl, carbonylamino, aminocarbonyl, -O-, -S-, -SO-, -SO 2 -, -NH-, Ci -3 alkyl, substituted Ci -3 alkyl, or an alkyl interrupted with -O-, -S-, -SO-, -SO 2 -, -NH-, carbonyl, carbonylamino, or aminocarbonyl, and
  • a 1 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylammo, acyloxy, ammo, substituted ammo, aminocarbonyl, aminothiocarbonyl, aminocarbonylammo, aminothiocarbonyla ⁇ uno, aminocarbonyloxy, ammosulfonyl, aminosulfonyloxy, aminosulfonylammo, amidmo, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, mtro, SO 3 H, sulfonyl, substituted sulfonyl, sulfonyloxy, sulfonylammo, thioacyl, thiol, alkylthio, substituted alkylthio
  • compounds of the invention have Formulae II- VII
  • R p is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylammo, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylammo, aminothiocarbonylammo, aminocarbonyloxy, ammosulfonyl, aminosulfonyloxy, aminosulfonylammo, amidmo, aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio,
  • R A is selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl and substituted heterocyclyl,
  • Het is selected from the group consisting of heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl, and x is 1, 2, 3, 4 or 5
  • compounds of the invention have Formula II
  • R p is independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, ammo, substituted ammo, aminocarbonyl, aminothiocarbonyl, aminocarbonylammo, ammothiocarbonylamino, ammocarbonyloxy, ammosulfonyl, aminosulfonyloxy, ammosulfonylammo, amidino, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guamdmo, substituted guanidino, halo, hydroxy, heteroaryl
  • x is 1, 2 or 3
  • the isolated phenyl ⁇ ng m Formula II has no substituents ortho to the NH to which it is attached
  • Preferred substitution patterns for this phenyl ring include mono-substitution at the 3-position ('meta' to the NH), mono-substitution at the 4-position ('para' to the NH), and disubstitution at the 3 and 4 positions or at the 3 and 5 positions
  • R 1 is H
  • R 2 is substituted alkoxy
  • R 2 is substituted alkoxy, heterocyclyloxy, or heterocyclylalkoxy
  • R 2 is H
  • R 3 is substituted alkoxy such as heteroarylmethoxy Suitable heteroaryl groups in these compounds include pyrazole, imidazole, thiazole, pyridine, and pyrazole and py ⁇ midine
  • R 3 is heterocyclyloxy or heterocyclyl-subshtuted alkoxy such as heterocyclylmethoxy
  • R 3 is heterocyclyl-substituted alkoxy such as heterocyclylmethoxy
  • Suitable heterocyclyl groups for these embodiments include pipe ⁇ dinyl, pyrrolidmyl, tetrahydrofuranyl, and the like
  • R p is a group of the formula -O- CH 2 -C(O)-NR'R", where R' and R" are independently H, alkyl, or substituted alkyl, and R' and R" can join together to form a heterocyclic ⁇ ng hi other embodiments, R p is a heterocyclyl group such as piperazmyl, pipendmyl, morpholrnyl, or R p is a heterocyclyl- substituted alkyl such as piperazinylmethyl, morph
  • compounds of the invention have Formula III
  • R 1 , R 2 , R 3 , A 1 , R p and x are as defined above These correspond to compounds wherein L is a bond
  • R 1 , R 2 and R 3 is a group other than H Frequently, R 1 is H or halo, and either R 2 or R 3 is H while the other of R 2 and R 3 is a group selected from alkoxy, substituted alkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, and substituted heterocyclyloxy
  • compounds of the invention have Formula IV
  • R 1 , R 2 , R 3 , A 1 , R p and x are as defined above
  • compounds of the invention have Formula V
  • R 1 , R 2 , R 3 , R p and x are as defined above, and
  • R A is selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl and substituted heterocyclyl Frequently, R A is selected from H, methyl, hydroxymethyl, methoxymethyl, and other alkoxymethyl groups Often in these compounds, R 1 , R 2 , R 3 , R p and x are as described for the compounds of Formula II above
  • compounds of the invention have Formula VI
  • Het is selected from the group consisting of heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl Often in these compounds, R 1 , R 2 , R 3 , R p and x are as desc ⁇ bed for the compounds of Formula II above In some of these embodiments, L is a bond, -O-, -OCH 2 -, ammo, ammocarbonyl, or carbonylamino
  • compounds of the invention have Formula VII
  • R 1 , R 2 , R 3 , R p and x are as described for the compounds of Formula II above
  • Het in these compounds can be any heterocyclic or heteroaryl group, and sometimes it is selected from thiazole, oxazole, isothiazole, isoxazole, pyrazole, pyridine, tnazole, and furan
  • the column marked "Activity” indicates the compound's activity in the PDKl Kinase Alpha Screen Assay desc ⁇ bed below
  • the symbol “+” indicates IC 50 values of 25 ⁇ m or greater (or compounds not evaluated)
  • the symbol “++” indicates IC 50 values between less than 25 ⁇ m and greater than 10 ⁇ m
  • the symbol “+++” indicates IC 50 values of 10 ⁇ m or less and greater than 5 ⁇ m
  • the symbol “++++” indicates IC 50 values less than 5 ⁇ m Accordingly, as shown in Table I, 131 of the Example compounds, or about 75% of the Example compounds have been shown to demonstrate IC 50 values of less than 5 ⁇ m
  • the compounds of the invention are stable as used herein "stable” refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and preferably capable of formulation into an efficacious therapeutic agent It is further intended that the compounds of the invention are those that can be prepared by one skilled m the art according to the methods descnbed herein and any other suitable method, routine or otherwise Further provided are compounds of the invention and mixtures thereof where any asymmetric carbon atom(s) present can have either the R or S configuration Substituents at a double bond or a ⁇ ng of the compounds of formula I may be present in either the cis (-Z-) or trans (-E-) configurations The compounds may thus be present as mixtures of isomers, 5 diastereomers, and enantiomers or may be present as pure isomers In some embodiments, the compounds are enantiome ⁇ cally pure where only one enantiomer is present In other embodiments, the compound may be present as a mixture of
  • the compounds of the invention include various solid forms such as crystalline, microcrystalhne, nanocrystallme, and amorphous forms, as well as hydrated, solvated, anhydrous, and non-solvated forms
  • Isotopes include those atoms having the same atomic number but different mass numbers
  • isotopes of hydrogen include t ⁇ tium and allegedum
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N,
  • isotopes are particularly preferred for their ease of preparation and detectability Further, substitution with heavier isotopes such as linium, i e , 2 H, may 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
  • Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out known or referenced procedures and by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent
  • the compounds of the invention, and their salts, esters, tautomers, etc are isolated
  • isolated or “substantially isolated” is meant that the compound is at least partially or substantially separated from the environment in which is was formed or discovered
  • Partial separation can include, for example, a composition enriched in the compound of the invention
  • Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, and at least about 99% by weight of the compound of the invention, or salt thereof
  • Methods for isolating compounds and their salts and other de ⁇ vatives are routine in the art
  • the present invention further provides prodrugs of the compounds desc ⁇ bed herein
  • prodrugs refer to any covalently bonded earners which release the active parent drug when administered to a mammalian subject
  • Prodrugs can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds
  • Prodrugs include compounds wherein hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, ammo, sulfhydryl, or carboxyl group respectively
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate de ⁇ vatives of alcohol and amine functional groups in the compounds of the invention
  • Preparation and use of prodrugs is discussed in T Higuchi and V Stella, "Pro-drugs as Novel Delivery Systems," VoI 14 of the A C S Symposium Se ⁇ es, and in Bioreversible Carriers in Drug Design,
  • compositions include a therapeutically effective amount of a compound of the invention ( ⁇ e , a compound of Formula I) and at least one pharmaceutically acceptable carrier
  • compositions that include the compounds desc ⁇ bed herein may include additives such as pharmaceutically acceptable earners or excipients
  • suitable pharmaceutically acceptable earners include processing agents and drug delivery modifiers and enhancers, such as, for example, calcium phosphate, magnesium stearate, talc, monosacchandes, disacchandes, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl- ⁇ -cyclodext ⁇ n, polyvinylpyrrohdinone, low melting waxes, ion exchange resms, and the like, as well as combinations of any two or more of these Other suitable pharmaceutically acceptable earners are desc ⁇ bed in Remington The Science And Practice Of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD, 21st ed (May 28, 2005), which is hereby incorporated herein by reference in its entirety and for all purposes as if fully set forth herein
  • compositions that include the compounds of the invention maybe in any form suitable for the intended method of administration, including, for example, as a solution, a suspension, or an emulsion Liquid earners are typically used in prepanng solutions, suspensions, and emulsions
  • Liquid earners contemplated for use in the practice of the present invention include, for example, water, saline, pharmaceutically acceptable organic solvent(s), pharmaceutically acceptable oils or fats, and the like, as well as mixtures of two or more of these
  • the liquid earner may include other suitable pharmaceutically acceptable additives such as solubihzers, emulsifiers, nutnents, buffers, preservatives, suspending agents, thickening agents, viscosity regulators, stabilizers, and the like
  • Suitable orgamc solvents include, for example, monohydnc alcohols, such as ethanol, and polyhydnc alcohols, such as glycols
  • Suitable oils include, but are not limited to, soybean oil, coconut oil
  • liposomes are generally denved from phospholipids or other lipid substances Liposomes are formed by mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium Any non-toxic, physiologically acceptable and metabohzable lipid capable of forming liposomes can be used
  • the present compositions in liposome form may include, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like
  • Preferred lipids include phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic Methods of forming liposomes are known in the art See, for example, Prescott, Ed , Methods in Cell Biology, Volume XIV, Academic Press, New York, N W , p 33 et seq (1976)
  • Controlled release delivery systems may also be used, such as a diffusion controlled matnx system or an erodible system, as descnbed for example in Lee, "Diffusion-Controlled Matnx Systems", pp 155-198 and Ron and Langer, “Erodible Systems", pp 199-224, in
  • the matrix may be, for example, a biodegradable material that can degrade spontaneously in situ and in vivo for, example, by hydrolysis or enzymatic cleavage, e g , by proteases
  • the delivery system may be, for example, a naturally occurring or synthetic polymer or copolymer, for example m the form of a hydrogel
  • Exemplary polymers with cleavable linkages include polyesters, polyorthoesters, polyanhydrides, polysacchandes, poly(phosphoesters), polyamides, polyurethanes, poly(imidocarbonates) and poly(phosphazenes)
  • the compounds of the invention may be administered enterally, orally, parenterally, sublingually, by inhalation spray, rectally, or topically in dosage unit formulations that include conventional nontoxic pharmaceutically acceptable earners, adjuvants, and vehicles as desired
  • suitable modes of administration mclude oral, subcutaneous, transdermal, transmucosal, lontophoretic, intravenous, intramuscular, intraperitoneal, intranasal, subdermal, rectal, and the like
  • Topical administration may also include the use of transdermal administration such as transdermal patches or ionophoresis devices
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, mtrasternal injection, or infusion techniques
  • Injectable preparations for example, ste ⁇ le injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents
  • the ste ⁇ le injectable preparation may also be a ste ⁇ le injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution m 1,3-propanediol
  • a nontoxic parenterally acceptable diluent or solvent for example, as a solution m 1,3-propanediol
  • the acceptable vehicles and solvents that may be employed are water, Rmger's solution, and isotomc sodium chloride solution hi addition
  • ste ⁇ le, fixed oils are conventionally employed as a solvent or suspending medium
  • any bland fixed oil may be employed including synthetic mono- or diglyce ⁇ des
  • fatty acids such as oleic acid find use in the preparation of mjectables
  • Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nomr ⁇ tating excipient such as cocoa butter and polyethylene glycols that are solid at ordinary temperatures but liquid at the rectal temperature and will, therefore, melt in the rectum and release the drug
  • Solid dosage forms for oral administration may mclude capsules, tablets, pills, powders, and granules
  • the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch
  • Such dosage forms may also include, as is normal practice, additional substances other than inert diluents, e g , lubricating agents such as magnesium stearate
  • the dosage forms may also include buffering agents Tablets and pills can additionally be prepared with ente ⁇ c coatings
  • Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs contaming inert diluents commonly used in the art, such as water
  • Such compositions may also comp ⁇ se adjuvants, such as wetting agents, emulsifying and suspending agents, cyclodextnns, and sweetening, flavoring, and perfuming agents
  • the amount of active ingredient that may be combined with the earner materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration It will be understood, however, that the specific dose level for any particular patient will depend upon a va ⁇ ety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and seventy of the particular disease undergoing therapy.
  • the therapeutically effective amount for a given situation can be readily determined by routine expenmentation and is within the skill and judgment of the ordinary clinician
  • the compounds of the invention can be admimstered to a patient in combination with one or more further pharmaceutical agents
  • Administration of the different agents can be made separately either sequentially or simultaneously, or the agents can be admimstered together in a single composition
  • Example further pharmaceutical agents include anti-cancer drugs including chemotherapeutics and other kinase inhibiting compounds
  • Aryl or refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single nng or multiple condensed nngs
  • Non-hmitmg examples of aryl groups include phenyl, naphthyl, anthryl, and the like
  • Substituted aryl refers to aryl groups which are substituted with 1 to 5, or 1 to 3, or 1 to 2 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, amino, substituted ammo, aminocarbonyl, aminothiocarbonyl, amino- carbonylamrno, aminothiocarbonylammo, ammocarbonyloxy, ammosulfonyl, ammosulfonyl- oxy, ammosulfonylammo, amidmo, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenyl
  • Substituted aryloxy refers to the group -O-(substituted aryl) where substituted aryl is as defined herein
  • Arylthio refers to the group — S-aryl, where aryl is as defined herein "Substituted arylthio” refers to the group -S-(substituted aryl), where substituted aryl is as defined herein
  • Alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms or from 1 to 6 carbon atoms This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH 3 -), ethyl (CH 3 CH 2 -), »-propyl (CH 3 CH 2 CH 2 -), isopropyl ((CH 3 J 2 CH-), n-butyl (CH 3 CH 2 CH 2 CH 2 -), isobutyl ((CH 3 J 2 CHCH 2 -), .sec-butyl ((CH 3 )(CH 3 CH 2 )CH-), tfjutyl ((CHs) 3 C-), n-pentyl (CH 3 CH 2 CH 2 CH 2 CH 2 -), and neopentyl ((CH 3 J 3 CCH 2 -)
  • Substituted alkyl refers to an alkyl group having from 1 to 5, or 1 to 3, or 1 to 2 substituents selected from the group consistmg of alkoxy, acyl, acylammo, acyloxy, ammo, substituted amino, ammocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, ammocarbonyloxy, ammosulfonyl, aminosulfonyloxy, aminosulfonylammo, amidmo, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl esterjammo, (carboxyl esterjoxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guanidmo, substituted guamdino,
  • Substituted alkoxy refers to the group -O-(substituted alkyl) wherein substituted alkyl is defined herein
  • Acyl refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocychc-C(O)-, and substituted heterocyclic-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substituted
  • Acylammo refers to the groups -NRC(O)alkyl, -NRC(O)substituted alkyl, -NRC(O)cycloalkyl, -NRC(O)substituted cycloalkyl, -NRC(0)cycloalkenyl, -NRC(O)substiruted cycloalkenyl, -NRC(O)alkenyl, -NRC(O)substituted alkenyl,
  • R is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein
  • Acyloxy refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O-, alkynyl-C(O)O-, substituted alkynyl-C(O)O-, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, cycloalkenyl-C(0)0-, substituted cycloalkenyl-C(O)O-, heteroaryl-C(O)O-, substituted heteroaryl-C(O)O-, heterocychc-C(O)O-, and substituted heterocychc-C(O)O- wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted substituted
  • “Ammo” refers to the group -NH 2 "Substituted amino” refers to the group -NR'R" where R' and R" are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, -S ⁇ 2 -alkyl, -SCh-alkenyl, -SC ⁇ -cycloalkyl, -SO 2 - cycloalkenyl, -S ⁇ 2 -aryl, -S ⁇ 2 -heteroaryl, and -S ⁇ 2 -heterocychc, wherein R' and R" are optionally joined, together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that R' and R" are both not hydrogen, wherem the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cyclo
  • R' is hydrogen and R" is alkyl
  • the substituted amino group is sometimes referred to herein as alkylamino
  • R' and R" are alkyl
  • the substituted ammo group is sometimes referred to herein as dialkylamino
  • referring to a monosubstituted amino it is meant that either R' or R" is hydrogen but not both
  • R' nor R" are hydrogen
  • “Ammocarbonyl” refers to the group -C(O)N R 10 R 11 where R 10 and R 11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 10 and R 11 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted
  • Aminothiocarbonyl refers to the group -C(S)NR 10 R 11 where R 10 and R 11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 10 and R 11 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted substituted
  • “Ammocarbonylammo” refers to the group -NRC(O)NR 10 R 11 where R is hydrogen or alkyl and R 10 and R 11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 10 and R n are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloal
  • Aminothiocarbonylamino refers to the group -NRC(S)NR 10 R 11 where R is hydrogen or alkyl and R 10 and R 11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 10 and R 11 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloal
  • “Ammocarbonyloxy” refers to the group -0-C(O)NR 10 R 11 where R 10 and R 11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 10 and R 11 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted
  • Aminosulfonyl refers to the group -SO 2 NR 10 R 11 where R 10 and R 11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 10 and R 11 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted substituted
  • Aminosulfonyloxy refers to the group 0-SO 2 NR 10 R 11 where R 10 and R 11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 10 and R 11 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted
  • Substituted alkenyl refers to alkenyl groups having from 1 to 3 substituents, or from 1 to 2 substituents, selected from the group consisting of alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, ammothiocarbonyl, aminocarbonylammo, amino- thiocarbonylamino, aminocarbonyloxy, aminosulfonyl, ammosulfonyloxy, ammosulfonyl- amino, amidino, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guamdmo, substituted guanidmo,
  • Substituted alkynyl refers to alkynyl groups having from 1 to 3 substituents, and, in some embodiments, 1 to 2 substituents, selected from the group consisting of alkoxy, acyl, acylammo, acyloxy, ammo, substituted amino, ammocarbonyl, aminothiocarbonyl, ammocarbonylammo, ammothiocarbonylamino, aminocarbonyloxy, ammosulfonyl, ammosulfonyloxy, ammosulfonylammo, amidino, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)ammo, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guamd
  • Carboxyl or “carboxy” refers to -COOH or salts thereof
  • Carboxyl ester or “carboxy ester” refers to the groups -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-alkenyl, -C(O)O-substituted alkenyl, -C(O)O-alkynyl, -C(O)O-substituted alkynyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)O-cycloalkyl, -C(O)O-substituted cycloalkyl, -C(O)O-cycloalkenyl, -C(O)O-substituted cycloalkenyl, -C(O)O-heteroaryl, -C(O)
  • (Carboxyl ester)amino refers to the group -NR-C(O)O-alkyl, substituted -NR-C(O)O-alkyl, -NR-C(O)O-alkenyl, -NR-C(O)O-substituted alkenyl, -NR-C(O)O-alkynyl, -NR-C(O)O-substituted alkynyl, -NR-C(O)O-aryl,
  • R is alkyl or hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted
  • (Carboxyl ester)oxy refers to the group -O-C(O)O-alkyl, substituted -O-C(O)O-alkyl, -O-C(O)O-alkenyl, -O-C(O)O-substituted alkenyl, -O-C(O)O-alkynyl, -O-C(O)O-substituted alkynyl, -O-C(O)O-aryl, -O-C(O)O-substituted aryl,
  • alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined here
  • Cycloalkyl refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single 5 or multiple cyclic rings including fused, b ⁇ dged, and spiro ring systems Cycloalkyl groups can include Also included in the definition of cycloalkyl are moieties that have one or more aromatic ⁇ ngs fused (i e , having a bond in common with) to the cycloalkyl ⁇ ng, for example, benzo de ⁇ vatives of cyclopentane, cyclopentene, cyclohexane, and the like A cycloalkyl group having one or more fused aromatic ⁇ ngs can be attached though either the aromatic or o non-aromatic portion One or more ring-forming carbon atoms of a cycloalkyl group can be oxidized, for example, having an oxo or sulfido substituent Examples of suitable cycloalkyl groups include, for instance, adamantyl,
  • Substituted cycloalkyl and “substituted cycloalkenyl” refers to a cycloalkyl or cycloalkenyl group having from 1 to 5 and, in some embodiments, 1 to 3 substituents selected from the group consisting of oxo, thione, alkyl, alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, ammo, substituted ammo, ammocarbonyl, atmnothiocarbonyl, aminocarbonylammo,0 aminothiocarbonylammo, ammocarbonyloxy, aminosulfonyl, aminosulfonyloxy, amino- sulfonylamino, amidmo, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)- ammo, (carboxyl ester)oxy, cyano, cyclo
  • Substituted cycloalkyloxy refers to -O-(substituted cycloalkyl)
  • Cycloalkylthio refers to -S-cycloalkyl
  • Substituted cycloalkylthio refers to -S-(substituted cycloalkyl)
  • Cycloalkenyloxy refers to -O-cycloalkenyl
  • Substituted cycloalkenyloxy refers to -O-(substituted cycloalkenyl)
  • Cycloalkenylthio refers to -S-cycloalkenyl
  • Substituted cycloalkenylthio refers to -S-(substituted cycloalkenyl)
  • Halo or “halogen” refers to fluoro, chloro, bromo and iodo
  • Hydroxyloxy or "hydroxyl” refers to the group -OH
  • Heteroaryl refers to an aromatic group of from 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur withm the ⁇ ng
  • Such heteroaryl groups can be monocyclic, 1 e , have a single ⁇ ng (e g , py ⁇ dmyl or fbryl) or polycyclic, 1 e , having multiple condensed rings (e g , lndolizmyl or benzothienyl) wherein the condensed ⁇ ngs may or may not be aromatic and/or contain a heteroatom provided that the point of attachment is through an atom of the aromatic heteroaryl group
  • the mtrogen and/or the sulfur ⁇ ng atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N ⁇ O), sulfinyl, or sulfonyl moieties
  • Monocyclic heteroaryls include without limitation, pyrrolyl, furany
  • Substituted heteroaryl refers to heteroaryl groups that are substituted with from 1 to 5, and, in some embodiments, 1 to 3, and, m some embodiments, 1 to 2 substituents selected from the group consisting of the same group of substituents defined for substituted aryl
  • Heteroaryloxy refers to -O-heteroaryl
  • Substituted heteroaryloxy refers to the group -O-(substituted heteroaryl)
  • Heteroarylthio refers to the group — S-heteroaryl
  • Substituted heteroarylthio refers to the group -S-(substituted heteroaryl) "Heterocycle” or “heterocyclic” or “heterocycloalkyl” or “heterocyclyl” refers to a non-aromatic heterocycle where one or more of the nng-formmg atoms is a heteroatom such as an O, N, or S atom Heterocycloalkyl groups can include mono- or polycyclic (e g , having 2, 3 or 4 fused ⁇ ngs) ⁇ ng systems as well as spirocycles
  • Example "heterocycloalkyl” groups include morpholino, thiomorpholmo, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3- dihydrobenzofuryl, 1,3-benzodioxole, benzo-l,4-dioxane, pipendinyl,
  • Substituted heterocyclylthio refers to the group -S-(substituted heterocyclyl)
  • heterocycles include, but are not limited to, azetidine, mdohzine, dihydroindole, indazole, qumohzine , isothiazole, isoxazole, phenoxazme, phenofhiazme, lmidazolidine, imidazoline, pipe ⁇ dine, piperazine, lndolme, phthalirmde, 1,2,3,4- tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazolidme, morphohnyl, thiomorpholinyl (also referred to as thiamorpholinyl), 1,1-dioxothiomorpholmyl, pipendmyl, pyrrolidine, tetrahydrofuranyl, and the like "
  • “Sulfonyl” or “sulfone” refers to the divalent group -S(O) 2 - "Substituted sulfonyl” refers to the group -SC> 2 -alkyl, -S ⁇ 2 -substituted alkyl, -SO 2 - alkenyl, -SO ⁇ -substituted alkenyl, -SC ⁇ -cycloalkyl, -S ⁇ 2 -substituted cycloalkyl, -SO 2 - cycloalkenyl, -S ⁇ 2 -substituted cycloalkenyl, -S ⁇ 2 -aryl, -S ⁇ 2 -substituted aryl, -SO 2 - heteroaryl, -S ⁇ 2 -substituted heteroaryl, -S ⁇ 2 -heterocyclic, -S ⁇ 2 -substituted heterocyclic, wherein alky
  • “Sulfonyloxy” refers to the group -OSO 2 -alkyl, -OSO 2 -substituted alkyl, -OSO 2 - alkenyl, -OSO 2 -substituted alkenyl, -OSO 2 -cycloalkyl, -OSO 2 -substituted cycloalkyl, -OSO 2 - 5 cycloalkenyl, -OSO 2 -substituted cylcoalkenyl,-OSO 2 -aryl, -OSO 2 -substituted aryl, -OSO 2 - heteroaryl, -OSO 2 -substituted heteroaryl, -OSO 2 -heterocyclic, -OSO 2 -substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted al
  • Thioacyl refers to the groups H-C(S)-, alkyl-C(S)-, substituted alkyl-C(S)-, alkenyl-C(S)-, substituted alkenyl-C(S)-, alkynyl-C(S)-, substituted alkynyl-C(S)-, cycloalkyl-C(S)-, substituted cycloalkyl-C(S)-, cycloalkenyl-C(S)-, substituted cyclo- alkenyl-C(S)-, aryl-C(S)-, substituted aryl-C(S)-, heteroaryl-C(S)-, substituted hetero-5 aryl-C(S)-, heterocyclic-C(S)-, and substituted heterocychc-C(S)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkyl,
  • Thiol refers to the group -SH 0
  • Thiocarbonyl refers to the divalent group -C(S)- which is equivalent to -C( ⁇ S)-
  • Alkylthio refers to the group -S-alkyl wherein alkyl is as defined herein "Substituted alkylthio" refers to the group -S-(substituted alkyl) wherein substituted alkyl is as defined herein 5
  • an alkyl interrupted with -O-, -S-, -SO-, -SO 2 -, -NH-, carbonyl, carbonylammo, or aminocarbonyl refers to an alkyl group wherein one divalent carbon unit, i e , a methylene (-CH 2 -) in the alkyl group is replaces by one of the listed divalent moieties
  • substituents of compounds of the invention are disclosed in groups or in ranges It is specifically intended that the invention0 include each and every individual subcombmation of the members of such groups and ranges
  • the term "Ci 6 alkyl” is specifically intended to individually disclose methyl, ethyl, C 3 alkyl (propyl and isopropyl), C 4 alkyl, C 5 alkyl, and C(, alkyl
  • arylalkyloxycabonyl refers to the group (aryl)-(alkyl)-O-C(O)-
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, mate ⁇ als, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human bemgs and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxyhc acids, and the like
  • the pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two, generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or A
  • tautomer or “tautomer thereof is meant to refer to any tautome ⁇ c form of a compound of the invention
  • Tautome ⁇ c forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton
  • Tautome ⁇ c forms include prototropic tautomers which are isomenc protonation states having the same empi ⁇ cal formula and total charge
  • Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, IH- and 3H-imidazole, IH-, 2H- and 4H- 1,2,4-t ⁇ azole, IH- and 2H- lsomdole, and IH- and 2H-pyrazole Tautomeric forms can be m equilibrium or
  • treating refers to (1) inhibiting a disease, for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder, (2) preventing the disease, for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease, (3) delaying recurrence of the disease, for example, increasing the duration of a pe ⁇ od of remission in a proliferative disorder such as a cancer, or (4) ameliorating the disease, for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder
  • Treatment of a patient is typically carried out by administration of a compound of the invention to the patient in a pharmaceutically effective amount
  • a “subject,” “individual” or “patient” is meant to describe a human or vertebrate animal including, for example, a dog, cat, horse, cow, pig, sheep, goat, monkey, owl, rat, and mouse
  • the "subject,” “individual” or “patient” is human
  • the "subject,” “individual” or “patient” is in need of treatment, that is, the patient can be afflicted with, is likely to be afflicted with, or might be afflicted with a disease which is treatable by administration of a compound of the invention, or pharmaceutically acceptable salt, ester, or tautomer thereof, or composition comprising the same
  • the phrase "therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is bemg sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician, such as prevent or inhibit a particular disease or medical disorder
  • the compounds of the invention are useful for human or veterinary use where, for example, inhibition of PDKl or inhibition of PDKl variants is indicated, such as in the treatment of various diseases associated with abnormal PDKl signaling and/or abnormal signaling upstream or downstream of PDKl (or variants thereof), such as that related to up- regulated activity of one or more receptor tyrosine kinases, Ras, PDK, PDKl, AKT, RSK, PKC, 70S6K, or SGK
  • the compounds of the invention are useful m inhibiting PDKl variants wherein the wild type PDKl contains one or more point mutations, insertions, or deletions
  • Example PDKl variants include as PDK1 T354M and PDK1 D527E
  • PDKl is meant to refer to wild type PDKl
  • PDKl variant or “variant of PDKl” is meant to refer to PDKl having at least one point mutation, insertion, or deletion
  • the compounds of the invention can be used in the treatment of diseases characterized by "abnormal cellular proliferation "
  • abnormal cellular proliferation includes, for example, any disease or disorder characterized by excessive or pathologically elevated cell growth such as is characteristic of various cancers and non- cancer proliferative disorders
  • Example cancers include, for example, lung cancer, bronchial cancer, prostate cancer, breast cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, thyroid cancer, liver cancer, intrahepatic bile duct cancer, hepatocellular cancer, gast ⁇ c cancer, glioma/glioblastoma, endometrial cancer, melanoma, kidney cancer, renal pelvic cancer, urinary bladder cancer, utenne corpus cancer, uterine cervical cancer, ovarian cancer
  • Example non-cancer proliferative disorders include neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis, proliferative diabetic retinopathy (PDR), hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, angiogenesis, and endotoxic shock
  • PDR proliferative diabetic retinopathy
  • the compounds of the invention are used to treat cancers of the prostate, lung, colon, and breast.
  • the present invention further provides methods of inhibiting tumor growth m a patient by administration of a compound of the invention, or salt, ester or tautomer thereof hi some embodiments, the tumor is characterized by elevated receptor tyrosine kinase, Ras, PI3K, PDKl, AKT, RSK, PKC, 70S6K, or SGK activity
  • the present invention further provides methods of treating cancer in a patient by administering to the patient a therapeutically effective amount of a compound of the invention, or pharmaceutically acceptable salt, ester, or tautomer thereof
  • the cancer is characte ⁇ zed by activity of PDKl
  • the cancer is charactenzed by activity of a PDKl variant such as PDKl T354M or PDKl D527E
  • the present invention provides methods for inhibition of Cdkl and/or Cdk2 Another embodiment provides a methods of treating diseases such as cancer which are responsive to inhibition of Cdkl and/or Cdk2 by administering a compound of the invention to a patient In further embodiments, the invention provides methods of inhibiting phosphorylation of Akt by administering a compound of the invention to a human m need thereof Another embodiment provides a method of treating diseases such as cancer which are responsive to inhibition of phosphorylation of Akt, by administering a compound of the invention to a patient Another embodiment provides a method of inhibiting phosphorylation of Akt comprising contacting a cell with a compound of the invention
  • Example compounds and their analogs can be synthesized by one skilled in the art from procedures described herein, as well as in patents or patent applications listed herein which are all hereby incorporated by reference in their entireties and for all purposes as if fully set forth herein
  • the compounds and/or intermediates were characterized by high performance liquid chromatography (HPLC) using a Waters Millemum chromatography system with a 2695 Separation Module (Milford, MA)
  • HPLC high performance liquid chromatography
  • the analytical columns were reversed phase Phenomenex Luna C18 -5 ⁇ , 4 6 x 50 mm, from Alltech (Deerfield, IL)
  • a gradient elution was used (flow 2 5 niL/min), typically starting with 5% acetonitnle/95% water and progressing to 100% acetomt ⁇ le over a penod of 10 minutes
  • AU solvents contained 0 1 % t ⁇ fluoroacetic acid (TFA)
  • UV ultraviolet light
  • HPLC solvents were from Burdick and Jackson (Muskegan, MI), or Fisher Scientific (Pittsburgh, PA)
  • TLC thin layer chromatography
  • glass or plastic backed silica gel plates such as, for example, Baker-Flex Silica Gel 1B2-F 5 flexible sheets
  • TLC results were readily detected visually under ultraviolet light, or by employing well known iodme vapor and other vanous staining techniques
  • Method A employed a Waters System (Alliance HT HPLC and a Micromass ZQ mass spectrometer for the LCMS 10 instrument, an Eclipse XDB-C 18, 2 1 x 50 mm for the chromatography column, and a solvent system that was a 5-95% gradient of acetomt ⁇ le in water with 0 05% TFA over a 4 mm penod (flow rate 0 8 niL/min molecular weight range 200-1500, cone Voltage 20 V, column temperature 40°C)
  • Method B employed a Hewlett Packard System (Se ⁇ es 1100 HPLC and a Micromass ZQ mass spectrometer for the LCMS instrument, an Eclipse XDB-C18, 2 1 x 15 50 mm for the chromatography column, and a solvent system that was a 5-95% gradient of acetonit ⁇ le m water with 0
  • Step 1 and Step 2 were earned out in one pot
  • a mixture of the starting material (4- (6-bromo-8-methoxyquinazolm-2-ylammo)benzenesulfonamide, synthesized following Example 1, 67 mg), ethynylt ⁇ methylsilane (0 12 mL), copper(I) iodide (6 mg), 1,1'- bis(diphenylphosphmo)ferrocenedichloro palladium(II) (12 mg), TEA (0 8 mL) and DMF (0 8 mL) was microwaved at 120 0 C for 6 mm LC/MS showed complete conversion of starting material to 4-(8-methoxy-6-((tnmethylsilyl)ethynyl)qumazolin-2-ylamino)benzene- sulfonamide
  • THF 0. 8 mL
  • tetramethylammoruum fluoride 60 mg
  • Step 6 N-(3-(6-Bromo-8-chloroqu ⁇ nazol ⁇ n-2-ylam ⁇ no)-5-((d ⁇ methylam ⁇ no)methyl)phenyl)- acetamide
  • 6-bromo-2,8-dichloroquinazohne (0 175 g), N-(3-amino-5-((dimethyl- amino)methyl)phenyl)acetamide (1 equiv ) and HCl in dioxane (1 equiv ) in isopropanol (2 5 mL) was heated to 75 0 C for 16 hrs
  • the resulting mixture was diluted with water, washed with ethyl acetate to remove organic impurities, basified the aqueous portion with sodium bicarbonate (aq ) to pH 9, and then brine was added
  • the basified aqueous solution was extracted with chloroform (3X)
  • the organic extracts were combined, washed with b ⁇ ne, d
  • Example 8 4-(8-Bromo-6-(trifluoromethyI)quinazolin-2-ylamino)benzenesulfonamide The subject compound was prepared according to the general Scheme 8, below
  • Step 2 8-Bromo-6-(tnfluoromethyl)-l,4-d ⁇ hydroqu ⁇ nazohne-2,4-d ⁇ ol, 8-3
  • Step 4 4-(8-bromo-6-(tnfluoromethyl)qu ⁇ nazohn-2-ylam ⁇ no)benzenesulfonam ⁇ de
  • Step 2 4-(6-Ethynylqu ⁇ nazol ⁇ n-2-ylam ⁇ no)benzenesulfonam ⁇ de
  • tetramethylammonium fluoride (1 5 eq)
  • the reaction was stirred for 30 mm at ambient temperature Volatiles were removed under reduced pressure, and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate The organic phase was d ⁇ ed over sodium sulfate, filtered, and concentrated
  • the crude material was purified by reverse-phase HPLC, and lyophihzed to give the desired compound as its t ⁇ fluoroacetic acid salt ES/MS m/z 325 (MH + )
  • Example 10 To the product of Example 10 was added [l,l'-bis(di ⁇ henyl ⁇ hos ⁇ hino)ferrocene]- dichloro ⁇ alladium(II) complex with DCM (0 10 eq) and a 0 5M solution of 2-thiazolyl zinc bromide in THF (3 0 eq) The reaction was microwaved at 120 °C for 10 mm The mixture was then diluted with ethyl acetate and washed with aqueous EDTA pH ⁇ 9 buffer The organic phase was dried over sodium sulfate, concentrated, purified by reverse-phase HPLC, and lyophihzed to give the desired compound as its t ⁇ fluoroacetic acid salt ES/MS m/z 390 (MH + )
  • Example 13 4-(6-Cyanoquinazolin-2-ylamino)-iV-isopropylbenzamide
  • step 1 using 2-amino-5-bromo-6-chloro-3-methoxybenzoic acid in place of 2-ammo-5-bromobenzoic acid ES/MS m/z 268 (MH + )
  • step 3 using 2-ammo-5-bromo-6-chloro-3- methoxybenzaldehyde in place of 2-ammo-5-bromobenzaldehyde ES/MS m/z 291 (MH + )
  • Step 6 6-Bromo-2,5-d ⁇ chloro-8-methoxyqu ⁇ nazol ⁇ ne Analogous to Example 9, step 4 using 6-bromo-5-chloro-2-hydroxy-8- methoxyqumazoline in place of 6-bromo-2-hydroxyqumazohne ES/MS m/z 309 (MH + )
  • Step 7 N-(3-(6-Bromo-5-chloro-8-methoxyqu ⁇ nazohn-2-ylam ⁇ no)-5-((d ⁇ methylam ⁇ no)- methyl)phenyl)acetam ⁇ de
  • 6-bromo-2,5-dichloro-8-methoxyquinazolme m 2-propanol was added 7V-(3-ammo-5-((dimethylamino)methyl)phenyl)acetamide (1 0 eq) and 4 OM HCl in dioxane (1 2 eq)
  • the reaction was stirred at 70 0 C for 14 h
  • the mixture was then concentrated and the resulting residue was used without further purification
  • the crude mate ⁇ al was purified by reverse-phase HPLC and lyophihzed to yield the desired product as its t ⁇ fluoroacetic acid salt ES/MS m/z 480 (MH + )
  • Step 2 (3,5-D ⁇ n ⁇ trophenyl)-4,4,5,5-tetramethyl-l,3,2-d ⁇ oxaborolane
  • Step 5 N-(3-(6-Bromoqu ⁇ nazol ⁇ n-2-ylam ⁇ no)-5-(l-methyl-6-oxo-l, 6-d ⁇ hydropyr ⁇ d ⁇ n-i-yl)- phenyl)acetam ⁇ de
  • Example 17 7V-(3-(6-EthynyIquinazolin-2-ylamino)-5-(l-methyl-6-oxo-l,6-dihydro- pyridin-3-yl)phenyl) acetamide
  • Example 18 Methyl 2-(4-sulfamoylphenylamino)quinazolin-6-carboxylate The subject compound was prepared according to the general Scheme 18, below
  • Step 2 4-(6-(l-Isobutyl-lH-pyrazol-4-yl)qu ⁇ nazol ⁇ n-2-ylam ⁇ no)benzenesulfonam ⁇ de To a solution of 2-(4-sulfamoylphenylamino)quinazohn-7-yltnfluoromethane
  • Step 4 (4-(5-Chloro-6-hydroxyqu ⁇ nazol ⁇ n-2-ylam ⁇ no)phenyl)(morphol ⁇ no)methanone 5
  • isopropanol 4-amino- phenyl)(morpholino)methanone (leq) and the reaction mixture was heated to 90 0 C for Ih
  • the reaction went to completion by LC/MS
  • the mixture was then concentrated and used without further purification ES/MS m/z 386(MH + )
  • Step 6 (4-(5-Chloro-6-ethynylqu ⁇ nazohn-2-ylam ⁇ no)phenyl)(morphohno) methanone
  • Example 25 iV-(3-(6-Bromo-5-fluoroquinazolin-2-ylamino)-5-(morpholinomethyl)- phenyl) acetamide
  • the subject compound was prepared according to the general Scheme 25 below
  • the second product of the reaction was identified as N-(4-morpholmophenyl)-5,6-di (thiazole-2-yl) qumazolin-2-amine ES/MS m/z 473 0(MH + )
  • Example 32 ⁇ r -(3-(6-Bromoquinazolin-2-ylamino)-5-(pyridine-3-yl) phenyl) acetamide;
  • Step 2 6, 7-D ⁇ methoxyqu ⁇ nazohn-2-ol
  • 2-amino-4, 5-dimethoxybenzaldehyde (leq) obtained from step 1
  • urea 15 eqmv
  • the reaction was cooled to RT and water was added A solid precipitate formed and was collected by filtration, and air-d ⁇ ed to give 6,7-dimethoxyqumazolm-2-ol as a brown solid in 40%yield ES/MS m/z
  • Step 4 4-(6, 7-D ⁇ methoxyqu ⁇ nazol ⁇ n-2-ylam ⁇ no) benzenesulfonamide
  • 2-chloro-6,7-dimethoxyquinazolme (leq) and 4-ammobenzenesulfon- amide (leq) in isopropanol was heated at 90 0 C for 16h
  • Step 6 6-Bromo-7-methoxyqu ⁇ nazol ⁇ n-2-ol
  • 2-amino-5-bromo-4-methoxybenzaldehyde, 36-3, (leq) and urea (14eq) was heated to 180 0 C in an oil bath under Argon for 2 h Water was added after cooling to ambient temperature The solid was collected by filtration and air dried to give product in 90% yield ES/MS m/z 255/257 (MH + )
  • Step 8 4-(6-Bromo-7-methoxyqu ⁇ nazohn-2-ylam ⁇ no)benzenesulfonam ⁇ de
  • Step 2 4-(6-Am ⁇ noqu ⁇ nazol ⁇ n-2-ylam ⁇ no)benzenesulfonam ⁇ de, 37-1
  • Example 135 ⁇ r -(3-(6-Bromo-8-fluoroquinazolin-2-ylamino)-5-((dimethylainino)- methyl)phenyl)acetamide
  • the subject compound was prepared according to the general Scheme 38 below
  • Step 6 N ⁇ (3-(6-Bromo-8-fluoroqu ⁇ nazol ⁇ n-2-ylam ⁇ no)-5-((d ⁇ methylam ⁇ no)methyl)phenyl)- acetamide
  • Example 139 7V-(3-((Dimethylamino)methyl)-5-(6-ethynyl-8-fluoroquinazolin-2-ylamino)- phenyDacctainidc
  • the subject compound was prepared according to the general Scheme 39 below
  • Step 3 Sonogashira & desilylatwn
  • the product from Step 2 was treated analogously to Example 281 step 2 and earned on to Step 4 without purification
  • Example 220 3-morpholino-5-(8-(piperidin-4-yloxy)-6-(lH-pyrazol-4-yl)quinazolin-2- ylamino)benzamide
  • Step 1 Displacement To a 0 3OM solution of the product from Example 283 step 1 in 2-propanol was added 3-carboxamido-5-morpholinoamline (1 0 eq) The reaction was stirred at 100 0 C for 14 h The crude mixture was concentrated and used without further purification
  • Step 1 Negishi To the product of Example 284 step 1 was added zmc(II) cyanide (4 0 eq) and [1,1'- bis(diphenylphosphmo)ferrocene]dichloropalladium(II) complex with DCM (0 10 eq) The reaction was microwaved at 130 °C for 10 mm The mixture was diluted with ethyl acetate and washed with aqueous EDTA ⁇ H ⁇ 9 buffer The organic phase was d ⁇ ed over sodium sulfate, and concentrated to give the desired product Step 2 Deprotection
  • Step 2 3 (6-bromonaphthalen-2-ylam ⁇ no)-5-(l-methyl-lH-pyrazol-4-yl)phenol
  • Step 5 6-ethynyl-N-(3-(l-methyl-lH-pyrazol-4-yl)-5-(2-(pyrrohdm-l- yl)ethoxy)phenyl)qu ⁇ nazol ⁇ n-2-am ⁇ ne
  • Example 536 6-ethvnyl-N-(3-(l-methyl-lH-pyrazol-4-yl)-5-(pyridin-2- vlnieth()xy)phe ⁇ yl)quinazolin-2-aniine
  • Step 1 N-(3-(l -methyl IH pyrazol-4-yl)-5-(pyr ⁇ d ⁇ n-2-ylmethoxy)phenyl)-6- ((tnmethyls ⁇ lyl)ethynyl)qu ⁇ nazohn-2-am ⁇ ne
  • Step 2 6-ethynyl-N-(3-(l-methyl-lH-pyrazol-4-yl)-5-(pyr ⁇ dm-2- ylmethoxy)phenyl)qu ⁇ nazol ⁇ n-2-am ⁇ ne
  • Step 3 tert-butyl 2-(3-am ⁇ no-5-(l-methyl-lH-pyrazol-4-yl)phenoxy)ethylcarbamate Analogous to Example 459, stepl but using tert-butyl 2-(3-(l-methyl-lH-pyrazol-4- yl)-5-mtrophenoxy)ethylcarbamate as starting material ES/MS m/z 333(MH + )
  • Step 6 N-(3-(2-am ⁇ noethoxy)-5-(l-methyl-lH-pyrazol-4-yl)phenyl)-6- ((tnmethyls ⁇ lyl)ethynyl)qu ⁇ nazol ⁇ n-2-am ⁇ ne
  • Step 7 N-(3-(2-am ⁇ noethoxy)-5-(l-methyl-lH-pyrazol-4-yl)phenyl)-6-ethynylqu ⁇ nazohn-2- amine
  • Step 8 N-(2-(3-(6-ethynylqu ⁇ nazohn-2-ylam ⁇ no)-5-(l-methyl-lH-pyrazol-4-
  • Step 2 (R)-tert-butyl l-(2-(3-(6-ethynylqu ⁇ nazohn-2-ylam ⁇ no)-5-(l-methyl-lH-pyrazol-4- yl)phenoxy)ethylam ⁇ no)-l-oxopropan-2-y ⁇ carbamate
  • Step 3 (R)-2-am ⁇ no-N-(2-(3-(6-ethynylqumazol ⁇ n-2-ylam ⁇ no)-5-(l-methyl-lH-pyrazol-4- yl)phenoxy)ethyl)propanam ⁇ de
  • Step 1 3-fluoro-N-(2-(3-(l-methyl-lH-pyrazol-4-yl)-5-(6-((tr ⁇ methyls ⁇ lyl)ethynyl)qu ⁇ nazohn- 2-ylam ⁇ no)phenoxy)ethyl)p ⁇ col ⁇ nam ⁇ de
  • Step 2 N-(2-(3-(6-ethynylqu ⁇ nazohn-2-ylam ⁇ no)-5-(l-methyl-lH-pyrazol-4- yl)phenoxy)ethyl)-3-fluorop ⁇ col ⁇ nam ⁇ de
  • 6 M NaOH O 100 ml, 0 60 mmol
  • the crude reaction mixture was purified by the addition of DMF about 0 7 ml, filtered, purified on prep HPLC and lyophihzed to give, N-(2- (3-(6-ethynylquinazolin-2-ylammo)-5-(l-methyl-lH-pyrazol-4-yl)phenoxy)ethyl)-3- fluoropicolinamide as TFA salt (6 3 mg) ES/MS m/z 508
  • Example 506 N-(2-(3-(6-ethynyIquinazolin-2-yIamino)-5-(l-methyl-lH-pyrazol-4- yl)phenoxy)ethyl)-2-(piperidin-l-yl)acetamide

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Abstract

The invention provides novel compounds that are inhibitors of PDK1. Also provided are pharmaceutical compositions including the compounds, and methods of treating proliferative diseases, such as cancers, with the compounds or compositions.

Description

QUINAZOLINES FOR PDKl INHIBITION
FIELD OF THE INVENTION
The present invention generally relates to small molecule inhibitors of 3- phosphomositide-dependent kinase (PDK1/PDPK1) In some embodiments, the compounds can be used as therapeutics in the treatment of cellular proliferative diseases
BACKGROUND PDKl (3-Phosphoinositide-dependent kinase 1) is a seπne/threomne kinase belonging to the AGC kinase super family PDKl was first identified as the upstream kinase responsible for activating protein kinase B/AKT in the presence of phosphomositide lipids (PIP3) PDKl activates AKT by phosphorylatmg a specific residue (threonine 308) located in the activation loop of this kinase Subsequent research has shown that PDKl is responsible for phosphorylatmg the activation-loop of many AGC kinases including p90 πbosomal S6 kinase (RSK), protein kinase C family members (PKC), p70 πbosomal S6 kinase (70S6K), and the serum and glucocorticoid-induced protein kinase (SGK) Thus, PDKl is a central activator of multiple signaling pathways that are involved m cell proliferation, survival and control of apoptosis Importantly, alterations m these signaling pathways are frequently observed m a variety of human cancers For example, AKT is highly activated in a large percentage of common tumor types including melanoma, breast, lung, prostate and ovarian cancers RSK levels are elevated in prostate cancers, and an RSK-specific inhibitor (SLOlOl) has recently been shown to inhibit the proliferation of multiple prostate cancer cell lines Similarly, PKCε has been shown to play an important role in regulating apoptosis and promoting survival of glioma cells
The human PDKl gene encodes a 556 ammo acid protein with an ammo-terminal catalytic domain and a non-catalytic carboxy terminal containing a pleckstπn homology domain (PH) Recent studies suggest that PDKl is a constitutively active kinase, and that PDKl regulation occurs through the localization or conformational state of PDKl target proteins For example, the PH domain of PDKl is required for the binding OfPIP3 lipids produced by PBkinase (PI3K) PDKl binding of PP3 lipids results in membrane co- locahzation with AKT, another PH domain containing protein Once co-localized, PDKl activates AKT by phosphorylatmg threonine308 Alternatively, PDKl can activate other AGC kinases independent of PIP3 lipids by bindmg directly to a conserved motif found on these targets Because PDKl regulates two distinct classes of downstream signaling substrates (PI3K-dependent and independent targets), inhibitors of this enzyme could have important therapeutic value in a variety of human cancers For instance, PDKl inhibitors could be efficacious m tumors m which the PI3K signaling pathway is upregulated due to activating mutations, amplification of PI3K itself or its upstream receptor tyrosine kinases, or deletion of PTEN, the phosphatase the counteracts PI3K activity The finding that mice expressing half the normal amount of PTEN are protected from developing a wide range of tumors by reducing PDKl expression levels supports this idea Alternatively, PDKl inhibitors could he useful in treating cancers driven by PllVmdependent PDKl signaling pathways (e g K-ras or H-ras dπven cancers)
Finally, the recent identification of PDKl mutations (PDK1T354M, PDK1D527E) m human colorectal cancers suggests that inhibitors of this kinase may have therapeutic value by directly inhibiting either wild-type or mutant forms of this protein See, Parsons et al , Nature 436, 792 (11 August 2005) "Colorectal cancer Mutations in a signaling pathway " In summary, PDKl is a central activator of several signaling pathways that are frequently altered in human cancers making it an attractive target for therapeutic intervention
SUMMARY
In one aspect, the present invention provides PDKl inhibitors that are useful as therapeutic agents, for the treatment of diseases and disorders characterized by abnormal cellular proliferation, for example cancers of the prostate, lung, colon, breast, among others The present invention provides, inter aha, compounds of Formula I
Figure imgf000004_0001
or pharmaceutically acceptable salts, ester, or tautomers thereof, wherein constituent members are provided herein
The present invention further provides compositions comprising a compound of Formula I and at least one pharmaceutically acceptable earner The present invention further provides methods of inhibiting PDKl or a PDKl variant in a patient comprising administering to said patient, a therapeutically effective amount of a compound of the invention, or pharmaceutically acceptable salt, ester, or tautomer thereof
The present invention further provides methods of treating a disease characteπzed by abnormal cellular proliferation in a patient comprising administering to said patient a therapeutically effective amount of a compound of the invention, or pharmaceutically acceptable salt, ester, or tautomer thereof
The present mvention further provides methods of inhibiting the tumor growth in a patient, the method comprising admimsteπng to said patient a therapeutically effective amount of a compound of the invention, or pharmaceutically acceptable salt, ester, or tautomer thereof
The present invention further provides methods of treating cancer in a patient, the method compπsing administering to said patient a therapeutically effective amount of a compound of the invention, or pharmaceutically acceptable salt, ester, or tautomer thereof
The present invention further provides a compound of the invention, or pharmaceutically acceptable salt, ester, or tautomer thereof for use in therapy
The present mvention further provides a compound of the mvention, or pharmaceutically acceptable salt, ester, or tautomer thereof for use in the preparation of a medicament for use in therapy
Other features, objects, and advantages of the invention will be apparent from the description, and from the claims
BMEF DESCRIPTION OF THE DRAWINGS
Figure 1 provides the chemical structures and activity data for Examples 177-681 Figure 2 provides the chemical structures and activity data for Examples 682-1185 In these two Figures, the column marked "Activity" indicates the compound's activity in the PDKl Kinase Alpha Screen Assay, the symbol "*" indicates that IC50 value is greater than 0 30 μM, the symbol "**" indicates that IC50 value is less than or equal to 0 30 μM but greater than 0 10 μM, the symbol "***" indicates that IC50 value is less than or equal to 0 10 μM but greater than 0 05 μM, and the symbol "****" indicates that IC50 value is less than or equal to 0 05 μM
DETAILED DESCRIPTION
In accordance with the present invention, Applicants have discovered novel quinazolme PDKl inhibitors that can provide effective treatments for disorders such as those descπbed herein and those apparent to one skilled in the art
In some embodiments, the invention provides compounds that have the Formula I
Figure imgf000006_0001
I or a pharmaceutically acceptable salt thereof, wherein
Ar is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, including fused bicyclic systems,
R1 is H, Ci 3 alkyl, halo, cyano, mtro, CF3, lmidazolyl, thiazolyl, oxazolyl, or amino, R2 and R3 are independently selected from the group consisting of H, alkoxy, substituted alkoxy, and halo,
L is a covalent bond, carbonyl, carbonylammo, armnocarbonyl, -O-, -S-, -SO-, -SO2-, -NH-, Ci 3 alkyl, substituted Ci 3 alkyl, or an alkyl interrupted with -O-, -S-, -SO-, -SO2-, -NH-, carbonyl, carbonylammo, or ammocarbonyl, and A1 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylammo, acyloxy, amino, substituted ammo, ammocarbonyl, aminothiocarbonyl, ammocarbonylamino, aminothiocarbonylamino, ammocarbonyloxy, aminosulfonyl, ammosulfonyloxy, ammosulfonylammo, amidino, carboxyl, carboxyl ester, (carboxyl ester)ammo, (carboxyl ester)oxy, cyano, halo, hydroxy, mtro, SO3H, sulfonyl, substituted sulfonyl, sulfonyloxy, sulfonylammo, thioacyl, thiol, alkylthio, substituted alkylthio, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl
According to some embodiments, when R1, R2, and R3 are each H and L is a covalent bond, then A1 is other than aryl or substituted aryl According to some embodiments, when R1, R2, and R3 are each H, L is a covalent bond, and A1 is Br, substituted phenyl, or substituted pyπdinyl, then Ar is other than phenyl, phenyl substituted with piperazmyl or heterocyclylalkyloxy, or pyndmyl
According to some embodiments, when R1, R2, and R3 are each H, L is a covalent bond, and A1 is hydroxy or alkoxy, then Ar is other than phenyl substituted with one or more alkyl or halo
According to some embodiments, when R1, R2, and R3 are each H and L is O, then A1 is other than pyndmyl or substituted pyndmyl
In some embodiments, the invention provides compounds that have the Formula I
Figure imgf000007_0001
I or a pharmaceutically acceptable salt thereof, wherein
Ar is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, including fused bicyclic systems,
R1 is H, Ci 3 alkyl, halo, cyano, mtro, CF3, lmidazolyl, thiazolyl, oxazolyl, or amino, R2 is selected from the group consisting of H, alkoxy, substituted alkoxy, alkyl, substituted alkyl, CN, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, and halo, R3 is selected from the group consisting of H, halo, CN, carboxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, cycloalkyloxy, substituted cycloalkyloxy, heterocyclylalkyloxy, substituted heterocyclylalkyloxy, heteroaryloxy, substituted heteroaryloxy, heteroaryl alkyloxy, substituted heteroarylalkyloxy, arylalkyloxy, substituted arylalkyloxy, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroarylalkyl, substituted heteroarylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl,
L is a covalent bond, carbonyl, carbonylamino, aminocarbonyl, -O-, -S-, -SO-, -SO2-, -NH-, Ci 3 alkyl, substituted Ci 3 alkyl, C2 3 alkenyl, C2 3 alkynyl or an alkyl interrupted with -O-, -S-, -SO-, -SO2-, -NH-, carbonyl, carbonylamino, or aminocarbonyl, and A1 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, ammocarbonylammo, aminothiocarbonylammo, aminocarbonyloxy, aminosulfonyl, ammosulfonyloxy, ammosulfonylammo, amidino, carboxyl, carboxyl ester, (carboxyl ester)ammo, (carboxyl ester)oxy, cyano, halo, hydroxy, mtro, SO3H, sulfonyl, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, substituted alkylthio, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl
According to some embodiments, when R1, R2, and R3 are each H and L is a covalent bond, then A1 is other than aryl or substituted aryl
According to some embodiments, when R1, R2, and R3 are each H, L is a covalent bond, and A1 is Br, substituted phenyl, or substituted pyπdmyl, then Ar is other than phenyl, phenyl substituted with piperazinyl or heterocyclylalkyloxy, or pyndmyl
According to some embodiments, when R1, R2, and R3 are each H, L is a covalent bond, and A1 is hydroxy or alkoxy, then Ar is other than phenyl substituted with one or more alkyl or halo
According to some embodiments, when R1, R2, and R3 are each H and L is O, then A1 is other than pyndinyl or substituted pyπdinyl
According to some embodiments, L is a covalent bond In some such embodiments, A1 is an optionally substituted alkyne or an optionally substituted heterocyclyl or heteroaryl Preferred alkynes include ethyne, 1-propyne, 3-hydroxypropyne, and 3-methoxypropyne, as well as other 3-alkoxypropynes Preferred heteroaryls for these embodiments include thiazole, pyridine, imidazole, furan, 1,2,3-tπazole, 1,2,4-tπazole, pyrazole, isothiazole, oxazole, and isoxazole, each of which can be substituted Specific heteroaryls for these embodiments include 2-thiazolyl, 5-hydroxymethyl-2-thiazolyl, 3-pyπdyl, 5-methoxy-3- pyπdyl, 6-ammo-3-pyridyl, 4-thiazolyl, 3-pyrazolyl, and 4-pyrazolyl Preferred heterocyclyl groups include pyrrolidine, morpholrne, pipeπdine, and piperazine, each of which can be substituted
Some specific embodiments include compounds wherein A1 is selected from the following group
OH, Br, methyl, ethyl, ethyne (-OCH), CN, CF3, phenyl, COOH, COOMe, CONH2,
1 -hydroxy- 1 -methyleth yl,
1 -amino- 1 -methylethyl,
2-thiazolyl, 5-thiazolyl,
4-thiazolyl, isoxazol-4-yl,
3-pyrazolyl, 4-pyrazolyl,
1 -methyl-4-pyrazolyl,
1 -methylpyrazol-5-yl,
2-fiiranyl, cyclopropyl,
4-hydroxymethyl-l,2-3-tnazol-5-yl, 5-methoxypyπdin-3-yl,
2-ammo-3 -methoxypyπdin-5-yl,
3-methylpyπdin-2-yl,
2-pyndyl,
3-pyπdyl, 4-ρyπdyl,
4-methylpyπdin-3 -yl,
3 -chloroρyπdin-4-yl,
1-morpholmyl,
1-pyrrolidmyl, 3-hydroxypyrrolidin-l-yl,
R-3 -hydroxypyrrolidin- 1 -yl,
5'-4-hydroxypipendin- 1 -yl,
3-ketopiperazin-l-yl,
1 -methyhmidazol-2-yl, 5-methylthiazol-2-yl,
1 -methylimidazol-5-yl,
3 -hydroxy- 1 -propynyl,
3-methoxy-l-propynyl,
2-ammopyπdm-4-yl, 3-methoxypyndin-5-yl,
2-ammopyndm-5-yl,
4-hydroxymethyl-l,2,3-tnazol-5-yl,
2-amino-3-methoxypyπdm-5-yl,
2-aminothiazol-5-yl, 1 -(2-hydroxyethyl)ρyrazol-4-yl,
1 -(2-methoxyethyl)pyrazol-4-yl,
4-hydroxymethyl-thiazol-2-yl,
5-hydroxymethyltmazol-2-yl, 2-methoxypynrmdin-5-yl,
2-methoxypyπdm5-yl,
2-hydroxyethylamino, tetrahydropyran-4-yloxy, lsopropylammo, 2-pyndinylmethylamino,
2-methoxyethylammo,
3-pyndylmethylammo,
4-pyndyImethylamino,
2-pyndylamino, 3-pyridylamino, 2-(2-ketopyiτolidin- 1 -yl)ethylammo,
4-methylpiperazin- 1 -yl,
1 -isopropylmethylpyrazol-4-yl, methylammo,
1 -methylpipeπdin-4-ylammo, 4-isopropylpiperazin-l-yl, lsopropylammo, pyrrolidin-1-yl, cyclopropylammo ,
2-fluoropyπdin-3-yl, 2-(4-methylpiperazm- 1 -yl)pyndine-4-yl,
3-(benzoylamino)phenyl, and
2-amuio-4-methoxypyπmidin-5-yl
According to some embodiments, L is -O- According to some embodiments, L is -S-
Accordnig to some embodiments, L is -SO2-
Accordmg to some embodiments, L is NH
According to some embodiments, L is carbonyl
According to some embodiments, L is ammocarbonyl or carbonylammo According to some embodiments, L is carbonyl ammo According to some embodiments, L is aminocarbonyl
According to some embodiments, L is an alkyl interrupted with -O-, -S-, -SO-, -SO2-, -NH-, carbonyl, carbonylammo or aminocarbonyl Accordmg to some embodiments, L is -CH=CH- or -C≡C-
Accordmg to some embodiments, A1 is alkyl Accordmg to some embodiments, A1 is substituted alkyl According to some embodiments, A1 is alkenyl Accordmg to some embodiments, A1 is substituted alkenyl According to some embodiments, A1 is alkynyl
According to some embodiments, A1 is ethynyl, propynyl, phenylethynyl or pyπdylethynyl
According to some embodiments, A1 is substituted alkynyl According to some embodiments, A1 is alkoxy Accordmg to some embodiments, A1 IS substituted alkoxy
According to some embodiments, A1 is acyl Accordmg to some embodiments, A1 is cyano Accordmg to some embodiments, A1 is aryl According to some embodiments, A is substituted aryl According to some embodiments, A1 is substituted phenyl
According to some embodiments, A1 is heteroaryl According to some embodiments, A1 is substituted heteroaryl Accordmg to some embodiments, the heteroaryl or substituted heteroaryl is selected from the group consisting of pyπdyl, pyrazolyl, thiazolyl, pyπmidyl, pyndazinyl, oxazolyl, isoxazolyl, substituted pyπdyl, substituted pyrazolyl, substituted thiazolyl, substituted pyπmidyl, substituted pyπdazinyl, substituted oxazolyl and substituted isoxazolyl According to some embodiments, A1 is cycloalkyl According to some embodiments, A1 is substituted cycloalkyl Accordmg to some embodiments, A1 is heterocyclyl According to some embodiments, A1 is substituted heterocyclyl
Accordmg to some embodiments, the heterocyclyl or substituted heterocyclyl is selected from the group consisting of pipendmyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, morpholmyl, thiomorpholino, substituted pipendmyl, substituted piperazinyl, substituted pyrrolidmyl, substituted tetrahydrofuranyl, substituted tetrahydrothiophenyl, substituted morpholinyl and substituted thiomorpholino
According to some embodiments, A1 is hydroxy
According to some embodiments, A1 is halo According to some embodiments, A is cyano
In some embodiments, -L-A1 is -Br, -C≡CH, -C≡N, 2-thiazolyl, or 1-methylimidazol- 2-yl
According to some embodiments, R1 is H, Ci 3 alkyl, halo, cyano, mtro, CF3 or amino
According to some embodiments, R1 is H, Ci 3 alkyl, halo, cyano, mtro or amino According to some embodiments, R1 is H, Ci 3 alkyl, halo, cyano, imidazolyl, thiazolyl, oxazolyl or ammo
According to some embodiments, R1 is H, Ci 3alkyl, halo or cyano
According to some embodiments, R1 is H, Ci 3alkyl, or halo
According to some embodiments, R1 is H or halo According to some embodiments, R1 is H
According to some embodiments, R1 is halo
According to some embodiments, R2 and R3 are independently selected from the group consisting of H, alkoxy, substituted alkoxy, and halo,
AAccccoorrddiinngg ttoo ssoommee eemmbbooddiimmeemnts, R2 and R3 are independently selected from the group consisting of H, halo and alkoxy
AAccccoorrddiinngg ttoo ssoommee eemmbbiodiments, R2 and R3 are independently selected from the group consisting of H, and halo
AAccccoorrddiinngg ttoo ssoommee eemmbbiodiments, R2 and R3 are independently selected from the group consisting of H and alkoxy According to some embodiments, R2 and R3 are independently selected from the group consisting of H and Ci 6 alkoxy
According to some embodiments, R2 and R3 are independently selected from the group consisting of H and methoxy
According to some embodiments, at least one of R2 and R3 is H According to some embodiments, both R2 and R3 are H
According to some embodiments, R2 is H
According to some embodiments, R3 is H
In some embodiments, one of R2 and R3 is H and the other of R2 and R3 is alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, cycloalkyloxy, substituted cycloalkyloxy, heterocyclylalkyloxy, substituted heterocyclylalkyloxy, heteroaryloxy, substituted heteroaryloxy, heteroarylalkyloxy, substituted heteroarylalkyloxy, arylalkyloxy, or substituted arylalkyloxy
In some embodiments, one of R2 and R3 is H and the other is arylalkoxy, alkoxy or substituted alkoxy, or a substituted or unsubstituted heteroaryloxy, heteroarylalkyloxy, heterocyclyloxy, or heterocyclylalkyloxy In such embodiments, R2 is often H and R3 is substituted or unsubstituted alkoxy or heterocyclyloxy group
In certain embodiments, R2 is selected from H, F, Cl, Br, CN, CF3, methoxy, ethoxy, isopropoxy, 4-pipendinyloxy, 3-azetidinyloxy, and 2-aminoethoxy In some embodiments, R3 is selected from
H, Cl, CF3, CN, COOH, isopropoxy, methoxy, cyclopentyloxy,
2-ammoethoxy,
4-pipeπdinyloxy, l-isopropyl-pipendin-4-yl,
4-pipendinylmethoxy, l-methylpipendm-3-ylmethoxy,
2-(4-ρiρendinyl)-ethoxy,
2-(l -methyl-4-piperidmyl)-ethoxy, (1 -methyl-4-pipeπdinyl)methoxy,
2-thiazolylmethoxy,
3 -pyπdylmethoxy,
4-pyπdylmethoxy,
1 -(4-pyπdyl)- 1 -ethoxy, 2-pyπdylmethoxy,
5-thiazolylmethoxy,
2-(4-pipendmyl)-ethoxy,
1 -methyl-4-piρeπdmyloxy, cyclopentyloxy, 2-(4-morphohnyl)-ethoxy,
2-methoxyethoxy,
1 -ammocyclopropylmethoxy,
1 -N-acetylammocycloprop- 1 -ylmethoxy, aminocarbonylmethoxy, N-methylammocarbonylmethoxy,
3 -pyrrohdmyloxy,
Λ-3 -pyrrohdmyloxy,
S-3 -pyrrolidinyloxy, Λ-(l-methylpyrrohdin-3-yl)oxy,
S'-(l-methylpyrrolidm-3-yl)oxy, pyrrolidmy-3 -ylmethoxy, pipeπdm-3 -ylmethoxy, ϋ-pipeπdin-3 -ylmethoxy, S-piperidin-3 -ylmethoxy,
2-(4-methyl- 1 -ρiρerazmyl)ethyl,
1 -methylpyrrolidm-3 -ylmethoxy,
R-(I -methylρiρendm-3 -ylmethoxy,
S-(I -methylpipeπdin-3 -ylmethoxy, (3-chloro-4-pyndyl)methoxy,
2-methoxypyπdyn-6-ylmethoxy,
(5-methyhsoxal-3-yl)methoxy,
5-thiazolylmethoxy,
(3-fluorophenyl)methoxy, (3-methoxyphenyl)methoxy, phenylmethoxy,
(3 -cyanophenyl)methoxy,
3 -fluorophenylmethoxy,
3 -methoxyphenylmethoxy, 2-pyrazinylmethoxy,
3-chloro-4-pyπdinyloxy,
2-(3-pyπdmyl)ethoxy,
1 -isopropylpipeπdm-4-yloxy,
3-azetidmyloxy, l-methyl-3-azetidinyloxy,
1 -isoρropyl-3 -azetidinyloxy, l-(2,2,2-tπfluoroethyl)pipendin-4-yloxy,
1 -methyl-4-pyrazolyl,
3-ammopyndin-4-yl, 1 -piperazmylmethyl,
1 -piperazinylcarbonyl, l-methylρiρeπdin-4-ylammocarbonyl,
2-(N-morpholmyl)ethoxy, 2-methoxyethoxy,
2-chloropyridm-5-ylmethoxy,
2-chloropyπdin-4-ylmethoxy,
1 -acetylpiperidin-4-yloxy, l-(2-fluoroethyl)pipeπdin-4-yloxy, 1 -(2,2-difluorethyl)pipendm-4-yloxy, l-(2-methoxyethyl)pipeπdin-4-yloxy, l-(2-hydroxyethyl)pipeπdm-4-yloxy, methylammocarbonylmethoxy, aminocarbonylmethoxy, 3-azetidinylmethoxy,
3 -( 1 -methylazetidinyl)methoxy,
2-aminopyndm-4-yl,
6-methoxypyπdui-2-ylmethoxy,
5-methyhsoxazol-3-yl, and 2-(Pyπdm-3-yl)ethoxy, or R3 can be one of the following heterocyclyloxy groups
Figure imgf000015_0001
According to some embodiments, Ar is substituted aryl or substituted heteroaryl According to some embodiments, Ar is substituted aryl
According to some embodiments, Ar is aryl, substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, amino, substituted ammo, armnocarbonyl, ammothiocarbonyl, ammocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, ammosulfonyloxy, aminosulfonylamino, amidino, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guamdino, substituted guanidmo, halo, hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylammo, thioacyl, thiol, and alkylthio, wherein the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heterocyclyl, and heteroaryl moieties contained within any of the listed substituted aryl groups are optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, ammo, substituted amino, aminocarbonyl, aminothiocarbonyl, ammocarbonylamino, aminothiocarbonylamino, ammocarbonyloxy, aminosulfonyl, ammosulfonyloxy, aminosulfonylamino, amidmo, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)ammo, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guamdino, guamdino, halo, hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, mtro, SO3H, sulfonyl, sulfonyloxy, sulfonylammo, thioacyl, thiol, alkylthio, and alkylthio
According to some embodiments, Ar is aryl substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of aminosulfonyl, aminocarbonyl, aryl, heteroaryl, heterocyclyl, amino, substituted amino, alkyl, halo, and cyano, wherein the alkyl, aryl, and heteroaryl moieties contained within any of the listed substituted aryl groups are optionally substituted by 1, 2, 3, 4 or 5 substituents mdependently selected from the group consisting of alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, ammo, substituted amino, aminocarbonyl, aminothiocarbonyl, ammocarbonylamino, aminothiocarbonylamino, ammocarbonyloxy, aminosulfonyl, ammosulfonyloxy, aminosulfonylamino, amidino, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)ammo, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guamdino, guamdino, halo, hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, mtro, SO3H, sulfonyl, sulfonyloxy, sulfonylammo, thioacyl, thiol, alkylthio, and alkylthio According to some embodiments, Ar is aryl selected from the group consisting of phenyl and naphthyl Where Ar is phenyl it is often unsubstituted at one or both of the positions adjacent to the NH depicted in Formula 1 (the ortho positions) According to some embodiments, Ar is substituted phenyl In some embodiments, the phenyl is substituted with two or more substituents In some such embodiments, two adjacent substituents are linked together to form a πng that is fused to the phenyl πng The fused ring may be saturated, unsaturated or aromatic, and may itself be substituted Preferred embodiments of these fused ring systems include phenyl fused to a 1,3-dioxolane, phenyl fused to a 1,4-dioxane, phenyl fused to a pyrazole, phenyl fused to imidazole, phenyl fused to tπazole, phenyl fused to pyrazole, and phenyl fused to a pyrrolidinyl or pipendinyl πng
In some embodiments, phenyl is substituted by 1 , 2 or 3 groups that are not attached to said phenyl ortho to the NH of formula I
In certain embodiments, Ar is of the formula
Figure imgf000017_0001
wherein Q is an optionally substituted acyl group,
and Q' is alkyl, alkoxy, halo, aryl, heteroaryl, aryloxy, heteroaryloxy, heterocyclyloxy, arylalkyl, heteroaryl, or heterocyclyloxy, each of which can be substituted, or Q' can be H, halo, CN, COOR', CONR'2, NR'2, S(O)qR', or S(O)qNR'2, where each R' is H or Ci-C4 alkyl
In many such embodiments, Q' is H or halo or alkoxy
Q in these fused systems can be, for example
1 -methylimidazol-2-ylcarbonyl,
3 -methoxypropionyl,
1 -methylimidazol-5-ylcarbonyl,
N,N-dimethylaminoacetyl,
Tetrahydropyran-4-ylcarbonyl,
1 -methylpipeπdin-4-ylcarbonyl, 1 -methylpipeπdm-3-ylcarbonyl,
2-pyndinoyl,
3-pyndinoyl,
4-pyπdmoyl, l-methylpyrrolidm-2-ylcarbonyl,
1 -methylpyrrolidin-2S-ylcarbonyl,
(2-N-morpholmo)pyπdm-5-ylcarbonyl,
(2-N-morphohno)pyπdin-4-ylcarbonyl,
(2-N-pipendmyl)pyndin-5-ylcarbonyl, l-methylρyrazol-4-ylcarbonyl,
1 -methylpipendin-3 -ylcarbonyl, pyπdm-3-yl-acetyl, imidazo[l,2-a]pyπdm-4-ylcarbonyl,
2-(piperazme- 1 -yl)pyπdin-5-ylcarbonyl, 2-ammo-3-hydroxybutanoyl, or
25-amino-3Λ-hydroxybutanoyl
In many embodiments, Ar is phenyl having either 1 or 2 substituents, or it is a phenyl with an additional ring fused to it Frequently, Ar is phenyl with a non-hydrogen substituent at one or both of the 'meta' positions of the phenyl πng, i e , it is a 3-substituted phenyl or a 3,5-disubstituted phenyl In other embodiments, Ar is phenyl with a non-hydrogen substituent at one or both of positions 3 and 4, e g , it is a 4-substituted phenyl or a 3,4- disubstituted phenyl
According to some embodiments, Ar is heteroaryl
According to some embodiments, Ar is heteroaryl selected from the group consisting of pyrrolyl, furanyl, thiophenyl (thienyl), imidazolyl, pyrazolyl, oxazolyl, lsoxazolyl, thiazolyl, lsothiazolyl, 1,2,3-tnazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyπdinyl, pyrazinyl, pyπmidinyl, pyπdazmyl, tπazmyl, rndolyl, isoindole, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzothiazolyl, quinolmyl, lsoqumolyl, qumazolyl, qumozalyl, cinnolyl, pteπdine, carbazole, carboline, phenanthndme, acndine, phenanthroline, phthalazine, naphthylpyridme, phenazme, and purine
According to some embodiments, Ar is a heteroaryl group selected from the group consisting of 2- pyπdmyl, 3-pyπdinyl, 4-pyπdmyl, 2-pyπrmdinyl, 4-pyπmidmyl, 5- pyranidniyl, 1-pyrazolyl, 3-pyrazolyl, 4-ρyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5- oxazolyl, and 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl According to some embodiments, Ar is aryl or heteroaryl, substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylammo, acyloxy, ammo, substituted ammo, aminocarbonyl, aminothiocarbonyl, ammocarbonylammo, ammothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, ammosulfonyloxy, ammosulfonylammo, amidino, aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)ammo, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkyltmo, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guamdmo, substituted guamdino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, mtro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylammo, thioacyl, thiol, alkylthio, and substituted alkylthio Typically in these embodiments, Ar has one or two non-hydrogen substituents
According to some embodiments, Ar is aryl or heteroaryl, substituted by 1 , 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, acyl, acylammo, acyloxy, ammo, substituted ammo, aminocarbonyl, aminothiocarbonyl, ammocarbonylammo, ammothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, ammosulfonyloxy, ammosulfonylammo, amidino, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guamdmo, substituted guamdino, halo, hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, mtro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylammo, thioacyl, thiol, and alkylthio, wherein the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heterocyclyl, and heteroaryl moieties contained withm any of the preceding "substituted aryl" groups are optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkenyl, alkynyl, alkoxy, acyl, acylammo, acyloxy, ammo, substituted ammo, aminocarbonyl, aminothiocarbonyl, ammocarbonylammo, ammothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, ammosulfonyloxy, ammosulfonylammo, amidmo, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)ammo, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guamdmo, guanidmo, halo, hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, nitro, SO3H, sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and alkylthio
According to some embodiments, Ar is heteroaryl, substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, acyl, acylammo, acyloxy, amino, substituted ammo, aminocarbonyl, ammothiocarbonyl, ammocarbonylammo, aminothiocarbonylammo, ammocarbonyloxy, ammosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guamdmo, substituted guamdmo, halo, hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, and alkylthio, wherein the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heterocyclyl, and heteroaryl moieties contained within any of the listed substituted aryl groups are optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkenyl, alkynyl, alkoxy, acyl, acylammo, acyloxy, ammo, substituted amino, aminocarbonyl, ammothiocarbonyl, aminocarbonylamino, aminothiocarbonylammo, ammocarbonyloxy, ammosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guanidmo, guamdmo, halo, hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, mtro, SO3H, sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and alkylthio According to some embodiments, Ar is aryl or heteroaryl substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of ammosulfonyl, aminocarbonyl, aryl, heteroaryl, heteroaryl, heterocyclyl, amino, substituted amino, alkyl, alkyl, halo, and cyano, wherein the alkyl, aryl, heterocyclyl, and heteroaryl moieties contained within any of the preceding "substituted aryl" groups are optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkenyl, alkynyl, alkoxy, acyl, acylammo, acyloxy, ammo, substituted amino, aminocarbonyl, ammothiocarbonyl, ammocarbonylammo, aminothiocarbonylammo, ammocarbonyloxy, ammosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guarudmo, guanidmo, halo, hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, mtro, SO3H, sulfonyl, sulfonyloxy, sulfonylammo, thioacyl, thiol, alkylthio, and alkylthio
According to some embodiments, Ar is heteroaryl substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of aminosulfonyl, aminocarbonyl, aryl, heteroaryl, heterocyclyl, amino, substituted amino, alkyl, halo, and cyano, wherein the alkyl, aryl, and heteroaryl moieties contained withm any of the listed substituted aryl groups are optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkenyl, alkynyl, alkoxy, acyl, acylammo, acyloxy, amino, substituted ammo, aminocarbonyl, ammotmocarbonyl, ammocarbonylammo, aminothiocarbonylamino, ammocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guanidmo, guamdino, halo, hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, mtro, SO3H, sulfonyl, sulfonyloxy, sulfonylammo, thioacyl, thiol, alkylthio, and alkylthio According to some embodiments, Ar is a 5- or 6-membered heteroaryl group having 1 or 2 heteroatoms as nng members, independently selected from the group consisting of O, S and N, that is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of aminosulfonyl, aminocarbonyl, aryl, heteroaryl, heterocyclyl, ammo, substituted ammo, alkyl, halo, and cyano According to some embodiments, Ar is selected from the group consisting of substituted pyπdyl, substituted pyrazolyl, substituted thiazolyl, substituted pyπmidyl, substituted pyndazinyl, substituted oxazolyl and substituted isoxazolyl
Specific examples of preferred Ar groups include the following
Phenyl, 3-aminocarbonyl-5-N-(morpholino)phenyl,
4-aminocarbonylphenyl,
3 -methanesulfonamidophenyl,
3-acetylamino-5-N-morpholmomethyl-phenyl,
3-methoxy-5-(5-methyl-l-tetrazolyl)-phenyl, 4-(N-morphohno)phenyl,
4-(N-morpholinocarbonyl)phenyl,
3-(5-oxazolyl)-phenyl,
3 -( 1 -hydroxy- 1 -methyl)- 1 -ethylphenyl, 3-(l-hydroxyethyl)phenyl,
3-fluorophenyl,
2-fluoroρhenyl,
3 ,4,5-tnfluorophenyl,
3 -tπfluoromethylphenyl, 2-tnfluoromethylpyπdm-5-yl,
3-(l -methylpyrazol-3-yl)phenyl,
3-(2-amino-4-pyπdyl)-5-acetylaminophenyl,
S-pyrrolidinylcarbonylamino-S-CN-morphohno^ethyl-phenyl,
3-acetylammo-5-(2-methoxy-5-pyπdmyl)phenyl, 3-acetylamino-5-(4-pyrazolyl)phenyl,
3-methoxycarbonylammo-5-(pyrazol-4-yl)phenyl,
3-aminocarbonyl-5-(4-pyrazolyl)phenyl,
3-ammocarbonyl-5-(l-methyl-4-pyrazolyl)phenyl,
3,5-bis(aminocarbonyl)phenyl, 3,5-bis(acetylamino)phenyl,
3-ammocarbonyl-5-(4-methyl-l-piperazinyl)phenyl,
4-(3 -pyrazolyl)phenyl,
3-ammocarbonyl-5-(2-methoxy-5-pyπdmyl)phenyl,
3-aminocarbonyl-5-(6-methoxy-2-pyrazinyl)phenyl, 3-aminocarbonyl-5-(N-methylpipeπdm-2-oπ-5-yl)phenyl,
3-(5-methyl-l-tetrazolyl)phenyl,
3-ammocarbonyl-5-(2-pyrazmyl)phenyl,
3-(methoxycarbonylamino)-5-(2-(N-moφholmo)pyrimidin-5yl)phenyl,
3-(N-morpholmocarbonyl)-5-(N-morpholino)phenyl, 3-ammocarbonyl-5-(l -methyl-4-pyrazolyl)phenyl,
3-aminocarbonyl-5-(5-pyπmidmyl)phenyl,
3 -(N-methylaminocarbonyl)phenyl,
4-(aminocarbonyl)phenyl,
4-(N-methylaminocarbonyl)phenyl, 3 -( 1 ,2,4-tnazolyl- 1 -methyl)phenyl, 3-(l,2,4-tnazolyl-4-methyl)ρhenyl, 3-(N-morpholmocarbonylmethyl)phenyl, 3 -methoxyphenyl, 3-methoxy-4-fluorophenyl,
3 -( 1 -methyl-3 -pyrazolyl)phenyl, (3 -N-morpholmomethyl)phenyl, (2-tπfluoromethyl)benzimidazol-6-yl, benzopyrazol-6-yl, 3-fluoro-4-isoρropylρhenyl,
3 -(2-oxopyrrolidin- 1 -yl)phenyl , 3-methoxy-4-(5-oxazolyl)phenyl, 3 -methanesulfonylphenyl, 3-methoxy-4-(isobutyrylamino)phenyl, 3-(l-pyrazolyl)phenyl,
4-(N-pyrrohdmylcarbonyl)phenyl, benzimidazol-5-yl,
3-(4-methyl-l,2,4-tπazol-3-yl)phenyl, 4-pyπdyl, 3-pyπdyl,
3-(N-morpholmylcarbonylmethyl)phenyl, 3-cyano-5-fluorophenyl, 4-(methylammocarbonylmethyl)phenyl, 3-(methylammocarbonylmethyl)phenyl, 3-(isopropylaminocarbonylmethyl)phenyl,
3-(cyclopropylaminocarbonylmethyl)phenyl, 4-(isopropylaminocarbonylmethyl)phenyl, 4-(cyclopropylammocarbonylmethyl)phenyl, 3-(imidazol-2-yl)phenyl, 3-(2-methyl-thiazol-4-yl)phenyl,
3-(5-ρynmidinyl)phenyl, 3-(2-methoxypyπmidm-5-yl)phenyl, 3-(l,3,5-tnmethylpyrazol-4-yl)phenyl, 3-(4,5-dimethyloxazol-2-yl)phenyl, 3 -(5-methylfuran-2-yl)phenyl,
3-(methylammocarbonyl-5-(l-methylpyrazol-4-yl)phenyl,
3-(methoxycarbonylamino)-5-(2-N-moφholmopyπmidin-5-yl)phenyl,
3 - (4-morρholmo)-5-(4-morpholinocarbonyl)phenyl, 3-(methoxycarbonylammo)-5-(pyrazol-4-yl)phenyl,
3-(methoxycarbonylammo)-5-(moφholm-4-ylmethyl)phenyl,
3-(ammocarbonyl)-5-(4-moφholmyl)phenyl,
3-methoxy-5-tπfluoromethylρhenyl,
3-(aminocarbonylmethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3,5-dimethoxyphenyl,
3 ,5-difluorophenyl,
3 ,4-difluorophenyl,
3 ,4,5-tnflurophenyl,
3-chloro-4-fluoroρhenyl, 3-fluoro-4-(thiazol-2-yl)phenyl,
3-ethoxyphenyl,
4-(oxazol-5-yl)phenyl,
3-fluoro-4-(morpholin-4-yl)phenyl,
4-(isopropylaminocarbonyl)phenyl, 4-(moφholm-4-ylsulfonyl)phenyl,
4-cyclohexylphenyl,
4-(pyπmidin-5-yl)phenyl,
4-(isoxazol-4-yl)phenyl,
2-fluoroρhenyl, 2,3-difluorophenyl,
2,4-difluorophenyl, benzotπazol-5-yl,
4-ammosulfonylphenyl ,
4-isopropylphenyl, 3-fluoro-4-isopropylphenyl,
3-methoxy-4-(oxazol-5-yl)ρhenyl,
4-(methylaminosulfonylmethyl)ρhenyl,
3-(ammosulfonyl)phenyl,
4-( 1 -methyl-4-pyrazolyl)phenyl, 2-methoxyphenyl,
2-tnfluoropyπdin-5-yl,
4-(isopropylammosulfonyl)phenyl,
4-cyanophenyl, 4-ethoxyρhenyl,
3 -difluormethoxyphenyl,
3 ,4-dioxolanylphenyl,
3 ,4-dimethoxyphenyl,
3 ,4-dioxanylphenyl, 3 -propoxyphenyl ,
3 -hydroxyphenyl,
4-( 1 -pyrazolylmethyl)phenyl,
4-(l,2,4-tnazol-l-ylmethyl)pheπyl,
4-(l -pyrazol- 1 -ylmethyl)phenyl, 4-(2-methylthiazol-4-yl)phenyl,
4-(l,2,3-thiadiazol-4-yl)phenyl,
4-(oxazohn-2-on-4-yl)phenyl,
4-(2-oxazolyl)phenyl,
3-[2-(2-hydroxypyndm-5-ylcarbonylammo)-ethoxy]-5-(l-methylpyrazol-4-yl)phenyl, 3-fluoro-4-(imidazol-2-yl)phenyl,
4-(3-methoxypyπdm-5-yl)ρhenyl,
3 -(2-methoxypyπdin-5 -yl)phenyl,
3-(3-pyπdinyl)phenyl,
3-(dimethylaminomethyl)-5-(raethanesulfonamido)phenyl, 3-(4-methylpiperazm-ylethyl)- 5-(methanesulfonamido)phenyl,
1 -methylbeπzimidazol-2-yl,
5,6-dimethylbenzimidazol-2-yl,
4,5-dicyanoirmdazol-2-yl,
S-armno-S-aminocarbonylmethylphenyl, imidazol-1-yl,
2-(pyndm-2-yl)ethyl, lmidazol- 1 -ylmethylphenyl,
3-(acetylamino)-5-(N-methyl-2-pyπdon-5-yl)phenyl,
3-(acetylammo)-5-iodophenyl, 3-(acetylamino)-5-(pyπdin-3-yl)phenyl,
4-(N-morpholinylsulfonyl)phenyl,
3-(acetylaimno)-5-(dimethylaminomethyl)phenyl,
4-(tetrazol-5-yl)phenyl, 3-(tetrazol-5-yl)phenyl,
3-chloro-4-(N-morρholmocarbonyl)ρhenyl,
3 -(tetrazol- 1 -yl)phenyl,
3-ammocarbonyl-4-(N-morpholmo)phenyl,
3-acetylamino-5-(pyrrohdin-l-ylmethyl)phenyl, δ-chlorobenzopyrazoM-yl,
6-fluorobenzopyrazol-4-yl,
S-acetylammo-S-ammomethylphenyl,
3-(acetylamino)-5-(piperazin-l-ylmethyl)phenyl,
3-(isobutyrylamino)-5-(N-moφholmomethyl)phenyl, 3-(methylsulfonamido)-5-(N-morpholinomethyl)phenyl,
3-(N-moφholmomethyl)-5-(5-tetrazolyl)phenyl,
3-acetylamino-5-(pyπdin-4-yl)phenyl,
3-cyano-5-(N-morρholinomethyl)phenyl,
3-methoxy-5-(5-methyltetrazol-l-yl)phenyl, 3-methoxy-5-(tetrazol- 1 -yl)phenyl,
3-(4-moφholmo)-5-(pyrazol-4-yl)phenyl,
3-(4-moφholmo)-5-(pyndine-4-yl)phenyl,
3-(4-moφholmo)-5-(3-fluoropyπdine-4-yl)phenyl,
3-(4-moφholmo)-5-(pyndme-3-yl)phenyl, 3-ammocarbonyl-5-(N-moφholmomethyl)phenyl,
3-(methoxycarbonylammo)-5-(moφhohn-4-ylmethyl)phenyl,
3-(4-tπfluoromethylpyrazol-2-yl)phenyl,
3-(cyclopropylaminocarbonyl)-5-(l-methylρyrazol-4-yl)phenyl,
3-(l-methylpyrazol-4-yl)-5-((l-methylpipeπdm-4-yl)aminocarbonyl)phenyl, 3-(methylaminocarbonyl)-5-(l-methylpyrazol-4-yl)phenyl,
3-(2-methoxyethylammocarbonyl)-5-(l-methylpyrazol-4-yl)phenyl,
3 -(aminocarbonyl)-5-fluorophenyl,
3-methylaminocarbonyl-5-(pyπmidin-5-yl)phenyl,
3-methylaminocarbonyl-5-(pyπdine-4-yl)phenyl, 3-methylammocarbonyl-5-(pyridine-3-yl)phenyl, 3-ammo-5-(N-morpholinomethyl)ρhenyl, 3-(cyanomethyl)-5-(l-methylpyrazol-4-yl)phenyl, 3-(aminocarbonyl)-5-(aminocarbonylmethoxy)phenyl, 4-(isobutyrylamino)-3-methoxyphenyl,
3-(isobutyrylamino)-5-methoxyphenyl, 3-(aminocarbonylmethyl)-5-(N-morpholinomethyl)phenyl, 3-cyano-4-( 1 ,2,4-tπazol- 1 -ylmethyl)phenyl, 3-(methoxycarbonylmethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(hydroxycarbonylmethoxy)-5-(l-methylpyrazol-4-yl)phenyl,
3-(cyclopropylaminocarbonylmethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2-(pyrrolidin-l-yl)ethylaminocarbonylmethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2-(methoxyethoxy)carbonylmethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2-(2-oxopyrrolidm-l-yl)ethylaminocarbonylmethoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-((2-tetrahydrofuranyl)methylammocarbonylmethoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-((2-tetrahydrofuranyl)methylammocarbonylmethoxy)-5-(l-methylpyrazol-4- yl)phenyl, 3-((2-5-tetrahydrofuranyl)methylammocarbonylmethoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3 -((2-_ff-tetrahydrofuranyl)methylaminocarbonylmethoxy)-5-( 1 -methylpyrazol-4- yl)phenyl,
3-((l-methylpipendin-4-yl)ammocarbonylmethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-((2-methylsulfonylethyl)aminocarbonylmethoxy)-5-(l-methylpyrazol-4-yl)phenyl,
3-((2-acetylammoethyl)aminocarbonylmethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3 -(tetrahydropyran-4-ylammocarbonylmethoxy)-5-( 1 -methylpyrazol-4-yl)phenyl, 3-((2-hydroxypropyl)ammocarbonylmethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(pyπdine-2-ylmethylaminocarbonylmethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(cyclohexylmethylammocarbonylmethoxy)-5-(l-methylpyrazol-4-yl)phenyl,
3-(pyπdme-3-ylmethylaminocarbonylmethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(N,N-dimethylaminocarbonylmethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(N-moiphohnocarbonylmethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(4-methylpiperazin-l-ylcarbonylmethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(3-oxopiperazm-l-ylcarbonylmethoxy)-5-(l-methylpyrazol-4-yl)phenyl,
3-(4-dimethylaminopipeπdm-l-ylcarbonylmethoxy)-5-(l-methylpyrazol-4-yl)phenyl,
4-(methylaminosulfonylmethyl)phenyl,
3-(cyclopropylaminocarbonyl)-5-(N-morpholinyl)phenyl, 3-(methylammocarbonyl)-5-(N-morpholmyl)phenyl,
3-(3-oxomorphohn-4-ylmethyl)phenyl,
3-(2-oxopyrrohdm-l-ylmethyl)phenyl,
3-(2-oxooxazol- 1 -ylmethyl)phenyl,
3-(methylaminocarbonylmethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 4-(N-morpholmomethyl)phenyl,
3-(3-methoxypropanoylammomethyl)phenyl,
3-(isoxazol-5-ylcarbonylammomethyl)phenyl,
3-(tetrahydrofuran-2Λ-ylcarbonylaminomethyl)phenyl,
3-(tetrahydrofaran-2S-ylcarbonylaminomethyl)phenyl, 3-(l-acetylpyrrohdm-2Λ-ylcarbonylammomethyl)phenyl,
3-(l-acetylpyrrolidm-25-ylcarbonylammomethyl)phenyl,
3 -(pyndm-3 -ylmethylacetylaminomethyl)phenyl,
3-(ρyπdin-3-oylammomethyl)ρhenyl,
3-(cyclopropylsulfonylaminomethyl)phenyl, 3 -(ethoxycarbonylaminomethyl)phenyl,
3-hydroxy-5-(methylaminocarbonyl)phenyl,
3-ethoxy-5-(methylaminocarbonyl)phenyl,
3-(methylaminocarbonylmethyl)-5-(N-morpholinomethyl)phenyl,
3-(N,N-dimethylaminocarbonylmethyl)-5-(N-morpholmomethyl)phenyl, 3-(isopropylaminocarbonylmethyl)-5-(N-moφhohnomethyl)phenyl,
3-(tetrahydrop5τ:an-4-ylaminocarbonylmethyl)-5-(N-morpholmomethyl)phenyl,
3-(t-butoxycarbonylammomethyl)phenyl,
3-(methylaminocarbonyl)-5-(5-(4-methylpiρerazin-l-yl))phenyl,
2-methoxyphenyl, 2-tnfluoropyπdin-5-yl,
3-(2-(pyrrolidin-l-yl)ethylammosulfonyl)phenyl,
3-(cyclopropylammocarbonylmethyl)phenyl,
3-(2Λ-(l-methylpyrrolidm-2-ylcarbonylammo)propoxy)-5-(l-methylpyrazol-4- yl)phenyl, 3-(25-(l-methylpyrrolidin-2-ylcarbonylamino)propoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-(l-methoxycarbonylpipeπdm-4-yl)phenyl,
3-(methoxycarbonylammo)-5-(2-(mθφholm-4-yl)pyπmidm-5-yl)phenyl, 3-(2-(l -pyrrolidinyl)ethylammocarbonylmethoxy)-5-(l -methylpyrazol-4-yl)phenyl,
3-n-propoxyphenyl,
3-(N-(l-methylpipendin-4-ylcarbonyl)ρiρeπdin-4-yl)phenyl, 3-(N-(N,N-dimethylammoacetyl)ρiρeπdin-4-yl)phenyl, 4-(ethoxycarbonylammomethyl)phenyl, 4-(methylsulfonylmethyl)phenyl,
4-(l-methylimidazol-5-ylcarbonylammomethyl)phenyl, 4-(l-methylpipeπdm-4-ylcarbonylaminomethyl)phenyl, 3,5-dimethoxyphenyl, 3-(l-methylpipendin-4-ylcarbonylaminomethyl)phenyl, 4-fIuoro-3-(N-morpholinocarbonylmethyl)phenyl,
3-(2-(N-moφhohno)ethyloxy)-5-(l-methylpyrazol-4-yl)ρhenyl, 3-(f/-αnj-(2-dimethylamino)cyclohexylammocarbonylmethoxy)-5-(l-methylpyrazol-4 yl)phenyl,
3-(3-(dimethylamino)propoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2-(pyrrolidm-l-yl)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl,
3-(2-(N-morpholmo)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2-(N-pipeπdmyl)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2-(ethoxycarbonylammo)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2-(pyrrolidm-2-on-l-ylacetylammo)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2-(isoxazol-2-ylcarbonylammo)ethoxy)-5-(l-methylpyrazoI-4-yl)phenyl,
3-(2-(N-pyrrolidinylacetylcarbonylammo)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2-(tetrahydrofuran-2Λ-ylcarbonylamino)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3 -(2-(tetrahydrofuran-25-ylcarbonylammo)ethoxy)-5-( 1 -methylpyrazol-4-yl)phenyl, 3 -(2-( 1 -methylpyrazol-3-ylcarbonylammo)ethoxy)-5-( 1 -methylpyrazol-4-yl)phenyl, 3-(2-(4-chloropyπdin-2-ylcarbonylamino)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl,
3-(2-(pipeπdm-3Λ-ylcarbonylammo)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2-(pipendm-35-ylcarbonylamino)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2-(pipendm-4-ylmethylcarbonylamino)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2-(pyiτolidm-2Λ-ylcarbonylamino)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2-(pyrrolidm-25'-ylcarbonylammo)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2-(2R-amino-3S-hydroxybutanoylammo)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2-(2S-amino-3R-hydroxybutanoylamino)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2-(l-methylpipendin-3/?-ylcarbonylamino)ethoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-(2-(l-methylpipendin-3>S-ylcarbonylammo)ethoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-(2-(l-methylpipeπdm-4-ylmethylcarbonylammo)ethoxy)-5-(l-methylpyrazol-4- yl)phenyl, 3-(2-( 1 -methylpyrrolidin-2Λ-ylcarbonylamino)eihoxy)-5-( 1 -methylpyrazol-4- yl)phenyl,
3-(2-(pipendin-4-ylmethylcarbonylammo)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(4-dimethylammopipeπdin-l-ylcarbonylmethyl)-5-(l-methylpyrazol-4-yl)phenyl, 3-(pyrrolidm-2Λ-ylmethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(pyrrolidm-2-ylmethoxy)-5-(l-methylpyrazol-4-yl)phenyl,
3-(pyrrohdiii-25'-ylmethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(3-hydroxy-2-aminopropoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2if-(N,N-dimethylammoacetylammo)propoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3 -(25'-(N,N-dimethylammoacetylammo)ρroρoxy)-5-( 1 -methylpyrazol-4-yl)ρhenyl, 3-(2Λ-(N,N-dimethylaminoρropoxy)-5-(l-methylρyrazol-4-yl)phenyl,
3-(25-(N,N-dimethylammopropoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2-(4-methylρipeπdin-l-ylacetylamino)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2-aminoethylaminocarbonyl)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2-(N,N-dimethylamino)ethylaminocarbonyl)-5-(l-methylpyrazol-4-yl)phenyl, 3 -(2-(N,N-diethylamino)ethylaminocarbonyl)-5-( 1 -methylpyrazol-4-yl)phenyl,
3-(2-(acetylainino)ethylaminocarbonyl)-5-(l-methylpyrazol-4-yl)phenyl, 3-((pyrrolidm-5-on-2-yl)methylaminocarbonyl))-5-(l-methylpyrazol-4-yl)phenyl, 3-(2-(3i?-hydroxypyrrolidin-l-yl-acetylammo)ethoxy)-5-(l-methylpyrazol-4- yl)phenyl, 3-(2-(35-hydroxypyrrolidin-l-yl-acetylaimno)ethoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-(2-(l,25'-dimethylpipeπdin-35'-yl-carbonylamino)ethoxy)-5-(l-methylpyrazol-4- yl)phenyl, 3-(2-(25'-N,N-dimethylaminopropionyl)aminoethoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-(2Λ-(2-pyπdinoylammo)propoxy)-5-(l-methylpyrazol-4-yl)phenyl,
3-(2S-(pyrrolidm-l-ylacetylammo)propoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2if-(pyrrolidin-l-ylacetylammo)propoxy)-5-(l-methylpyrazol-4-yl)phenyl,
3-(2J?-(l-methylimidazol-4-carbonylamino)propoxy)-5-(l-methylpyrazol-4-yl)phenyl,
3-(2i?-(l-methylpipendinyl-3-carbonylamino)propoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-(2iJ-(tetrahydrofuran-2/?-ylcarbonylamino)propoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-(2Λ-(tetrahydrofuran-251-ylcarbonylammo)propoxy)-5-(l-methylρyrazol-4- yl)phenyl,
3-(2/?-(3-methoxypropionylammo)propyl)-5-(l-methylpyrazol-4-yl)phenyl,
3 -(3 -hydroxypropyl)-5 -(I -methylpyrazol-4-yl)phenyl 3-(2-(l-t-butoxycarbonyl-25-methylpipendm-35'-yl-carbonylammo)ethoxy)-5-(l- methylpyrazol-4-yl)phenyl,
3-(2-(l-methyl-35'-methylpipeπdm-4Λ-yl-carbonylammo)ethoxy)-5-(l- methylpyrazol-4-yl)phenyl,
3-(2-(3Λ-fluoropyrrolidm-l-ylacetylamino)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2-(3Λ-dimethylammopyiτolidm-l-ylacetylammo)ethoxy)-5-(l-methylpyrazol-4- yl)ρhenyl,
3-(2-(35-fluoropyrrohdm-l-ylacetylamino)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl,
3-(2-methylthiazol-4-yl)phenyl,
3-(2-(pyndm-2-ylmethylaminoacetylamino)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2-(2-ammocarbonyl)pyrrolidin-l-ylacetylammo)ethoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-(2-(45'-fluoropyrrohdin-2iS'-ylcarbonylammo)ethoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-(2-(45'-hydroxypyrrolidm-25-ylcarbonylamino)ethoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-(2-(l-methyl-45-fluoropyrrolidm-25'-ylcarbonylammo)ethoxy)-5-(l-methylpyrazol- 4-yl)phenyl,
3-(2-(l-methyl-45-hydroxypyrrohdin-2i5-ylcarbonylammo)ethoxy)-5-(l- methylpyrazol-4-yl)phenyl, 3-(2-(4,4-difluoropyrrolidm-2iS'-ylcarbonylammo)ethoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-(2-(4,4-difluoropyrrolidm-2i?-ylcarbonylammo)ethoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-(2-(l-methyl-4,4-difluoropyrrolidin-25'-ylcarbonylamino)ethoxy)-5-(l- methylpyrazol-4-yl)phenyl,
3-(2-(l-methyl-4,4-difluoropyrrolidin-2i?-ylcarbonylammo)ethoxy)-5-(l- methylρyrazol-4-yl)phenyl, 3-(2-(45'-hydroxypyrrolidin-25-ylcarbonylamino)ethoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-(2-(4-fluoropyrrohdm-2-ylcarbonylammo)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2-(4-hydroxypyrrolidm-2-ylcarbonylammo)ethoxy)-5-(l-methylpyrazol-4- yl)phenyl, 3-(2i?-(25-methylρiρendin-3S'-yl-carbonylammo)propoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-(2-aminoethoxy)-5-(thiazol-5-yl)phenyl, 3-(2-aminoethoxy)-5-(l-methyhmidazol-5-yl)phenyl, 3-(2-methoxyethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2-(2-ammopyndin-4-ylcarbonylammo)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl,
3-(2-(2-hydroxypyπdin-4-ylcarbonylamino)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3 -(2-pyπdylmethoxy)-5-( 1 -methylpyrazol-4-yl)phenyl, 3-(2-ammopyπdm-4-ylmethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-((2-(4-methylpiperazin-l-yl)ethylammocarbonyl)methoxy)-5-(l-methylpyrazol-4- yl)ρhenyl,
3-(2-(dimethylammo)ethoxy)-5-(pynmidm-5-yl)phenyl, 3-(2-(3-methoxypropionylamino)ethoxy)-5-(pyπmidm-5-yl)phenyl, 3-(2-(l-methylpyrrolidin-2S-ylcarbonylamino)ethoxy)-5-(pynmidin-5-yl)phenyl, 3-(l-methylimidazol-5-yl)-5-(N-morpholinomethyl)phenyl, 3-(l-ammocycloprop-l-ylmethoxy)-5-(l-methylpyrazol-4-yl)phenyl,
3-(3-azetidinylmethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(25-anuno-3-hydroxypropyl)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2i?-(methylaminocarbonyl)pyrrolidm-4Λ-yloxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-((imidazo[l,2-a]ρyndin-4-ylcarbonyl)aminomethyl)phenyl, 3-(N-acetylpyrrohdm-2-ylcarbonylammomethyl)phenyl,
3-(2-morpholinopyndin-5-yl)carbonylammomethylphenyl,
3-(2-(cyclopropylsulfonylamino)ethoxy)phenyl,
3-(2-(N,N-diethylamrnoethyl)-N-methylcarbonylmethoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-((4-N,N-dimethylaminocyclohexylamino)carbonylmethoxy)-5-(l-methylpyrazol-4- yl)ρhenyl,
3-(4-(2-methoxyethoxy)piperazin-l-ylaminocarbonylmethoxy)-5-(l-methylpyrazol-4- yl)phenyl, 3-(2-( 1 -methylpyrrolidin-2-yl)ethylaminocarbonylmethoxy)-5-( 1 -methylpyrazol-4- yl)phenyl,
3-(35'-qumuclidylaminocarbonylmethoxy)-5-(l-methylpyrazol-4-yl)phenyl,
3 -(3/?-qumuclidylaminocarbonylraethoxy)-5-( 1 -methylpyrazol-4-yl)phenyl,
3-(N-ethylpyrrolidin-2S-ylmethylammocarbonylmethoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-(N-ethylpyrrolidm-2R-ylmethylammocarbonylmethoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-(4-methyl-l,4-diazepin-l-ylcarbonylmethoxy)-5-(l-methylpyrazol-4-yl)phenyl,
3-(pyrrolidmo[carbonylmethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(N-tetrahydropyran-4-yl-N-methylaminocarbonylmethoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-(N-tetrahydropyran-3-ylaminocarbonylmethoxy)-5-(l-methylpyrazol-4-yl)phenyl,
3-(N-tetrahydropyran-4-yl)methylaminocarbonylmethoxy)-5-(l-methylpyrazol-4- yl)phenyl, 3-(2-(l,2,4,-tπazol-l-yl)ethylammocarbonylmethoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-((ρyrrohdin-2-on-5-ylmethyl)aminocarbonylmethoxy)-5-(l-methylpyrazol-4- yl)ρhenyl,
3-((pyπdin-2-on-4-ylmethyl)ammocarbonylmethoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-((2R-ammocyclohex-lR-yl)aminocarbonylmethoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-(2-(4-methylpiperazm-l-yl)ethylammocarbonylmethoxy)-5-(l-methylρyrazol-4- yl)phenyl, 3 -(^R-NjN-dimethylaminocyclohex- 1 R-yl)aminocarbonylmethoxy)-5-( 1 - methylpyrazol-4-yl)phenyl,
3-((2S-N,N-dimethylaminocyclohex- 1 S-yl)aminocarbonylmethoxy)-5-( 1 - methylpyrazol-4-yl)phenyl, 3-(2-(pyrrohdin-2-on-l-ylmethyl)carbonylamino)ethoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-(2-(ethoxycarbonylamino)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2-{N-morpholmocarbonylamuio)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2-(l-methylpyrazol-4-ylcarbonylamino)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3 -(2-(isoxazol-5-ylcarbonylamino)ethoxy)-5-( 1 -methylpyrazol-4-yl)phenyl,
3-(2-(pyrrolidm-2R-ylcarbonylammo)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2-(pyrrolidin-2S-ylcarbonylamino)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2-(pipeπdm-2R-ylcarbonylamino)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2-(pipeπdin-2S-ylcarbonylamino)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2-(pipeπdin-3R-ylcarbonylammo)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl,
3-(2-(pipeπdin-3S-ylcarbonylamino)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl,
3-(2-(l-methylpyrrolidin-2R-ylcarbonylamino)ethoxy)-5-(l-methylpyrazol-4- yl)phenyl, 3-(2-(l-methylpyrrolidin-2S-ylcarbonylammo)ethoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-(2-(l-methylpipeπdiπ-2R-ylcarbonylaramo)ethoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-(2-(l-methylpipeπdin-2S-ylcarbonylammo)ethoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-(2-(l-methylpiρendin-3R-ylcarbonylammo)ethoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-(2-(l -methylρipeπdm-3 S-ylcarbonylaπuno)ethoxy)-5-(l -methylpyrazol-4- yl)phenyl, 3-(2-(2R-aminopropionylammo)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl,
3-(2-(2S-aminopropionylammo)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl,
3-(2-(2R-methylpipeπdin-3S-ylcarbonylamino)ethoxy)-5-(l-methylpyrazol-4- yl)phenyl, 3-(2-(2S-methylpipeπdm-3R-ylcarbonylammo)ethoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-(2-(4-methylpipeπdin-l-ylammomethylcarbonyl)ethoxy)-5-(l-methylpyrazol-4- yl)phenyl, 3-(2-(2R-N,N-dimethylaminopropionylamino)ethoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-(2-(2S-N,N-dimethylammopropionylammo)ethoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-(2-(3R-hydroxypyrrohdm-l-ylmethylcarbonylammo)ethoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3 -(2-(3 S- hydroxypyrrolidm- 1 -ylmethylcarbonylammo)ethoxy)-5-(l -methylpyrazol- 4-yl)phenyl,
3-(2-(3R-fluoropyrrolidm-l-ylmethylcarbonylamino)ethoxy)-5-(l-methylpyrazol-4- yl)phenyl, 3-(2-(3S- fluoropyrrolidin-l-ylmethylcarbonylamino)ethoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3 -(2-(3R-N,N-dimethylaminopyrrobdin- 1 -ylmethylcarbonylammo)ethoxy)-5-( 1 - methylρyrazol-4-yl)phenyl,
3-(2-(3S- N,N-dimethylaminopyrrolidin-l-ylmethylcarbonylamino)ethoxy)-5-(l- methylpyrazol-4-yl)phenyl,
3-(2-(4-hydroxypipendm-l-ylaminomethylcarbonyl)ethoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-(2-(4-fluoropipendin-l-ylammomethylcarbonyl)ethoxy)-5-(l-methylpyrazol-4- yl)phenyl, 3-(2-(N-morpolmo)pyπdm-5-ylmethoxy)-5-(l-methylpyrazol-4-yl)phenyl,
3-(6-hydroxymethylpyπdin-2-ylmethoxy)-5-(l-methylpyrazol-4-yl)phenyl,
3-(2-(2S-methoxycarbonylpyrrohdm-4R-yloxy)-5-(l-methylpyrazol-4-yl)phenyl,
3-(2-(2S-methoxycarbonylpyrrohdin-4S-yloxy)-5-(l-methylpyrazol-4-yl)phenyl,
3-(2-(2S-carboxypyrrolidm-4R-yloxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2-(2S-carboxypyrrolidm-4S-yloxy)-5-(l-methylpyrazol-4-yl)phenyl,
3-(2-(2S-N-methylaminocarbonylpyrrolidiii-4R-yloxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-(2-(2S-N-methylartiinocarbonylpyrrolidm-4S-yloxy)-5-(l-methylpyrazol-4- yl)phenyl, 3-(2-(2S-N-(2-methoxyethyl)aminocarbonylpyrrolidm-4R-yloxy)-5-(l- methylpyrazol-4-yl)phenyl,
3-(2-(2S-N-(2-methoxyethyl)aminocarbonylpyrrobdin-4S-yloxy)-5-(l-methylpyrazol- 4-yl)phenyl,
3-(2-(2-aπunothiazol-4-ylmethylcarbonylammo)ethoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-(2-(thiazol-4-ylcarbonylamino)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl,
3-(2-(2-aminothiazol-5-ylcarbonylamino)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3-(2-(2-aminothiazol-4-ylcarbonylammo)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl,
3-(2-(2-N-acetylammothiazol-4-ylcarbonylamino)ethoxy)-5-(l-methylpyrazol-4- yl)phenyl,
3-(2-(tetrahydropyran-4-ylammo)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl,
3-(2-(l-methylpipeπdin-4-ylamino)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl, 3 -(2-hydroxymethyl-3 -hydroxypropoxy)-5 -( 1 -methylpyrazol-4-yl)phenyl,
3-(2R-(cyclopropylsulfonylammo)propoxy)-5-(l-methylpyrazol-4-yl)phenyl,
3 -(octahydropyrrolo[ 1 ,2-a]pyrazm-2-ylcarbonylammomethoxy)-5-( 1 -methylpyrazol- 4-yl)phenyl,
3-(aminosulfonyl)-5-(aminocarbonyl)phenyl, 3-(N-methylammosulfonyl)-5-(N-methylaminocarbonyl)phenyl, and
3-(2-(2-hydroxypyπdin-5-ylcarbonylammo)ethoxy)-5-(l-methylpyrazol-4-yl)phenyl
In some embodiments, the invention provides compounds that have the Formula I
Figure imgf000036_0001
I or a pharmaceutically acceptable salt thereof, wherein
Ar is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, including fused bicyclic systems, R1 is H, Ci 3 alkyl, halo, cyano, mtro, CF3, lmidazolyl, thiazolyl, oxazolyl, or amino, R2 and R3 are independently selected from the group consisting of H, alkoxy, substituted alkoxy, and halo,
L is a covalent bond, carbonyl, carbonylamino, aminocarbonyl, -O-, -S-, -SO-, -SO2-, -NH-, Ci-3 alkyl, substituted Ci-3 alkyl, or an alkyl interrupted with -O-, -S-, -SO-, -SO2-, -NH-, carbonyl, carbonylamino, or aminocarbonyl, and
A1 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylammo, acyloxy, ammo, substituted ammo, aminocarbonyl, aminothiocarbonyl, aminocarbonylammo, aminothiocarbonylaπuno, aminocarbonyloxy, ammosulfonyl, aminosulfonyloxy, aminosulfonylammo, amidmo, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, mtro, SO3H, sulfonyl, substituted sulfonyl, sulfonyloxy, sulfonylammo, thioacyl, thiol, alkylthio, substituted alkylthio, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl
According to some embodiments, compounds of the invention have Formulae II- VII
Figure imgf000037_0001
wherein Rp is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylammo, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylammo, aminothiocarbonylammo, aminocarbonyloxy, ammosulfonyl, aminosulfonyloxy, aminosulfonylammo, amidmo, aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guamdmo, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, mtro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio,
RA is selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl and substituted heterocyclyl,
Het is selected from the group consisting of heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl, and x is 1, 2, 3, 4 or 5
According to some embodiments, compounds of the invention have Formula II
Figure imgf000038_0001
II wherein Rp is independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, ammo, substituted ammo, aminocarbonyl, aminothiocarbonyl, aminocarbonylammo, ammothiocarbonylamino, ammocarbonyloxy, ammosulfonyl, aminosulfonyloxy, ammosulfonylammo, amidino, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guamdmo, substituted guanidino, halo, hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, mtro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, and alkylthio, wherein the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heterocyclyl, and heteroaryl moieties contained within any of the preceding "substituted aryl" groups are optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, ammo, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylammo, ammothiocarbonylammo, amino- carbonyloxy, aminosulfonyl, ammosulfonyloxy, aminosulfonylamino, amidino, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)ammo, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guanidmo, guamdmo, halo, hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, mtro, SO3H, sulfonyl, sulfonyloxy, sulfonylammo, thioacyl, thiol, alkylthio, and alkylthio, x is 1, 2, 3, 4 or 5, and R1, R2, R3, L and A1 are as defined above
In some embodiments of Formula II, x is 1, 2 or 3, and the isolated phenyl πng m Formula II has no substituents ortho to the NH to which it is attached Preferred substitution patterns for this phenyl ring include mono-substitution at the 3-position ('meta' to the NH), mono-substitution at the 4-position ('para' to the NH), and disubstitution at the 3 and 4 positions or at the 3 and 5 positions
In certain embodiments of the compounds of Formula II, R1 is H In certain embodiments of the compounds of Formula II, R2 is substituted alkoxy In certain embodiments of the compounds of Formula II, R2 is substituted alkoxy, heterocyclyloxy, or heterocyclylalkoxy In other embodiments, R2 is H In some embodiments of Formula II, R3 is substituted alkoxy such as heteroarylmethoxy Suitable heteroaryl groups in these compounds include pyrazole, imidazole, thiazole, pyridine, and pyrazole and pyπmidine In other such embodiments, R3 is heterocyclyloxy or heterocyclyl-subshtuted alkoxy such as heterocyclylmethoxy In other such embodiments, R3 is heterocyclyl-substituted alkoxy such as heterocyclylmethoxy Suitable heterocyclyl groups for these embodiments include pipeπdinyl, pyrrolidmyl, tetrahydrofuranyl, and the like
In some embodiments, at least one Rp present compπses a heteroaryl or heterocyclic group In some embodiments, it is a heteroaryl group, which may be substituted Suitable heteroaryls include pyπdmyl, imidazolyl, pyrazolyl, pynmidmyl, thiazolyl, tπazolyl, tetrazolyl, oxazolyl, thiazolyl, and thiadiazolyl In others, Rp is a group of the formula -O- CH2-C(O)-NR'R", where R' and R" are independently H, alkyl, or substituted alkyl, and R' and R" can join together to form a heterocyclic πng hi other embodiments, Rp is a heterocyclyl group such as piperazmyl, pipendmyl, morpholrnyl, or Rp is a heterocyclyl- substituted alkyl such as piperazinylmethyl, morpholmylmethyl, oxazohnylmethyl, and the like In some embodiments, RP is a heterocyclyl or heteroaryl group linked to the phenyl πng of Formula II through -O- or -OCH2- or -OCH2-CH2-
According to some embodiments, compounds of the invention have Formula III
Figure imgf000040_0001
III wherein R1, R2, R3, A1, Rp and x are as defined above These correspond to compounds wherein L is a bond Typically in these embodiments, at least one of R1, R2 and R3 is a group other than H Frequently, R1 is H or halo, and either R2 or R3 is H while the other of R2 and R3 is a group selected from alkoxy, substituted alkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, and substituted heterocyclyloxy
According to some embodiments, compounds of the invention have Formula IV
Figure imgf000040_0002
IV wherein R1, R2, R3, A1, Rp and x are as defined above
According to some embodiments, compounds of the invention have Formula V
Figure imgf000040_0003
wherein R1, R2, R3, Rp and x are as defined above, and
RA is selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl and substituted heterocyclyl Frequently, RA is selected from H, methyl, hydroxymethyl, methoxymethyl, and other alkoxymethyl groups Often in these compounds, R1, R2, R3, Rp and x are as described for the compounds of Formula II above
According to some embodiments, compounds of the invention have Formula VI
Figure imgf000041_0001
VI wherein R1, R2, R3, L, Rp and x are as defined above, and
Het is selected from the group consisting of heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl Often in these compounds, R1, R2, R3, Rp and x are as descπbed for the compounds of Formula II above In some of these embodiments, L is a bond, -O-, -OCH2-, ammo, ammocarbonyl, or carbonylamino
According to some embodiments, compounds of the invention have Formula VII
Figure imgf000041_0002
VII wherein R1, R2, R3, Rp, x and Het are as defined above Often in these compounds,
R1, R2, R3, Rp and x are as described for the compounds of Formula II above Het in these compounds can be any heterocyclic or heteroaryl group, and sometimes it is selected from thiazole, oxazole, isothiazole, isoxazole, pyrazole, pyridine, tnazole, and furan
It is further appreciated that certain features of the invention, which are, for clarity, descπbed in the context of separate embodiments, can also be provided in combination in a single embodiment Conversely, various features of the invention which are, for brevity, descπbed in the context of a single embodiment, can also be provided separately or in any suitable subcombmation Some compounds of the invention include those of Table 1, below The compounds in Table 1 were prepared as indicated in the column labeled "Prep Ex #" and the details of certain exemplary synthetic procedures are provided herein Physical data is provided m the column marked "MS (M+l) " for each of the compounds, as is retention time data This physical data was acquired using one of two methods, Method A and Method B, which are provided herein in the Examples Method B was used for the data collected for Examples 36, 19, 110, and 111, and Method A was used to collect all the remaining physical data in Table 1 Additional compounds of the invention are included in Table 2 (Figure 1) and in Table 3 (Figure 3) Methods for preparation of representative compounds from Tables 2 and 3 are provided herein, the Examples for which are numbered to correspond to the numbering of the compounds in the Tables
The column marked "Activity" indicates the compound's activity in the PDKl Kinase Alpha Screen Assay descπbed below The symbol "+" indicates IC50 values of 25 μm or greater (or compounds not evaluated), the symbol "++" indicates IC50 values between less than 25 μm and greater than 10 μm, the symbol "+++" indicates IC50 values of 10 μm or less and greater than 5 μm, and the symbol "++++" indicates IC50 values less than 5 μm Accordingly, as shown in Table I, 131 of the Example compounds, or about 75% of the Example compounds have been shown to demonstrate IC50 values of less than 5 μm
Table 1
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
CH3 4-(6,7-dimethoxy- 361 0 35
N quinazokn-2-ylamino)-
HN-^N' benzenesulfonamαde 2 01 CH3
0^NH2
4-(6-methoxyqmnazolin-2- 295 1 21 ylamino)benzamide
N-methyl-2-(4-sulfamoyl- 358 +++ 18,19, phenylamino)quinazokne- 20
6-carboxamide 2 0
N-(I -methylpipeπdin-4- 441 18,19, yl)-2-(4-sulfamoylphenyl- 20 amino)quinazolme-6- 1 71 carboxamide
4-(6-(4-isopropyl- 427 1 18,19, piperazine-1-carbonyl)- 20 quinazolin-2-ylamino)- 1 54 benzenesulfonamide
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
71 N-(3-((dimethylamino)- 303 1 9, 10 methyl)phenyl)-6- ethynylquinazolin-2-amine 2 11
72 4-(6-ethynylquinazolin-2- 331 2 9, 10 ylamino)-N-isopropyl- benzamide 2 75
73 4-(6-ethynyl-7-methoxy- 361 ++++ 47, 2 quinazolin-2-ylammo)-N- lsopropylbenzamide 3 38
74 (4-(6-ethynyl-7-methoxy- 389 47, 2 quinazolin-2-ylamino)- phenyl)(morpholmo)- 3 00 methanone
75 4-(6-(thiazol-2-yl)- 348 1 12 quinazolin-2-ylamino)- benzamide 227
Figure imgf000058_0001
Figure imgf000059_0001
10
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
us 5-chloro-8-methoxy-N-(4- 454 1 ++++ 14, 12 morpholinophenyl)-6- (thiazol-2-yl)quinazolin-2- 2 59
116 6-bromo-5 -chloro-8 - 451 O 14 methoxy-N-(4- morpholmophenyl)- 2 68 quuiazolin-2-amine
117 (4-(5-chloro-8-methoxy-6- 482 1 14, 12 (thiazol-2-yl)quinazolin-2- ylamino)phenyl)- 2 80 (morpholuio)-methanone
118 (4-(6-bromo-5-chloro-8- 479 0 ++++ 14 methoxyqumazolin-2- ylamino)phenyl)- 2 93 (morpholino)-methanone
119 4-(5-chloro-8-methoxy-6- 454 1 ++++ 14, 12
(thiazol-2-yl)quinazolin-2- ylamino)-N-isopropyl- 3 04 benzamide
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
10 10
Figure imgf000072_0001
Figure imgf000073_0001
32
Figure imgf000074_0001
Figure imgf000075_0001
24
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
The Compounds in Table 1 were named using the structure naming program in ChemDraw 9 0 1, implementing IUPAC standardized nomenclature
Additional compounds of the invention are listed in Table 2 (Figure 1), and Table 3 (Figure 2)
It is intended that the compounds of the invention are stable As used herein "stable" refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and preferably capable of formulation into an efficacious therapeutic agent It is further intended that the compounds of the invention are those that can be prepared by one skilled m the art according to the methods descnbed herein and any other suitable method, routine or otherwise Further provided are compounds of the invention and mixtures thereof where any asymmetric carbon atom(s) present can have either the R or S configuration Substituents at a double bond or a πng of the compounds of formula I may be present in either the cis (-Z-) or trans (-E-) configurations The compounds may thus be present as mixtures of isomers, 5 diastereomers, and enantiomers or may be present as pure isomers In some embodiments, the compounds are enantiomeπcally pure where only one enantiomer is present In other embodiments, the compound may be present as a mixture of enantiomers which includes more of one enantiomer than it does of the other, or a racemic mixture Where absolute stereochemistry is indicated in the specific examples, the compound as isolated is believed to
10 correspond substantially to the indicated absolute stereochemistry but will often contain at least some of the opposite stereochemistry
It is further intended that the compounds of the invention include various solid forms such as crystalline, microcrystalhne, nanocrystallme, and amorphous forms, as well as hydrated, solvated, anhydrous, and non-solvated forms
15 Compounds of the invention can also include different atomic isotopes Isotopes include those atoms having the same atomic number but different mass numbers For example, isotopes of hydrogen include tπtium and deutenum Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N,
20 180, 170, 31P, 32P, 35S, 18F and 36Cl, respectively Compounds of the present invention, tautomers thereof, prodrugs thereof, and pharmaceutically acceptable salts of the compounds and of the prodrugs that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are
25 incorporated, are useful in drug and/or substrate tissue distribution assays Tritiated, i e , 3H, and carbon-14, i e , 14C, isotopes are particularly preferred for their ease of preparation and detectability Further, substitution with heavier isotopes such as deutenum, i e , 2H, may 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
30 some circumstances Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out known or referenced procedures and by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent In some embodiments, the compounds of the invention, and their salts, esters, tautomers, etc , are isolated By "isolated" or "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which is was formed or discovered Partial separation can include, for example, a composition enriched in the compound of the invention Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, and at least about 99% by weight of the compound of the invention, or salt thereof Methods for isolating compounds and their salts and other deπvatives are routine in the art The present invention further provides prodrugs of the compounds descπbed herein
As used herein, "prodrugs" refer to any covalently bonded earners which release the active parent drug when administered to a mammalian subject Prodrugs can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds Prodrugs include compounds wherein hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, ammo, sulfhydryl, or carboxyl group respectively Examples of prodrugs include, but are not limited to, acetate, formate and benzoate deπvatives of alcohol and amine functional groups in the compounds of the invention Preparation and use of prodrugs is discussed in T Higuchi and V Stella, "Pro-drugs as Novel Delivery Systems," VoI 14 of the A C S Symposium Seπes, and in Bioreversible Carriers in Drug Design, ed Edward B Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference in their entirety
In accordance with further embodiments of the present invention, therapeutic compositions are provided Such compositions include a therapeutically effective amount of a compound of the invention (ι e , a compound of Formula I) and at least one pharmaceutically acceptable carrier
Pharmaceutical compositions that include the compounds descπbed herein may include additives such as pharmaceutically acceptable earners or excipients Suitable pharmaceutically acceptable earners include processing agents and drug delivery modifiers and enhancers, such as, for example, calcium phosphate, magnesium stearate, talc, monosacchandes, disacchandes, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl-β-cyclodextπn, polyvinylpyrrohdinone, low melting waxes, ion exchange resms, and the like, as well as combinations of any two or more of these Other suitable pharmaceutically acceptable earners are descπbed in Remington The Science And Practice Of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD, 21st ed (May 28, 2005), which is hereby incorporated herein by reference in its entirety and for all purposes as if fully set forth herein
Pharmaceutical compositions that include the compounds of the invention maybe in any form suitable for the intended method of administration, including, for example, as a solution, a suspension, or an emulsion Liquid earners are typically used in prepanng solutions, suspensions, and emulsions Liquid earners contemplated for use in the practice of the present invention include, for example, water, saline, pharmaceutically acceptable organic solvent(s), pharmaceutically acceptable oils or fats, and the like, as well as mixtures of two or more of these The liquid earner may include other suitable pharmaceutically acceptable additives such as solubihzers, emulsifiers, nutnents, buffers, preservatives, suspending agents, thickening agents, viscosity regulators, stabilizers, and the like Suitable orgamc solvents include, for example, monohydnc alcohols, such as ethanol, and polyhydnc alcohols, such as glycols Suitable oils include, but are not limited to, soybean oil, coconut oil, olive oil, safflower oil, cottonseed oil, and the like For parenteral administration, the earner may be an oily ester such as ethyl oleate, isopropyl mynstate, and the like Compositions of the present invention may also be in the form of microparticles, microcapsules, and the like, as well as combinations of any two or more of these
The compounds and combinations of the present invention can also be administered in the form of liposomes As is known in the art, liposomes are generally denved from phospholipids or other lipid substances Liposomes are formed by mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium Any non-toxic, physiologically acceptable and metabohzable lipid capable of forming liposomes can be used The present compositions in liposome form may include, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like Preferred lipids include phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic Methods of forming liposomes are known in the art See, for example, Prescott, Ed , Methods in Cell Biology, Volume XIV, Academic Press, New York, N W , p 33 et seq (1976)
Controlled release delivery systems may also be used, such as a diffusion controlled matnx system or an erodible system, as descnbed for example in Lee, "Diffusion-Controlled Matnx Systems", pp 155-198 and Ron and Langer, "Erodible Systems", pp 199-224, in
"Treatise on Controlled Drug Delivery", A Kydorueus Ed , Marcel Dekker, Inc , New York
SO 1992 The matrix may be, for example, a biodegradable material that can degrade spontaneously in situ and in vivo for, example, by hydrolysis or enzymatic cleavage, e g , by proteases The delivery system may be, for example, a naturally occurring or synthetic polymer or copolymer, for example m the form of a hydrogel Exemplary polymers with cleavable linkages include polyesters, polyorthoesters, polyanhydrides, polysacchandes, poly(phosphoesters), polyamides, polyurethanes, poly(imidocarbonates) and poly(phosphazenes)
The compounds of the invention may be administered enterally, orally, parenterally, sublingually, by inhalation spray, rectally, or topically in dosage unit formulations that include conventional nontoxic pharmaceutically acceptable earners, adjuvants, and vehicles as desired For example, suitable modes of administration mclude oral, subcutaneous, transdermal, transmucosal, lontophoretic, intravenous, intramuscular, intraperitoneal, intranasal, subdermal, rectal, and the like Topical administration may also include the use of transdermal administration such as transdermal patches or ionophoresis devices The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, mtrasternal injection, or infusion techniques
Injectable preparations, for example, steπle injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents The steπle injectable preparation may also be a steπle injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution m 1,3-propanediol Among the acceptable vehicles and solvents that may be employed are water, Rmger's solution, and isotomc sodium chloride solution hi addition, steπle, fixed oils are conventionally employed as a solvent or suspending medium For this purpose, any bland fixed oil may be employed including synthetic mono- or diglyceπdes In addition, fatty acids such as oleic acid find use in the preparation of mjectables
Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nomrπtating excipient such as cocoa butter and polyethylene glycols that are solid at ordinary temperatures but liquid at the rectal temperature and will, therefore, melt in the rectum and release the drug
Solid dosage forms for oral administration may mclude capsules, tablets, pills, powders, and granules In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch Such dosage forms may also include, as is normal practice, additional substances other than inert diluents, e g , lubricating agents such as magnesium stearate In the case of capsules, tablets, and pills, the dosage forms may also include buffering agents Tablets and pills can additionally be prepared with enteπc coatings
Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs contaming inert diluents commonly used in the art, such as water Such compositions may also compπse adjuvants, such as wetting agents, emulsifying and suspending agents, cyclodextnns, and sweetening, flavoring, and perfuming agents
The amount of active ingredient that may be combined with the earner materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration It will be understood, however, that the specific dose level for any particular patient will depend upon a vaπety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and seventy of the particular disease undergoing therapy The therapeutically effective amount for a given situation can be readily determined by routine expenmentation and is within the skill and judgment of the ordinary clinician
In some embodiments, the compounds of the invention can be admimstered to a patient in combination with one or more further pharmaceutical agents Administration of the different agents can be made separately either sequentially or simultaneously, or the agents can be admimstered together in a single composition Example further pharmaceutical agents include anti-cancer drugs including chemotherapeutics and other kinase inhibiting compounds
"Aryl" or refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single nng or multiple condensed nngs Non-hmitmg examples of aryl groups include phenyl, naphthyl, anthryl, and the like
"Substituted aryl" refers to aryl groups which are substituted with 1 to 5, or 1 to 3, or 1 to 2 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, amino, substituted ammo, aminocarbonyl, aminothiocarbonyl, amino- carbonylamrno, aminothiocarbonylammo, ammocarbonyloxy, ammosulfonyl, ammosulfonyl- oxy, ammosulfonylammo, amidmo, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guanidmo, substituted guanidmo, halo, hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylammo, thioacyl, thiol, and alkylthio, wherein the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heterocyclyl, and heteroaryl moieties contained within any of the preceding "substituted aryl" groups are optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkenyl, alkynyl, alkoxy, acyl, acylammo, acyloxy, ammo, substituted ammo, ammocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, amino- carbonyloxy, ammosulfonyl, ammosulfonyloxy, aminosulfonylammo, amidino, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)ammo, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guanidmo, guamdino, halo, hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, mtro, SO3H, sulfonyl, sulfonyloxy, sulfonylammo, thioacyl, thiol, alkylthio, and alkylthio, and wherein said substituents are defined herein "Aryloxy" refers to the group -O-aryl, where aryl is as defined herein, that includes, by way of example, phenoxy and naphthoxy
"Substituted aryloxy" refers to the group -O-(substituted aryl) where substituted aryl is as defined herein
"Arylthio" refers to the group — S-aryl, where aryl is as defined herein "Substituted arylthio" refers to the group -S-(substituted aryl), where substituted aryl is as defined herein
"Alkyl" refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms or from 1 to 6 carbon atoms This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), »-propyl (CH3CH2CH2-), isopropyl ((CH3J2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3J2CHCH2-), .sec-butyl ((CH3)(CH3CH2)CH-), tfjutyl ((CHs)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3J3CCH2-)
"Substituted alkyl" refers to an alkyl group having from 1 to 5, or 1 to 3, or 1 to 2 substituents selected from the group consistmg of alkoxy, acyl, acylammo, acyloxy, ammo, substituted amino, ammocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, ammocarbonyloxy, ammosulfonyl, aminosulfonyloxy, aminosulfonylammo, amidmo, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl esterjammo, (carboxyl esterjoxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guanidmo, substituted guamdino, halo, hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, and alkylthio, wherein the alkyl, aryl, cycloalkyl, cycloalkenyl, heterocyclyl, and heteroaryl moieties contained within any of the preceding "substituted alkyl" groups, are optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkenyl, alkynyl, alkoxy, acyl, acylammo, acyloxy, ammo, substituted ammo, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, ammothiocarbonylammo, aminocarbonyloxy, aminosulfonyl, ammosulfonyloxy, ammosulfonylammo, amidmo, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guamdino, substituted guamdino, halo, hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, mtro, SO3H, sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and alkylthio, and wherein said substituents are defined herein "Alkoxy" refers to the group -O-alkyl wherein alkyl is defined herein Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, f-butoxy, iec-butoxy, and n-pentoxy
"Substituted alkoxy" refers to the group -O-(substituted alkyl) wherein substituted alkyl is defined herein
"Acyl" refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocychc-C(O)-, and substituted heterocyclic-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herem Acyl mcludes the "acetyl" group CH^C(O)-
"Acylammo" refers to the groups -NRC(O)alkyl, -NRC(O)substituted alkyl, -NRC(O)cycloalkyl, -NRC(O)substituted cycloalkyl, -NRC(0)cycloalkenyl, -NRC(O)substiruted cycloalkenyl, -NRC(O)alkenyl, -NRC(O)substituted alkenyl,
-NRC(O)alkynyl, -NRC(O)substituted alkynyl, -NRC(O)aryl, -NRC(O)substituted aryl, -NRC(O)heteroaryl, -NRC(O)substituted heteroaryl, -NRC(O)heterocychc, and -NRC(O)substituted heterocyclic wherein R is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein
"Acyloxy" refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O-, alkynyl-C(O)O-, substituted alkynyl-C(O)O-, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, cycloalkenyl-C(0)0-, substituted cycloalkenyl-C(O)O-, heteroaryl-C(O)O-, substituted heteroaryl-C(O)O-, heterocychc-C(O)O-, and substituted heterocychc-C(O)O- wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein
"Ammo" refers to the group -NH2 "Substituted amino" refers to the group -NR'R" where R' and R" are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, -Sθ2-alkyl, -SCh-alkenyl, -SC^-cycloalkyl, -SO2- cycloalkenyl, -Sθ2-aryl, -Sθ2-heteroaryl, and -Sθ2-heterocychc, wherein R' and R" are optionally joined, together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that R' and R" are both not hydrogen, wherem the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heterocyclyl, and heteroaryl moieties contained within any of the preceding "substituted amino" groups are optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkenyl, alkynyl, alkoxy, acyl, acylammo, acyloxy, amino, aminocarbonyl, ammothiocarbonyl, ammocarbonylammo, aminothiocarbonylammo, ammocarbonyloxy, ammosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidmo, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guamdino, substituted guamdmo, halo, hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, mtro, SO3H, sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, and alkylthio, and wherein said substituents are defined herein
When R' is hydrogen and R" is alkyl, the substituted amino group is sometimes referred to herein as alkylamino When R' and R" are alkyl, the substituted ammo group is sometimes referred to herein as dialkylamino When referring to a monosubstituted amino, it is meant that either R' or R" is hydrogen but not both When referring to a disubstituted amino, it is meant that neither R' nor R" are hydrogen
"Ammocarbonyl" refers to the group -C(O)N R10R11 where R10 and R11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R10 and R11 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein
"Aminothiocarbonyl" refers to the group -C(S)NR10R11 where R10 and R11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R10 and R11 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein
"Ammocarbonylammo" refers to the group -NRC(O)NR10R11 where R is hydrogen or alkyl and R10 and R11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R10 and Rn are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein
"Aminothiocarbonylamino" refers to the group -NRC(S)NR10R11 where R is hydrogen or alkyl and R10 and R11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R10 and R11 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein
"Ammocarbonyloxy" refers to the group -0-C(O)NR10R11 where R10 and R11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R10 and R11 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein
"Aminosulfonyl" refers to the group -SO2NR10R11 where R10 and R11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R10 and R11 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein
"Aminosulfonyloxy" refers to the group 0-SO2NR10R11 where R10 and R11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R10 and R11 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein "Aminosulfonylammo" refers to the group NR-SC^NR10R1 ' where R is hydrogen or alkyl and R10 and R11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R10 and R11 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein "Amidmo" refers to the group -C(=NR12)R1ORU where R10, R11, and R12 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R10 and R11 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein "Alkenyl" refers to alkenyl groups having from 2 to 6 carbon atoms or from 2 to 4 carbon atoms and having at least 1 and in some embodiments, from 1 to 2 sites of alkenyl unsaturation Such groups are exemplified, for example, by vinyl, allyl, and but-3-en-l-yl
"Substituted alkenyl" refers to alkenyl groups having from 1 to 3 substituents, or from 1 to 2 substituents, selected from the group consisting of alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, ammothiocarbonyl, aminocarbonylammo, amino- thiocarbonylamino, aminocarbonyloxy, aminosulfonyl, ammosulfonyloxy, ammosulfonyl- amino, amidino, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guamdmo, substituted guanidmo, halo, hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, rutro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, and alkylthio, wherein the alkyl, aryl, cycloalkyl, cycloalkenyl, heterocyclyl, and heteroaryl moieties contained within any of the preceding "substituted alkenyl" groups are optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, acyl, acylammo, acyloxy, amino, substituted amino, ammocarbonyl, aminothiocarbonyl, ammocarbonylammo, ammothiocarbonylamino, aminocarbonyloxy, ammosulfonyl, amino sulfonyloxy, ammosulfonylammo, amidino, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)ammo, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guamdmo, substituted guamdmo, halo, hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, mtro, SO3H, sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, and alkylthio, wherein said substituents are defined herein and with the proviso that any hydroxy substitution is not attached to a vinyl (unsaturated) carbon atom "Alkynyl" refers to alkynyl groups having from 2 to 6 carbon atoms or from 2 to 3 carbon atoms and having at least 1 and, in some embodiments, 1 to 2 sites of alkynyl unsaturation
"Substituted alkynyl" refers to alkynyl groups having from 1 to 3 substituents, and, in some embodiments, 1 to 2 substituents, selected from the group consisting of alkoxy, acyl, acylammo, acyloxy, ammo, substituted amino, ammocarbonyl, aminothiocarbonyl, ammocarbonylammo, ammothiocarbonylamino, aminocarbonyloxy, ammosulfonyl, ammosulfonyloxy, ammosulfonylammo, amidino, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)ammo, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guamdmo, substituted guamdmo, halo, hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, mtro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, and alkylthio, wherein the alkyl, aryl, cycloalkyl, cycloalkenyl, and heteroaryl moieties contained within any of the preceding "substituted alkynyl" are optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, acyl, acylammo, acyloxy, amino, substituted ammo, ammocarbonyl, aminothiocarbonyl, ammocarbonylammo, ammothiocarbonylamino, aminocarbonyloxy, ammosulfonyl, ammosulfonyloxy, ammosulfonylammo, amidmo, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)ammo, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guamdmo, substituted guanidino, halo, hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, rutro, SO3H, sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, and alkylthio, wherein said substituents are defined herein and with the proviso that any hydroxy substitution is not attached to an acetylemc carbon atom
"Carbonyl" refers to the divalent group -C(O)- which is equivalent to -C(=O)-
"Carboxyl" or "carboxy" refers to -COOH or salts thereof "Carboxyl ester" or "carboxy ester" refers to the groups -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-alkenyl, -C(O)O-substituted alkenyl, -C(O)O-alkynyl, -C(O)O-substituted alkynyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)O-cycloalkyl, -C(O)O-substituted cycloalkyl, -C(O)O-cycloalkenyl, -C(O)O-substituted cycloalkenyl, -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heterocychc, and -C(O)O-substituted heterocyclic wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein
"(Carboxyl ester)amino" refers to the group -NR-C(O)O-alkyl, substituted -NR-C(O)O-alkyl, -NR-C(O)O-alkenyl, -NR-C(O)O-substituted alkenyl, -NR-C(O)O-alkynyl, -NR-C(O)O-substituted alkynyl, -NR-C(O)O-aryl,
-NR-C(O)O-substituted aryl, -NR-C(O)O-cycloalkyl, -NR-C(O)O-substituted cycloalkyl, -NR-C(O)O-cycloalkenyl, -NR-C(O)O-substituted cycloalkenyl, -NR-C(O)O-heteroaryl, -NR-C(O)O-substituted heteroaryl, -NR-C(0)0-heterocychc, and -NR-C(O)O-substituted heterocyclic wherein R is alkyl or hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein
"(Carboxyl ester)oxy" refers to the group -O-C(O)O-alkyl, substituted -O-C(O)O-alkyl, -O-C(O)O-alkenyl, -O-C(O)O-substituted alkenyl, -O-C(O)O-alkynyl, -O-C(O)O-substituted alkynyl, -O-C(O)O-aryl, -O-C(O)O-substituted aryl,
-O-C(O)O-cycloalkyl, -O-C(O)O-substituted cycloalkyl, -O-C(O)O-cycloalkenyl, -O-C(O)O-substituted cycloalkenyl, -O-C(O)O-heteroaryl, -O-C(O)O-substituted heteroaryl, -O-C(O)O-heterocychc, and -O-C(O)O-substituted heterocyclic wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein "Cyano" refers to the group -CN
"Cycloalkyl" refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single 5 or multiple cyclic rings including fused, bπdged, and spiro ring systems Cycloalkyl groups can include Also included in the definition of cycloalkyl are moieties that have one or more aromatic πngs fused (i e , having a bond in common with) to the cycloalkyl πng, for example, benzo deπvatives of cyclopentane, cyclopentene, cyclohexane, and the like A cycloalkyl group having one or more fused aromatic πngs can be attached though either the aromatic or o non-aromatic portion One or more ring-forming carbon atoms of a cycloalkyl group can be oxidized, for example, having an oxo or sulfido substituent Examples of suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl
"Cycloalkenyl" refers to non-aromatic cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic πngs and having at least one >C~C< πng unsaturation5 and, in some embodiments, from 1 to 2 sites of >C=C< nng unsaturation
"Substituted cycloalkyl" and "substituted cycloalkenyl" refers to a cycloalkyl or cycloalkenyl group having from 1 to 5 and, in some embodiments, 1 to 3 substituents selected from the group consisting of oxo, thione, alkyl, alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, ammo, substituted ammo, ammocarbonyl, atmnothiocarbonyl, aminocarbonylammo,0 aminothiocarbonylammo, ammocarbonyloxy, aminosulfonyl, aminosulfonyloxy, amino- sulfonylamino, amidmo, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)- ammo, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guamdmo, substituted guamdino, halo, hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio,5 mtro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylammo, thioacyl, thiol, and alkylthio, wherein the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heterocyclyl, and heteroaryl moieties contained within any of the preceding "substituted cycloalkyl" or "substituted cycloalkenyl" groups, are optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkenyl, alkynyl, alkoxy, acyl,0 acylamino, acyloxy, ammo, substituted ammo, ammocarbonyl, ammothiocarbonyl, aminocarbonylammo, aminothiocarbonylammo, ammocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidmo, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)ammo, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyl, cycloalkyloxy, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guamdino, substituted guanidino, halo, hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, mtro, SO3H, sulfonyl, sulfonyloxy, sulfonylammo, thioacyl, thiol, alkylthio, and alkylthio, and wherein said substituents are defined herein "Cycloalkyloxy" refers to -O-cycloalkyl
"Substituted cycloalkyloxy refers to -O-(substituted cycloalkyl) "Cycloalkylthio" refers to -S-cycloalkyl "Substituted cycloalkylthio" refers to -S-(substituted cycloalkyl) "Cycloalkenyloxy" refers to -O-cycloalkenyl "Substituted cycloalkenyloxy refers to -O-(substituted cycloalkenyl)
"Cycloalkenylthio" refers to -S-cycloalkenyl
"Substituted cycloalkenylthio" refers to -S-(substituted cycloalkenyl) "Guamdino" refers to the group -NHC(=NH)NH2
"Substituted guamdino" refers to -NRI3C(=NR13)N(R13)2 where each R13 is independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, heterocyclic, and two R13 groups attached to a common guanidmo nitrogen atom are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that at least one R13 is not hydrogen, wherein the alkyl, aryl, heterocyclyl, and heteroaryl moieties contained within any of the preceding "substituted guamdino" groups are optionally substituted by 1 , 2, 3, 4 or 5 substituents independently selected from the group consisting of alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, amino, ammocarbonyl, aminothiocarbonyl, aminocarbonylammo, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, amino- sulfonylammo, amidino, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)- amino, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guamdino, substituted guamdino, halo, hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, mtro, SO3H, sulfonyl, sulfonyloxy, sulfonylammo, thioacyl, thiol, and alkylthio
"Halo" or "halogen" refers to fluoro, chloro, bromo and iodo "Hydroxy" or "hydroxyl" refers to the group -OH
"Heteroaryl" refers to an aromatic group of from 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur withm the πng Such heteroaryl groups can be monocyclic, 1 e , have a single πng (e g , pyπdmyl or fbryl) or polycyclic, 1 e , having multiple condensed rings (e g , lndolizmyl or benzothienyl) wherein the condensed πngs may or may not be aromatic and/or contain a heteroatom provided that the point of attachment is through an atom of the aromatic heteroaryl group In one embodiment, the mtrogen and/or the sulfur πng atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N→O), sulfinyl, or sulfonyl moieties Monocyclic heteroaryls include without limitation, pyrrolyl, furanyl, thiophenyl (thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-traizolyl, 1,2,4- tnazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyπdmyl, pyrazmyl, pyπmidinyl, pyπdazmyl, tπazinyl and the like Polycyclic heteroaryls include without limitation, mdolyl, lsomdolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzothiazolyl, quinohnyl, lsoqumolyl, quinazolyl, qumozalyl, cinnolyl, pteπdine, carbazole, carboline, phenanthπdme, acndme, phenanthroline, phthalazine, naphthylpyπdine, phenazme, puπne and the like
"Substituted heteroaryl" refers to heteroaryl groups that are substituted with from 1 to 5, and, in some embodiments, 1 to 3, and, m some embodiments, 1 to 2 substituents selected from the group consisting of the same group of substituents defined for substituted aryl "Heteroaryloxy" refers to -O-heteroaryl
"Substituted heteroaryloxy refers to the group -O-(substituted heteroaryl) "Heteroarylthio" refers to the group — S-heteroaryl
"Substituted heteroarylthio" refers to the group -S-(substituted heteroaryl) "Heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyl" refers to a non-aromatic heterocycle where one or more of the nng-formmg atoms is a heteroatom such as an O, N, or S atom Heterocycloalkyl groups can include mono- or polycyclic (e g , having 2, 3 or 4 fused πngs) πng systems as well as spirocycles Example "heterocycloalkyl" groups include morpholino, thiomorpholmo, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3- dihydrobenzofuryl, 1,3-benzodioxole, benzo-l,4-dioxane, pipendinyl, pyrrohdmyl, lsoxazohdinyl, lsothiazohdmyl, pyrazolidinyl, oxazohdmyl, thiazohdinyl, lmidazohdinyl, and the like Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic πngs fused (; e , having a bond in common with) to the nonaromatic heterocyclic πng, for example phthalimidyl, naphthalimidyl, and benzo deπvatives of heterocycles such as indolene and isomdolene groups A heterocycloalkyl group having one or more fused aromatic nngs can be attached though either the aromatic or non-aromatic portion In some embodiments, the heterocycloalkyl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms In some embodiments, the heterocycloalkyl group contains 3 to about 20, 3 to about 14, 3 to about 7, or 5 to 6 nng- formmg atoms In some embodiments, the heterocycloalkyl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds In some embodiments, the heterocycloalkyl group contains 0 to 2 tnple bonds In some embodiments, the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, sulfoxide, and sulfone moieties "Substituted heterocyclic" or "substituted heterocycloalkyl" or "substituted heterocyclyl" refers to heterocyclyl groups that are substituted with from 1 to 5 and, in some embodiments, 1 to 3 of the same substituents as defined for substituted cycloalkyl "Heterocyclyloxy" refers to the group -O-heterocyclyl "Substituted heterocyclyloxy refers to the group -0-(substituted heterocyclyl) "Heterocyclylfhio" refers to the group -S -heterocyclyl
"Substituted heterocyclylthio" refers to the group -S-(substituted heterocyclyl) Examples of heterocycles include, but are not limited to, azetidine, mdohzine, dihydroindole, indazole, qumohzine , isothiazole, isoxazole, phenoxazme, phenofhiazme, lmidazolidine, imidazoline, pipeπdine, piperazine, lndolme, phthalirmde, 1,2,3,4- tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazolidme, morphohnyl, thiomorpholinyl (also referred to as thiamorpholinyl), 1,1-dioxothiomorpholmyl, pipendmyl, pyrrolidine, tetrahydrofuranyl, and the like "Nitro" refers to the group -NO2 "Oxo" refers to the atom (=O) or (-O-) "Spirocycloalkyl" refers to divalent cyclic groups from 3 to 10 carbon atoms having a cycloalkyl nng with a spiro union (the union formed by a single atom which is the only common member of the nngs) as exemplified by the following structure
Figure imgf000096_0001
"Sulfonyl" or "sulfone" refers to the divalent group -S(O)2- "Substituted sulfonyl" refers to the group -SC>2-alkyl, -Sθ2-substituted alkyl, -SO2- alkenyl, -SO∑-substituted alkenyl, -SC^-cycloalkyl, -Sθ2-substituted cycloalkyl, -SO2- cycloalkenyl, -Sθ2-substituted cycloalkenyl, -Sθ2-aryl, -Sθ2-substituted aryl, -SO2- heteroaryl, -Sθ2-substituted heteroaryl, -Sθ2-heterocyclic, -Sθ2-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein Substituted sulfonyl includes groups such as methyl-SC>2-, phenyl-SO2-, and 4-methylphenyl-SO2-
"Sulfonyloxy" refers to the group -OSO2-alkyl, -OSO2-substituted alkyl, -OSO2- alkenyl, -OSO2-substituted alkenyl, -OSO2-cycloalkyl, -OSO2-substituted cycloalkyl, -OSO2- 5 cycloalkenyl, -OSO2-substituted cylcoalkenyl,-OSO2-aryl, -OSO2-substituted aryl, -OSO2- heteroaryl, -OSO2-substituted heteroaryl, -OSO2-heterocyclic, -OSO2-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted o heterocyclic are as defined herein
"Thioacyl" refers to the groups H-C(S)-, alkyl-C(S)-, substituted alkyl-C(S)-, alkenyl-C(S)-, substituted alkenyl-C(S)-, alkynyl-C(S)-, substituted alkynyl-C(S)-, cycloalkyl-C(S)-, substituted cycloalkyl-C(S)-, cycloalkenyl-C(S)-, substituted cyclo- alkenyl-C(S)-, aryl-C(S)-, substituted aryl-C(S)-, heteroaryl-C(S)-, substituted hetero-5 aryl-C(S)-, heterocyclic-C(S)-, and substituted heterocychc-C(S)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein
"Thiol" refers to the group -SH 0 "Thiocarbonyl" refers to the divalent group -C(S)- which is equivalent to -C(~S)-
"Thione" refers to the atom (=S)
"Alkylthio" refers to the group -S-alkyl wherein alkyl is as defined herein "Substituted alkylthio" refers to the group -S-(substituted alkyl) wherein substituted alkyl is as defined herein 5 The expression "an alkyl interrupted with -O-, -S-, -SO-, -SO2-, -NH-, carbonyl, carbonylammo, or aminocarbonyl" refers to an alkyl group wherein one divalent carbon unit, i e , a methylene (-CH2-) in the alkyl group is replaces by one of the listed divalent moieties
At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges It is specifically intended that the invention0 include each and every individual subcombmation of the members of such groups and ranges For example, the term "Ci 6 alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl (propyl and isopropyl), C4 alkyl, C5 alkyl, and C(, alkyl
Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment For example, the substituent "arylalkyloxycabonyl" refers to the group (aryl)-(alkyl)-O-C(O)-
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, mateπals, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human bemgs and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio
As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxyhc acids, and the like The pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two, generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or ACN are preferred Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 17th ed , Mack Publishing Company, Easton, Pa , 1985, p 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety
As used herein, the term "tautomer" or "tautomer thereof is meant to refer to any tautomeπc form of a compound of the invention Tautomeπc forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton Tautomeπc forms include prototropic tautomers which are isomenc protonation states having the same empiπcal formula and total charge Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, IH- and 3H-imidazole, IH-, 2H- and 4H- 1,2,4-tπazole, IH- and 2H- lsomdole, and IH- and 2H-pyrazole Tautomeric forms can be m equilibrium or sterically locked into one form by appropriate substitution As used herein, the term "ester" or "pharmaceutically acceptable ester" refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof Suitable ester groups include, for example, those denved from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms Representative examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccmates
As used herein, the term "treating" or "treatment" refers to (1) inhibiting a disease, for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder, (2) preventing the disease, for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease, (3) delaying recurrence of the disease, for example, increasing the duration of a peπod of remission in a proliferative disorder such as a cancer, or (4) ameliorating the disease, for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder Treatment of a patient is typically carried out by administration of a compound of the invention to the patient in a pharmaceutically effective amount
A "subject," "individual" or "patient" is meant to describe a human or vertebrate animal including, for example, a dog, cat, horse, cow, pig, sheep, goat, monkey, owl, rat, and mouse In some embodiments, the "subject," "individual" or "patient" is human In further embodiments, the "subject," "individual" or "patient" is in need of treatment, that is, the patient can be afflicted with, is likely to be afflicted with, or might be afflicted with a disease which is treatable by administration of a compound of the invention, or pharmaceutically acceptable salt, ester, or tautomer thereof, or composition comprising the same
As used herein, the phrase "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is bemg sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician, such as prevent or inhibit a particular disease or medical disorder
The compounds of the invention are useful for human or veterinary use where, for example, inhibition of PDKl or inhibition of PDKl variants is indicated, such as in the treatment of various diseases associated with abnormal PDKl signaling and/or abnormal signaling upstream or downstream of PDKl (or variants thereof), such as that related to up- regulated activity of one or more receptor tyrosine kinases, Ras, PDK, PDKl, AKT, RSK, PKC, 70S6K, or SGK In some embodiments, the compounds of the invention are useful m inhibiting PDKl variants wherein the wild type PDKl contains one or more point mutations, insertions, or deletions Example PDKl variants include as PDK1T354M and PDK1D527E
The term "PDKl " is meant to refer to wild type PDKl The term "PDKl variant" or "variant of PDKl" is meant to refer to PDKl having at least one point mutation, insertion, or deletion The compounds of the invention can be used in the treatment of diseases characterized by "abnormal cellular proliferation " The term "abnormal cellular proliferation" includes, for example, any disease or disorder characterized by excessive or pathologically elevated cell growth such as is characteristic of various cancers and non- cancer proliferative disorders Example cancers include, for example, lung cancer, bronchial cancer, prostate cancer, breast cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, thyroid cancer, liver cancer, intrahepatic bile duct cancer, hepatocellular cancer, gastπc cancer, glioma/glioblastoma, endometrial cancer, melanoma, kidney cancer, renal pelvic cancer, urinary bladder cancer, utenne corpus cancer, uterine cervical cancer, ovarian cancer, multiple myeloma, esophageal cancer, acute myelogenous leukemia, chronic myelogenous leukemia, lymphocytic leukemia, myeloid leukemia, bram cancer, oral cavity cancer, and pharyngeal cancer, laryngeal cancer, small intestinal cancer, non-Hodgkin lymphoma, and villous colon adenoma
Example non-cancer proliferative disorders include neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis, proliferative diabetic retinopathy (PDR), hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, angiogenesis, and endotoxic shock
In some embodiments, the compounds of the invention are used to treat cancers of the prostate, lung, colon, and breast. The present invention further provides methods of inhibiting tumor growth m a patient by administration of a compound of the invention, or salt, ester or tautomer thereof hi some embodiments, the tumor is characterized by elevated receptor tyrosine kinase, Ras, PI3K, PDKl, AKT, RSK, PKC, 70S6K, or SGK activity The present invention further provides methods of treating cancer in a patient by administering to the patient a therapeutically effective amount of a compound of the invention, or pharmaceutically acceptable salt, ester, or tautomer thereof In some embodiments, the cancer is characteπzed by activity of PDKl In some embodiments, the cancer is charactenzed by activity of a PDKl variant such as PDKl T354M or PDKl D527E
In further embodiments, the present invention provides methods for inhibition of Cdkl and/or Cdk2 Another embodiment provides a methods of treating diseases such as cancer which are responsive to inhibition of Cdkl and/or Cdk2 by administering a compound of the invention to a patient In further embodiments, the invention provides methods of inhibiting phosphorylation of Akt by administering a compound of the invention to a human m need thereof Another embodiment provides a method of treating diseases such as cancer which are responsive to inhibition of phosphorylation of Akt, by administering a compound of the invention to a patient Another embodiment provides a method of inhibiting phosphorylation of Akt comprising contacting a cell with a compound of the invention
The foregoing is further illustrated by reference to the following Examples that are not intended to limit the scope of the inventive concepts The Example compounds and their analogs can be synthesized by one skilled in the art from procedures described herein, as well as in patents or patent applications listed herein which are all hereby incorporated by reference in their entireties and for all purposes as if fully set forth herein
EXAMPLES
Referring to the examples that follow, compounds representing specific embodiments were synthesized using the methods descπbed herein, or other methods, which are known in the art
The compounds and/or intermediates were characterized by high performance liquid chromatography (HPLC) using a Waters Millemum chromatography system with a 2695 Separation Module (Milford, MA) The analytical columns were reversed phase Phenomenex Luna C18 -5 μ, 4 6 x 50 mm, from Alltech (Deerfield, IL) A gradient elution was used (flow 2 5 niL/min), typically starting with 5% acetonitnle/95% water and progressing to 100% acetomtπle over a penod of 10 minutes AU solvents contained 0 1 % tπfluoroacetic acid (TFA) Compounds were detected by ultraviolet light (UV) absorption at either 220 or 254 nm HPLC solvents were from Burdick and Jackson (Muskegan, MI), or Fisher Scientific (Pittsburgh, PA)
In some instances, purity was assessed by thin layer chromatography (TLC) using glass or plastic backed silica gel plates, such as, for example, Baker-Flex Silica Gel 1B2-F 5 flexible sheets TLC results were readily detected visually under ultraviolet light, or by employing well known iodme vapor and other vanous staining techniques
Mass spectrometnc analysis was performed according to two different liquid chromatography / mass spectroscopy (LCMS) methods Method A employed a Waters System (Alliance HT HPLC and a Micromass ZQ mass spectrometer for the LCMS 10 instrument, an Eclipse XDB-C 18, 2 1 x 50 mm for the chromatography column, and a solvent system that was a 5-95% gradient of acetomtπle in water with 0 05% TFA over a 4 mm penod (flow rate 0 8 niL/min molecular weight range 200-1500, cone Voltage 20 V, column temperature 40°C) Method B employed a Hewlett Packard System (Seπes 1100 HPLC and a Micromass ZQ mass spectrometer for the LCMS instrument, an Eclipse XDB-C18, 2 1 x 15 50 mm for the chromatography column, and a solvent system that was a 5-95% gradient of acetonitπle m water with 0 05% TFA over a 4 mm penod (flow rate 0 8 mL/mm molecular weight range 150-850, cone Voltage 50 V, column temperature 3O0C) All masses were reported as those of the protonated parent ions
Gas chromatography / mass spectroscopy (GCMS) analysis was performed on a 20 Hewlett Packard instrument (HP6890 Seπes gas chromatograph with a Mass Selective Detector 5973, injector volume 1 μL, initial column temperature 5O0C, final column temperature 25O0C, ramp time 20 minutes, gas flow rate 1 mL/min, column 5% phenyl methyl siloxane, Model No HP 190915-443, dimensions 30 0 m x 25 m x 025 m) Nuclear magnetic resonance (NMR) analysis was performed on some of the 25 compounds with a Vaπan 300 MHz NMR (Palo Alto, CA) The spectral reference was either tetramethylsilane (TMS) or the known chemical shift of the solvent Some compound samples were run at elevated temperatures (e g , 75°C) to promote increased sample solubility
The purity of some of the compounds was assessed by elemental analysis (Desert 30 Analytics, Tucson, AZ)
Melting pomts were determined on a Laboratory Devices Mel-Temp apparatus (Holhston, MA) Preparative separations were carried out using a Flash 40 chromatography system and KP-SiI, 6OA (Biotage, Charlottesville, VA), or by flash column chromatography using silica gel (230-400 mesh) packing material, or by HPLC using a Waters 2767 Sample Manager, C-18 reversed phase column, 30X50 mm, flow 75 mL/min Typical solvents employed for the Flash 40 Biotage system and flash column chromatography are dichloromethane (DCM), methanol (MeOH), ethyl acetate (EtOAc), hexane (hex), acetone, aqueous ammonia (or ammonium hydroxide), and tπethylamine (TEA) Typical solvents employed for the reverse phase HPLC are varying concentrations of acetonitnle (ACN) and water with 0 1% tπfluoroacetic acid (TFA)
Example 1: 4-(6-Bromo-8-methoxyquinazoIin-2-ylamino)benzenesulfonamide
The subject compound was prepared according to the general Scheme 1, below
Scheme 1
mm ~Me 1-PrOH
1
Figure imgf000103_0001
Step 1 2-Amιno-5-bromo-3-methoxybenzoιc acid To a 0 24 M chloroform solution of 2-amino-3-methoxybenzoic acid (4, 11 87 g, 71 7 mmol) at 0 0C was added bromine (1 08 eq 0 31 M) in chloroform dropwise The mixture was warmed to room temperature (RT) and stirred under argon for 16 hours A precipitate formed and was collected by filtration and washed thoroughly with chloroform The crude material was dried in vacuo to give the title as a hydrobromide (HBr) salt in 99% yield ES/MS m/z 248/250 (MH+)
Step 2 (2-Amιno-5-bromo-3-methoxyphenyl)methanol To a 024 M tetrahydrofuran (THF) suspension of 2-amino-5-bromo-3- methoxybenzoic acid, Ia (71 7 mmol) at 0 0C was added borane THF solution (1 M, 220 mL, 220 mmol) The mixture was stirred under argon at RT for 66 hours The reaction was quenched by adding ethanol (15 mL) at 0 0C and stirred for 15 minutes The mixture was poured into water and extracted with DCM The organic extracts were combined, washed with bπne, dπed with sodium sulfate and concentrated in vacuo to give crude matenal as a white solid (10 16 g, 62% yield) ES/MS m/z 230/232 (MH+)
Step 3 2-Amιno-5-bromo-3-methoxybenzaldehyde To a 0 15 M chloroform solution of (2-amino-5-bromo-3-methoxyphenyl)methanol
(10 16 g, 43 96 mmol) was added manganese dioxide (19 9 g, 280 5 mmol) The mixture was stirred under argon at RT for 16 hours The mixture was then filtered through diatomaceous earth and washed with DCM The filtrate was concentrated to dryness and used in next step ES/MS m/z 228/230 (MH+)
Step 4 6-Bromo-8-methoxyquιnazolιn-2-ol, Ia
The mixture of 2-ammo-5-bromo-3-methoxybenzaldehyde (43 96 mmol, crude matenal from Step 3) and urea (35 g, 583 mmol) from the previous step was heated to 180 0C under argon for 1 hour Water (300 mL) was added after cooling to RT A solid precipitate formed and was collected by filtration and air dried to give 12 45 g of a powder ES/MS m/z 254/256 (MH+)
Step 5 6-Bromo-2-chloro-8-methoxyquinazohne, Ib
A suspension of 6-bromo-8-methoxyquinazolm-2-ol, Ia (43 96 mmol) m POCl3 (120 mL) was heated to 110 0C for 30 minutes The mixture was cooled to RT, evaporated POCI3 and partitioned between water and DCM The organic portion was concentrated to give a crude matenal which was purified by column chromatography (silica gel, eluted with 2%
MeOH in DCM) to yield a pure matenal as a yellow solid in 30% yield (3 steps, 3 62 g)
ES/MS m/z 212121 A (MH+)
Step 6 4-(6-Bromo-8-methoxyquιnazolιn-2-ylamιno)benzenesulfonamιde
To a solution of 50 mg of Ib in 2-propanol (1 mL) was added sulfanilamide (1 0 eq)
The reaction was stirred at 90 °C for 18 hours The hydrochlonde was collected by vacuum filtration and air dried to give a crude mateπal (80 mg) which can be used for further chemical modifications The pure mateπal was obtained by HPLC purification ES/MS m/z 409/411 (MH+)
Example 2 : 4-(6-Ethynyl-8-methoxyquinazolin-2-ylamino)benzenesulfonamide
The subject compound was prepared according to the general Scheme 2, below
Scheme 2
CuI, DMF
Figure imgf000105_0001
Example 1
Figure imgf000105_0002
Example 2
Step 1 and Step 2 were earned out in one pot A mixture of the starting material (4- (6-bromo-8-methoxyquinazolm-2-ylammo)benzenesulfonamide, synthesized following Example 1, 67 mg), ethynyltπmethylsilane (0 12 mL), copper(I) iodide (6 mg), 1,1'- bis(diphenylphosphmo)ferrocenedichloro palladium(II) (12 mg), TEA (0 8 mL) and DMF (0 8 mL) was microwaved at 1200C for 6 mm LC/MS showed complete conversion of starting material to 4-(8-methoxy-6-((tnmethylsilyl)ethynyl)qumazolin-2-ylamino)benzene- sulfonamide To this intermediate was added THF (0 8 mL) and tetramethylammoruum fluoride (60 mg) The resulting mixture was stirred at RT for 16 hrs The mixture was then diluted with water and extracted with ethyl acetate (3X) The organic extracts were combined, washed with bπne, dπed with sodium sulfate and concentrated to give a crude mateπal which was punfied by HPLC to yield the title compound 4-(6-ethynyl-8- methoxyquinazolm-2-ylamino)benzenesulfonamide ES/MS m/z 355 (MH+)
Example 3: 4-(6-Ethyl-8-methoxyqumazolin-2-ylamino)benzenesuIfonamide
The subject compound was prepared according to the general Scheme 3, below
Figure imgf000106_0001
To a 0 015M solution of the product of Example 2 (1 0 eq) in MeOH was added 10% palladium on carbon (20% by mass) The reaction vessel was evacuated and flushed with hydrogen gas The resulting mixture was stirred 14 h at ambient temperature and then filtered through diatomaceous earth and concentrated The crude product was purified by reverse-phase HPLC, and lyophihzed to give the desired compound as its tπfluoroacetic acid salt ES/MS m/z 359 (MH+)
Example 4: 4-(6-Cyano-8-methoxyquinazolin-2-ylamino)benzenesulfonamide The subject compound was prepared according to the general Scheme 4, below
Scheme 4
Figure imgf000106_0002
Example 1 Example 4
A mixture of 4-(6-bromo-8-methoxyqmnazolm-2-ylammo)benzenesulfonamide (synthesized following Example 1, 36 mg), zinc(II) cyanide (36 mg), l,l'-bis(diphenyl- phosphino)ferrocenedichloro ρalladium(II) (12 mg) and DMF (1 mL) was microwaved at 120 0C for 22 mm The resulting mixture was diluted with ethyl acetate, washed with water and brine, dπed with sodium sulfate and concentrated The crude mateπal was purified by HPLC to give the pure title compound 4-(6-cyano-8-methoxyquinazolin-2-ylamino)benzene- sulfonamide ES/MS m/z 356 (MH+)
Example 5: 4-(8-Methoxy-6-methylqumazolin-2-ylamino)benzenesulfonamide
The subject compound was prepared according to the general Scheme 5, below Scheme 5
5
Figure imgf000107_0001
A mixture of 4-(6-bromo-8-methoxyqmnazolm-2-ylamiαo)benzenesulfonamide (synthesized following Example 1, 20 mg), tπmethylboroxine (20 μL), l,l'-bis(diphenyl- phosphino)ferrocenedichloro palladium(II) (12 mg), potassium carbonate (0 6 mL of 2 M aqueous solution) and DMF (1 2 mL) was micro waved at 130 0C for 10 mm The resulting mixture was diluted with ethyl acetate, washed with water and bπne, dπed with sodium sulfate and concentrated The crude material was purified by HPLC to give the pure title compound 4-(8-methoxy-6-methylquinazolm-2-ylammo)benzenesulfonamide ES/MS m/z 345 (MH+)
Example 6: 7V-(3-(6-Bromo-8-chloroquinazolin-2-ylaøiino)-5-((dimethylamino)- methyl)phenyl)acetamide
The subject compound was prepared according to the general Scheme 6, below
Scheme 6
Figure imgf000107_0002
Step 1
To a suspension of 2-ammo-3-chlorobenzoic acid (2 g, 11 6 mmol) in chloroform (120 mL) was added dropwise bromine (1 1 equiv ) in chloroform (12 mL) solution The mixture was stirred at RT for 16 hrs The resulting white solid was collected by filtration and washed thoroughly with DCM until the filtrate was colorless The solid was air-dπed to give 3 35 g of white powder as HBr salt of 2-ammo-5-bromo-3-chlorobenzoic acid (87% yield) ES/MS m/z 250/252 (MH+)
Step 2 To the above intermediate (3 35 g, 10 1 mmol) in THF (40 mL) at 00C was added borane-THF complex solution (I M m THF, 40 mL, 4 equiv ) The mixture was stirred at RT for 18 hrs Additional borane-THF (20 mL) was added and continued reaction for another 24 hrs until the complete conversion of the starting material The solvent was removed in vacuo and the excess reagent was quenched by addition of ethanol (20 mL) slowly Water was added and the pH (~3) was adjusted by adding sodium bicarbonate (sat aq ) to pH 7 The resulting mixture was extracted with DCM The organic extracts were combined, washed with bnne, dπed with sodium sulfate and concentrated to give a crude mateπal as white solid ES/MS m/z 236/238 (MH+)
Step 3
To the above intermediate (10 1 mmol) in DCM (80 mL) was added manganese dioxide (Mnθ2, 6 g, 70 mmol) The mixture was stirred at RT under argon for 40 hrs Additional manganese dioxide (6 g) was added and the reaction was continued for another 20 hrs until the complete conversion of the starting material The mixture was filtered through diatomaceous earth and washed thoroughly with DCM The filtrate was concentrated m vacuo to give a crude product, (2-ammo-5-bromo-3-chlorophenyl)methanol (3 3 g, orange solid) which was used for the next step without further purification ES/MS m/z 234/236 (MH+)
Step 4
A mixture of (2-amino-5-bromo-3-chlorophenyl)methanol (3 3 g, obtained from Step 3) and urea (10 5 g, 15 equiv ) was heated to 180 0C with vigorous stirring for 1 hr The reaction was cooled to RT and water was added The solid was collected by filtration The filtered solid was air-dπed to give 2-hydroxyqumazohne as a yellow powder ( 2 18 g, crude) ES/MS m/z 259/261 (MH+)
Step 5 6-Bromo-2,8-dιchloroquιnazolιne
To the above crude material was added phosphorus oxychloπde (POCI3, 25 mL) and heated to 130 0C for 30 mm The resulting mixture was cooled to RT and concentrated m vacuo to nearly dryness Ice water was added and pH was adjusted to ~8 using sodium bicarbonate The mixture was extracted with DCM and the extract was dπed with sodium sulfate and concentrated in vacuo yielded desired product 6-bromo-2,8-dichloroqmnazoline as brown foam (1 4 g) This material was used in the following step and in other chemical medications without further purification
Step 6 N-(3-(6-Bromo-8-chloroquιnazolιn-2-ylamιno)-5-((dιmethylamιno)methyl)phenyl)- acetamide A mixture of 6-bromo-2,8-dichloroquinazohne (0 175 g), N-(3-amino-5-((dimethyl- amino)methyl)phenyl)acetamide (1 equiv ) and HCl in dioxane (1 equiv ) in isopropanol (2 5 mL) was heated to 75 0C for 16 hrs The resulting mixture was diluted with water, washed with ethyl acetate to remove organic impurities, basified the aqueous portion with sodium bicarbonate (aq ) to pH 9, and then brine was added The basified aqueous solution was extracted with chloroform (3X) The organic extracts were combined, washed with bπne, dπed with sodium sulfate and concentrated to give a crude material which was used for the next step Purification by HPLC then yielded pure N-(3 -(6-bromo-8-chloroqumazolm-2- ylammo)-5-((dimethylammo)methyl)phenyl)acetamide ES/MS m/z 448/450 (MH+)
Example 7: JV-(3-(8-Chloro-6-ethynylquinazoIin-2-yIamino)-5((dimethylamino)methyl)- phenyDacetamide
The subject compound was prepared according to the general Scheme 7, below
Scheme 7
Figure imgf000109_0001
Step l
A mixture of iV-(3-(6-bromo-8-chloroqumazolin-2-ylammo)-5-((dimethylamino)- methyl)phenyl)acetamide (63 mg, from Example 6), ethynyltπmethylsilane (0 063 ml), copper(I) iodide (6 mg), l,r-bis(diphenylphosphino)ferrocenedichloro palladmm(II) (12 mg), TEA (0 8 mL) and DMF (0 8 mL) was microwaved at 120 0C for 8 mm The resulting mixture was diluted with ethyl acetate, washed with water and bπne, dπed with sodium sulfate and concentrated to give a dark brown residue
Step 2 N-(3-(8-Chloro-6-ethynylquinazolιn-2-ylamino)-5-((dιmethylamιno)methyl)phenyl)- acetamide
To the intermediate from Step 1 was added THF (3 mL), 2-propanol (0 4 mL) and tetramethylammonium fluoride (18 mg) The mixture was stirred at RT for 20 mm The resulting mixture was diluted with water and extracted with ethyl acetate (3X) The organic extracts were combined, washed with brine, dried with sodium sulfate and concentrated to give a crude matenal which was purified by HPLC to yield the title compound N-(3-(8- chloro-6-ethynylqumazolin-2-ylammo)-5-((dimethylammo)methyl)phenyl)acetamide ES/MS m/z 394 (MH+)
Example 8: 4-(8-Bromo-6-(trifluoromethyI)quinazolin-2-ylamino)benzenesulfonamide The subject compound was prepared according to the general Scheme 8, below
Scheme 8
Figure imgf000110_0001
Step 1 2-Amιno-3-bromo-5-(tnfluoromethyl)benzαldehyde, 8-2 2,6-Dibromo-4-(tnfluoromethyl)amlme, 8-1 (3 19 g, 10 0 mmol, 1 00 eq) was dissolved in THF (50 mL) and cooled to -78 0C A 2 5 M solution of n-butyllithium in hexanes (8 40 mL, 21 0 mmol, 2 10 eq) was added dropwise over 15 mm The mixture was stirred at -78 0C for 1 h A solution of DMF (1 03 mL, 14 0 mmol, 1 40 eq) in THF (5 mL) was added, and the mixture was stirred an additional 1 h at -78 0C The reaction was allowed to come to -15 0C over 30 min and then quenched with brine The mixture was diluted with ethyl acetate, washed sequentially with water and bnne, dπed over sodium sulfate, filtered, and concentrated to give 1 74 g of the desired product as a pale yellow, crystalline solid ES/MS m/z 268,270 (MH+)
Step 2 8-Bromo-6-(tnfluoromethyl)-l,4-dιhydroquιnazohne-2,4-dιol, 8-3
2-Amino-3-bromo-5-(tπfluoromethyl)benzaldehyde, 8-2 (1 74 g, 6 49 mmol, 1 00 eq) and urea (5 85 g, 974 mmol, 15 0 eq) were stirred at 190 0C for 3 h The resulting solid was returned to ambient temperature, stirred in water (60 mL) for 20 mm, and filtered This was repeated for a total of three washes The solid was dπed in a desiccator to give 3 79 g of the desired product as an off-white solid ES/MS m/z 311 ,313 (MH+)
Step 3 8-Bromo-2-chloro-6 (trιfluoromethyl)quιnazolιne, 8-4
8-Bromo-6-(tπfluoromethyl)-l,4-dihydroqumazohne-2,4-diol, 8-3 (3 79 g, 6 49 mmol, 1 00 eq) and phosphorus oxychloπde (20 mL) were stirred together at 110 °C for 1 5 h Volatiles were removed under reduced pressure Ice water was added, and the pH was adjusted to 6-7 with aqueous sodium hydroxide and sodium bicarbonate The precipitate was filtered off, πnsed with water, and dπed under high vacuum The crude mateπal was tπturated with THF The mother liquor was concentrated to yield 332 mg of the desired product as an orange, crystalline solid ES/MS m/z 313 (MH+)
Step 4 4-(8-bromo-6-(tnfluoromethyl)quιnazohn-2-ylamιno)benzenesulfonamιde
To a 030 M solution of 8-bromo-2-chloro-6-(tnfluoromethyl)quinazolme, 8-4, in 2- propanol was added sulfanilamide (1 0 eq) The reaction was stirred at 110 °C for 14 h The hydrochloπde was collected by vacuum filtration and then stirred in aqueous sodium bicarbonate The solid was collected by vacuum filtration and πnsed with water The light yellow solid was dned in a desiccator to give 343 mg of the desired product ES/MS m/z 447 ',449 (MH+) Example 9: 4-(6-Bromoquinazolin-2-ylamino)benzenesulfonamide
The subject compound was prepared according to the general Scheme 9, below
Scheme 9
Figure imgf000112_0001
Step 1 2-Amino-5-bromobenzylalcohol
To a 0 5OM solution of 2-ammo-5-bromobenzoic acid (1 0 eq) m THF was added a 1 0 M solution of borane-THF complex in THF (2 0 eq) dropwise over 15 mm at 0 0C The mixture was stirred for 2 d at ambient temperature The reaction was quenched by the sequential addition ethanol (6 0 eq) and water The mixture was extracted with ethyl acetate The combined extracts were washed with bπne, dried over sodium sulfate, filtered, and concentrated to give the desired product ES/MS m/z 202,204 (MH+)
Step 2 2-Amιno-5-bromobenzaldehyde
Manganese (IV) oxide (6 0 eq) was added to a 0 2OM solution of 2-ammo-5- bromobenzyl alcohol (1 0 eq) in DCM The mixture was stirred at ambient temperature for 16 h and then filtered through Celite The filtrate was concentrated to give the desired product as an orange-brown, crystalline solid ES/MS m/z 200,202 (MH+)
Step 3 6-Bromo-2-hydroxyquιnazolιne 2-Amino-5-bromobenzaldehyde (1 0 eq) and urea (8 0 eq) were stirred at 170 0C for 1 h The resulting solid was returned to ambient temperature, stirred m water for 20 min, and filtered This was repeated for a total of three washes The solid was dπed in a desiccator to give the desired product as an off-white solid ES/MS m/z 225,227 (MH+)
Step 4 6-Bromo-2-chloroquιnazolιne
A 0 50M solution of 6-bromo-2-hydroquinazoline in phosphorus oxychloride was stirred at 110 0C for 1 5 h Volatiles were removed under reduced pressure Ice water was added, and the pH was adjusted to 6-7 with aqueous sodium hydroxide and sodium bicarbonate The precipitate was filtered off, πnsed with water, and dned under high vacuum to yield the desired product as a yellow solid ES/MS m/z 245 (MH+)
Step 5 4-(6-Bromoquιnazohn-2-ylamιno)benzenesulfonamιde
To a 0 50 M solution of 6-bromo-2-chloroqumazolme in 2-propanol was added sulfanilamide (1 0 eq) The reaction was stirred at 90 0C for 14 h The hydrochloride was collected by vacuum filtration and used without further purification Alternatively, the crude reaction mixture was concentrated, purified by reverse-phase HPLC, and lyophihzed to give the desired compound as its tπfluoroacetic acid salt ES/MS m/z 379,381 (MH+)
Example 10: 4-(6-Ethynylquinazolin-2-yIamino)benzenesulfonamide
The subject compound was prepared according to the general Scheme 10, below
Scheme 10
Figure imgf000113_0001
Step 1
To a 0 15 M solution of the product of Example 9 in 1 1 DMF TEA was added tπmethylsilylacetylene (TMS-acetylene) (4 0 eq), copper(I) iodide (0 10 eq), and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM (0 050 eq) The reaction was microwaved at 120 0C for 10 mm The mixture was diluted with ethyl acetate and filtered through a pad of silica gel The filtrate was concentrated and used without further purification ES/MS m/z
397 (MH+)
Step 2 4-(6-Ethynylquιnazolιn-2-ylamιno)benzenesulfonamιde To a 0 10 M solution of the product of Step 1 in 1 1 THF MeOH was added tetramethylammonium fluoride (1 5 eq) The reaction was stirred for 30 mm at ambient temperature Volatiles were removed under reduced pressure, and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate The organic phase was dπed over sodium sulfate, filtered, and concentrated The crude material was purified by reverse-phase HPLC, and lyophihzed to give the desired compound as its tπfluoroacetic acid salt ES/MS m/z 325 (MH+)
Example 11: 4-(6-Bromoquinazolin-2-yIamino)-iV-isopropylbenzamide
The subject compound was prepared according to the general Scheme 11 , below
Scheme 11
11
6-b
Figure imgf000114_0001
The procedure is analogous to Example 9 Step 5, using 4-amino-iV-isopropyl- benzamide in place of sulfanilamide ES/MS m/z 385,387 (MH+)
Example 12: JV-Isopropyl-4-(6-(thiazoI-2-yl)qumazolm-2-ylamino)benzamide
The subject compound was prepared according to the general Scheme 12, below
Figure imgf000114_0002
To the product of Example 10 was added [l,l'-bis(diρhenylρhosρhino)ferrocene]- dichloroρalladium(II) complex with DCM (0 10 eq) and a 0 5M solution of 2-thiazolyl zinc bromide in THF (3 0 eq) The reaction was microwaved at 120 °C for 10 mm The mixture was then diluted with ethyl acetate and washed with aqueous EDTA pH~9 buffer The organic phase was dried over sodium sulfate, concentrated, purified by reverse-phase HPLC, and lyophihzed to give the desired compound as its tπfluoroacetic acid salt ES/MS m/z 390 (MH+) Example 13: 4-(6-Cyanoquinazolin-2-ylamino)-iV-isopropylbenzamide
The subject compound was prepared according to the general Scheme 13, below
Scheme 13
13
Figure imgf000115_0001
To a 0 10 M solution of the product of Example 11 in DMF was added zinc(II) cyanide (4 0 eq) and [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM (0 10 eq) The reaction was microwaved at 130 °C for 10 mm The mixture was diluted with ethyl acetate and washed with aqueous EDTA pH~9 buffer The organic phase was dried over sodium sulfate, concentrated, purified by reverse-phase HPLC, and lyophilized to give the desired compound as its tnfluoroacetic acid salt ES/MS ra/z 332 (MH+)
Example 14: Λr-(3-(6-Bromo-5-chloro-8-methoxyquinazolin-2-ylamino)-5-((dimethyl- amino)methyl)phenyl)acetamide
The subject compound was prepared according to the general Scheme 14, below
Scheme 14
Example •
Figure imgf000115_0002
Step 1 5-Bromo-4-chloro-7-methoxyιsatιn
To a 0 5OM solution of 4-chloro-7-methoxyisatm (1 0 eq) in ethanol at 80 0C was added a 1 OM ethanolic solution of bromine (2 0 eq) over 45 mm The reaction was stirred at 70 0C for 14 h and then concentrated The residue was re-dissolved to make a 0 2OM solution in 10 1 acetone water and stirred for 45 mm The mixture was concentrated to give the desired product as a dark red solid ES/MS m/z 292 (MH+)
Step 2 2-Amιno-5-bromo-6-chloro-3-methoxybenzoιc acid 5-Bromo-4-chloro-7-methoxyisatm (1 0 eq) was suspended in 1 ON aqueous sodium hydroxide (10 eq) A 30% solution of hydrogen peroxide m water (4 0 eq) was added, and the reaction was stirred for 20 mm at ambient temperature The mixture was cooled to 0 0C Glacial acetic acid (10 eq) and 3 ON aqueous hydrochloric acid (10 eq) were added The solid was collected by vacuum filtration and dried in a vacuum desiccator to give the desired product ES/MS m/z 282 (MH+)
Step 3 2-Amιno-5-bromo-6-chloro-3-methoxybenzylalcohol
Analogous to Example 9, step 1 using 2-amino-5-bromo-6-chloro-3-methoxybenzoic acid in place of 2-ammo-5-bromobenzoic acid ES/MS m/z 268 (MH+)
Step 4 2-Amιno-5-bromo-6-chloro-3-methoxybenzaldehyde
Analogous to Example 9 step 2 using 2-ammo-5-bromo-6-chloro-3-methoxybenzyl alcohol in place of 2-amino-5-bromobenzyl alcohol ES/MS m/z 266 (MH+)
Step 5 6-Bromo-5-chloro-2-hydroxy-8-methoxyquιnazohne
Analogous to Example 9, step 3 using 2-ammo-5-bromo-6-chloro-3- methoxybenzaldehyde in place of 2-ammo-5-bromobenzaldehyde ES/MS m/z 291 (MH+)
Step 6 6-Bromo-2,5-dιchloro-8-methoxyquιnazolιne Analogous to Example 9, step 4 using 6-bromo-5-chloro-2-hydroxy-8- methoxyqumazoline in place of 6-bromo-2-hydroxyqumazohne ES/MS m/z 309 (MH+)
Step 7 N-(3-(6-Bromo-5-chloro-8-methoxyquιnazohn-2-ylamιno)-5-((dιmethylamιno)- methyl)phenyl)acetamιde To a 0 25M solution of 6-bromo-2,5-dichloro-8-methoxyquinazolme m 2-propanol was added 7V-(3-ammo-5-((dimethylamino)methyl)phenyl)acetamide (1 0 eq) and 4 OM HCl in dioxane (1 2 eq) The reaction was stirred at 70 0C for 14 h The mixture was then concentrated and the resulting residue was used without further purification Alternatively the crude mateπal was purified by reverse-phase HPLC and lyophihzed to yield the desired product as its tπfluoroacetic acid salt ES/MS m/z 480 (MH+)
Example IS: 4-(8-Bromo-6-fluoroquinazolin-2-yIamino)benzenesulfonanιide
The subject compound was prepared according to the general Scheme 15, below
Scheme 15
Figure imgf000117_0001
Step 1
To 2-ammo-5-fluorobenzoic acid 15-1, (5 g, 32 2 mmol) in chloroform (90 mL) was added bromine (1 82 mL, 35 4 mmol) in chloroform (10 mL) solution dropwise via an additional funnel The mixture was stirred at RT for 16 hrs and LC/MS showed about 50% conversion of the starting mateπal Additional bromine (1 8 mL) was added to the reaction and continued stirring for another 24 hrs The resulting white precipitate was collected by filtration, washed thoroughly with DCM and air-dned to give 2-ammo-3-bromo-5- fluorobenzoic acid, as its HBr salt ES/MS m/z 234/236 (MH+)
Step 2 (2-Amino-3-bromo-5-fluorophenyl)methanol
To a 0 5M suspension of 2-amino-3-bromo-5-fluorobenzoic acid m THF in an ice bath was slowly added borane (1 OM /THF, 3eq) The reaction mixture was stirred at ambient temperature for 24 h The mixture was recooled to 00C and quenched with MeOH and concentrated to remove solvent The residue was taken into ethyl acetate and organic phase was washed with water, saturated sodium bicarbonate, bπne, dned over sodium sulfate and concentrated to give yellow solid in 90% yield ES/MS m/z 220/222 (MH+)
Step 3 2-Amιno-3-bromo-5-fluorobenzaldehyde, 15-2 Manganese (IV) oxide (5eq) was added to a 02M solution of (2-amino-3-bromo-5- fluorophenyl)methanol in DCM The resulting suspension was stirred at ambient temperature under Argon for 12 h The reaction mixture was filtered through diatomaceous earth and the filter cake was washed with DCM The combined filtrate was concentrated to give brown color solid ES/MS m/z 218/220 (MH+)
Step 4 8-Bromo-6-fluoroquιnazohn-2-ol
Solid 8-bromo-6-fluoroqumazolm-2-ol (leq) and urea (14eq) were thoroughly mixed together m a round bottom flask The mixture was heated to 180 0C m an oil bath for 2 5 h The reaction mixture was cooled to ambient temperature and water was added to the flask Filtration gave yellow color solid, which was rinsed with ether and air dπed Yield 62% ES/MS m/z 243/245 (MH+)
Step 5 S-Bromo^-chloro-δ-fluoroquinazohne, 15-3 A O 5M suspension of 8-bromo-6-fluoroqmnazolin-2-ol in phosphorus oxychloπde was heated to 110 0C in an oil bath The suspension was turned to a brown color solution in 20mm LCMS data showed that the reaction was complete after 1 h The phosphorus oxychlonde was removed by concentration The residue was mixed with ice water, and adjusted pH to 7 by adding sodium bicarbonate Reaction mixture was extracted with ethyl acetate Combined organic phase was washed with water, bπne, dπed over sodium sulfate and concentrated to give desired product in 89% yield ES/MS m/z 261/263 (MH+)
Step 6 4-(8-Bromo-6-fluoroquιnazohn-2-ylamιno)benzensulfonamιde
To a 04M suspension of 8-bromo-2-chloro-6-fluoroquinazohne, 15-3 in isopropanol was added 4-aminobenzensulfonamide (leq) The reaction mixture was heated to 120 °C in an oil bath for 2days LCMS showed that reaction was complete under the condition Ethyl acetate was added to the reaction flask and the suspension was stirred at ambient temperature for 30 mm and was filtered Filter cake was rinsed with hexane and dπed in vacuum to give product in 81% yield ES/MS m/z 397/399 (MH+)
Example 16: iV-(3-(6-Broinoquinazolin-2-ylamino)-5-(l-methyl-6-oxo-l,6-dihydro- pyridin-3-yl)^phenyl)acetamide
The subject compound was prepared according to the general Scheme 16, below Scheme 16
Figure imgf000119_0001
Step 1 5-Bromo-l-methylpyrιdιn-2(lH)-one
To a 0 3M suspension of 5-bromo-2(lH)-pyπdone in THF in an ice bath was added sodium hydπde (2 Oeq) After stirring at O °C for 5mm, iodomethane (4 Oeq) was added The reaction mixture was stirred at ambient temperature for 15 h Solvent was removed under reduced pressure The residue was diluted with ethyl acetate and was washed with water, bπne, dried over sodium sulfate and concentrated The crude compound was triturated with hexane and filtered off to collect desired product m 72% yield ES/MS m/z 188/190 (MH+)
Step 2 2 (3,5-Dιnιtrophenyl)-4,4,5,5-tetramethyl-l,3,2-dιoxaborolane
To a 0 2M solution of l-iodo-3,5-dimtrobenzene in dioxane were added bis(pmacolate)diboron (1 5eq), Pd(dppf)2Cl2CH2Cl2 (0 2eq) and flame dπed potassium carbonate (2 Oeq) The mixture was purged with Argon for 10mm and was heated to 120 °C for in an oil bath 12 h The reaction mixture was filtered through diatomaceous earth, and the filter cake was πnsed with dioxane The combined filtrate was concentrated to provide a residue The crude residue was purified by Biotage using 20% ethyl acetate in hexane, to give desired product The structure was confirmed by 1 H NMR spectrum
Step 3 5-(3,5-Dιnιtrophenyl)-l-methylpyrιdιn-2(lH)-one A 0 2 M mixture of 5-bromo-l-methylpyπdin-2(lH)-one (1 Oeq), 2-(3,5- dimtrophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (3 Oeq), PdCdPPf)2Cl2CH2Cl2 (0 leq), 2 OM potassium carbonate (leq) in DME was microwave at 120 0C for 15mm The reaction mixture was diluted with ethyl acetate, and was washed with water, bπne, dried and concentrated The residue was purified by Biotage using 5% MeOH in dichloromethane (DCM) Product was a brown color solid in 38% yield ES/MS m/z 276 (MH+)
Step 4 N-(3-Amιno-5-(l-methyl-6-oxo-l , 6-dιhydropyrιdιn-3-yl)phenyl)acetamιde Acetic anhydride (1 Oeq) was added to a O 06M solution of 5-(3,5-diaminophenyl)-l- methylpyπdm-2(lH)-one (1 Oeq), TEA (1 2eq) in THF in an ice bath The reaction was monitored by LCMS and was complete in Ih Solvent was removed under reduced pressure and residue was purified by RP HPLC Lyophilization gave product as TFA salt ES/MS m/z 5 258 (MH+)
Step 5 N-(3-(6-Bromoquιnazolιn-2-ylamιno)-5-(l-methyl-6-oxo-l, 6-dιhydropyrιdιn-i-yl)- phenyl)acetamιde
A 0 08 M suspension of 6-bromo-2-chloroquinazolme(l Oeq), iV-(3-ammo-5-(l- 10 methyl-6-oxo-l ,6-dihydropyπdin-3-yl)phenyl)acetarmde (1 Oeq) in isopropanol was heated to 120 0C m an oil bath for 15 h LCMS showed that conversion was complete under the condition Solvent was removed under reduced pressure and residue was punned by RP HPLC to give desired product as TFA salt ES/MS m/z 464/466 (MH+)
15 Example 17: 7V-(3-(6-EthynyIquinazolin-2-ylamino)-5-(l-methyl-6-oxo-l,6-dihydro- pyridin-3-yl)phenyl) acetamide
The subject compound was prepared according to the general Scheme 17, below
Scheme 17
Figure imgf000120_0001
To a 0 04 M mixture of Λ7-(3-(6-bromoquinazolm-2-ylammo)-5-(l-methyl-6-oxo-l,6-
20 dihydropyndin-3-yl)phenyl)acetamide (from Example 16)(0 08 mmol), TEA ( 04mL), Pd(dppl)2Cl2CH2Cl2 (0 leq), copper(I) iodide (0 leq), in DMF was added tπmethylsilyl- acetylene (10eq) The suspension was microwaved at 120 0C for 20min The reaction mixture was diluted with ethyl acetate and was washed with water, bπne, dπed and concentrated The oil residue was treated with tetramethylammomum fluoride (1 Oeq) in THF/MeOH (1 1,
25 0 02M) at ambient temperature for 1 h Solvent was removed under reduced pressure, and the residue was diluted with ethyl acetate The orgamc phase was washed with water, bπne, dried and concentrated The crude product was purified by RP HPLC Lyophihzation gave the desired product ES/MS m/z 410 (MH+)
Example 18: Methyl 2-(4-sulfamoylphenylamino)quinazolin-6-carboxylate The subject compound was prepared according to the general Scheme 18, below
Figure imgf000121_0001
iSep 7 Methyl i-formyl-4-amιnobeπzoate, 18-1
To a 1 1 mixture of ethanol and acetic acid was added methyl-3-formyl-4- mtrobenzoate (leq) and Fe dust (3eq)was added in portions The reduction was complete in Ih The reaction mixture was filtered and then concentrated and partitioned between ethyl acetate and water The organic layer was washed with saturated sodium bicarbonate and dπed and concentrated to give methyl 3-formyl-4-aminobenzoate in 85 % yield ES/MS m/z 180(MH+)
Step 2 Methyl 2-hydroxyqmnazoιn-6-carboxylate
To methyl 3-fbrmyl-4-ammobenzoate, 18-1 (leq) was added urea (5eq) and the mixture was heated tol45°C for 16h To the crude was added water and the precipitated solid was filtered to give methyl 2-hydroxyquinazoin-6-carboxylate m quantitative yield
ES/MS m/z 205(MH+)
Step 3 Methyl 2-chloroquιnazoιn-6-carboxylate 18-2
To 2-hydroxyquinazom-7-carboxylate was added POCL3 and the mixture was added heated to 100°C for 20mm when the reaction went to completion To the reaction mixture was added ice and water and the precipitated solid was filtered and dπed on the high vacuum overnight to give methyl 2-chloroquinazom-7-carboxylate in 60% yield ES/MS m/z
223(MH+)
Step 4 Methyl 2-(4-sulfamoylphenylammo)quιnazolιn-6-carboxylate To methyl 2-chloroquinazom-6-carboxylate (leq) was added sulfanilamide (leq) and isopropanol and the mixture was heated to 900C for 2h The reaction went to completion The reaction mixture was cooled to RT and filtered to give methyl 2-(4-sulfamoylphenyl amino)quinazolin-7-carboxylate in quantitative yield ES/MS m/z 359(MH+)
Example 19: Methyl 2-(4-sulfamoylphenylamino)quinazolin-6-carboxylic acid
The subject compound was prepared according to the general Scheme 19, below
Figure imgf000122_0001
To methyl-2-(4-sulfamoylphenyl armno)quinazolin-7-carboxylate (the compound of Example 18) was added 2N sodium hydroxide (4eq) and MeOH and the resulting mixture was heated to 80 °C for 1 Omm The saponification went to completion The reaction mixture was concentrated and IN HCl was added to precipitate methyl 2-(4-sulfamoylphenylammo)- qumazolm-7-carboxylic acid as the HCl salt in quantitative yield ES/MS m/z 344(MH+)
Example 20: 4-(6-(4-Methylpiperazine-l-carbonyl)quinazolin-2-ylamino-benzene sulfonamide
The subject compound was prepared according to the general Scheme 20, below
Scheme 20
Figure imgf000122_0002
To 2-(4-sulfamoylphenylamino)qumazolm-6-carboxylic acid (from example 19)(leq) was added Λf-methylpiperazme, THF and dπsopropylethylamine (DIEA) (4eq) and HBTU (2eq) and the mixture was stirred at RT overnight The coupling went to completion and the mixture was concentrated and partitioned between ethyl acetate and water The organic layers were concentrated and purified on the prep HPLC to give 4-(6-(4-methylprperazine-l- carbonyl)quinazolm-2-ylamino-benzene sulfonamide in 50% yield ES/MS m/z 427(MH+)
5 Example 21: 4-(6-(l-Isobutyl-lH-pyrazol-4-yl)quinazolin-2-yIamino)benzene- sulfonamide
The subject compound was prepared according to the general Scheme 21, below
Scheme 21
Figure imgf000123_0001
Step 1 2-(4-Sulfamoylphenylamιno) qumazolιn-6-yltrιfluoromethane sulfonate 10 To a solution of 4-(6-hydroxyquinazolm-2-ylammo) benzenesulfonamide, 21-1 (leq) in NMP was added phenyltrifiuoromethanesulfonate (1 2eq) and DIEA (2 5eq) and the reaction mixture was stirred over night at ambient temperature The reaction mixture was then partitioned between ethyl acetate and water The organic layers were washed with saturated sodium chloride and dried and concentrated To the crude was added DCM and few 15 drops of MeOH The white solid hence formed was filtered to give 2-(4-sulfamoylphenyl- ammo)quinazolm-6-yltrifluoromethane sulfonate in 80% yield ES/MS m/z 447(MH+)
Step 2 4-(6-(l-Isobutyl-lH-pyrazol-4-yl)quιnazolιn-2-ylamιno)benzenesulfonamιde To a solution of 2-(4-sulfamoylphenylamino)quinazohn-7-yltnfluoromethane
20 sulfonate (leq) in DME was added 2M sodium carbonate solution and l-isobutyl-3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (3eq) and Pd(dppf)2Cl2 CH2Cl2 (0 05eq) and the mixture was micro waved for 10 mm at 1200C The reaction mixture was then partitioned between ethyl acetate and water The organic layer was concentrated to yield 4- (6-(l-isobutyl-lH-pyrazol-4-yl)quinazolin-2-ylammo)benzenesulfonamide ES/MS m/z
25 423(MH+) Example 22 : (4-(5-Chloro-6-ethynyIquinazolin-2-ylamino)phenyl)(morpholino) methanone
The subject compound was prepared according to the general Scheme 22 below
Scheme 22
DIEA
Figure imgf000124_0001
Step 1 2-Chloroqumazohn-6-ol, 22-2
To 2-chloro-6-methoxy quinazolme, 22-1 in DCM was added boron tnbromide (2eq) and the mixture was heated at 400C for 16h The deprotection of the methyl ether goes to completion by LC/MS The mixture was concentrated and the solid was filtered and washed with ice/water and the solid was dπed on high vacuum to give 2-chloroquinazohn-6-ol ES/MS m/z 181(MH+)
Step 2 2,5-Dichloroquinazohn-6-ol, 22-3
To 2-chloroqumazolm-6-ol, 22-2 (leq) m chloroform was added N-chlorosuccinimide (leq) and the mixture was heated to 4O0C for 16h The reaction goes to completion to give 2,5-dichloroquinazohn-6-ol that was observed by LC/MS and the structure was confirmed by 1HNMR The mixture was concentrated and purified on silica gel to give the product ES/MS m/z 215(MH+)
Step 3 2-Chloro5-bromoquιnazohn-6-ol To 2-chloroquinazolin-6-ol, 22-2 (1 eq) in chloroform was added iV-bromosuccmimide
(leq) and the mixture was stirred at ambient temperature for Ih The reaction goes to completion to give 2-chloro5-bromoquinazolm-6-ol that was observed by LC/MS and the structure was confirmed by 1HNMR The mixture was concentrated and passed through a silica gel plug to give the product in quantitative yield ES/MS m/z 260(MH+)
Step 4 (4-(5-Chloro-6-hydroxyquιnazolιn-2-ylamιno)phenyl)(morpholιno)methanone 5 To 2,5-dichloroqumazolin-6-ol, 22-3 (leq) in isopropanol was added (4-amino- phenyl)(morpholino)methanone (leq) and the reaction mixture was heated to 90 0C for Ih The reaction went to completion by LC/MS The mixture was then concentrated and used without further purification ES/MS m/z 386(MH+)
10 Step 5 5-Chloro-2-(4-(morphohne-4-carbonyl)phenylamιno)quιnazolιn-6-yl trφuoro- methanesulfonates, 22-4
To a solution of (4-(5-chloro-6-hydroxyquinazolin-2-ylammo)phenyl)(morpholino) methanone (leq) m NMP was added phenyltnfluoromethanesulfonate (1 2eq) and DIEA (2 5eq) and the reaction mixture was stirred over night at ambient temperature The reaction
15 mixture was then partitioned between ethyl acetate and water The organic layers were washed with saturated sodium chloride and dπed and concentrated To the crude was added methylene chloride and few drops of MeOH The white solid hence formed was filtered to give 5-chloro-2-(4-(morpholine-4-carbonyl)phenylammo) qumazolin-6-yl tnfluoromethane- sulfonate in 80% yield ES/MS m/z 517(MH+)
20
Step 6 (4-(5-Chloro-6-ethynylquιnazohn-2-ylamιno)phenyl)(morphohno) methanone
To 5-chloro-2-(4-(morpholme-4-carbonyl)phenylamino) qmnazolm-6-yl tnfluoro- methanesulfonate, 22-4 (leq) m 4 1 DMF and TEA was added TMS acetylene (4eq) and copper iodide (0 2eq) and Pd(dppf)2Cl2 CH2CI2 (0 2eq) and the mixture was microwaved for
25 10 mm at 120 °C The reaction mixture was then partitioned between ethyl acetate and water The organic layer was concentrated to yield (4-(5-chloro-6-((tπmethylsilyl)ethynyl)- qumazolm-2-ylamino)ρhenyl)(morpholmo)methanone ES/MS m/z 465(MH+) To the crude was added THF and tetramethylammonium fluoride (leq) and the mixture was stirred at ambient temperature for Ih It was then partitioned between ethyl acetate and water and the
30 organic layer was concentrated and purified on prep HPLC to give (4-(5-chloro-6-ethynyl- qumazolm-2-ylammo)phenyl)(morpholmo) methanone ES/MS m/z 393(MH+) Example 23: 6-Bromo-5-fluoro-N-(4-morpholinophenyl)quinazolin-2-amine
The subject compound was prepared according to the general Scheme 23 below
Scheme 23
Figure imgf000126_0001
Step 1 6-Ammo-3-bromo-2-fluorobenzoic acid
To 2-amino-6-fluorobenzoic acid, 23-1 (leq) in chloroform at 0 0C was added bromine (1 2eq) drop-wise and the mixture was stirred at ambient temperature for 16h Formation of 6-amino-3-bromo-2-fluorobenzoic acid (47%) was observed by LC/MS along with 2-amino-3-bromo-6-fluorobenzoic acid (22%) and 20% of 2-ammo-3,5-dibromo-6- fluorobenzoic acid and 9% starting mateπal remained The structures of the isomers were confirmed by 1HNMR The reaction mixture was concentrated and filtered and the solid was washed with chloroform to give an off white solid The crude mixture was earned on to the next step without purification ES/MS m/z 235(MH+)
Step 2 (6-Amιno-3-bromo-2-fluorophenyl)methanol
To the crude mixture from step 1 in THF at O0C in a flame dry flask was added borane-THF complex (4eq) dropwise The mixture was brought to ambient temperature and was stirred for 16h The formation of (6-amino-3-bromo-2-fluoroρhenyl)methanol was observed by LC/MS The reaction mixture was concentrated and to the crude was partitioned between water and ethyl acetate The organic layer was washed with bπne and dried
(Na2SO4) The crude yellow oil was purified on silica gel and the formation of (6-ammo-3- bromo-2-fluorophenyl)methanol was confirmed by 1HNMR ES/MS m/z 218(MH+) Step 3 6-Amιno-3-bromo-2-fluorobenzaldehyde, 23-2
To (6-ammo-3-bromo-2-fluorophenyl)methanol (leq) in methylene chloride was added manganese dioxide (8eq) and the mixture was stirred at ambient temperature for 16h Formation of 6-ammo-3-bromo-2-fluorobenzaldehyde was confirmed by LC/MS The mixture was then filtered and the filtrate was concentrated to give 6-amino-3-bromo-2- fluorobenzaldehyde ES/MS m/z 218(MH+)
Step 4 6-Bromo-5-fluoroquιnazohn-2-ol To methyl 6-amino-3-bromo-2-fluorobenzaldehyde, 23-2 (leq) was added urea (8eq) and the mixture was heated tol 800C for Ih To the crude was added water and the precipitated solid was filtered and dπed under vacuum to give 6-bromo-5-fluoroqumazohn-2- ol ES/MS m/z 242(MH+)
Step 5 ό-Bromo-l-chloroS-fluoroquinazohne, 23-3
To 6-bromo-5-fluoroqumazolm-2-ol was added POCI3 and the mixture was added heated to 100 0C for 2h when the reaction went to completion To the reaction mixture was added ice and water and the precipitated solid was filtered and dπed on the high vacuum overnight to give 6-bromo-2-chloro-5-fluoroqumazohne ES/MS m/z 260(MH+)
Step 6 6-Bromo-5-fluoro-N-(4-morpholιnophenyl)qumazolιn-2-amιne
To a solution of 6-bromo-2-chloro-5-fluoroquinazolme, 23-3 (leq) in isopropanol was added 4-morpholinoanilme (1 eq) and the mixture was heated to 900C for Ih in a sealed tube The SNAR went to completion by LC/MS and purification on prep HPLC yielded 6-bromo- 5-fluoro-N-(4-morpholinophenyl)quinazolm-2-amine in quantitative yield ES/MS m/z 403(MH+)
Example 24: 6-Ethynyl-5-fluoro-N-(4-morpholinophenyl)quinazolin-2-amine
The subject compound was prepared according to the general Scheme 24 below
Figure imgf000128_0001
To 6-bromo-5-fluoro-N-(4-morpholmophenyl)quinazolin-2-amme (the compound of Example 2O)(I eq) in 4 1 DMF and TEA was added TMS acetylene (4eq) and copper iodide (02eq) and Pd(dppf)2Cl2 CH2Cl2 (02eq) and the mixture was microwaved for 10 mm at 120 0C The reaction mixture was then partitioned between ethyl acetate and water The organic layer was concentrated to yield 6-ethynyl-5-fluoro-N-(4-morpholmophenyl)- quinazolin-2-amme ES/MS m/z 420(MH+) To the crude was added THF and tetramethyl ammonium fluoride (leq) and the mixture was stirred at ambient temperature for Ih It was then partitioned between ethyl acetate and water and the organic layer was concentrated and the resulting residue was purified on prep HPLC to give (4-(5-chloro-6-ethynylqumazolin-2- ylammo)phenyl)(morpholmo) methanone ES/MS m/z 349(MH+)
Example 25: iV-(3-(6-Bromo-5-fluoroquinazolin-2-ylamino)-5-(morpholinomethyl)- phenyl) acetamide The subject compound was prepared according to the general Scheme 25 below
Scheme 25
25
Figure imgf000128_0002
The compound iV-(3-(6-bromo-5-fluoroquinazolin-2-ylamino)-5-(morpholmomethyl)- phenyl) acetamide, was prepared by a procedure analogous to Example 23 Example 26: ΛL(3-(5-Fluoro-6-(thiazol-2-yl)quinazolin-2-ylamino)-5-(morpholino- methyl)phenyl)acetamide
The subject compound was prepared according to the general Scheme 26 below
Figure imgf000129_0001
ro iV-(3-(6-bromo-5-fluoroquinazolin-2-ylammo)-5-(morpholinomethyl)phenyl) acetamide (from Example 25) (leq) was added 2-thiazolylzinc bromide solution in THF an the mixture a microwaved at 120 0C for lOmin Formation of 7V-(3-(5-fluoro-6-(fhiazol-2- yl)quinazolm-2-ylammo)-5-(moφholinomethyl)phenyl)acetamide was confirmed by LC/MS It was then concentrated and purified on prep HPLC to give the product ES/MS m/z
10 479(MH+)
Example 27: 4-(6-(Thiazol-2-yl)quinazolin-2-ylamino)benzenesulfonamide
The subject compound was prepared according to the general Scheme 27 below
Scheme 27
Figure imgf000129_0002
15 To 2-(4-sulfamoylphenylammo)quinazolin-6-yltπfluoromethane sulfonate (prepared by following Example 18 step 1) (leq) m DMF was added 2-(tnbutylstannyl)thiazole (3eq) and TEA (6eq) The mixture was microwaved at 120 0C for 1 Omin The LC/MS showed formation of the 4-(6-(thiazol-2-yl)quinazolin-2-ylamino)benzenesulfonamide The crude mixture after work up was then purified on prep HPLC to give 4-(6-(thiazol-2-yl)quinazolin-0 2-ylamino) benzene sulfonamide ES/MS m/z 384(MH+) Example 28: 5-Chloro-Λ''-(4-morpholinophenyl)-6-(thiazole-2-yl) quinazolin-2-amine
The subject compound was prepared according to the general Scheme 28 below
Scheme 28
Figure imgf000130_0001
Step 1 5-Chloro-2- (4-(morphohnophenylamιno) quιnazolιn-6-yltrιfluoromethane sulfonate See, Example 22 for the synthesis ES/MS m/z 489 1(MH+)
Step 2 5-Chloro-N-(4-morpholιnophenyl)-6-(thιazole-2-yl) quιnazolιn-2 -amine
A mixture of 5-chloro-2- (4-(morpholinophenylammo) qumazolin-6-yltnfluoro- methane sulfonate (leq), 2-thiazolylzmcbromide (5eq, 0 5M soln in THF)) and Pd (dppf)2Cl2 CH2Cl2 (0 2eq) in THF was microwaved for 20 mm at 1200C The LC-MS shows formation of two products m i l ratio The reaction mixture was concentrated and purified by semi-preparative HPLC to provide 5-chloro-N-(4-morpholinophenyl)-6-(thiazole-2-yi) quinazolin-2-amme in 25%yield ES/MS m/z 424 1(MH+)
The second product of the reaction was identified as N-(4-morpholmophenyl)-5,6-di (thiazole-2-yl) qumazolin-2-amine ES/MS m/z 473 0(MH+)
Example 29: N-(3-(6-Bromoquinazolin-2-ylamino)-5-(morpholinomethyl) phenyl) acetamide
The subject compound was prepared according to the general Scheme 29 below
Scheme 29
Figure imgf000130_0002
The compound, 7V-(3-(6-bromoquinazolm-2-ylammo)-5-(morpholmomethyl) phenyl) acetamide, was prepared by a synthesis analogous to that used in Example 9 ES/MS m/z 456 0 (MH+)
Example 30: JV-(3-(6-(lH-Pyrazol-4-yl) quinazolin-2-ylamino)-5-(morpholinomethyl) phenyl) acetamide
The subject compound was prepared according to the general Scheme 30 below
Scheme 30
Figure imgf000131_0001
To a solution of iV-(3-(6-bromoquinazolin-2-ylammo)-5-(morpholmomethyl) phenyl) acetamide (from Example 29) (leq) in DME was added 2M sodium carbonate solution and 4- (4,4,5,5,-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (3eq) and Pd (dppf)2Cl2 CH2Cl2 (0 05eq) and the mixture was microwaved for 10 mm at 120 0C The reaction mixture was then partitioned between ethyl acetate and water The organic layer was washed with bπne, dπed, concentrated and purified by semi-preparative HPLC to provide 7V-(3-(6-(lH-pyrazol- 4-yl) qumazolm-2-ylammo)-5-(morphohnomethyl) phenyl) acetamide, 25%yield ES/MS m/z 444 3 (MH+) 7V-(3-(morpholinomethyl)-5-(qumazohn-2-ylamino) phenyl) acetamide was isolated as a side product ES/MS m/z 378 2 (MH+)
Example 31: ΛL(3-(6-Bromoqumazolin-2-ylamino)-5-iodophenyI)acetamide
The subject compound was prepared according to the general Scheme 31 below
Figure imgf000131_0002
A mixture of 6-bromo-2-chloroqumazoline, 31-1 (leq) and N- (3-amino-5-iodo- phenyl) acetamide (1 eq) m 2-propanol was heated at 110°C overnight Product was precipitated in the reaction mixture The precipitate was filtered, washed and dried under vacuum to provide pure product as a yellow solid in 99% yield ES/MS m/z 482 9(MH+)
Example 32: Λr-(3-(6-Bromoquinazolin-2-ylamino)-5-(pyridine-3-yl) phenyl) acetamide; and
Example 33: 7V-(3-(Pyridin-3-yl)-5-(6-(pyridin-3-yl) quinazolin-2-ylamino) phenyl) acetamide
The subject compounds were prepared according to the general Scheme 32/33, below
Figure imgf000132_0001
Example 31 Example 32 Example 33
To the compound of Example 26 (leq) in DME was added 2M sodium carbonate solution, 3-pyπdyl boromc acid (2eq) and Pd(dppf)2Cl2 CH2CI2 (0 05eq) and the mixture was microwaved for 10 mm at 1200C LC-MS shows formation of two products The reaction mixture was then partitioned between ethyl acetate and water The organic layer was washed with bnne, dπed, concentrated and purified by semi-preparative HPLC to provide N-(3-(6- bromoquinazolm-2-ylamino)-5-(pyπdine-3-yl) phenyl) acetamide in 60%yield ES/MS m/z 434 1 (MH+)
The second product of this reaction (Example 33), was identified as 7V-(3-(pyndm-3- yl)-5-(6-(pyπdin-3-yl) quinazohn-2-ylamino) phenyl) acetamide. ES/MS m/z 433 2 (MH+)
Example 34: ΛL(3-(6-Ethynylyquinazolin-2-ylamino)-5-(pyridine-3-yl) phenyl) acetamide
The subject compound was prepared according to the general Scheme 34 below Scheme 34
DMF
Figure imgf000133_0002
Figure imgf000133_0001
To 7V-(3-(6-bromoquinazolm-2-ylamino)-5-(pyπdme-3-yl) phenyl) acetamide (leq) in 4 1 DMF and TEA was added TMS acetylene (4eq) and copper iodide (02eq) and Pd(dppf)2Cl2 CH2Cl2 (02eq) and the mixture was micro waved for 10 mm at 1200C The reaction mixture was then partitioned between ethyl acetate and water The organic layer was concentrated to yield JV-(3-(pyπdme-3-yl)-5-(6-((tπmethylsilyl)ethynyl) quinazolin-2- ylarmno)phenyl) acetamide ES/MS m/z 452 1(MH+) To the crude was added THF and tetramethyl ammonium fluoride (leq) and the mixture was stirred at ambient temperature for Ih It was then partitioned between ethyl acetate and water and the organic layer was
10 concentrated and purified by semi-prep HPLC to provide N-(3-(6-ethynylyquinazolm-2-yl- ammo)-5-(pyπdme-3-yl) phenyl) acetamide. ES/MS m/z 380 1(MH+)
Example 35: 4-(6,7-Dimethoxyquinazolin-2-ylamino) benzenesulfonamide
The subject compound was prepared according to the general Scheme 35 below
Figure imgf000133_0003
Step 1 2-Amιno-4,5-dιmethoxybenzaldehyde
To a solution of 4, 5-dimethoxy-2-mtrobenzaldehyde (leq) in ethanol and water (2 1) was added ammonium chloride (10eq) The solution was heated at 900C followed by the addition of iron powder (4eq) in portions The reaction mixture was heated at 90 0C for
20 30mm , cooled, diluted with DCM and filtered through diatomaceous earth The organic layer was separated from aq layer, washed with bπne and dried over sodium sulfate, filtered, concentrated and dπed under vacuum to provide the product in 93% yield ES/MS m/z 182 1 (MH+)
Step 2 6, 7-Dιmethoxyquιnazohn-2-ol A mixture of 2-amino-4, 5-dimethoxybenzaldehyde (leq) (obtained from step 1) and urea (15 eqmv ) was heated to 175 0C with vigorous stirring for 2h The reaction was cooled to RT and water was added A solid precipitate formed and was collected by filtration, and air-dπed to give 6,7-dimethoxyqumazolm-2-ol as a brown solid in 40%yield ES/MS m/z
207 0 (MH+)
Step 3 2-Chloro-6, 7-dιmethoxyquιnazohne, 35-2
The crude 6,7-dimethoxyqumazohn-2-ol was heated in neat phosphorus oxychlonde
(POCI3) at 110 0C for 2h The resulting mixture was cooled to RT and concentrated in vacuo to nearly dryness Ice water was added and the pH was adjusted to ~6 using sodium bicarbonate Extraction with DCM followed by drying with sodium sulfate and concentration in vacuo yielded 2-chloro-6, 7-dimethoxyqumazoline as a brown solid ES/MS m/z 225 0
(MH+)
Step 4 4-(6, 7-Dιmethoxyquιnazolιn-2-ylamιno) benzenesulfonamide A mixture of 2-chloro-6,7-dimethoxyquinazolme (leq) and 4-ammobenzenesulfon- amide (leq) in isopropanol was heated at 90 0C for 16h The product precipitated in the reaction mixture, and was separated by filtration, washed and dπed to provide the pure product as a yellow solid in 87%yield ES/MS m/z 361 0 (MH+)
Example 47: 4-(6-Bromo-7-methoxyquiiiazolin-2-ylamino)benzenesulfonamide
The subject compound was prepared according to the general Scheme 36 below
Scheme 36
Figure imgf000134_0001
Step 1 Methyl 4-methoxy-2-nιtrobenzoate
To an ice cooled 04M solution of 4-methoxy-2-mtrobenzoic acid 36-1, in THF was added TEA (6 Oeq), followed by the addition of dimethyl sulfate (4 Oeq) The resulting mixture was stirred at 0 0C for 1 h, and then at ambient temperature overnight LCMS showed about 90% conversion to the product The solvent was removed under reduced pressure The resulting residue was diluted with ethyl acetate and then washed sequentially with saturated sodium bicarbonate and brine, and then dπed over sodium sulfate Concentration of the dπed solution provided the desired product as an off-white solid in 94% yield The structure of the product was confirmed by proton NMR spectrum
Step 2 Methyl 2-amιno-4-methoxybenzoate 36-2
To a 04M solution of methyl 4-methoxy-2-mtrobenzoate in DMF in an ice bath was added Tm(II) chloride dihydrate (7 Oeq) The mixture was stirred at ambient temperature overnight, then diluted with ethyl acetate (4OmL ethyl acetate for each mM of the nitro compound) TEA (14eq) was added, and the resulting white suspension was stirred for 1 h, and was then filtered The filter cake was πnsed with ethyl acetate The combined organic phase was washed with water and then bπne, and was then dπed over sodium sulfate Concentration of the dπed organic phase provided the desired product in 95% yield ES/MS m/z 182 (MH+)
Step 3 Methyl 2-amιno-5-brorno-4-methoxybenzoate
To a 0 06M solution of methyl 2-ammo-4-methoxybenzoate, 36-2, in chloroform was added bromine (1 Oeq as a 0 05M solution m chloroform) via an additional funnel The resulting mixture was stirred at RT for 3 h LCMS data showed that the bromination reaction had proceeded to about 72% conversion The resulting white precipitate was collected by filtration, washed thoroughly with DCM and then air-dπed to provide methyl 2-ammo-5- bromo-4-methoxybenzoate as its HBr salt Yield 70% ES/MS m/z 260/262 (MH+)
Step 4 (2-Amιno-5-bromo-4-methoxyphenyl)methanol
To a 025M suspension of methyl 2-amino-5-bromo-4-methoxybenzoate m THF m an ice bath was slowly added borane (4 5eq as a 1 OM THF solution) The reaction mixture was stirred at ambient temperature for 48 h The mixture was then recooled to 0°C, quenched with MeOH and concentrated to remove the solvent The resulting residue was dissolved in ethyl acetate and the resulting organic phase was washed with water, and then brine, and then dried over sodium sulfate and concentrated to provide (2-amino-5-bromo-4-methoxyphenyl)- methanol, as a brown colored oil ES/MS m/z 214/216 (MH+)
Step 5 2-Amιno-5-bromo-4-methoxybenzaldehyde, 36-3
Manganese (IV) oxide (8eq) was added to a 022M solution of (2-ammo-5-bromo-4- methoxyphenyl)methanol in DCM The resulting suspension was stirred at ambient temperature under Argon for 12 h The reaction mixture was then filtered through diatomaceous earth and the resulting filter cake was washed with DCM The combined filtrate was concentrated to provide the product as a brown colored solid in 67% yield ES/MS m/z 230/232 (MH+)
Step 6 6-Bromo-7-methoxyquιnazolιn-2-ol A mixture of 2-amino-5-bromo-4-methoxybenzaldehyde, 36-3, (leq) and urea (14eq) was heated to 180 0C in an oil bath under Argon for 2 h Water was added after cooling to ambient temperature The solid was collected by filtration and air dried to give product in 90% yield ES/MS m/z 255/257 (MH+)
Step 7 6-Bromo-2-chloro-7-methoxyquinazohne, 36-4
A 0 5M suspension of 6-bromo-7-methoxyquinazohn-2-ol m phosphorus oxychloπde was heated to 110 0C in an oil bath for 3 h The mixture was then cooled to RT The volatiles were removed under reduced pressure The resulting residue was triturated with ice water The resultmg solid was collected by filtration and air dπed to provide the product in 55% yield ES/MS m/z 2131215 (MH+)
Step 8 4-(6-Bromo-7-methoxyquιnazohn-2-ylamιno)benzenesulfonamιde
To a solution of 50 mg of 36-4 in 2-propanol (1 mL) was added sulfanilamide (1 0 eq) The reaction was stirred at 90 0C for 18 hours The hydrochloride was collected by vacuum filtration and air dπed to give a crude matenal which can be used for further chemical modifications The pure material was obtained by HPLC purification ES/MS m/z 409/411 (MH+) Example 68: JV-(2-(4-Sulfamoylphenylamino)quinazolin-6-yl)acetamide
The subject compound was prepared according to the general Scheme 37 below
Scheme 37
Figure imgf000137_0001
Step 1 2-(4-Sulfamoylphenylamιno)quιnazolιn-6-yl tert-butylcarbamate
To 2-(4-sulfamoylphenylamino) quinazoline-6-carboxylic acid (leq) (prepared as in Example 19) in toluene was added diphenylphosphorylazide (DPPA) (1 2eq), tert-butanol (lOeq) and TEA (2eq) The resulting mixture was heated to 700C for 30mm, and was then heated further to 100 0C and maintained at 100 0C overnight The reaction mixture was then
10 concentrated and the resulting residue was purified by semi-prep HPLC to provide the pure product
Step 2 4-(6-Amιnoquιnazolιn-2-ylamιno)benzenesulfonamιde, 37-1
A solution of 2-(4-sulfamoylphenylamino)quinazolm-6-yl tert-butylcarbamate in 15 30%TFA / DCM was stirred at RT for 30 mm The solvent was then evaporated, and the resulting crude residue was purified by semi-prep HPLC to provide the product
Step 3 N-(2-(4-Sulfamoylphenylamιno)quιnazohn-6-yl)acetamιde
To a solution of 4-(6-ammoquinazolm-2-ylammo)benzenesulfonamide, 37-1 (leq) in
20 THF was added acetic acid (5eq), HBTU (4eq) and DIEA (1 Oeq) The resulting mixture was stirred at RT for 48h The reaction does not go to completion The reaction mixture was diluted with ethyl acetate and the resulting diluted mixture was washed with water, and then bnne and then was dried over sodium sulfate The dried mixture was filtered, and then concentrated The concentrate was purified by semi-prep HPLC to provide JV-(2-(4-
25 sulfamoylphenylamino)qumazolin-6-yl)acetamide
Example 135: Λr-(3-(6-Bromo-8-fluoroquinazolin-2-ylamino)-5-((dimethylainino)- methyl)phenyl)acetamide The subject compound was prepared according to the general Scheme 38 below
Scheme 38
Figure imgf000138_0001
Step 1 2-Amino-5-bromo-3-fluorobenzoic acid
To a suspension of 2-ammo-3-fluorobenzoic acid, 38-1, (5 g, 32 2 mmol) in chloroform (200 mL) was added dropwise bromine (1 1 equiv ) in chloroform (125 mL) solution The mixture was stirred at RT for 16 hrs The resulting white solid was collected by filtration and washed thoroughly with DCM until the filtrate was colorless The solid was air-dried to give 9 6 g of white powder as the HBr salt of 2-amino-5-bromo-3-fluorobenzoic acid (95% yield) ES/MS m/z 234/236 (MH+)
Step 2
To the above intermediate (30 6 mmol) in THF (100 mL) at 0 0C was added boron- THF complex solution (1 M in THF, 129 mL, 4 equiv ) The resulting mixture was stirred at RT for 40 hrs The solvent was removed in vacuo and the excess reagent was quenched by the addition of water (30 mL) slowly The pH (~3) of the quenched mixture was adjusted to pH 7 by adding sodium bicarbonate (sat aq ) The mixture was then extracted with DCM The organic extracts were combined, washed with bπne, dned with sodium sulfate and concentrated to provide a crude mateπal as a white solid ES/MS m/z 220/222 (MH+)
Step 3 2-Amιno-5-bromo-3-fluorophenyl)methanol
To the above intermediate (30 6 mmol) in DCM (450 mL) was added manganese dioxide (Mnθ2, 22 g, 258 mmol) The resulting mixture was stirred at RT under argon for 18 his The mixture was then filtered through diatomaceous earth and washed thoroughly with DCM The filtrate was then concentrated in vacuo to provide the crude product (2-amino-5- bromo-3-fluorophenyl)methanol (5 6 g) which was used for the next step without further purification ES/MS m/z 218/220 (MH+)
Step 4 2-Hydroxyquιnazolιne
A mixture of (2-amino-5-bromo-3-fluorophenyl)methanol (5 6 g, 23 7 mmol, obtained from step 3) and urea (21 g, 15 equiv ) was heated to 175 0C with vigorous stirring for 15 mm The reaction was then cooled to RT and water was added A solid precipitate formed and was collected by filtration and air-dπed to provide 2-hydroxyqumazoline as a light brown solid
Step 5 6-Bromo-2-chloro-8-fluoroqumazohne, 38-2
To the above crude matenal was added phosphorus oxychloπde (POCI3, 20 mL) and this mixture was heated to 110 0C for 30 mm The mixture was then cooled to RT and concentrated in vacuo to nearly dryness Ice water was added to the concentrate and the pH of the resulting mixture was adjusted to ~6 using sodium bicarbonate The pH adjusted mixture was extracted with DCM The extract was dπed with sodium sulfate and concentrated in vacuo to provide the desired product, 6-bromo-2-chloro-8-fluoroquinazolme, as light brown powder (1 63 g)
Step 6 N~(3-(6-Bromo-8-fluoroquιnazolιn-2-ylamιno)-5-((dιmethylamιno)methyl)phenyl)- acetamide
A mixture of θ-bromo^-chloro-S-fluoroquinazohne, 38-2, JV-(3-armno-5-((dimethyl- amino)methyi)phenyl)acetamide (1 equiv ) and HCl in dioxane (1 equiv ) in isopropanol (2 5 mL) was heated to 75 0C for 16 hrs The resulting mixture was diluted with water, washed with ethyl acetate to remove organic impurities, basified the aqueous portion with sodium bicarbonate (aq ) to pH 9, and then brine was added The basified aqueous solution was extracted with chloroform (3X) The organic extracts were combined, washed with bπne, dπed with sodium sulfate and concentrated to give a crude matenal which was purified by HPLC
Example 139: 7V-(3-((Dimethylamino)methyl)-5-(6-ethynyl-8-fluoroquinazolin-2-ylamino)- phenyDacctainidc The subject compound was prepared according to the general Scheme 39 below
Figure imgf000140_0001
Step 1
A mixture of 7V-(3-(6-bromo-8 fluoroquinazolin-2-ylammo)-5-((dimethylamino)- methyl)phenyl)acetamide, (from Example 135), ethynyltnmethylsilane, copper(I) iodide, l,r-bis(diρhenylphosρhmo)ferrocenedichloro ρalladram(II), TEA and DMF, prepared according to the same stoichiometry as employed m the reaction of Example 7, step 1, is microwaved at 120 0C for 8 mm The resulting mixture is diluted with ethyl acetate, washed with water and brine, dried with sodium sulfate and concentrated to provide a crude residue
Step 2 N-(3-(8-Fluoro-6-ethynylquιnazolιn-2 ylamino) 5-((dιmethylamιno)methyl)phenyl)- acetamide (Example 139)
To the intermediate from Step 1 is added THF, 2-propanol and tetramethylammonium fluoride, according to the same stoichiometry as employed in the reaction of Example 7, step 2 The mixture is stirred at RT for 20 mm The resulting mixture is diluted with water and extracted with ethyl acetate (3X) The organic extracts are combined, washed with bπne, dried with sodium sulfate and concentrated to provide a crude material which is purified by HPLC to yield the title compound
Example 216: N-(3-(6-ethynyl-8-(piperidin-4-yloxy)qulnazolin-2-ylamino)-5- (pyrimidin-5-yl)phenyl)acetamide
100 C 120 c"
Figure imgf000140_0002
Step 1 Preparation of 2 6-dιbromo -8-(N-Boc-pιpetidιn-4 yloxy)quιnazolιne To a 0 3OM solution of tπphenylphosphme (2 0 eq) in THF was added diethylazodicarboxylate (2 0 eq) The mixture was stirred 15 min at ambient temperature N- Tert-butyl-4-Hydroxy-l-pipeπdine carboxylate (4 0 eq) was added The mixture was stirred 15 mm at ambient temperature 2,6-Dibromo-8-hydroxyquinazolme (l 0 eq) was added The mixture was stirred an additional 24 h The crude mixture was concentrated, purified by flash chromatography (2 1 hexanes EtOAc), and concentrated to give the desired product
Step 2 Displacement
To a 0 3OM solution of 2,6-dibromo-8-(N-Boc-pipendin-4-yloxy)qumazolme in 2- propanol was added 3-acetamido-5-ρynmidm-5-ylanilme (1 0 eq) The reaction was stirred at 100 °C for 14 h The crude mixture was concentrated and used without further punfi cation
Step 3 Sonogashira & desilylatwn The product from Step 2 was treated analogously to Example 281 step 2 and earned on to Step 4 without purification
Step 4 Deprotection
The product from Step 3 was dissolved in enough 1 1 DCM TFA to make a 0 2OM solution The mixture was stirred for 30 mm at ambient temperature and concentrated The crude product was purified by reverse-phase HPLC and lyophihzed to give the desired product as its trifluoroacetic acid salt ES/MS nt/z 480 (MH+)
Example 220: 3-morpholino-5-(8-(piperidin-4-yloxy)-6-(lH-pyrazol-4-yl)quinazolin-2- ylamino)benzamide
2 acid piπacol Na2CO3 120 C
Figure imgf000141_0002
Step 1 Displacement To a 0 3OM solution of the product from Example 283 step 1 in 2-propanol was added 3-carboxamido-5-morpholinoamline (1 0 eq) The reaction was stirred at 100 0C for 14 h The crude mixture was concentrated and used without further purification
Step 2 Suzuki
To a 0 1OM solution of the product from Step 1 (1 Oeq) in DME was added N-Boc- pyrazole-4-boromc acid pinacol ester (4 0 eq), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM (0 10 eq), and 2 OM aqueous sodium carbonate (5 0 eq) The reaction was microwaved at 120 C for 10 mm The mixture was diluted with THF, filtered, concentrated, and earned on to Step 4 without purification
Step 3 Deprotection
The product from Step 2 was dissolved in enough 1 1 DCM TFA to make a 0 2OM solution The mixture was stirred for 30 mm at ambient temperature and concentrated The crude product was purified by reverse-phase HPLC and lyophilized to give the desired product as its tnfluoroacetic acid salt ES/MS m/z 515 (MH+)
Example 229 : 3-morpholino-5-(8-(piperidin-4-yIoxy)-6-(thiazol-2-yl)quinazolin-2- ylamino)benzamide
Figure imgf000142_0001
Step 1 Negishi To the product of Example 284 step 1 was added zmc(II) cyanide (4 0 eq) and [1,1'- bis(diphenylphosphmo)ferrocene]dichloropalladium(II) complex with DCM (0 10 eq) The reaction was microwaved at 130 °C for 10 mm The mixture was diluted with ethyl acetate and washed with aqueous EDTA ρH~9 buffer The organic phase was dπed over sodium sulfate, and concentrated to give the desired product Step 2 Deprotection
The product from Step 1 was dissolved in enough 1 1 DCM TFA to make a 02OM solution The mixture was stirred for 30 mm at ambient temperature and concentrated The crude product was purified by reverse-phase HPLC and lyophilized to give the desired product as its tnfluoroacetic acid salt ES/MS m/z 532 (MH+)
Example 459: 6-ethynyl-NK3-(l-methyl-lH-pyrazol-4-yl)-5-(2-(pyrrolidin-l- yl)ethoxy)phenyl)quinazolin-2-amine
The subject compound was prepared according to the general Scheme, below
Figure imgf000143_0001
Step 1 3-amιno-5-(l-methyl-lH-pyrazol-4-yl)phenol To the starting crude material 3-(l-methyl-lH-pyrazol-4-yl)-5-mtrophenol (7 04g, 32 mmol) was added 10% Pd on Carbon (2 Ig, 30% by wt ) under argon Under argon with a syringe carefully add 95 ml methanol To this reaction mixture was added a hydrogen balloon and was evacuated and refilled 6 times The reaction was stirred at room temperature for 22 hours or until done by LC To the reaction mixture add ethyl acetate and under argon filtered through celite and washed with a l l solution of ethyl acetate and methanol The filtrate was concentrated under reduced pressure to give 3-ammo-5-(l-methyl-lH-pyrazol-4- yl)phenol, as crude material (8 0 grams) ES/MS m/z 190(MH+) 5
Step 2 3 (6-bromonaphthalen-2-ylamιno)-5-(l-methyl-lH-pyrazol-4-yl)phenol
To the reaction mixture of 3-amino-5-(l-methyl-lH-pyrazol-4-yl)phenol (2 6 g, 13 68 mmol) m 20 ml of dioxane was added 6-bromo-2-chloroqmnazolme (1 75g, 7 20 mmol) and acetic acid (1 73 ml, 28 8mmol) The reaction solution was stirred at 95-100 CC for 60 hours
10 or until done by LCMS To the crude reaction mixture add 30ml dioxane, let cool, filter solids off and the concentrate the filtrate (product) The crude residue was purified by silica gel column chromatography and concentrated in vaccuo to give 3-(6-bromonaphthalen-2- ylammo)-5-(l-methyl-lH-pyrazol-4-yl)phenol, (1 13 grams) ES/MS m/z 396/398(MH+) Additional purification can be done by prep HPLC and lyophilized to make a TFA salt
15
Step 3 3-(l-methyl-lH-pyrazol-4-yl)-5-(6-((tnmethylsιlyl)ethynyl)quιnazohn-2- ylamιno)phenol
To the reaction mixture of 3-(6-bromonaphthalen-2-ylammo)-5-(l-methyl-lH- pyrazol-4-yl)phenol (1 13 g, 2 85 mmol) in 7 ml of DMF was added Pd(dppf)2Cl2 (232 mg,
20 0 28 mmol), CuI (119 mg, 0 622 mmol), ethynyltπmethylsilane (838 mg , 8 55 mmol) and last add N-ethyl-N-isopropylpropan-2-amme (DIPEA) (1 5 ml, 8 55 mmol) This reaction mixture was stirred at 95 0C for 1 hour or until done by LCMS Concentrate most of the DMF off, add 350ml of ethyl acetate, 75 ml of saturated sodium bicarbonate and briefly stirred The mixture formed an emulsion that was filtered through celite and flushed with 100
25 ml ethyl acetate The organic layer was extracted and washed with water, saturated NaCl, dπed with Na2SC^, filtered through a 2"x 3" silica gel plug, flushed with ethyl acetate and concentrated in vaccuo to give 3-(l-methyl-lH-pyrazol-4-yl)-5-(6- ((tπmethylsilyl)ethynyl)qumazolm-2-ylamino)phenol, (1 20 grams) ES/MS m/z 414(MH+)
30 Step 4 N-(3-(l-methyl-lH-pyrazol-4-yl)-5-(2-(pyrrohdιn-l-yl)ethoxy)phenyl)-6- ((tnmethylsιlyl)ethynyl)quιnazohn-2-amιne
To the reaction mixture of tnphenyl phosphine (32 mg, 0 12mmol) in 0 5 ml of THF add 2-(pyrrolidin-l-yl)ethanol ( 17 3 mg, 0 15 mmol), then add DEAD (21 mg, 0 12 mmol) and stir at room temperature for 10 minutes The above reaction mixture was added to 3-(l - methyMH-pyrazol-4-yl)-5-(6-((1nmethylsilyl)ethynyl)quinazohn-2-ylamino)phenol (24 8 mg, 0 06 mmol) and stirred at room temperature for 20 hours or until done by LCMS The reaction mixture was concentrated under reduced pressure to give N-(3-(l-methyl-lH- pyrazol-4-yl)-5-(2-(pyrrolidin-l-yl)ethoxy)phenyl)-6-((tπmethylsilyl)ethynyl)quinazolm-2- amine as a crude residue used in the next step ES/MS m/z 511(MH+)
Step 5 6-ethynyl-N-(3-(l-methyl-lH-pyrazol-4-yl)-5-(2-(pyrrohdm-l- yl)ethoxy)phenyl)quιnazolιn-2-amιne
To the crude reaction mixture of N-(3-(l-methyl-lH-pyrazol-4-yl)-5-(2-(pyrrolidm-l- yl)ethoxy)phenyl)-6-((tπmethylsilyl)ethynyl)qumazolm-2-amme (0 06 mmol) in ImI of DMF was added 6M NaOH (0 06 ml, 0 36mmol) and stirred at room temperature for 10 minutes and checked by LCMS If the de-protection is incomplete add more 6 M NaOH and recheck in 10 mmutes The crude reaction mixture was filtered, purified on prep HPLC and lyophihzed to give 6-ethynyl-N-(3-(l-methyl-lH-pyrazol-4-yl)-5-(2-(pyrrolidm-l- yl)ethoxy)phenyl)qumazolin-2-amme as TFA salt (44 mg) ES/MS m/z 439(MH+)
Example 536: 6-ethvnyl-N-(3-(l-methyl-lH-pyrazol-4-yl)-5-(pyridin-2- vlnieth()xy)pheπyl)quinazolin-2-aniine
The subject compound was prepared according to the general Scheme, below
Figure imgf000145_0001
Step 1 N-(3-(l -methyl IH pyrazol-4-yl)-5-(pyrιdιn-2-ylmethoxy)phenyl)-6- ((tnmethylsιlyl)ethynyl)quιnazohn-2-amιne
To the reaction mixture of 3-(l-methyl-lH-pyrazol-4-yl)-5-(6-
((tπmethylsilyl)ethynyl)quinazolm-2-ylammo)phenol (24 8 mg, 0 06 mmol) in 04 ml of THF add pyπdm-2-ylmethanol ( 16 5, 0 15 mmol), triphenyl phosphine (32 mg, 0 12mmol) and then DEAD (21 mg, 0 12 mmol) last The reaction mixture was stirred at room temperature for 20 hours or until done by LCMS If the reaction is not done add more DEAD (10 5mg, 0 06 mol) and stir at room temperature 1 to 2 hours The reaction mixture was concentrated under reduced pressure to give N-(3-(l-methyl-lH-pyrazol-4-yl)-5-(pyπdin-2- ylmethoxy)phenyl)-6-((tπmethylsilyl)ethynyl)quinazolm-2-amine as a crude residue used in the next step ES/MS m/z 505(MH+)
Step 2 6-ethynyl-N-(3-(l-methyl-lH-pyrazol-4-yl)-5-(pyrιdm-2- ylmethoxy)phenyl)quιnazolιn-2-amιne
To the crude reaction mixture of N-(3-(l-methyl-lH-pyrazol-4-yl)-5-(pyπdm-2- ylmethoxy)phenyl)-6-((tπmethylsilyl)ethynyl)qumazolm-2-amine (0 06 mrøol) in 1 2 ml of DMF was added 6M NaOH (0 125 ml, 0 75 mmol) and stirred at room temperature for 10 minutes and checked by LCMS If the de-protection is incomplete add more 6 M NaOH and recheck in 10 minutes The crude reaction mixture was filtered, purified on prep HPLC and lyophihzed to give 6-ethynyl-N-(3-(l-methyl-lH-pyrazol-4-yl)-5-(pyπdin-2- ylmethoxy)phenyl)qmnazolm-2-amine as TFA salt (5 6 mg) ES/MS m/z 433(MH+)
Example 469: N-(2-(3-(6-ethynylquinazolin-2-ylamino)-5-(l-methyl-lH-pyrazol-4- yI)phenoxy)ethyl)-l-methyI-lH-pyrazole-4-carboxamide
The subject compound was prepared according to the general Scheme, below
Pd(dppf)2CI2 DME 2M Na2CO3
Figure imgf000147_0002
Pd(CiPPf)2CI2 CuI DIPEA DMF
Figure imgf000147_0003
HATU DMF DIPEA
Step 1 tert-butyl 2-(3-bromo-5-nιtrophenoxy)ethylcarbamate
To the reaction mixture of 3-bromo-5-mtrophenol (4 Og, 18 35 mmol) in 40 ml of DMF add cesmm carbonate (12 O g, 367 mmol) and stir at room temperature for 30 minutes To the above reaction mixture was added tert-butyl 2-bromoethylcarbamate (6 16 g, 27 5 mmol), cap with argon balloon and stirred at 40°C for 18 hours or until done by LCMS Concentrate about half of the DMF off, add 500 ml of ethyl acetate, wash organic layer IM NaOH (3x), water, saturated NaCl, dried with Na2SO4, filtered and concentrated in vaccuo to give crude, tert-butyl 2-(3-bromo-5-mtrophenoxy)ethylcarbamate (6 6 grams) used in the next reaction
Step 2 tert-butyl 2-(3-(l-methyl-lH-pyrazol-4-yl)-5-nιtrophenoxy)ethylcarbamate
To the reaction mixture of above crude tert-butyl 2-(3-bromo-5- mtrophenoxy)ethylcarbamate (6 6 g, 18 28 mmol) in 125 ml of DME was added
Pd(dppf)2Cl2 (1 2 g, 1 46 mmol), l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazole (5 7 g, 27 4 mmol) and last add 2M Na2CO3 (41 3 ml, 82 5 mmol) This reaction mixture was stirred at 100 0C for 2 hours or until done by LCMS Concentrate most of the DME off, add 600ml of ethyl acetate, 100 ml of water and briefly stirred The mixture formed an emulsion that was filtered The organic layer was extracted and washed with IM NaOH (2x), water, saturated NaCl, dπed Na2SO4, filtered and concentrated m vaccuo to give tert-butyl 2-(3-(l-methyl-lH-pyrazol-4-yl)-5-mtrophenoxy)ethylcarbamate, (62 grams) ES/MS m/z 363(MH+)
Step 3 tert-butyl 2-(3-amιno-5-(l-methyl-lH-pyrazol-4-yl)phenoxy)ethylcarbamate Analogous to Example 459, stepl but using tert-butyl 2-(3-(l-methyl-lH-pyrazol-4- yl)-5-mtrophenoxy)ethylcarbamate as starting material ES/MS m/z 333(MH+)
Step 4 tert-butyl 2-(3-(6-bromoquιnazolιn-2-ylamιno)-5-(l-methyl-lH-pyrazol-4- yl)phenoxy)ethylcarbamate To the reaction mixture of tert-butyl 2-(3-amino-5-(l-methyl-lH-pyrazol-4- yl)phenoxy)ethylcarbamate (5 53 g, 16 66 mmol) in 50 ml of IPA m a glass bomb was added 6-bromo-2-chloroquinazohne (3 9 g, 16 66 mmol) and caped The reaction solution was stirred at 95-100 0C for 22 hours or until done by LCMS To the crude reaction mixture add 20 ml of IPA, let cool, collect solids (product) wash 2 x IPA The crude solid was dπed in vaccuo to give, tert-butyl 2-(3-(6-bromoqumazolin-2-ylammo)-5-(l-methyl-lH-pyrazol-4- yl)phenoxy)ethylcarbamate, (6 88 grams) ES/MS m/z 539/541(MH+) Additional purification can be done by prep HPLC and lyophihzed to make TFA salt
Step 5 tert-butyl 2-(3-(l-methyl-lH-pyrazol-4-yl)-5-(6-((trιmethylsιlyl)ethynyl)quιnazohn-2- ylamιno)phenoxy)ethylcarbamate
To the reaction mixture of tert-butyl 2-(3-(6-bromoqumazolm-2-ylamino)-5-(l- methyl-lH-pyrazol-4-yl)phenoxy)ethylcarbamate (6 0 g, 11 13 mmol) in 38 ml of DMF was added Pd(dppf)2Cl2(l 09g, 1 36 mmol), CuI (529 mg, 2 78 mmol), ethynyltπmethylsilane (3 3 g , 33 4 mmol) and last add DIPEA (5 81 ml, 33 4 mmol) This reaction mixture was stirred at 95 °C for 1 hour or until done by LCMS The BOC group may come partially off , if so add di-tert-butyl dicarbonate (1 5 g, 6 88 mmol) and stir at room temperature 30 minutes, re-check LCMS, add more if needed Concentrate most of the DMF off, add 750ml of ethyl acetate, 200 ml of saturated sodium bicarbonate and shake The mixture formed an emulsion that was filtered, as necessary The organic layer was extracted and washed with water (2x), saturated NaCl, dπed Na2SC>4, filtered through a 3 5"x 3" silica gel plug, flushed with ethyl acetate and concentrated in vaccuo to give, tert-butyl 2-(3-(l-methyl-lH-pyrazol- 4-yl)-5-(6-((tπmethylsilyl)ethynyl)qumazolin-2-ylamino)phenoxy)ethylcarbamate (5 45 grams) ES/MS m/z 557(MH+) 5
Step 6 N-(3-(2-amιnoethoxy)-5-(l-methyl-lH-pyrazol-4-yl)phenyl)-6- ((tnmethylsιlyl)ethynyl)quιnazolιn-2-amιne
To the reaction mixture of tert-butyl 2-(3-(l -methyl- lH-pyrazol-4-yl)-5-(6- ((tπmethylsilyl)ethynyl)qmnazolm-2-ylamino)phenoxy)ethylcarbamate (1 3 g, 2 3 mmol) 10 add excess 4 M HCl m Dioxane (20 ml, 80 mmol) This reaction mixture was stirred at room temperature for 1 hour or until done by LCMS and concentrated in vaccuo to give crude, N-(3-(2-aminoethoxy)-5-(l-methyl-lH-pyrazol-4-yl)phenyl)-6- ((tnmethylsilyl)ethynyl)qumazolin-2-amine, (1 49 grams) ES/MS m/z 457(MH+)
15 Step 7 N-(3-(2-amιnoethoxy)-5-(l-methyl-lH-pyrazol-4-yl)phenyl)-6-ethynylquιnazohn-2- amine
To the above crude reaction mixture of, N-(3-(2-ammoethoxy)-5-(l-methyl-lH- pyrazol-4-yl)phenyl)-6-((tπmethylsilyl)ethynyl)qmnazolm-2-amine (2 33 mmol) in 20 ml of THF and 12 ml of MeOH add 6M NaOH (1 16 ml, 6 99 mmol) stir at room temperature for
20 15 minutes or until done by LCMS add more 6 M NaOH if necessary The reaction mixture was concentrated in vaccuo until dry to give crude, N-(3-(2-aminoethoxy)-5-(l-methyl-lH- pyrazol-4-yl)phenyl)-6-ethynylquinazolm-2-amine, (1 72 grams) ES/MS m/z 385(MH+)
Step 8 N-(2-(3-(6-ethynylquιnazohn-2-ylamιno)-5-(l-methyl-lH-pyrazol-4-
25 yl)phenoxy)ethyl)-l-methyl-lH-pyrazole-4-carboxamιde
To the reaction mixture of 1 -methyl- lH-pyrazole-4-carboxylic acid (11 mg, 00875 mmol) ni 0 65 ml of NMP add HATU (40 mg, 0 105 mmol), DIPEA (0 031 ml, 0 175 mmol) and stir at room temperature for about 3 minutes To the above reaction mixture add N-(3-(2- ammoethoxy)-5-(l-methyl-lH-pyrazol-4-yl)phenyl)-6-ethynylquinazolm-2-amme (22 4 mg,
30 0 058 mmol) and stir at room temperature for 2 hours or until done by LCMS The crude reaction mixture was filtered, purified on prep HPLC and lyophilized to give N-(2-(3-(6- ethynylqumazolm-2-ylamino)-5-(l-methyl-lH-pyrazol-4-yl)phenoxy)ethyl)-l-methyl-lH- pyrazole-4-carboxamide as TFA salt (2 9 mg) ES/MS m/z 493(MH+) Example 400: N-(2-(3-(6-ethynylquinazolin-2-ylamino)-5-(l-methyl-lH-pyrazol-4- yl)phenoxy)ethyl) acetamide
The subject compound was prepared according to the general Scheme below
Figure imgf000150_0001
To the reaction mixture of N-(3-(2-aminoethoxy)-5-(l-methyl-lH-pyrazol-4- yl)phenyl)-6-ethynylqumazolm-2-amine (21 mg, 0 055 mmol) in 0 65 ml of DMF add DIPEA (0 035 ml, 0 195mmol), and acetic anhydride (11 3 mg , 0 111 mmol) The reaction mixtue was stirred at room temperature for about 90 minutes or until done by LCMS The crude reaction mixture was filtered, purified on prep HPLC and lyophilized to give, N-(2-(3- (6-ethynylqumazolin-2-ylammo)-5-(l-methyl-lH-pyrazol-4-yl)phenoxy)ethyl)acetamide as TFA salt (4 3 mg) ES/MS m/z 427(MH+)
Example 491: (R)-2-amino-N-(2-(3-(6-ethynylquinazolin-2-ylamino)-5-(l-methyl-lH- pyrazol-4-yl)phenoxy)ethyl)propanamide
The subject compound was prepared according to the general Scheme below
Figure imgf000150_0002
Step 1 (R)-tert-butyl l-(2-(3-(l-methyl-lH-pyrazol-4-yl)-5-(6-
((tnmethylsιlyl)ethynyl)qumazolιn-2-ylamιno)phenoxy)ethylamιno)-l-oxopropan-2- ylcarbamate
To the reaction mixture of (R)-2-(tert-butoxycarbonylammo)propanoic acid (25 5 mg, 0 135 mmol) in 0 15 ml of DMF add HATU (55 mg, 0 144 mmol), DIPEA (0 028 ml, 0 16 mmol) and stir at room temperature for about 10 mmutes To the above reaction mixture add a solution of N-(3 -(2-ammoethoxy)-5-( 1 -methyl- 1 H-pyrazol-4-yl)phenyl)-6- ((tπmethylsilyl)ethynyl)quinazolm-2-amme (41 mg, 0 09 mmol) in 0 5 ml DMF with DIPEA (0 028 ml, 0 16 mmol) and stir at room temperature for 18 hours or until done by LCMS The crude reaction solution with the product (R)-tert-butyl l-(2-(3-(l-methyl-lH-pyrazol-4- yl)-5-(6-((tπmethylsilyl)ethynyl)quinazolin-2-ylamino)phenoxy)ethylammo)-l-oxopropan-2- ylcarbamate, was used in the next step without purification ES/MS m/z 628(MH+)
Step 2 (R)-tert-butyl l-(2-(3-(6-ethynylquιnazohn-2-ylamιno)-5-(l-methyl-lH-pyrazol-4- yl)phenoxy)ethylamιno)-l-oxopropan-2-y {carbamate
To the above crude material (R)-tert-butyl l-(2-(3-(l-methyl-lH-pyrazol-4-yl)-5-(6- ((tπmethylsilyl)ethynyl)qumazohn-2-ylamino)phenoxy)ethylamino)-l-oxopropan-2- ylcarbamate (0 09 mmol) add 6 M NaOH (0 120 ml, 0 72 mmol) and stir at room temperature for 10 minutes or until done by LCMS If the reaction is not complete add more 6M NaOH as needed The crude reaction mixture with product, (R)-tert-butyl 1 -(2-(3-(6- ethynylquinazolm-2-ylamino)-5-(l-methyl-lH-pyrazol-4-yl)phenoxy)ethylamino)-l- oxopropan-2-ylcarbamate was use in the next step without purification ES/MS m/z 556(MH+)
Step 3 (R)-2-amιno-N-(2-(3-(6-ethynylqumazolιn-2-ylamιno)-5-(l-methyl-lH-pyrazol-4- yl)phenoxy)ethyl)propanamιde
To the above crude material (R)-tert-butyl l-(2-(3-(6-ethynylqumazolin-2-ylamino)-5- (l-methyl-lH-pyrazol-4-yl)phenoxy)ethylammo)-l-oxopropan-2-ylcarbamate (0 09 mmol) add 4 M HCl in dioxane (3 ml, 12 mmol) and stir at room temperature for 1 hour The reaction mixture was concentrated, 1 ml DMF added, filtered, purified on prep HPLC and lyophilized to give (R)-2-ammo-N-(2-(3-(6-ethynylqumazolm-2-ylamino)-5-(l-methyl-lH- pyrazol-4-yl)phenoxy)ethyl)propanamide, as TFA salt (14 1 mg) ES/MS m/z 456(MH+)
Example 495: (R)-2-(dimethylamino)-N-(2-(3-(6-ethynylquinazolin-2-ylamlno)-5-(l- methyl-lH-pyrazol-4-yl)phenoxy)ethyl)propanamide
The subject compound was prepared according to the general Scheme, below
Figure imgf000152_0001
To the reaction mixture of (R)-2-amino-N-(2-(3-(6-ethynylqumazohn-2-ylamino)-5- (l-methyl-lH-pyrazol-4-yl)phenoxy)ethyl)propanamide (12 mg, 0 026 mmol) m l 2 ml of methanol add acetic acid (0 08 ml , 1 3 mmol) and 37 % formaldehyde solution in water (0 034 ml, 0 39 mmol) The reaction mixture was stirred at room temperature for about 20 minutes To this reaction solution was added sodium triacetoxy borohydπde (44 mg, 0208 mmol) and stirred at room temperature 1-2 hours or until done by LCMS The crude reaction mixture was concentrated, 1 ml of DMF added, filtered, purified on prep HPLC and lyophihzed to give, (R)-2-(dimethylammo)-N-(2-(3-(6-ethynylqmnazolin-2-ylamino)-5-(l- methyl-lH-pyrazol-4-yl)phenoxy)ethyl)propanamide as TFA salt (1 1 mg) ES/MS m/z 484(MH+)
Example 523: N-(2-(3-(6-ethynylquinazolin-2-ylamino)-5-(l-methyl-lH-pyrazol-4- yl)phenoxy)ethyl)-3-fluoropicolinamide
The subject compound was prepared according to the general Scheme below
DIPEA
Figure imgf000152_0003
Figure imgf000152_0002
Step 1 3-fluoro-N-(2-(3-(l-methyl-lH-pyrazol-4-yl)-5-(6-((trιmethylsιlyl)ethynyl)quιnazohn- 2-ylamιno)phenoxy)ethyl)pιcolιnamιde
Analogous to Example 114, stepl but using 3-fluoropicolmic acid as starting mateπal ES/MS m/z 457(MH+)
Step 2 N-(2-(3-(6-ethynylquιnazohn-2-ylamιno)-5-(l-methyl-lH-pyrazol-4- yl)phenoxy)ethyl)-3-fluoropιcolιnamιde To the above crude product from step 1 (O 048 mmol) add 6 M NaOH (O 100 ml, 0 60 mmol) and stir at room temperature for 10 minutes or until done by LCMS If the reaction is not complete add more 6M NaOH as needed The crude reaction mixture was purified by the addition of DMF about 0 7 ml, filtered, purified on prep HPLC and lyophihzed to give, N-(2- (3-(6-ethynylquinazolin-2-ylammo)-5-(l-methyl-lH-pyrazol-4-yl)phenoxy)ethyl)-3- fluoropicolinamide as TFA salt (6 3 mg) ES/MS m/z 508(MH+)
Example 506: N-(2-(3-(6-ethynyIquinazolin-2-yIamino)-5-(l-methyl-lH-pyrazol-4- yl)phenoxy)ethyl)-2-(piperidin-l-yl)acetamide
The subject compound was prepared according to the general Scheme below
Figure imgf000153_0001
Step 1 2-bromo-N-(2-(3-(l-methyl-lH-pyrazol-4-yl)-5-(6-
((trιmethylsιlyl)ethynyl)quιnazolιn-2-ylamιno)phenoxy)ethyl)acetamιde
To the reaction mixture of N-(3-(2-ammoethoxy)-5-(l-methyl-lH-pyrazol-4- yl)ρhenyl)-6-((tπmethylsilyl)ethynyl)qumazolm-2-amine (295 mg, 0 646 mmol) in 9ml of chloroform was added DIPEA (0 394 ml, 2 26 mmol) and cooled to (-5 0C) with stirring To the above reaction mixture at (-5 0C) add dropwise a solution of 2-bromoacetyl chloride (122 5 mg, 0 775 mmol) in 2 ml of chloroform This reaction mixture was stirred at ( -5 0C) for 20 minutes then allowed to warm to room temperature for 70 minutes or until done by LCMS The chloroform was concentrated off, 300 ml of ethyl acetate was added, washed with saturated NaHCθ3, water, bnne, dried with Na2SO4, filtered and concentrated to residue The crude residue was purified by silica gel column chromatography and concentrated in vaccuo to give 2-bromo-N-(2-(3-(l-methyl-lH-pyrazol-4-yl)-5-(6-
((tπmethylsilyl)ethynyl)qumazohn-2-ylammo)phenoxy)ethyl)acetamide, (155 mg) ES/MS m/z 577/579(MH+)
Step 2 N-(2-(3-(l-methyl-lH-pyrazol-4-yl)-5-(6-((tnmethylsιlyl)ethynyl)quιnazohn-2- ylamιno)phenoxy)ethyl)-2-(pιpendιn-l-yl)acetamιde
To the reaction mixture of 2-bromo-N-(2-(3-(l-methyl-lH-pyrazol-4-yl)-5-(6-
((tπmethylsilyl)ethynyl)qumazohn-2-ylammo)phenoxy)ethyl)acetamide (10 3 mg, 0 0178 mmol) in 04ml of DMF was added pipendme (6 mg, 0 0712 mmol) and stirred at room temperature for 4 5 hours or until done by LCMS The crude reaction mixture with product,
N-(2-(3 -( 1 -methyl- 1 H-pyrazol-4-yl)-5-(6-((tπmethylsilyl)ethynyl)qumazolm-2- ylammo)phenoxy)ethyl)-2-(pipendin-l-yl)acetamide was use m the next step without purification ES/MS m/z 582(MH+)
Step 3 N-(2-(3-(6-ethynylquιnazolin-2-ylamιno)-5-(l-methyl-lH-pyrazol-4- yl)phenoxy)ethyl)-2-(pιperιώn-l-yl)acetamιde
To the above crude material, N-(2-(3-(l-methyl-lH-pyrazol-4-yl)-5-(6-
((tnmethylsilyl)ethynyl)quinazolm-2-ylammo)phenoxy)ethyl)-2-(pipeπdm-l-yl)acetamide (0 0178 mmol) add 6 M NaOH (0 03 ml, 0 18 mmol) and stir at room temperature for 10 minutes or until done by LCMS If the reaction is not complete add more 6M NaOH as needed The crude reaction mixture was purified by the addition of 0 5ml of DMF, filtered, purified on prep HPLC and lyophihzed to give, N-(2-(3-(6-ethynylqumazolin-2-ylammo)-5-
(l-methyl-lH-pyrazol-4-yl)phenoxy)ethyl)-2-(pipeπdin-l-yl)acetamide as TFA salt (6 9 mg) ES/MS m/z 510(MH+)
Example 379: tert-butyl 3-(6-bromoquinazolin-2-yIamino)benzylcarbamate
The subject compound was prepared according to the general Scheme below
Figure imgf000155_0001
Step 1 tert-butyl 3-nιtrobenzylcarbamate
To the reaction mixture of (3 -mtrophenyl)methanamine HCl (2 00g, 10 6 mmol) in 15 ml of DCM was added TEA (3 7 ml, 26 5 mmol) and di-tert-butyl dicarbonate (2 78 g, 12 72 mmol) The reaction was stirred at room temperature for 90 minutes or until done by LC Concentrate most of the DCM of add 200 ml ethyl acetate and washed with sat NaHCθ3 (2x), water (2x), bπne, dried withNa2SC>4, filtered and concentrated m vaccuo to give, tert- butyl 3-nitrobenzylcarbamate as crude material used m next step (2 96 grams) ES/MS m/z 253(MH+)
Step 2 tert-butyl 3-amιnobenzylcarbamate
To the starting crude material tert-butyl 3-mtrobenzylcarbamate (2 96 g crude,10 6 mmol) was added 10% Pd on Carbon (444 mg, 15% by wt ) under argon Under argon with a syringe carefully add 19 ml methanol To this reaction mixture was added a hydrogen balloon and was evacuated and refilled 5 times The reaction was stirred at room temperature for 18 hours or until done by LC To the reaction mixture add ethyl acetate and under argon filtered through cehte and washed with a l l solution of ethyl acetate and methanol The filtrate was concentrated to residue To the residue add 150 ml ethyl acetate and wash with sat NaHCO3 (2x), water (2x), bπne, dried with Na2SO4, filtered and concentrated in vaccuo to give, tert-butyl 3-aminobenzylcarbamate as crude matenal used in next step (2 45 grams) ES/MS m/z 223(MH+)
Step 3 tert-butyl 3-(6-bromoquinazohn-2-ylamino)benzylcarbamate
To the reaction mixture of tert-butyl 3 -aminobenzyl carbamate (840 mg, 3 76 mmol) m 6 ml of IPA m a glass bomb was added 6-bromo-2-chloroquinazoline (750 mg, 3 08 mmol) and caped The reaction solution was stirred at 95 0C for 20 hours or until done by LCMS To the crude reaction mixture add 6 ml of IPA, filter solids off and the concentrate the filtrate (product) The crude matenal was purified by silica gel column chromatography and concentrated in vaccuo to give, tert-butyl 3-(6-bromoqumazolm-2-ylamino)benzylcarbamate (860 mg) ES/MS mjz 429/431(MH+) Additional purification can be done by prep HPLC, lyophilized and converted to an TFA ammonium salt
Example 340: 2-(3-(6-ethynylquinazolin-2-ylamino)-5-(l-methyl-lH-pyrazol-4- yl)phenoxy)-N-(l-methyIpiperidin-4-yl)acetamide
The subject compound was prepared according to the general Scheme below
Figure imgf000156_0001
Step 1 methyl 2-(3-(l-methyl-lH pyrazol-4-yl)-5-nιtrophenoxy)acetate To the reaction mixture of methyl 2-(3-bromo-5-mtrophenoxy)acetate (1 65 g, 5 69 mmol) in 35 ml of DME was added Pd(dppf)2Cl2 (465 mg, 0 569 mmol), l-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (24 g, 11 4 mmol) and last add 2M Na2CO3 (11 4 ml, 22 8 mmol) This reaction mixture was stirred at 85°C for 90 minutes or until done by LCMS Concentrate about half of the DME off, add 350ml of ethyl acetate and 50 ml of water The organic layer was extracted and washed with saturated Na2CO3, water (2x), saturated NaCl, dried Na2SO^ filtered and concentrated to residue The crude mateπal was purified by silica gel column chromatography and concentrated in vaccuo to give, methyl 2-(3-(l-methyl-lH-pyrazol-4-yl)-5-mtrophenoxy)acetate, (480 mg) ES/MS m/z 292(MH+)
Step 2 methyl 2-(3-amιno-5-(l-methyl-lH-pyrazol-4-yl)phenoxy)acetate Analogous to Example 459, stepl but using, methyl 2-(3-(l-methyl-lH-pyrazol-4-yl)-
5-mtrophenoxy)acetate as starting matenal ES/MS m/z 262(MH+)
Step 3 methyl 2-(3-(6-bromoquιnazolιn-2-ylamιno)-5-(l-methyl-lH-pyrazol-4- yl)phenoxy)acetate Analogous to Example 112, step 4 but using, methyl 2-(3-amino-5-(l-methyl-lH- pyrazol-4-yl)phenoxy)acetate as starting matenal ES/MS m/z 468/470(MH+)
Step 4 methyl 2-(3-(l-methyl-lH-pyrazol-4-yl)-5-(6-((trimethylsilyl)ethynyl)quinazohn-2- ylamιno)phenoxy)acetate Analogous to Example 459, step 3 but using, methyl 2-(3-(6-bromoquinazolm-2- ylamino)-5-(l-methyl-lH-pyrazol-4-yl)phenoxy)acetate as starting matenal ES/MS m/z 486(MH+)
Step 5 2-(3-(6-ethynylqumazolιn-2-ylammo)-5-(l-methyl-lH-pyrazol-4-yl)phenoxy)acetιc
To the reaction mixture of, methyl 2-(3-(l-methyl-lH-pyrazol-4-yl)-5-(6- ((tnmethylsilyl)ethynyl)qumazolm-2-ylamino)phenoxy)acetate
(740 mg, 1 52 mmol) in 6 ml of THF and 3 ml of MeOH add 6M NaOH (0 75 ml, 4 52 mmol) stir at room temperature for 1 hour or until done by LCMS add more 6 M NaOH if necessary The reaction mixture was concentrated in vaccuo until dry to give crude residue To this residue add 6M HCl aq (0 91 ml, 5 48 mmol) stir bnefly and concentrated in vaccuo until dry to give, 2-(3-(6-ethynylqumazolin-2-ylammo)-5-(l-methyl-lH-pyrazol-4- yl)phenoxy)acetic acid , as crude solid used in next step (840 mg) ES/MS m/z 400(MH+)
Step 6 2-(3-(6-ethynylquιnazolιn-2-ylamιno)-5-(l-methyl-lH-pyrazol-4-yl)phenoxy)-N-(l- methylpιperιdιn-4-yl)acetamιde
To the reaction mixture of, 2-(3-(6-ethynylquinazolm-2-ylamino)-5-(l-methyl-lH- pyrazol-4-yl)phenoxy)acetic acid (24 mg, 0 060 mmol) in 0 5 ml of NMP add HATU (39 mg,
0 102 mmol), DIPEA (0 023 ml, 0 132 mmol) and stir at room temperature for about 3 minutes To the above reaction mixture add l-methylpipeπdin-4-amme (27 mg, 0 24 mmol) and stir at room temperature for 4 hours or until done by LCMS The crude reaction mixture was filtered, purified on prep HPLC and lyophihzed to give, 2-(3-(6-ethynylquinazolin-2- ylamino)-5-(l-methyl-lH-pyrazol-4-yl)ρhenoxy)-N-(l-methylpipeπdin-4-yl)acetamide as TFA salt (7 6 mg) ES/MS m/z 496(MH+)
Example 356: 2-(3-(6-cyanoquinazolin-2-ylamino)-5-(l-methy]-lH-pyrazol-4- yl)phenoxy)-N-methylacetamide
The subject compound was prepared according to the general Scheme below
Figure imgf000158_0001
Pd(dppf)2CI2 DME, 2M Na2CO3
Figure imgf000158_0002
Pd(dppf)2CI2 DIPEA
Step 1 methyl 2-(3-bromo-5-nιtrophenoxy)acetate
To the reaction mixture of 3-bromo-5-mtrophenol (7 O g, 32 1 mmol) in 30 ml of DMF add K2CO3 (9 8 g, 70 6 mmol) and stir for 3-5 minutes To the reaction mixture add methyl 2-bromoacetate (5 4 g, 35 3 mmol) and stir at room temperature 18 hours or until done by LC To the crude reaction add 450 ml of ethyl acetate and wash with saturated Na2CO3, water (3x), saturated NaCl, dπed Na2SC>4, filtered and concentrated in vaccuo to give crude, methyl 2-(3-bromo-5-mtrophenoxy)acetate, (9 O g)
Step 2 2-(3-bromo-5-nιtrophenoxy)-N-methylacetamιde
To the crude product from stepl, methyl 2-(3-bromo-5-rutrophenoxy)acetate (1 75 g, 6 0 mmol) add 2M methylamine in methanol (18 ml, 36 mmol) and stir at room temperature 24 hours or until done by LCMS The crude reaction mixture was concentrated m vaccuo to give crude, 2-(3-bromo-5-mtrophenoxy)-N-methylacetamide, (1 74 g) ES/MS m/z 289/291(MH+)
Step 3 N-methyl-2-β-(l-methyl-lH-pyrazol-4-yl)-5-mtrophenoxy)acetamιde
To the reaction mixture of 2-(3-bromo-5-mtrophenoxy)-N-methylacetamide (800 mg, 2 77 mmol) in 17 ml of DME was added Pd(dppf)2Cl2 (226 mg, 0 277 mmol), l-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (1 04 g, 5 0 mmol) and last add 2M Na2CO3 (5 5 ml, 11 mmol) This reaction mixture was stirred at 85-90°C for 18 hours or until done by LCMS Concentrate most of the DME off, add about 200 ml of ethyl acetate and 50 ml of water and stir The solids (product) were collected by filtration, washed with water (Ix) and dried under vaccum to give crude, N-methyl-2-(3-(l-methyl-lH-pyrazol-4-yl)- 5-mtrophenoxy)acetamide, (660 mg) ES/MS m/z 291(MH+)
Step 4 2-(3-amιno-5-(l-methyl-lH-pyrazol-4-yl)phenoxy)-N-methylacetamιde
To the starting crude mateπal, N-methyl-2-(3-(l-methyl-lH-pyrazol-4-yl)-5- mtrophenoxy)acetamide (660 mg, 2 27 mmol) was added 10% Pd on Carbon (132 mg, 20% by wt ) under argon Under argon with a syringe carefully add 5 ml methanol To this reaction mixture was added a hydrogen balloon and was evacuated and refilled 5 times The reaction was stirred at room temperature for 22 hours or until done by LC To the reaction mixture add ethyl acetate and under argon filtered through celite and washed with a l l solution of ethyl acetate and methanol The filtrate was concentrated in vaccuo to give, 2-(3- amino-5-(l-methyl-lH-pyrazol-4-yl)phenoxy)-N-methylacetamide as crude mateπal used in next step (565mg) ES/MS m/z 261(MH+)
Step5 2-(3-(6-bromoquιnazohn-2-ylamιno)-5-(l-methyl-lH-pyrazol-4-yl)phenoxy)-N- methylacetamide
Analogous to Example 112, step 4 but using, 2-(3-amino-5-(l-methyl-lH-pyrazol-4- yl)phenoxy)-N-methylacetamide as starting material ES/MS m/z 467/469(MH+)
Step 6 2-(3-(6-cyanoquιnazolιn-2-ylamιno)-5-(l-methyl-lH-pyrazol-4-yl)phenoxy)-N- methylacetamide
To the reaction mixture of 2-(3-(6-bromoqumazolin-2-ylammo)-5-(l-methyl-lH- pyrazol-4-yl)phenoxy)-N-methylacetamide (30 mg, 0 064 mmol) in 0 6ml of DMF was added Pd(dppf)2Cl2 (10 5 mg, 0 0128 mmol), Zn(CN)2 (30 mg, O 256mmol) and DIPEA (34 ul, O 192 mmol) This reaction mixture was microwaved at 1700C for 800 seconds then again at 210°C for 800 seconds The crude reaction mixture was filtered, purified on prep HPLC and lyophilized to give, 2-(3-(6-cyanoqmnazolm-2-ylamino)-5-(l-methyl-lH-pyrazol-4- yl)phenoxy)-N-methylacetamide as TFA salt (82 mg) ES/MS m/z 414(MH+)
Example 543: (2S,4S)-methyl 4-(3-(6-ethynylquinazolin-2-ylamino)-5-(l-methyl-lH- pyrazol-4-yl)phenoxy)pyrrolidine-2-carboxylate
The subject compound was prepared according to the general Scheme below
in MeOH
Figure imgf000160_0001
Figure imgf000160_0002
Step 1 (2S14S)-l-tert-butyl 2-methyl 4-(3-(l-methyl-lH-pyrazol-4-yl)-5-(6- ((trιmethylsιlyl)ethynyl)qumazohn-2-ylamιno)phenoxy)pyrrohdιne-l,2-dιcarboxylate Analogous to Example 459, step 4 but using, (2S,4R)-l-tert-butyl 2-methyl 4- hydroxypyrrolidme-l,2-dicarboxylate as the starting matenal (alcohol) ES/MS m/z 641(MH+)
Step 2 (2S,4S)-l-tert-butyl 2-methyl 4-(3-(6-ethynylquιnazohn-2-ylamιno)-5-(l-methyl-lH- pyrazol-4-yl)phenoxy)pyrrohdιne-l,2-dιcarboxylate
To the reaction mixture of (2S,4S)-l-tert-butyl 2-methyl 4-(3-(l-methyl-lH-pyrazol- 4-yl)-5-(6-((tnmethylsilyl)ethynyl)qmnazolm-2-ylamino)phenoxy)pyrrolidme-l,2- dicarboxylate (38 mg, 0 06 mmol) in 0 375 ml of THF was added 2M methylamme in MeOH (2 0 ml, 4 0 mmol) The reaction mixture was stirred at room temperature for 20 hours or until done by LCMS The crude reaction mixture was concentrated m vaccuo until dry, to give a crude product used in next step, (2S,4S)-l-tert-butyl 2-methyl 4-(3-(6- ethynylquinazolin-2-ylamino)-5-(l-methyl-lH-pyrazol-4-yl)phenoxy)pyrrolidme-l,2- dicarboxylate ES/MS m/z 569(MH+) Step 3 (2S,4S)-methyl 4-(3-(6-ethynylquιnazolιn-2-ylamιno)-5-(l-methyl-lH-pymzol-4- yl)phenoxy)pyrrohdιne-2-carboxylate
To the reaction mixture of (2S,4S)-l-tert-butyl 2-methyl 4-(3-(6-ethynylqumazolin-2- ylamino)-5-(l-methyl-lH-pyrazol-4-yl)phenoxy)pyrrolidme-l,2-dicarboxylate (0 06 mrπol) was added 4M HCl in Dioxane (3 5 ml, 14 0 mmol) The reaction mixture was stirred at room temperature for 1 hours or until done by LCMS The crude reaction mixture was concentrate, about 1 ml of DMF was added, filtered, purified on prep HPLC and lyophilized to give, (2S,4S)-methyl 4-(3-(6-ethynylqumazolin-2-ylammo)-5-(l-methyl-lH-pyrazol-4- yl)phenoxy)pyrrohdme-2-carboxylate as TFA salt (3 7 mg) ES/MS m/z 469(MH+)
Example 555: (2S,4S)-4-(3-(6-ethynylquinazolin-2-ylamino)-5-(l-methyl-lH-pyrazol-4- yl)phenoxy)pyrrolidine-2-carboxylic acid
The subject compound was prepared according to the general Scheme below
Figure imgf000161_0001
Step 1 (2S,4S)-l-(tert-butoxycarbonyl)-4-(3-(6-ethynylquιnazohn-2-ylamιno)-5-(l-methyl- lH-pyrazol-4-yl)phenoxy)pyrrolιdιne-2-carboxylιc acιd
To the reaction mixture of (2S,4S)-l-tert-butyl 2-methyl 4-(3-(l-methyl-lH-pyrazol- 4-yl)-5-(6-((tnmethylsilyl)ethynyl)quinazolm-2-ylamino)phenoxy)pyrrolidine- 1 ,2- dicarboxylate (115 mg, 0 lδ mmol) in 0 75 ml of THF was added 6M NaOH (0 9 ml, 5 4 mmol) and 1 ml of methanol The reaction mixture was stirred at room temperature for 1 hour or until done by LCMS The crude reaction mixture was concentrated in vaccuo until solid, 2 ml of DMF was added, filtered, purified on prep HPLC and lyophilized to give (2S,4S)-l-(tert-butoxycarbonyl)-4-(3-(6-ethynylquinazolin-2-ylamino)-5-(l -methyl- IH- pyrazol-4-yl)phenoxy)pyrrohdine-2-carboxylic acid as TFA salt (45 mg) ES/MS m/z 555(MH+) Step 2 (2S,4S)-4-(3-(6-ethynylquιnazohn-2-ylamιno)-5-(l-methyl-lH-pyrazol-4- yl)phenoxy)pyrrohdιne-2-carboxyhc acid
To the reaction mixture of (2S,4S)-l-(tert-butoxycarbonyl)-4-(3-(6-ethynylqumazolin- 2-ylamino)-5-(l-methyl-lH-pyrazol-4-yl)phenoxy)pyrrolidine-2-carboxylic acid (15 mg, 0 027 rπmol) was added 4M HCl in Dioxane (1 5 ml, 6 0 mmol) The reaction mixture was stirred at room temperature for 1 hour or until done by LCMS The crude reaction mixture was concentrate, aboutl ml of DMF was added, filtered, purified on prep HPLC and lyophihzed to give (2S,4S)-4-(3-(6-ethynylquinazolin-2-ylamino)-5-(l-methyl-lH-pyrazol- 4-yl)phenoxy)pyrrolidine-2-carboxylic acid as TFA salt (3 2 mg) ES/MS m/z 455(MH+)
Example 557: (2S,4S)-4-(3-(6-ethynylquinazolin-2-ylamino)-5-(l-methyl-lH-pyrazol-4- yl)phenoxy)-N-methylpyrrolidine-2-carboxamide
The subject compound was prepared according to the general Scheme below
2M Methylamine in THF HATU DMF DIPEA
2 4 M HCI in dioxane
Figure imgf000162_0001
Figure imgf000162_0002
Step 1 (2S,4S)-tert-butyl 4-(3-(6-ethynylquιnazohn-2-ylamιno)-5-(l-methyl-lH-pyrazol-4- yl)phenoxy)-2-(methylcarbamoyl)pyrrohdme-l-carboxylate
To the reaction mixture of (2S,4S)-l-(tert-butoxycarbonyl)-4-(3-(6-ethynylqumazohn- 2-ylamino)-5-(l-methyl-lH-pyrazol-4-yl)phenoxy)pyrrohdine-2-carboxylic acid (15 mg, 0 027 mmol) in 0 5 ml of DMF add HATU (31 mg, 0 081 mmol), DIPEA (0 014 ml, 0 081 mmol) and stir at room temperature for about 3-5 minutes To the above reaction mixture add 2M methylamine in THF (0 081 ml, 0 162 mmol) and was stirred at room temperature for 20 hours or until done by LCMS The crude reaction mixture with product, (2S,4S)-tert-butyl 4-(3-(6-ethynylquinazolin-2-ylammo)-5-(l-methyl-lH-pyrazol-4-yl)phenoxy)-2-
(methylcarbamoyl)pyrrolidine-l-carboxylate was use in the next step without purification ES/MS m/z 568(MH+) Step 2 (2S, 4S)-4-(3-(6-ethynylquιnazohn-2-ylamιno)-5-(l-methyl~lH-pyrazol-4- yl)phenoxy)-N-methylpyrrolιdιne-2-carboxamιde
To the reaction mixture of (2S,4S)-tert-butyl 4-(3-(6-ethynylqmnazolm-2-ylamino)-5- (l-methyl-lH-pyrazol-4-yl)ρhenoxy)-2-(methylcarbamoyl)pyrrolidme-l-carboxylate (0 027 mmol) was added 4M HCl m Dioxane (20 ml, 8 0 mmol) The reaction mixture was stirred at room temperature for 1 hours or until done by LCMS The crude reaction mixture was concentrate, about 1 ml of DMF was added, filtered, purified on prep HPLC and lyophihzed to give (2S,4S)-4-(3-(6-ethynylqumazolin-2-ylamino)-5-(l-methyl-lH-pyrazol-4- yl)phenoxy)-N-methylpyrrolidine-2-carboxamide as TFA salt (5 0 mg) ES/MS m/z
10 468(MH+)
Example 552: 6-ethynyl-N-(3-(l-methyl-lH-pyrazol-4-yl)-5-(2-(tetrahydro-2H-pyran-4- ylaniino)ethoxy)phenyl)quinazolin-2-aniinc
The subject compound was prepared according to the general Scheme below
15
TMOF
Figure imgf000163_0001
Figure imgf000163_0002
Step 1 N-(3-(l-methyl-lH-pyrazol-4-yl)-5-(2-(tetrahydro-2H-pyran 4- ylamιno)ethoxy)phenyl)-6-((trιmethylsιlyl)ethynyl)quιnazohn-2-amιne
20 To the reaction mixture of N-(3-(2-ammoethoxy)-5-(l-methyl-lH-pyrazol-4- yl)phenyl)-6-((tπmethylsilyl)ethynyl)quinazolm-2-amine (41 mg, 0 09 mmol) in 0 75 ml of methanol add acetic acid (0 162 ml, 2 7 mmol), dihydro-2H-pyran-4(3H)-one (90 mg, 0 9 mmol) and tnmethylorthoformate (TMOF) (57 mg, 0 54 mmol) The reaction mixture was stirred at room temperature for about 4 hours To this reaction solution was added sodium
25 tπacetoxy borohydπde (76 mg, 0 36 mmol) and stirred at room temperature 20 hours To the crude reaction mixture was added more sodium tπacetoxy borohydπde (38 mg, 0 18 mmol) and stirred at room temperature for another 26 hours The crude reaction mixture with product, N-(3-(l-methyl-lH-pyrazol-4-yl)-5-(2-(tetrahydro-2H-pyran-4- ylamino)ethoxy)phenyl)-6-((tπmethylsilyl)ethynyl)quinazolm-2-amme was concentrated to solid and used in the next step without purification ES/MS m/z 541 (MH+)
Step 2 6-ethynyl-N-(3-(l-methyl-lH-pyrazol-4-yl)-5-(2-(tetrahydro-2H-pyran-4- ylamιno)ethoxy)phenyl)quιnazolm-2-amιne
To the crude reaction mixture of N-(3-(l-methyl-lH-pyrazol-4-yl)-5-(2-(tetrahydro- 2H-pyran-4-ylamino)ethoxy)phenyl)-6-((tπmethylsilyl)ethynyl)qumazolin-2-amine (0 09 mmol) in 2 ml of methanol was added 6M NaOH (2 0 ml, 12 0 rnmol) and stirred at room temperature for 10 minutes and checked by LCMS If the de-protection is incomplete add more 6 M NaOH and recheck in 10 minutes To the crude reaction add 100 ml of ethyl acetate and wash with water (2x), saturated NaCl, dried Na2SO4, filtered and concentrated to residue To the crude residue add DMF, filter, purified on prep HPLC and lyophihzed to give 6-ethynyl-N-(3 -( 1 -methyl- 1 H-pyrazol-4-yl)-5-(2-(tetrahydro-2H-pyran-4- ylamino)ethoxy)phenyl)quinazolm-2-amine as TFA salt (2 0 mg) ES/MS m/z 469(MH+)
Example 530: 6-(2-(3-(6-ethynylquinazolin-2-ylamino)-5-(l-methyl-lH-pyrazol-4- yl)pheπoxy)ethylamiiio)nicotinoiiitrilc
The subject compound was prepared according to the general Scheme below
Figure imgf000164_0001
Step 1 6-(2-(3-(l-methyl-lH-pyrazol-4-yl)-5-(6-((trιmethylsιlyl)ethynyl)qumazohn-2- ylamιno)phenoxy)ethylamιno)nιcotιnonιtrύe
To the reaction mixture of N-(3-(2-ammoethoxy)-5-(l-methyl-lH-pyrazol-4- yl)phenyl)-6-((tπmethylsilyl)ethynyl)quinazolm-2-amine (26 7 mg, 0 0479 mmol) in DMF add 6-chloromcotmonitπle (13 2 mg, 0 096) and DIPEA (0025 ml, 0 144 mmol) This reaction mixture was stirred at 1050C for 20 hours The crude reaction mixture with product, 6-(2-(3-(l-methyl-lH-pyrazol-4-yl)-5-(6-((tπmethylsilyl)ethynyl)qmnazolin-2- ylammo)phenoxy)ethylammo)nicotinomtπle was used in the next step without purification ES/MS m/z 559(MH+) Step 2 6-(2-(3-(6-etkynylquιnazohn-2-ylamιno)-5-(l-methyl-lH-pyrazol-4- yl)phenoxy)ethylamιno)nicotιnonitrιle
To the crude reaction mixture of, 6-(2-(3-(l-methyl-lH-pyrazol-4-yl)-5-(6- ((tπmethylsilyl)ethynyl)qumazolm-2-ylammo)phenoxy)ethylammo)nicotmonitπle (0 0479 mmol) was added 6M NaOH (0 08 ml, 048 mmol) and stirred at room temperature for 10 minutes and checked by LCMS If the de-protection is incomplete add more 6 M NaOH and recheck in 10 minutes To the crude reaction mixture add DMF, filter, purified on prep HPLC and lyophihzed to give, 6-(2-(3-(6-ethynylquinazolm-2-ylamino)-5-(l-methyl-lH- pyrazol-4-yl)phenoxy)ethylammo)nicotmonitnle as TFA salt (1 7 mg) ES/MS m/z 487(MH+)
Example 606: (R)-2-(dimethyIamino)-N-(l-(3-(6-ethynylquinazolin-2-ylamino)-5-(l- methyl-lH-pyrazoI-4-yl)phenoxy)propan-2-yl)acetamide 3-(l-methyl-lH-pyrazol-4-yl)-5-nιtrophenol
The subject compound was prepared according to the general Scheme below
Figure imgf000165_0001
Step! Preparation of 3-bromo-5-nιtrophenol
To the solution of l-bromo-3-methoxy-5-mtrobenzene (13 5 g, 58 2 mmole) in 50 ml of dichloromethane was added the solution of 1 M of boron tπbromide (163 ml, 163 mmole) in dichloromethane slowly over 10 minutes at 0cc The reaction mixture was stirred at O0C for 20 minutes and then at room temperature for 48 hour The deprotection of the methyl ether went to completion and was monitored by LC/MS Removal of all solvent in vaccuo, followed by quenching with water and diluted NaHCθ3 solution at O0C, and extraction of aqueous phase with ethyl acetate and drying of combined organic extracts over Na2SO4 and subsequent removal of ethyl acetate in vaccuo yielded the desired product that was dried under vacuum to give 12 3 g of 3-bromo-5-mtrophenol as purple solid
Step 2 Preparation of3-(l-methyl-lH-pyrazol-4-yl)-5-nιtrophenol
To the reaction mixture of 3-bromo-5-nitrophenol (2 2 g, 10 mmole) and l-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (2 7 g, 13 mmole) in 37 5 ml of 1,2-dimethoxyethane, Pd(dppf)Cl2 (660 mg, 0 8 mmole) and aq 2M Na2CO3 (12 5 ml, 25 mmole) were added The reaction mixture was stirred at 85°c for 24 hours or until done by LC The reaction mixture was diluted with 250 ml of acetone and filtered through celite and washed with a l l solution of ethyl acetate and methanol The combined organic filtrate was evaporated in vaccuo to give a brown solid (4g) that was purified by silica gel column plug eluting with ethyl acetate to give 3-(l-methyl-lH-pyrazol-4-yl)-5-mtrophenol as yellow brown powder (1 87 g) ES/MS m/z 220 0(MH+)
(S)-tert-butyl l-(3-amino-5-(l-methyl-lH-pyrazol-4-yl)phenoxy)propan-2- ylcarbamate
The subject compound was prepared according to the general Scheme below
Figure imgf000166_0001
Step 1 Preparation of (S)-tert-butyl l-(3-(l-methyl-lH-pyrazol-4-yl)-5- nιtrophenoxy)propan-2-ylcarbamate
To the reaction solution of 3-(l-methyl-lH-pyrazol-4-yl)-5-mtrophenol (700 mg, 3 2 mmole) and tπphenyl phosphine (1 26 g, 4 84 mmole) in 26 ml of tetrahydrofuran, (S)-tert- butyl l-hydroxypropan-2-ylcarbamate (848 mg, 4 84 mmole) and diethyl azodicarboxylate (860 ul, 5 46 mmole) were added The resulting solution was stirred at 65°c for 20 hours or until done by LCMS The reaction solution was concentrated under reduced pressure to give dark brown glue (4 g) as a crude product that was purified by column chromatography over silica gel with ethyl acetate hexane (60 40) to give 1 08 g of (S)-tert-butyl l-(3-(l-methyl- lH-pyrazol-4-yl)-5-mtrophenoxy)propan-2-ylcarbamate as yellow solid ES/MS m/z 377 2 (MH+)
Step 2 Preparation of (S)-tert-butyl l-(3-amιno-5-(l-methyl-lH-pyrazol-4-yl)phenoxy) propan-2-ylcarbamate
To the starting crude mateπal (S)-tert-butyl l-(3-(l-methyl-lH-pyrazol-4-yl)-5- nitrophenoxy)propan-2-ylcarbamate (1 09 g, 2 89 mmole) was added 10% Pd on Carbon (1 02 g, 0 96 mmole, 30% by wt ) under argon Under argon add 11 ml of methanol with a syringe carefully To this reaction mixture was added a balloon of hydrogen and was evacuated and refilled 6 times The reaction mixture was stirred at room temperature for 22 hours or until done by LC To the reaction mixture add ethyl acetate and under argon filtered through celite and washed with a l l solution of ethyl acetate and methanol The filtrate was concentrated under reduced pressure to give (S)-tert-butyl l-(3-ammo-5-(l-methyl-lH- pyrazol-4-yl)phenoxy)propan-2-ylcarbamate as powder (945 mg) ES/MS m/z 347 1 (MH+)
(S)-N-(3-(2-aminopropoxy)-5-(l-methyl-lH-pyrazol-4-yl)phenyl)-6- ((trimethylsilyl)ethynyl)quinazolin-2-amine
The subject compound was prepared according to the general Scheme below
Figure imgf000168_0001
Figure imgf000168_0003
Figure imgf000168_0002
Figure imgf000168_0004
Step 1 Preparation of (S)-tert-butyl l-(3-(6-bromoquιnazohn-2-ylamιno)-5 (1-methyl-lH- pyrazol-4-yl)phenoxy)propan-2-ylcarhamate
To the reaction mixture give (S)-tert-butyl l-(3-amino-5-(l-methyl-lH-pyrazol-4- yl)phenoxy)propan-2-ylcarbamate (945 mg, 2 73 mmole) in 25 ml of isopropyl alcohol m a glass bomb was added 6-bromo-2-chloroquinazoline (665 mg, 2 73 mmole) and sealed The reaction solution was stirred at 95°c for 22 hours or until done by LCMS The reaction solution was concentrated under reduced pressure to give a reddish brown oil that was then diluted with 160 ml of ethyl acetate The organic phase was washed with saturated NaHCθ3 solution (2x60 ml), water (30 ml) and bπne (50 ml), then dried over MgSθ4 and evaporated in vacuo to give a reddish brown solid The crude solid was purified by column chromatography over silica gel with ethyl acetate hexane (70 30) to give (S)-tert-butyl l-(3- (6-bromoquinazolin-2-ylarmno)-5-(l-methyl-lH-pyrazol-4-yl)phenoxy)propan-2- ylcarbamate (131 mg) as yellow solid ES/MS m/z 553 1/555 1 (MH+)
Step 2 Preparation of (S)-tert-butyl l-(3-(l-methyl-lH-pyrazol-4-yl)-5-(6- ((tnmethylsιlyl)ethynyl)quιnazolιn-2-ylamιno)phenoxy)propan-2-ylcarbamate To the reaction mixture of (S)-tert-butyl l-(3-(6-bromoquinazolin-2-ylammo)-5-(l- methyl-lH-pyrazol-4-yl)phenoxy)propan-2-ylcarbamate (131 mg, 237 umole), Pd(dppf)Cl2 (20 mg, 24 umole), CuI (lOmg, 47 4 umole) and DIPEA (200 ul, 1 15 mmole) in 2 ml of N,N-dimethylformamide, tnmethylsilylacetylene (99 ul, 710 umole) was added The reaction mixture was stirred at 60°c for 2 hour The crude reaction mixture was partitioned between 80 ml of ethyl acetate and 20 ml of saturated NaHCθ3 solution The organic layer was washed with water (30 ml) and bπne (50 ml), then dried over Na∑SCU and evaporated m vacuo to give a brown solid that was purified by column chromatography over silica gel with ethyl acetate hexane (50 50) to give (S)-tert-butyl l-(3-(l-methyl-lH-pyrazol-4-yl)-5-(6- ((tnmethylsilyl)ethynyl)qumazolm-2-ylamino)phenoxy)propan-2-ylcarbamate (73 mg) as yellow solid ES/MS m/z 571 3 (MH+)
Step 3 Preparation of(S)-N-(3-(2-amιnopropoxy)-5-(l-methyl-lH-pyrazol-4-yl)phenyl)-6- ((trιmethylsιlyl)ethynyl)quιnazohn-2-amιne To the reaction mixture (S)-tert-butyl l-(3-(l-methyl-lH-pyrazol-4-yl)-5-(6-
((tπmethylsilyl)ethynyl)quinazolm-2-ylamino)phenoxy)propan-2-ylcarbamate (73 mg, 0 13 mmole) add excess 4 M HCl in dioxane (4 ml, 16 mmole) This reaction mixture was stirred at room temperature for 1 hour or until done by LCMS and concentrated in vaccuo to give a yellow solid that was dissolved with 60 ml of ethyl acetate The organic phase was washed with IN NaOH solution (10 ml), water (10 ml) and bnne solution (20 ml), then dried over Na2SO4 and evaporated in vacuo to give (S)-N-(3-(2-ammopropoxy)-5-(l-methyl-lH- pyrazol-4-yl)phenyl)-6-((tπmethylsilyl)ethynyl)quinazolm-2-amine as a yellow brown powder (60 mg) ES/MS m/z All 2 (MH+)
(R)-tert-butyl l-(3-amino-5-(l-methyl-lH-pyrazol-4-yl)phenoxy>) propan-2- ylcarbamate
The subject compound was prepared according to the general Scheme below
Figure imgf000170_0001
Step 1 Preparation of (R)-tert-butyl l-(3-(l-methyl-lH-pyrazol-4-yl)-5- nιtrophenoxy)propan-2-ylcarbamate
To the reaction solution of 3-(l-methyl-lH-pyrazol-4-yl)-5-mtrophenol (700 mg, 3 2 mmole) and tnphenyl phosphme (1 26 g, 4 84 mmole) in 26 ml of tetrahydrofuran, (R)-tert- butyl l-hydroxyproρan-2-ylcarbamate (848 mg, 4 84 mmole) and diethyl azodicarboxylate (790 ul, 5 mmole) were added The resulting solution was stirred at 65°c for 20 hours or until done by LCMS The reaction solution was concentrated under reduced pressure to give brown glue (4 g) as a crude product that was purified by column chromatography over silica gel with ethyl acetate hexane (60 40) to give 1 03 g of (R)-tert-butyl l-(3-(l-methyl-lH- pyrazol-4-yl)-5-mtrophenoxy)propan-2-ylcarbamate as yellow glue ES/MS m/z 377 1 (MH+)
Step 2 Preparation of (R)-tert-butyl l-(3-amιno-5-(l-methyl-lH-pyrazol-4- yl)phenoxy)propan-2-ylcarbamate
To the starting crude matenal (R)-tert-butyl l-(3-(l-methyl-lH-pyrazol-4-yl)-5- nitrophenoxy)propan-2-ylcarbamate (1 03 g, 2 73 mmole) was added 10% Pd on Carbon (968 mg, 0 91 mmole, 30% by wt ) under argon Under argon add 11 ml of methanol with a syringe carefully To this reaction mixture was added a balloon of hydrogen and was evacuated and refilled 6 times The reaction mixture was stirred at room temperature for 22 hours or until done by LC To the reaction mixture add ethyl acetate and under argon filtered through cehte and washed with a l l solution of ethyl acetate and methanol The filtrate was concentrated under reduced pressure to give (R)-tert-butyl l-(3-ammo-5-(l-methyl-lH- pyrazol-4-yl)phenoxy)propan-2-ylcarbamate as powder (905 mg) ES/MS m/z 3472 (MH+) (R)-N-(3-(2-aminopropoxy)-5-(l-methyl-lH-pyvazol-4-yl)phenyl)-6- ((trimethylsilyl)ethynyl)quinazolin-2-amine
The subject compound was prepared according to the general Scheme below
Figure imgf000171_0001
Figure imgf000171_0003
Figure imgf000171_0002
Figure imgf000171_0004
Step 1 Preparation of (R)-tert-butyl l-(3-(6-bromoquιnazohn-2-ylamιno)-5-(l-methyl-lH- pyrazol-4-yl)phenoxy)propan-2-ylcarbamate
To the reaction mixture of (R)-tert-butyl l-(3-amino-5-(l-methyl-lH-pyrazol-4- yl)phenoxy)propan-2-ylcarbamate (905 mg, 2 35 mmole) and 6-bromo-2-chloroquinazolme (572 mg, 2 35 mmole) in 11 ml of dioxane in a glass bomb, acetic acid (350 ul) was added and then sealed The reaction solution was stirred at 92°c for 22 hours or until done by LCMS The reaction solution was concentrated under reduced pressure to give a brown solid that was then diluted with 180 ml of ethyl acetate The organic phase was washed with saturated NaHCCb solution (2x60 ml), water (30 ml) and bnne (50 ml), then dπed over Na2SO4 and evaporated in vacuo to give a brown solid The crude solid was purified by column chromatography over silica gel with ethyl acetate hexane (70 30) to give (R)-tert- butyl l-(3-(6-bromoquinazohn-2-ylamino)-5-(l-methyl-lH-pyrazol-4-yl)phenoxy)propan-2- ylcarbamate (405 mg) as yellow solid ES/MS m/z 553 1/555 1 (MH+)
Step 2 Preparation of (R)-tert-butyl l-(3-(l-methyl-lH-pyrazol-4-yl)-5-(6- ((tnmethylsilyl)ethynyl)qumazolin-2-ylamino)phenoxy)propan-2-ylcarbamate
To the reaction mixture of (R)-tert-butyl l-(3-(6-bromoquinazolm-2-ylamino)-5-(l- methyl-lH-ρyrazol-4-yl)ρhenoxy)propan-2-ylcarbamate (408 mg, 737 umole), Pd(dppf)Cl2 (90 mg, 111 umole), CuI (43 mg, 222 umole) and DIPEA (500 ul, 2 87 mmole) in 5 ml of N,N-dimethylformamide, tnmethylsilylacetylene (307 ul, 2 21 mmole) was added The reaction mixture was stirred at 80°c for 1 5 hour The crude reaction mixture was partitioned between 100 ml of ethyl acetate and 40 ml of saturated NaHCCh solution The organic layer was washed with water (30 ml) and bnne (50 ml), then dried over Na2SO4 and evaporated in vacuo to give a brown solid that was purified by column chromatography over silica gel with ethyl acetate hexane (60 40) to give (R)-tert-butyl l-(3-(l-methyl-lH-pyrazol-4-yl)-5-(6- ((tπmethylsilyl)ethvnyl)qumazolin-2-ylammo) phenoxy)propan-2-yl carbamate (370 mg) as yellow solid ES/MS m/z 571 3 (MH+)
Step 3 Preparation of(R)-N-(3-(2-amιnopropoxy)-5-(l-methyl-lH-pyrazol-4-yl)phenyl)-6- ((tnmethylsύyl)ethynyl)quιnazolιn-2-amιne To the reaction mixture (R)-tert-butyl l-(3-(l-methyl-lH-pyrazol-4-yl)-5-(6-
((tπmethylsilyl)ethynyl)quinazolin-2-ylammo)phenoxy)propan-2-ylcarbamate (370 mg, 0 65 mmole) add excess 4 M HCl in dioxane (16 ml, 64 mmole) This reaction mixture was stirred at room temperature for 1 hour or until done by LCMS and concentrated in vaccuo to give a yellow solid that was dissolved with 100 ml of ethyl acetate The organic phase was washed with IN NaOH solution (20 ml), water (30 ml) and bnne solution (40 ml), then dπed over Na∑SCM and evaporated in vacuo to give (R)-N-(3-(2-ammopropoxy)-5-(l-methyl-lH- pyrazol-4-yl)phenyl)-6-((tπmethylsilyl)ethynyl) quinazolm-2-amine as a yellow brown powder (304 mg) ES/MS m/z 471 2 (MH+)
(R)-2-(dimethylamino)-N-(l-(3-(6-ethynylquinazolin-2-ylamino)-5-(l-methyl-lH- pyrazol-4-yl)phenoxy)propan-2-yl)acetamide
The subject compound was prepared according to the general Scheme below
Figure imgf000173_0001
Step 1 Preparation of(R)-2-(dιmethylamιno)-N-(l-(3-(6 ethynylqumazohn-2-ylamιno)-5-(l- methyl-lH-pyrazol-4-yl)phenoxy)propan-2-yl)acetamιde
To the reaction mixture of 2-(dimethylammo)acetic acid (11 mg, 100 umole) in 0 7 ml of N,N-dimethylformamide add HATU (38 mg, 100 umole), DIPEA (45 ul, 250 umole) and stir at room temperature for about 3 minutes To the above reaction mixture add (R)-N- (3-(2-ammopropoxy)-5-(l-methyl-lH-pyrazol-4-yl)phenyl)-6-((tπmethylsilyl)ethynyl) qumazolin-2-amme (19 mg, 32 umole) and stir at room temperature for 1 hours or until done by LCMS The crude product was deprotected with 60 ul of 6N NaOH solution for 5 minutes and then neutralized with 60 ul of acetic acid The crude reaction mixture was filtered, purified on prep HPLC and lyophilized to give (R)-2-(dimethylammo)-N-(l-(3-(6- ethynylqumazolin-2-ylamino)-5-( 1 -methyl- 1 H-pyrazol-4-yl)phenoxy)propan-2-yl)acetamide as TFA salt (10 3 mg) ES/MS m/z 483 2(MH+)
Example 607: (R)-N-(3-(2-(dimethylamino)propoxy)-5-(l-methyl-lH-pyrazol-4- yl)phenyl)-6-ethynylquinazolin-2-amine
The subject compound was prepared according to the general Scheme below
Figure imgf000173_0002
Step 1 Preparation of(R)-N-(3-(2-(dιmethylamιno)propoxy)-5-(l-methyl-lH-pyrazol-4- yl)phenyl)-6-ethynylquιnazohn-2-amιne
To the reaction mixture of (R)-N-(3-(2-aminopropoxy)-5-(l-methyl-lH-pyrazol-4- yl)ρhenyl)-6-((tπmethylsilyl)ethynyl)qmnazolin-2-amine (18 5 mg, 32 umole) in 0 6 ml of methanol, add acetic acid (36 ul, 600 umole) and 37 % formaldehyde solution in water (26 ul, 300 umole) The reaction mixture was stirred at room temperature for about 30 minutes To this reaction solution was added sodium tπacetoxy borohydπde (51 mg, 240 umole) and stirred at room temperature 1 -2 hours or until done by LCMS The crude product was deprotected with 60 ul of 6N NaOH solution for 5 minutes and then neutralized with 60 ul of acetic acid The crude reaction mixture was concentrated, 1 ml of DMF added, filtered, purified on prep HPLC and lyophilized to give (R)-N-(3-(2-(dimethylamino)propoxy)-5-(l- methyl-lH-pyrazol-4-yl)phenyl)-6-ethynylquinazolin-2-amine as TFA salt (8 mg) ES/MS m/z 426 2(MH+)
Example 618: (R)-N-(l-(3-(6-ethynylquinazolin-2-y]amino)-5-(l-methyl-lH-pyrazol-4- yl)phenoxy)propan-2-yl)acetamide
The subject compound was prepared according to the general Scheme below
Figure imgf000174_0001
Step 1 Preparation of(R)-N-(l-(3-(6-ethynylquιnazohn-2-ylamιno)-5-(l-methyl-lH-pyrazol- 4-yl)phenoxy)propan-2-yl)acetamιde
To the reaction mixture of (R)-N-(3-(2-ammopropoxy)-5-(l-methyl-lH-pyrazol-4- yl)phenyl)-6-((tπmethylsilyl)ethynyl)qumazolin-2-amine (15 mg, 30 umole) in 0 5 ml of N,N-dimethylformamide, acetic anhydride (9 ul , 90 umole) and DIPEA (17 ul, 100 umole) were added The reaction solution was stirred at room temperature for about 90 minutes or until done by LCMS The crude product was deprotected with 60 ul of 6N NaOH solution for 5 minutes and then neutralized with 60 ul of acetic acid The crude reaction mixture was filtered, purified on prep HPLC and lyophilized to give (R)-N-(l-(3-(6-ethynylquinazolm-2- ylamino)-5-(l-methyl-lH-ρyrazol-4-yl)phenoxy)ρroρan-2-yl)acetamide as TFA salt (4 2 mg) ES/MS m/z 441 2(MH+) Example 619: (R)-N-(l-(3-(6-ethynylquinazolin-2-ylamino)-S-(l-methyl-lH-pyrazol-4- yl)phenoxy)propan-2-yl)cyclopropanesulfonamide
The subject compound was prepared according to the general Scheme below
Figure imgf000175_0001
Step 1 Preparation of(R)-N-(l-β-(6-ethynylquιnazolιn-2-ylamιno)-5-(l-methyl-lH-pyrazol- 4-yl)phenoxy)propan-2-yl)cyclopropanesulfonamιde
To the reaction mixture of (R)-N-(3-(2-armnopropoxy)-5-(l-methyl-lH-pyrazol-4- yl)phenyl)-6-((tπmethylsilyl)ethynyl)qmnazolm-2-amine (15 mg, 30 umole) in 0 5 ml of N,N-dimethylformamide, cyclopropanesulfonyl chloride (10 ul , 98 umole) and DIPEA (35 ul, 200 umole) were added The reaction solution was stirred at room temperature for 16 hours minutes or until done by LCMS The crude product was deprotected with 60 ul of 6N NaOH solution for 5 minutes and then neutralized with 60 ul of acetic acid The crude reaction mixture was filtered, purified on prep HPLC and lyophihzed to give (R)-N-(I -(3 -(6- ethynylquinazolm-2-ylammo)-5-(l-methyl-lH-pyrazol-4-yl)phenoxy)propan-2- yl)cyclopropanesulfonamideas TFA salt (4 3 mg) ES/MS m/z 503 2(MH+)
Example 593: 4-(6-bromo-8-isopropoxyquinazolin-2-ylammo)benzenesulfonamide and 4-(6-ethynyl-8-isopropoxyquinazolin-2-ylamino) benzenesulfonamide
The subject compound was prepared according to the general Scheme below
Figure imgf000176_0001
■Step 1 Preparation of6-bromo-2-chloro-8-ιsopropoxyquιnazohne
To the reaction solution of tnphenyl phosphine (1 91 g, 7 3 mmole), isopropyl alcohol (782 ul, 1022 mmole) and diethyl azodicarboxylate (1 15 ml, 7 3 mmole) m 18 ml of tetrahydrofuran, 6-bromo-2-chloroquinazohn-8-ol (928 mg, 3 64 mmole) m 20 ml of tetrahydrofuran was added The resulting solution was stirred at 65°c for 24 hours or until done by LCMS The reaction solution was concentrated under reduced pressure to give brown glue as a crude product that was purified by column chromatography over silica gel with ethyl acetate hexane (15 85) to give 587 mg of 6-bromo-2-chloro-8- lsopropoxyquinazolme as yellow solid ES/MS m/z 300 9/302 9 (MH+)
Step2 Preparation of4-(6-bromo-8-ιsopropoxyquιnazolιn-2-ylamιno) benzenesulfonamide To the reaction mixture of 6-bromo-2-chloro-8-isopropoxyqumazolme (45 mg, 150 umole) in 0 8 ml of isopropyl alcohol, 4-aminobenzenesulfonamide (51 mg, 300 umole) was added and stirred at 82°c for 20 hours or until done by LCMS The crude reaction mixture was filtered, purified on prep HPLC and lyopmlized to give 4-(6-bromo-8- isopropoxyqumazolm-2-ylamino)benzenesulfonamide as TFA salt (57 mg) ES/MS m/z 437 0/439 0(MH+)
The ethynyl compound was prepared accordmg to the general Scheme below
Figure imgf000177_0001
Step 1 Preparation of4-(6-ethynyl-8-ιsopropoxyquιnazohn-2-ylamιno) benzenesulfonamide
To the reaction mixture of4-(6~bromo-8-ιsopropoxyquιnazolιn-2-ylamιno) benzenesulfonamide (57 mg, 130 umole), Pd(dppf)Cl2 (11 mg, 13 umole), CuI (5 mg, 26 umole) and DIPEA (80 ul, 460 umole) in 0 8 ml of N,N-dimethylformamide, tπmethylsilylacetylene (55 ul, 390 umole) was added The reaction mixture was stirred at 55°c for 2 hour or until done by LCMS The crude product was deprotected with 50 ul of 6N NaOH solution for 5 minutes and then neutralized with 60 ul of acetic acid The crude reaction mixture was filtered, purified on prep HPLC and lyophihzed to give 4-(6-ethynyl-8- isopropoxyquinazohn-2-ylamino)benzenesulfonamide as TFA salt (22 mg) ES/MS m/z 383 1(MH+)
INTERMEDIATE for 5-Chloro Compounds: 5-chloro-2-(methylsulfonyl)-6- ((trimethylsilyl)ethynyl)quinazoline
The subject compound was prepared according to the general Scheme below in dichloromethaπe
Figure imgf000177_0002
Λ 1
N-chlorosuccιπιmιde
Figure imgf000177_0004
acetonitπle
Figure imgf000177_0005
Figure imgf000177_0003
N phenyl bιs(trιfluoromethanesulfonιmιde) DIEA VC
>Λ I "
N N dimethylformamide
Figure imgf000178_0001
3 chloroperbenozic acid
Figure imgf000178_0002
dichloromethane
Figure imgf000178_0003
Step 1 Preparation of 2-chloroquιnazohn-6-ol
To the solution of 2-chloro-6-methoxy quinazohne (leq) in dichloromethane was added the solution of 1 M of boron tnbromide (2eq) in dichloromethane slowly over 3 minutes at 0°c The reaction mixture was stirred at 0°c for 20 minutes and heated at 40°c for 16 hours The deprotection of the methyl ether went to completion and was monitored by LC/MS Removal of all solvent in vaccuo, followed by quenching with water and diluted NaHCCh solution at 0°c, and extraction of aqueous phase with ethyl acetate and drying of combined organic extracts over Na2SC>4 and subsequent removal of ethyl acetate in vaccuo yielded the desired product that was dπed under vacuum to give 2-chloroqumazolin- 6-ol as brown solid ES/MS m/z 181 0(MH+)
Step 2 Preparation of 2 5-dιchloroquιnazolιn-ό-ol To the solution of 2-chloroquinazolin - 6-ol (3 61 g, 20 mmole) in acetomtπle was added N-chlorosuccmimide (2 67g, 20 mmole) and the mixture was stirred at room temperature and became a deep brown reaction solution The reaction went to completion in 30 minutes to give 2,5-dichloroqumazolm-6-ol (85% of the desired isomer) that was observed by LC/MS and the structure was confirmed by 1HNMR The reaction solution was concentrated and then dissolved into 300 ml of ethyl acetate The organic phase was washed with diluted hydrochloric acid (2x70 ml), water (2x50 ml) and brine (50 ml), then dπed over Na2SO4 and evaporated in vacuo to give a brown solid (3 1 g) that was purified by column chromatography over silica gel with ethyl acetate hexane (30 70) to give yellow powder as 2,5-dichloroquinazolrn-6-ol (1 92 g) ES/MS m/z 215 0(MH+)
Step 3 Preparation of 5-chloro-2- (methylthio) quιnazolm-6-ol To the solution of 2,5-dichloroquinazolm-6-ol (1 75 g, 7 41 mmole) in 23 ml of N- methyl-2-pyrrolidone, sodium thiomethoxide (1 5 g, 2223 mmole) was added The reaction mixture was stirred at 60°c for overnight The reaction mixture was poured into 100 ml of saturated NaHCC>3 solution and extracted with ethyl acetate (2x150 ml) The combined organic layers were washed with diluted NaHCC>3 solution (80 ml), water (2x30 ml) and bπne (40 ml), then dπed over Na2SO4 and evaporated in vacuo to give a brown glue that was recrystallized in hexane/dichloromethane to give 5-chloro-2- (methylthio) quinazolm-6-ol as brown solid ES/MS m/z 227 0(MH+)
Step 4 Preparation of S-chloro-2- (methylthio) quιnazolιn-6-yl trifluoromethanesulfonate To the solution of 5-chloro-2- (methylthio) qumazolm-6-ol (1 98 g, 7 93 mmole) in 30 ml of N, N-dimethylformamide at 0°c was added N-phenyl-bis (tπfluoromethanesulfonimide) (2 55g, 7 13 mmole) and DIPEA (2 76 ml, 15 86 mmole) The resulting solution was stirred at room temperature for 2 5 hour and became a deep brown reaction solution The reaction solution was partitioned between 250 ml of ethyl acetate and 80 ml of diluted hydrochloπc acid The organic layer was washed with diluted hydrochloπc acid (60 ml), water (50 ml) and bπne (50 ml), then dπed over Na2SC>4 and evaporated m vacuo to give a brown solid (472 g) that was punfied by column chromatography over silica gel with ethyl acetate hexane (10 90) to give beige color solid as 5-chloro-2- (methylthio) quinazolm-6-yl tπfluoromethanesulfonate (2 8 g) ES/MS m/z 358 8(MH+)
Step 5 Preparation of 5-chloro-2- (methylthιo)-6-((trιmethylsιlyl) ethynyl) quinazohne
To the reaction mixture of 5-chloro-2- (methylthio) quinazolin-6-yl tπfluoromethanesulfonate (2 05 g, 5 39 mmole), Pd(dppf)Cl2 (440 mg, 0 539 mmole), CuI (220 mg, 1 15 mmole) and DIPEA (3 6 ml, 207 mmole) m 36 ml of N,N-dimethylformarmde was added tπmethylsilylacetylene (2 2 ml, 16 2 mmole) The reaction mixture was stirred at 100°c for l 5 hour The crude reaction mixture was partitioned between 300 ml of ethyl acetate and 80 ml of diluted hydrochlonc acid The organic layer was washed with diluted hydrochloπc acid (60 ml), water (50 ml) and bnne (50 ml), then dned over Na2SO4 and evaporated in vacuo to give a brown glue (~2.5 g) that was purified by column chromatography over silica gel with ethyl acetate : hexane (10 : 90) to give 5-chloro-2- (methylthio)-6-((trimethylsilyl)ethynyl)quinazolme (723mg) as yellow solid . ES/MS m/z 351.0 (MH+).
Step 6: Preparation of5-chloro-2-(methykulfonyl)-6-((trimethylsilyl)ethynyl)quinazoline To the solution of 5-chloro-2-(methylthio)-6-((trimethylsilyl)ethynyl)quinazoline (723 mg, 2.2 mmole) m 20 ml of dichloromethane at 0cc was added the solution of 3- chloroperbenozic acid (-77% pure, 926 mg, 4.13 mmole) in 10 ml of dichloromethane. The reaction solution was stirred at room temperature for overnight and was monitored by
LC/MS. After completion, the reaction solution was diluted with 200 ml of dichloromethane. The organic phase was washed with saturated NaHCCh solution (2x60 ml), water (30 ml) and brine (50 ml), then dried over Na2SO4 and evaporated in vacuo to give 5-chloro-2- (methylsulfonyl)-6-((trimethylsilyl)ethynyl)quinazoline as yellowish brown powder (732 mg) that was used in next step without further purification. ES/MS m/z 339.0(MH+).
Example 1020: N- (3-methoxyphenyl)-7-(l-methylpiperidin-4-yIoxy)-6-(thiazol-2-yl) quinazolin-2-amine
2 fert-butyl 4-hydroxy
Br pιperιdιne-1-carboxylate
1 NaoMe DIAD, Ph3P, THF
OMe NMp
Figure imgf000180_0001
3 Oxone /THF / Water
bromide
Figure imgf000180_0002
Figure imgf000180_0003
Step 1 Preparation of 6-Bromo-2- (methylthio) qumazolιn-7-ol
To a solution of 6-bromo-2-chloro-7-methoxyqumazoline (leq) (See example 11) in NMP (5ml) was added NaOMe (2eq) The reaction mixture was heated at 8O0C for 2h The reaction mixture was diluted with water and pH was adjusted to 5 5 with INHCl The precipitate was filtered, washed and dπed under vacuum to provide title product as a yellow solid (yield, 60%) ES/MS m/z 271 0 / 273 0 (MH+)
2,6-bis (methylthio) quinazolm-7-ol was formed as a side product (40%)
Step 2 Preparation oftert-butyl-4- (6-bromo-2- (methylthio) quιnazolιn-7-yloxy) pψendine- 1-carboxylate
To a solution of tπphenylphosphme (2eq) in THF was added di-ethylazodicarboxylate (2eq) The mixture was stirred 15 minutes at ambient temperature under nitrogen atmosphere To that was added tert-butyl-4-hydroxypipendme- 1-carboxylate (3eq) The mixture was stirred 15 minutes at ambient temperature followed by addition of 6-bromo-2- (methylthio) qmnazolin-7-ol (leq) The mixture was stirred overnight at ambient temperature The reaction mixture was concentrated and purified by flash column chromatography (10%EtOAc / Hexane) to provide product as a white solid in 70% yield ES/MS m/z 454 0 / 456 0 (MH+)
Step 3 Preparation oftert-butyl 4-(6-bromo-2- (methyl sulfonyl) quιnazohn-7-yloxy) pipendine- 1-carboxylate
To a solution oftert-butyl-4- (6-bromo-2- (methylthio) quinazolm-7-yloxy) pipendine- 1-carboxylate (leq) in THF (10ml) was added a solution of oxone in water (10ml) at 0°C The reaction mixture was stirred for 30min at 00C then warmed to room temperature and stirred overnight The reaction was cooled to 00C and quenched with satd sodmm thiosulfate solution The product was extracted in ethylacetate The ethylacetate extracts were combined together, washed with brme and dried over sodium sulfate Filtered, evaporated and dπed under vacuum to provide product in 90%yield ES/MS m/z 486 0 / 488 0(MH+) Used for next step without further purification
Step 4 Preparation oftert-butyl 4-(6-bromo-2- (3-methoxyphenylamιno) quιnazohn-7-yloxy) pιpendιne-1- carboxylate
A solution oftert-butyl 4-(6-bromo-2- (methyl sulfonyl) quinazolin-7-yloxy) pipendine- 1-carboxylate (leq) and 3-methoxyamlme (2eq) in dioxane was heated in sealed tube at 1100C for 24h The product was purified by semi-prep HPLC and lyophilyzed to provide pure product as a yellow solid in 50% yield ES/MS m/z 529 0 / 531 0 (MH+)
Step 5 Preparation oftert-butyl 4-(2-(3-methoxyphenylamιno)-6-(thιazol-2-yl) quιnazolιn-7- yloxy) pιperιdιne-1- carboxylate
A mixture oftert-butyl 4-(6-bromo-2- (3-methoxyphenylammo) qmnazolin-7-yloxy) pipeπdine-1- carboxylate (leq), 2-thiazolylzincbromide (5eq, 0 5M solution in THF) and Pd(dppf)2Ci2 (0 leq) was heated in microwave at 1200C for 10mm The reaction mixture was diluted with ethylacetate and washed with water and bπne Dπed over sodium sulfate, filtered, evaporated to provide crude product in quantitative yield ES/MS m/z 5342 (MH+)
Step 6 Preparation of N- (3-methoxyphenyl)-7-(pιperιdιn-4-yloxy)-6-(thιazol-2-yl) quιnazolιn-2-amιne A solution of crude tert-butyl 4-(2-(3-methoxyphenylamino)-6-(thiazol-2-yl) quinazohn-7-yloxy) piperidine-1- carboxylate in 30%TFA / DCM was stirred at room temperature for 30min The solvent was evaporated and crude was purified by semi-prep HPLC to provide pure product in 40% yield ES/MS m/z 4342 (MH+)
Step 7 Preparation of N- (3-methoxyphenyl)-7-(l-methylpιpendιn-4-yloxy)-6-(thιazol-2-yl) quιnazolιn-2-amιne
To a solution of N- (3-methoxyphenyl)-7-(pipendin-4-yloxy)-6-(thiazol-2-yl) qumazolin-2-amme (leq) in methanol was added HCHO (10eq) and a drop of acetic acid Stirred 10mm at room temperature, followed by the addition of Na(OAc)3BH (4eq) The reaction mixture was stirred Ih / rt Purified by semi-prep HPLC to provide product as a yellow solid in 70% yield ES/MS m/z 448 2 (MH+)
Example 1075: Synthesis of 7-(piperidin-4-yloxy)-N- (3-propoxyphenyl)-6-(thiazol-2-yl) quinazolin-2-amine
Figure imgf000183_0001
Stepl Preparation oftert-butyl-4- (2- (3-propoxyphenylamιno)-6-(thιazol-2-yl) quinazohn- 7-yloxy) pιpendιne-1-carboxylate To tert-butyl-4- (2- (3-hydroxyphenylamino)-6-(thiazol-2-yl) quinazolm-7-yloxy) pipeπdme-1-carboxylate (leq) (For synthesis, see example 21) m DMF (2ml) was added K2CO3 (5eq) and iodopropane (3eq) The reaction mixture was heated at 100°C for 48h
The reaction mixture was partitioned between ethylacetate and water Ethylacetate layer was separated and washed with water, bπne and dried over sodium sulfate Filtered and evaporated to provide crude product ES/MS m/z 562 2 (MH+)
Step2 Preparation 7-(pιperιdιn-4-yloxy)-N- (3-propoxyphenyl)-6-(thιazol-2-yl) quinazohn- 2-amιne
For synthesis, see example 1020, step 6 ES/MS m/z 462 2 (MH+)
Example 1082: 7-(l-(2-fluoromethylpiperidin-4-yIoxy)-N-(3-fluorophenyl)-6-(thiazol-2- yl) quinazolin-2-amine
Figure imgf000183_0002
To N- (3-fluorophenyl)-7-(pipendin-4-yloxy)-6-(thiazol-2-yl) qumazolm-2 -amine (leq) (For synthesis, see example 11) in DMF was added K2CO3 (5eq) and l-fluoro-3- iodoethane (1 2eq) The reaction mixture was stirred overnight at rt Product was purified by semi-prep HPLC ES/MS m/z 468 2 (MH+)
Example 1084
Synthesis of N- (3-fluorophenyI)-7-(l-methylpiperidin-4-yloxy)~6-(thiazol-4-yl) quinazolin-2-amine
Figure imgf000184_0001
Step 7 Preparation oftert-butyl 4-(2-(3-fluorophenylamιno)-6-(thιazol-4-yl) quιnazohn-7- yloxy) pιperιdιn-1-carboxylate
A mixture of tert-butyl-4- (6-bromo-2- (3-fluorophenylamino) qmnazolm-7-yloxy) pipendme-1-carboxylate (leq, see examplel 1 for synthesis), 4-tπbutyltm thiazole (3eq), TEA (3 5eq) and Pd (dppf)2Cl2 (0 leq) m DMF (1 5ml) was heated in microwave at 12O0C for lOmin The reaction mixture was partitioned between ethylacetate and water Ethylacetate layer was separated and washed with water, bπne and dπed over sodium sulfate Filtered, evaporated and purified by serm-prep HPLC to provide pure product in 50%yield ES/MS m/z 522 1 (MH+)
Step 2 Preparation of N- (3-fluorophenyl)-7-(pιpendιn-4-yloxy)—6-(thιazol-4-yl) quinazolin- 2-amιne
For synthesis see example 21, step 6 ES/MS m/z 422 1 (MH+)
Step 3 Preparation of N- (3-fluorophenyl)-7-(l-methylpιpendιn-4-yloxy)—6-(thιazol-4-yl) qumazohn-2-amιne For synthesis see example 1020, step 7 ES/MS m/z 436 1 (MH+) Example 1066
Synthesis of N- (3-fluorophenyl)- 6-(isoxazol-4-yl) -7-(piperidin-4-yIoxy) quinazolin-2-amine
Figure imgf000185_0001
Step] Preparation oftert-butyl 4-(2-(3-fluorophenylamιno)-6-(ιsoxazol-4-yl) quιnazolιn-7- yloxy) pιperιdιn-1-carboxylate
A mixture of tert-butyl-4- (6-bromo-2- (3-fluorophenylammo) quinazolm-7-yloxy) piperidine-1-carboxylate (leq, see examplel 1 for synthesis), 4-isoxazole boronic ester (3eq), l,l'-bis(diphenylphosphmo)ferrocenedichloro palladiιim(II) (0 leq), sodium carbonate (0 5ml of 2M aqueous solution) in DME (2ml) was heated in microwave at 1200C for 10mm The reaction mixture was partitioned between ethylacetate and water Ethylacetate layer was separated and washed with water, bπne and dried over sodium sulfate Filtered, evaporated and purified by semi-prep HPLC to provide pure product in 50%yield ES/MS m/z 506 1 (MH+)
Note Some debrominated product was also observed in above reaction
Step 2 Preparation of N- (3-fluorophenyl)- 6-(ιsoxazol-4-yl) -7-(pψendιn-4-yloxy) quιnazohn-2-amιne For synthesis see example 1020, step 6 ES/MS m/z 406 1 (MH+)
Example 1135
Synthesis of 7-(piperidin-4-yloxy)-N- (3-(pyridine-3-yl) phenyl)-6-(thiazol-2-yl) quinazolin-2-amine The subject compound was prepared according to the general Scheme below
Figure imgf000186_0001
3 30%TFA/ DCM Step 1 Preparation oftert-butyl 4-(6-bromo-2- (3-(pyrιdme-3-yl) phenylamino) quinazolin- 7-yloxy) pιpendιn-1-carboxylate
A mixture of tert-butyl-4- (6-bromo-2- (3-iodophenylamino) qmnazolm-7-yloxy) pipeπdine-1-carboxylate (leq, see examplel 1 for synthesis), 3-pyπdme boronic ester (1 2eq), l,r-bis(diphenylphosphino)ferrocenedichloro palladmm(II) (0 leq), sodium carbonate (0 5ml of 2M aqueous solution) m DME (2ml) was heated in microwave at 120°C for 10mm The reaction mixture was partitioned between ethylacetate and water Ethylacetate layer was separated and washed with water, bπne and dried over sodium sulfate Filtered, evaporated and purified by semi-prep HPLC to provide pure product in 50%yield ES/MS m/z 576 2 / 578 2 1 (MH+)
Note Some bis-substituted product was also isolated in above reaction
Step 2 Preparation oftert-butyl 4-(2- (3-(pyrιdme-3-yl) phenylamιno)-6-(thιazol-2-yl) quιnazolιn-7-yloxy) pιperιdιn-1-carboxylate
For Synthesis, see example 1020, step5 ES/MS m/z 581 2 (MH+)
Step 3 Preparation of7-(pιperιdιn-4-yloxy)-N- (3-(pyrιdιne-3-yl)phenyl)-6-(thιazol-2-yl) quιnazolιn-2-amιne
For Synthesis, see example 1020, step 6 ES/MS m/z 481 2 (MH+) Example 1117
Synthesis of (5-(2-(3-(oxazol-5-yl) phenylamino (7-(piperidin-4-yloxy) quinazolin- 6-yl)-lH-l, 2, 3-triazol-4-yl) methanol
The subject compound was prepared according to the general Scheme below
Figure imgf000187_0001
Step 1 Preparation oftert-butyl 4-(6- (3-hydroxyprop-l-ynyl)-2-(3-(oxazol-5-yl) phenylamιno)quιnazolιn-7-yloxy) pιperιdιn-1 -carboxylate
To tert-butyl 4-(6-bromo-2- (3-(oxazol-5-yl) phenylammo)qmnazolm-7-yloxy) piperidm-1 -carboxylate (leq) and tetrakis (PPHa)Pd(O) (O 02eq) in pyrrolidine(l 5ml) at room temperature was added propargyl alcohol (2eq, in ImI of pyrrolidine) The reaction mixture was heated in sealed tube at 80°C for Ih The reaction was quenched with satd NH4CI and product was extracted with diethyl ether Ether extracts were washed with bπne, dπed over sodium sulfate, filtered and evaporated Purified by semi-prep HPLC to provide pure product as a yellow solid in 40% yield ES/MS m/z 542 2 (MH+)
Step 2 Preparation oftert-butyl 4-(2-(3-(oxazol-5-yl) phenylamιno)-6-(3-oxoprop-l-ynyl) quinazohn- 7-yloxy) pιpendιn-1 -carboxylate A mixture of tert-butyl 4-(6- (3-hydroxyprop-l-ynyl)-2-(3-(oxazol-5-yl) phenylammo) qumazolin-7-yloxy) pipendin-1-carboxylate (leq) and Mnθ2 (5eq) in DCM (5ml) was stirred overnight at rt The product was filtered through celite and solvent was evaporated to provide pure prduct in 90% yield ES/MS m/z 540 3 (MH+)
Step 3 Preparation of tert-butyl 4-(6-(4-formyl-lH-l,2,3-tnazol-5yl)-2-(3-(oxazol-5-yl) phenylammo) qumazolin-7-yloxy) pipendin-1-carboxylate
To a stirred solution of sodium azide (1 2eq) in DMSO (2ml) in ice-water bath was added tert-butyl 4-(2-(3-(oxazol-5-yl) phenylammo)-6-(3-oxoprop-l-ynyl) quinazolin-7- yloxy) pipeπdin-1-carboxylate m DMSO (ImI) The reaction mixture was stirred 30mm at room temperature then poured to vigorously stirred biphasic solution of 5%KH2PO4 and diethyl ether Ether layer was separated, washed with bπne and dried over sodium sulfate Filtered, evaporated and dried under vacuum to provide product as a white solid in 70% yield ES/MS m/z 583 31 (MH+)
Step 4 Preparation of tert-butyl 4-(6-(4-(hydroxymethyl)-lH-l,2,3-trιazol-5yl)-2-(3-(oxazol- 5 -y I) phenylammo) quinazohn-'i '-yloxy) pιperιdιn-1-carboxylate
To tert-butyl 4-(6-(4-formyl- IH-1, 2,3 -tπazol-5yl)-2-(3-(oxazol-5-yl) phenylammo) quinazolm-7-yloxy) pipeπdm-l-carboxylate(leq) in methanol was added Na(OACbBH (5eq) The reaction mixture was stirred Ih at room temperature Purified by semi-prep HPLC to provide pure product as a yellow solid in 40% yield ES/MS m/z 584 2 (MH+)
Step 5 Preparation of (5-(2-(3-(oxazol-5-yl) phenylammo (7-(pιpendm-4-yloxy) quinazohn- 6-yl)-lH-l, 2, 3-trιazol-4-yl) methanol For Synthesis, see example 1020, step 6 ES/MS m/z 484 2 (MH+)
EXAMPLE 1140: (2R,4S)-4-(2-(3-fluorophenylamino)- 6-(thiazol-2-yl)quinazolin -7- yloxy)piperidine-2-carboxamide
Synthesis of 4-((tert-butyIdimethylsilyIoxy) methyl)-2-(tributylstannyl)thiazole The subject compound was prepared according to the general Scheme below
Step 1 Preparation of 2-bromo-4- (tert-butylsιlyloxy)methyl)thιazole
A mixture of 2-bromothiazol-4-yl) methanol (leq), imidazole (4eq) and tert-butyl- dimethylsilyl chloride (2eq) in DMF(IOmI) was stirred 2h at room temperature. The reaction mixture was partitioned between ethylacetate and water Ethylacetate layer was separated and washed with water, brine and dried over sodium sulfate Filtered, evaporated and purified by flash chromatography (10%EtOAc / Hexane) to provide pure product as a colorless liquid in 95%yield ES/MS m/z 307 9 / 309 9 (MH+) Step 2 Preparation of4-((tert-butyldιmethylsιlyloxy)methyl)-2-(trιbutylstannyl)thιazole
To flame dried flask under nitrogen at-78cC was added anhydrous ether (10ml) and n- butyl lithium (1 5eq, 2 5M solution in hexane) followed by addition of 2-bromo-4- (tert- butylsilyloxy) methyl) thiazole solution in ether (leq, 3ml) Stirred at -78°C for Ih Then a solution of tπbutyltinchloπde in ether (1 5eq, ImI) was added dropwise Stirred at this temperature additional Ih The reaction mixture was quenched with satd sodium bicarbonate and compound was extracted in ether Ether extracts were combined, washed with bπne and dned over sodium sulfate Filtered, evaporated and dπed under vacuum to provide product as a light yellow liquid Used without further purification
Synthesis of(2R,4S)-4-(2-(3-fluorophenylamino)- 6-(thiazol-2-yl)quinazolin -7- yloxy)piperidine-2-carboxamide
The subject compound was prepared according to the general Scheme below
Figure imgf000190_0001
Stepl Preparation of(2R,4S)-l-(tert-butoxycarbonyl)-4-(2-(3-fluorophenylamino)- 6- (thιazol-2-yl)quιnazolιn -7-yloxy)pιperιdme-2-carboxyhc acid
To (2R,4S)-l-tert-butyl-2-methyl-4-(2-(3-fluorophenylamino)- 6-(thiazol-2- yl)qumazolm -7-yloxy)pipendine-l,2-dicarboxylate (leq) in methanol (3ml) was added aqueous solution of sodium hydroxide (5eq) The reaction mixture was stirred overnight at rt The solvent was evaporated, residue was taken in water and made acidic with INHCl Product was extracted in ethylacetate The extracts were combined, washed with bπne and dried over sodium sulfate Filtered, evaporated and dπed under vacuum to provide product as a light brown solid m 70% yield ES/MS m/z 566 1 (MH+)
Step2 Preparation of (2R,4S)-tert-butyl-2-carbamoyl-4-(2-(3-fluorophenylamino)- 6-(thiazol- 2-yl)quinazolin -7-yloxy)pipeπdine- 1 -carboxylate
A mixture of (2R,4S)-l-(tert-butoxycarbonyl)-4-(2-(3-fluorophenylammo)- 6- (thiazol-2-yl)quinazolin -7-yloxy)pipeπdme-2-carboxyhc acid (leq), NH4CI (lOeq), HATU(I 75eq) and DIEA (5eq) in NMP (2ml) was stirred overnight at rt The product was purified by semi-prep HPLC ES/MS m/z 565 1 (MH+)
Step3 Preparation of (2R,4S)-4-(2-(3-fluorophenylammo)- 6-(thiazol-2-yl)qumazolin -7- yloxy)pipeπdine-2-carboxamide
For Synthesis, see example 21, stepό ES/MS m/z 465 1 (MH+)
Example 997: Preparation of N-(3-fhiorophenyl)-7-(piperidin-4-yloxy)-6-(thiazoI-2- yI)quinazolin-2-amine
Figure imgf000191_0001
A Preparation of 4-methoxy-2-amιnobenzaldehyde To a mixture of 4-methyl-3-mtroamsole m pyrrolidine (1 9eq) was added NjNdimethylformamidedimethylacetal and the mixture was heated to 12O0C or 16h The formation of the enaminone was confirmed by TLC The mixture was cooled to RT and poured in to ice and was then extracted with ethyl acetate, dried (Na2SO4) and concentrated To the crude enaminone in THF was added NaI(It (2 5eq) dissolved m water while maintaining the reaction temperature at 400C with an ice/water bath After the addition the pale yellow suspension was stirred at 350C for 16h The reaction mixture was then concentrated and the aqueous phase was then extracted with ethyl acetate , dried (Na2SO4) and the crude 4-methoxy-2-nitrobenzaldehyde was obtained as a brown solid The crude brown solid was purified on silica gel to get the product The hence obtained 4-methoxy-2- mtrobenzaldehyde was hydrogenated in methanol with catalytic amounts of 10% Pd/C to give the 4-methoxy-2-ammobenzaldehyde in quantitative yield ES/MS m/z 152(MH+) B Preparation of 5-bromo-4-methoxy-2-nιtrobenzaldehyde To 4-methoxy-2-aminobenzaldehyde in chloroform was added NBS(I eq) and the reaction goes to completion by LC/MS and IH NMR To the reaction mixture was added dichloromethane and water and the separated organic layer was dπed (Na2SO4) and concentrated to give the 5-bromo-4-methoxy-2-mtrobenzaldehyde ES/MS m/z 229/231(MH+)
C Preparation of 2-chloro-6-bromo-7-methoxyquιnazoline
5-bromo-4-methoxy-2- ammobenzaldehyde (1 0 eq) and urea (8 0 eq) were stirred at 170 0C for 1 h The resulting solid was returned to ambient temperature, stirred in water for 20 mm, and filtered This was repeated for a total of three washes The solid was dπed in a desiccator to give the 6-bromo-7-methoxyqumazolm-2-ol as the desired product A 0 5OM solution of 6-bromo-7-methoxyquinazohn-2-ol in phosphorus oxychloπde was stirred at 110 °C for 1 5 h Volatiles were removed under reduced pressure Ice water was added and the precipitate was filtered off, rinsed with water, and dπed under high vacuum to yield the 2- chloro-6-bromo-7-methoxyquinazoline as a yellow solid ES/MS m/z 272/274(MH+)
D Preparation of 6-bromo-2-(3-fluorophenylamιno)quιnazolιn-7-ol
To a solution of 2-chloro-6-bromo-7-methoxyqumazolme in isopropanol was added 3-fluoroamlme(l 0 eq) The reaction was stirred at 90 0C for 18 hours The hydrochloπde was collected by vacuum filtration and air dπed to give a crude mateπal which can be used for further chemical modifications The pure mateπal was obtained by HPLC punfication To the crude product was added NMP and NaSMe(4eq) and the mixture was heated to 800C for 2h The conversion in to the phenol was observed by LC/MS The reaction mixture was cooled and to it was added ethyl acetate and IN HCl to bπng it to neutral pH The 6-bromo- 2-(3-fluorophenylammo)qumazolm-7-ol crashed out as a solid which was filtered and dπed on high vacuum to give the product in quantitative yield ES/MS m/z 333/335(MH+)
E Preparation oftert-butyl 4-(6-bromo-2-(3-fluorophenylamιno)quιnazolιn-7- yloxy)pιperιdιne-l-carboxylate
To a mixture of DEAD (2eq) and tπphenylphosphme (2eq) was added tert-butyl 4- hydroxyprpendme-1-carboxylate (4eq) and to the resulting mixture was added 6-bromo-2-(3- fluorophenylamino)qumazolm-7-ol and was stirred for 16h at RT The formation of the product was observed on LC/MS The mixture was then concentrated and purified on silica gel to obtain tert-butyl 4-(6-bromo-2-(3-fluorophenylamino)qumazolin-7-yloxy)piperidine-l- carboxylate as the product ES/MS m/z 517/519(MH+)
F Preparation ofN-(3-fluorophenyl)-7-(pιperιdιn-4-yloxy)-6-(thιazol-2- yl)quιnazolιn-2-amιne
To tert-butyl 4-(6-bromo-2-(3 -fluorophenylamino)quinazolm-7-yloxy)pipendine- 1 - carboxylate (50mgs) was added 0 5M 2-thiazolylzincbromide and the mixture was micro waved at 12O0C for lOmins Complete conversion to the product was seen by LC/MS The mixture was concentrated and partitioned between ethyl acetate and water The organic layer was dπed (Na2SO4) and the product was isolated To the crude product was added 30% TFA/DCM and stirred for 2h for the deprotection of the tert-butyl group The formation of N-(3-fluorophenyl)-7-(pipeπdm-4-yloxy)-6-(thiazol-2-yl)quinazohn-2-amine was observed by LC/MS It was then purified by preparative chromatography to give the product ES/MS m/z 421(MH+)
Example 889: Preparation of N-(3-fluorophenyl)-7-(l-methyl-lH-pyrazol-4-yl)-6- (thiazol-2-yl)quinazolin-2-ainine
Figure imgf000193_0001
A Preparation of2-(3-fluorophenylamιno)-6-(thιazol-2-yl)qumazolιn-7-ol To 6-bromo-2-(3-fluoroρhenylamino)quinazohn-7-ol was added 0 5M 2- thiazolylzmcbromide and the mixture was micro waved at 1200C for lOmms Complete conversion to the product was seen by LC/MS The mixture was concentrated and partitioned between ethyl acetate and water The organic layer was dried (Na2SO4) and the product was isolated ES/MS m/z 330(MH+)
B Preparation of2-(3-fluorophenylamιno)-6-(thιazol-2-yl)quιnazohn- 7-yl tnfluoromethanesulfonate
To a solution of 2-(3-fluoroρhenylammo)-6-(thiazol-2-yl)quinazolin-7-ol (leq) in NMP was added phenyltπfluoromethanesulfonate (1 2eq) and DIEA (2 5eq) and the reaction mixture was stirred over night at ambient temperature The reaction mixture was then partitioned between ethyl acetate and water The organic layers were washed with saturated sodium chloπde and dπed and concentrated To the crude was added methylene chloride and few drops of methanol The white solid hence formed was filtered to give 2-(3- fluorophenylamino)-6-(thiazol-2-yl)quinazohn-7-yl tnfluoromethanesulfonate m 80% yield ES/MS m/z 471(MH+)
C Preparation ofN-(3-fluorophenyl)-7-(l-methyl-lH-pyrazol-4-yl)-6-(thιazol-2- yl)quιnazolιn-2-amιne To a solution of 2-(3-fluorophenylamino)-6-(thiazol-2-yl)qumazolm-7-yl tnfluoromethanesulfonate (leq) in DME was added 2M sodium carbonate solution and 4- (4,4,5,5,-tetramethyl-l,3,2-dioxaborolan-2-yl)-lmethyl-pyrazole (3eq) and Pd (dppf)2Cl2 CH2Cl2 (0 05eq) and the mixture was micro waved for 10 mm at 120 0C The reaction mixture was then partitioned between ethyl acetate and water The organic layer was washed with bnne, dπed, concentrated and punfied by semi-preparative HPLC to provide N- (3-fluorophenyl)-7-(l-methyl-lH-pyrazol-4-yl)-6-(thiazol-2-yl)qmnazolin-2-amine ES/MS m/z 402 (MH+)
Example 804: Preparation of 6-ethynyl-N-(3-(morpholinomethyl)phenyl)-7-(pyridin-3- ylmethoxy)quinazolin-2-amine
The subject compound was prepared according to the general Scheme below
Figure imgf000195_0001
^4 Preparation of 6-bromo-7-methoxy-N-(3-(morpholιnomethyl)phenyl)quιnazolιn-2-
To a 0 25M suspension of 6-bromo-2-chloro-7-methoxyqumazolme in isopropanol was added 3-(morpholin-4-ylmethyl)anihne (1 leq), and 4 OM hydrogen chloride in 1,4- dioxane (0 5eq) The reaction mixture was heated to 95 0C in an oil bath for 15 h Reaction mixture was diluted with ethyl acetate and filtered to collect desired product ES/MS m/z 429/431 (MH+)
B Preparation of6-bromo-2-β-(morpholιnomethyl)phenylamιno)quιnazohn-7-ol
A 0 2M suspension of 6-bromo-7-methoxy-N-(3-
(morpholinomethyl)phenyl)quinazolin-2-amine (1 Oeq) and sodium thiomethoxide (4 Oeq) in DMF was heated to 90 0C in an oil bath for 10 h The mixture was partitioned between ethyl acetate and water The pH of aqueous phase was adjusted to 4 by adding saturated ammonium hydrochloride Aqueous phase was extracted with ethyl acetate, and combined organic phase was washed with bπne, dπed over sodium sulfate, concentrated to give desired product ES/MS m/z 415/417 (MH+) C Preparation of6-bromo-N-(3-(morphohnomethyl)phenyl)-7-(pyrιdιn-3- ylmethoxy)quιnazohn-2-amιne
To a 0 55M solution of tnphenylphosphme (3 Oeq) in THF was added di-tert- butylazodicarboxylate (3 Oeq) The mixture was stirred for 20 mm at ambient temperature 3- pyndylcarbinol (3 Oeq) was added, and reaction mixture was stirred at ambient temperature for another 30 mm Then, 6-bromo-2-(3-(morpholmomethyl) phenylammo) quinazolm-7-ol (1 Oeq) was added to reaction flask The mixture was stirred at ambient temperature for additional 14 h Solvent was removed under reduced pressure and the residue was triturated with ethyl acetate and filtered Filter cake was rinsed with cold ethyl acetate and was air dπed to give 6-bromo-N-(3-(morpholinomethyl)phenyl)-7-(pyπdin-3-ylmethoxy)qmnazohn-2- amine ES/MS m/z 506/508 (MH+)
D Preparation of6-ethynyl-N-(3-(morpholιnomethyl)phenyl)-7-(pyrιdιn-3- ylmethoxy)quιnazolιn-2-amιne To a 0 05M mixture of 6-bromo-N-(3-(morpholinomethyl)phenyl)-7-(pyπdm-3- ylmethoxy)quinazolin-2-amme (0 1 mmol), tπethylamine (04ml), Pd(dppf)C12CH2C12 (0 leq), Copper(I) iodide (0 leq) in DMF was added tπmethylsilylacetylene (10eq) The mixture was microwaved at 120 0C for 15 mm Reaction mixture was diluted with ethyl acetate and was washed with water, bπne, dried and concentrated Without further purification, the crude compound was treated with tetramethylammonium fluoride (2 Oeq) in THF/isopropanol (10 1, 0 02M) at ambient temperature for 15 mm Solvent was removed under reduced pressure The residue was taken into ethyl acetate and was washed with water, bπne, dried and concentrated The crude product was purified by RP HPLC Lyophilization gave desired product 6-ethynyl-N-(3-(morpholinomethyl)phenyl)-7-(pyndm-3- ylmethoxy)qumazolm-2-amme ES/MS m/z 452 (MH+)
Example 724: Preparation of N-methyl-4-(7-(piperidin-4-ylmethoxy)-6-(thiazol-2- yl)quinazolin-2-ylamino)benzamide
Figure imgf000197_0001
To a 0 05M solution of tert-butyl 4-((6-bromo-2-(4-(methylcarbamoyl)phenylammo) quinazolin-7-yloxy)methyl)piperidine-l-carboxylate (0 12 mmol) m THF was added 0 5M 2- thiazolylzincbromide (3 Oeq), Pd(dppf)C12CH2C12 (02eq) The mixture was microwaved at 1200C for 15mins Complete conversion to the product was seen by LC/MS The mixture was concentrated and partitioned between ethyl acetate and water The organic layer was dried (Na2SO4) and was concentrated The residue was treated with 50% TFA/DCM and stirred for 10 mm to remove tert-butylcarboxylate group The crude compound was then purified by RP HPLC to give desired product N-methyl-4-(7-(pipeπdin-4-ylmethoxy)-6- (thiazol-2-yl)qumazolin-2-ylamino)benzamide ES/MS m/z 475 (MH+)
Example 729: Preparation of N-methyI-4-(7-(piperidin-4-ylmethoxy)-6-(thiazol-2- yl)quinazolin-2-ylamino)benzamide
Figure imgf000197_0002
A solution of N-methyl-4-(7-(pipendm-4-ylmethoxy)-6-(thiazol-2-yl)quinazolin-2- ylamino)benzamide (0 05 mmol), formaldehyde (10eq), catalytic amount acetic acid in methanol (2 0 ml) was stared at ambient temperature for 1 h Then sodium tnacetoxyborohydnde (2 Oeq) was added and reaction mixture was stirred at ambient temperature for 2 h LCMS data showed reaction was complete Solvent was removed under reduced pressure The residue was taken into ethyl acetate and was washed with water, bπne, 5 dried and concentrated Purification by RP HPLC gave desired product N-methyl-4-(7- (pipeπdin-4-ylmethoxy)-6-(thiazol-2-yl)qmnazohn-2-ylammo)benzamide ES/MS m/z 489 (MH+)
Example 767: Preparation of (S)-2-(3-((lH-l,2,4-triazol-l-yl)methyl)phenylamino)-7- 10 (pyrrolidin-3-yIoxy)quinazoline-6-carbonitrile
Figure imgf000198_0001
To a 0 IM solution of (S)-tert-butyl 3-(2-(3-((lH-l,2,4-triazol-l-yl)methyl) 15 phenylamino)-6-bromoquinazolin-7-yloxy)pyrrolidine-l-carboxylate (0 18 mmol) in DMF was added zmc cyanide (5 Oeq), Pd(dppf)C12CH2C12 (0 2eq), and dusopropylethyl amine (1 5eq) The mixture was microwaved at 150°C for 20mms Complete conversion to the product was seen by LC/MS The mixture was partitioned between ethyl acetate and water The organic layer was dπed (Na∑SC^) and was concentrated The residue was treated with 20 50% TFA/DCM and stirred for 10 mm to remove tert-butylcarboxylate group The crude compound was then purified by RP HPLC to give desired product (S)-2-(3-((lH-l,2,4- tπazol-l-yl)methyl)phenylamino)-7-(pyrrohdm-3-yloxy)quinazoline-6-carbonitπle ES/MS m/z 413 (MH+)
25 Example 765: Preparation of (S)-N-(3-((lH-l,2,4-triazol-l-yl)methyl)phenyl)-6-methyl- 7-(pyrrolidin-3-yloxy)quinazolin-2-amine
Figure imgf000199_0001
To a 0 06 M solution of (S)-tert-butyl 3-(2-(3-((lH-l,2,4-tnazol-l-yl)methyl) phenylammo)-6-bromoquinazolin-7-yloxy)pyrrolidine-l-carboxylate (0 11 mmol) in DMF was added tπmethylboroxme (4 Oeq), Pd(dppf)C12CH2C12 (0 leq), and 2 OM potassium carbonate aqueous solution (4 Oeq) The mixture was microwaved at 120 0C for 20mms Complete conversion to the product was seen by LC/MS The mixture was partitioned between ethyl acetate and water The organic layer was dπed (Na2SO<ι) and was concentrated The residue was treated with 50% TFA/DCM and stirred for 10 min to remove teit-butylcarboxylate group The crude compound was then purified by RP HPLC to give desired product (SJ-N^S-CClH-l^^-tnazol-l-ylJmethyOphenylJ-e-methyl-V-Cpyrrolidin-S- yloxy)qumazolm-2-amine ES/MS m/z 402 (MH+)
Example 764: Preparation of (S)-N-(3-((lH-l,2,4-triazol-l-yl)methyl)phenyl)-6- cyclopropyl-7-(pyrrolidln-3-yloxy)quinazolin-2-amine
Figure imgf000199_0002
To a 0 06 M solution of (S)-tert-butyl 3-(2-(3-((lH-l,2,4-tnazol-l-yl)methyl) phenylamino)-6-bromoqumazolm-7-yloxy)pyrrolidine-l-carboxylate (0 13 mmol) in DME was added 2-cyclopropyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (10eq), Pd(dppf)C12CH2C12 (O 2eq), and 2 OM potassium carbonate aqueous solution (4 Oeq) The mixture was microwaved at 120°C for 20mins Complete conversion to the product was confirmed by LC/MS The mixture was partitioned between ethyl acetate and water The organic layer was dried (Na∑SC^) and was concentrated The residue was treated with 50% TFA/DCM and stirred for 10 mm to remove tert-butylcarboxylate group The crude compound was then purified by RP HPLC to give desired product (S)-N-(3-((lH-l,2,4- tπazol- 1 -yl)methyl)phenyl)-6-cyclopropyl-7-(pyrrolidm-3-yloxy)quinazolm-2-amme ES/MS m/z 428 (MH+)
Example 797: Preparation of 7-(2-chloropyridin-4-yloxy)-N-(3-fluorophenyl)-6- (thiazol-2-yl)quinazolin-2-amine
Figure imgf000200_0001
A O l M suspension of 2-(3-fluorophenylammo)-6-(thiazol-2-yl)qumazolm-7-ol (0 15 mmol), 2-chloro-4-fluoropyπdine (1 5eq), Cesium carbonate (3 Oeq) in DMF was heated to 95 0C in an oil bath for 18 h LCMS data indicated desired product formation The mixture was partitioned between ethyl acetate and water The organic layer was dried (Na2SO4) and was concentrated The crude compound was then purified by RP HPLC to give desired product 7-(2-chloropyndin-4-yloxy)-N-(3-fluorophenyl)-6-(thiazol-2-yl)quinazolin-2-amme ES/MS m/z 450 (MH+)
Example 902: N-(3-(6-(thiazol-2-yl)quinazolin-2-ylamino)phenyl)acetamide
2-
Figure imgf000201_0001
130 C
Figure imgf000201_0002
Step 1 Displacement
A mixture of 6-bromo-2-chloroqumazoline (1 eq) and 3-aminoacetaruhde (0 9 eq) in 5 2-propanol was heated to 70 0C for 16 hr and concentrated to give the crude product which was used without further purification
Step 2 Negishi
To the product of step 1 was added a 0 5 M THF solution of 2-thiazolylzinc bromide
10 (4 0 eq) and [l,r-bis(diphenylphosphmo)ferrocene]dichloropalladmm(II) complex with DCM (O 10 eq) The reaction was microwaved at 130 °C for lO min The mixture was diluted with ethyl acetate and washed with aqueous EDTA pH~9 buffer The organic phase was dried over sodium sulfate, and concentrated Purification by reverse-phase HPLC and lyophilization gave the desired product as its TFA salt ES/MS m/z 392 (MH+)
15
6-Bromo-2,7-dichloroquinazoline
Figure imgf000201_0003
20 Step 1 Bromination
To a suspension of 2-ammo-4-chlorobenzoic acid (2 g, 11 6 mmol) in chloroform (120 mL) was added dropwise bromine (1 1 eqmv ) in chloroform (12 mL) solution The mixture was stirred at RT for 16 hrs The resulting white solid was collected by filtration and washed thoroughly with DCM until the filtrate was colorless The solid was air-dπed to give
25 3 35 g of white powder as HBr salt of 2-ammo-5-bromo-4-chlorobenzoic acid (87% yield) ES/MS m/z 250/252 (MH+) Step 2 Reduction
To the above intermediate (3 35 g, 10 1 mmol) in THF (40 mL) at 0 0C was added borane-THF complex solution (I M m THF, 40 mL, 4 eqmv ) The mixture was stirred at RT for l8 hrs Excess reagent was quenched by addition of ethanol (2O mL) slowly Water was added and the pH (~3) was adjusted by adding sodium bicarbonate (sat aq ) to pH 7 Volatiles were removed under reduced pressure The resulting mixture was extracted with DCM The organic extracts were combined, washed with bπne, dπed with sodium sulfate and concentrated to give the crude product as a white solid ES/MS m/z 236/238 (MH+)
Step 3 Oxidation
To the above intermediate (10 1 mmol) in DCM (80 mL) was added manganese (IV) oxide (Mnθ2, 6 g, 70 mmol) The mixture was stirred at RT under argon for 40 hrs The mixture was filtered through diatomaceous earth and washed thoroughly with DCM The filtrate was concentrated in vacuo to give crude 2-amino-5-bromo-4-chlorobenzyl alcohol (3 3 g, orange solid) which was used for the next step without further purification ES/MS m/z 234/236 (MH+)
Step 4 Cyclizatwn A mixture of crude 2-amino-5-bromo-4-chlorobenzyl alcohol (3 3 g, obtained from
Step 3) and urea (10 5 g, 15 eqmv ) was heated to 170 0C with vigorous stirring for 1 hr The reaction was cooled to RT and water was added The solid was collected by filtration The filtered solid was air-dned to give the crude product as a yellow powder (2 18 g, crude) ES/MS m/z 259/261 (MH+)
Step 5 Chlonnation
To the above crude material was added phosphorus oxychlonde (POCl3, 25 mL) and heated to 110 0C for 30 mm The resulting mixture was cooled to RT and concentrated in vacuo to nearly dryness Ice water was added and pH was adjusted to ~8 using sodium bicarbonate The mixture was extracted with DCM and the extract was dπed with sodium sulfate and concentrated in vacuo Crude 6-bromo-2,7-dichloroqumazohne was purified by flash chromatography over silica gel elutmg with 2 1 hexanes ethyl acetate ES/MS m/z 279 (MH+) Example 904: 3-(7-chloro-6-ethynylquinazolin-2-ylamino)-N-methyl-5-(l-methyl-lH- pyrazol-4-yI)benzamide
110 C *~
Figure imgf000203_0001
Figure imgf000203_0002
Step 1 Displacement
A mixture of 6-bromo-2,7-dichloroqumazohne (1 eq) and 3-ammo-N-methyl-5-(l- methyl-lH-pyrazol-4-yl)benzamide (1 eq) in 2-propanol was heated to 110 0C for 16 hi and concentrated to give the crude product which was used without further purification
Step 2 Sonogashira and desilylation
To a 0 15 M solution of the product of step 1 in de-gassed 1 1 DMF TEA was added TMS-acetylene (4 0 eq), copper(I) iodide (0 10 eq), and [1,1 '- bis(diphenylphosphino)ferrocene]dichloropalladmm(II) complex with DCM (0 050 eq) The reaction was stirred at 100 °C for 40 min The mixture was concentrated and re-dissolved m 3 2 tetrahydrofuran methanol to make a 0 15 M solution A 6M aqueous solution of sodium hydroxide (2 5 eq) was added, and the mixture was stirred for 20 min Volatiles were removed under reduced pressure The residue was purified by reverse-phase HPLC and lyophihzed to give the desired product as its TFA salt ES/MS m/z 417 1 (MH+)
Example 905: 3-(6-ethynyl-7-(trifluoromethyl)quinazolin-2-ylamino)-N-methyl-5-(l- methyl-lH-pyrazol-4-yl)benzamide
-methyl-1 H- 110 C *"
Figure imgf000203_0003
Figure imgf000203_0004
3-(6-Ethynyl-7-(tπfluoromethyl)qumazolin-2-ylamino)-N-methyl-5-(l-methyl-lH- pyrazol-4-yl)benzamide was prepared following Examples 62 and 63 ES/MS m/z 451 0 (MH+)
Example 907: 2-(3-fluorophenylamino)-6-(thiazol-2-yl)quinazoline-7-carbaldehyde
The subject compound was prepared according to the general Scheme below
Figure imgf000204_0001
CO 500 pεi
Figure imgf000204_0002
2-(3-fluorophenylamιno)-6-(thιazol-2-yl)quιnazolιne-7-carbaldehyde
To the reaction mixture of 2-(3-fluorophenylammo)-6-(thiazol-2-yl)qumazolm-7-yl tnfluoromethanesulfonate (50 mg, 0 lOόmmol) in 1 4 ml of DMF in a steel bomb was added Pd(dppf)2Cl2 (8 7 mg, 0 0106 mmol), tπethylsilane (37 mg , 0 318 mmol) and TEA (0 037 ml, 0265 mmol) The steel bomb was sealed and carefully CO was added to 500 psi and slowly released (3x m a Hood) then recharged to 500 psi and stirred at 50-550C for 18 hours This reaction mixture was cooled and vented in a hood The crude reaction mixture was filtered, purified on prep HPLC and lyophihzed to give, 2-(3-fmorophenylammo)-6-(thiazol- 2-yl)qumazolme-7-carbaldehyde as TFA salt (6 0 mg) ES/MS m/z 351(MH+)
Side Products hi addition two side products were also collect on prep HPLC and lyophihzed to give, 2-(3-fluoroρhenylamino)-6-(thiazol-2-yl)qumazolme-7-carboxylic acid as TFA salt (8 0 mg) ES/MS m/z 367(MH+) and N-(3-fluorophenyl)-6-(thiazol-2-yl)quinazolm-2-amme as TFA salt (3 3 mg) ES/MS m/z 323(MH+) Example 916: N-(3-fluorophenyl)-7-(piperidin-4-yloxy)-6-(pyridin-3-yl)quinazolin-2- aniinc
The subject compound was prepared according to the general Scheme below
2M Na2CO3
Figure imgf000205_0001
Figure imgf000205_0002
Step 1 tert-butyl 4-(2-(3-fluorophenylamιno)-6-(pyndιn-3-yl)quιnazohn-7-yloxy)pιperιdιne- 1-carboxylate
To the reaction mixture of, tert-butyl 4-(2-(3-fluorophenylamino)-6- (tπfluoromethylsulfonyloxy)quinazolm-7-yloxy)pipeπdine-l-carboxylate (30 mg, 0 058 mmol) in 0 7 ml of DME was added Pd(dppf)2Cl2 (9 5 mg, 0 0116 mmol), 3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyπdine (36 mg, 0 174 mmol) and last add 2M NajCθ3 (02 ml, 0 4 mmol) This reaction mixture was stirred at 100 0C for 3 hours or until done by LCMS To the crude reaction mixture add 1 5 ml of methanol, transfer the reaction and concentrate to solid to give a crude product, tert-butyl 4-(2-(3-fluorophenylamino)-6- (ρyπdin-3-yl)quinazolin-7-yloxy)pipeπdme-l-carboxylate used m next step without purification ES/MS m/z 516(MH+)
Step 2 N-(3-fluorophenyl)-7-(pφerιdm-4-yloxy)-6-(pyrιdιn-3-yl)quιnazohn-2-amιne
To the crude reaction mixture of tert-butyl 4-(2-(3-fiuorophenylammo)-6-(pyridin-3- yl)qumazolin-7-yloxy)pipendme- 1-carboxylate (0 058 mmol) was added 4M HCl in Dioxane (4 0 ml, 16 0 mmol) The reaction mixture was stirred at room temperature for 1 hours or until done by LCMS The crude reaction mixture was concentrate, about 1 ml of DMF was added, filtered, purified on prep HPLC and lyophihzed to give N-(3-fiuorophenyl)- 7-(pipendm-4-yloxy)-6-(pyπdin-3-yl)qumazolm-2-amine as TFA salt (8 3 mg) ES/MS m/z 416(MH+) Example 913: N-(3-fluorophenyl)-7-(piperidin-4-yloxy)-6-(pyridin-2-yl)quinazolin-2- aπiine
The subject compound was prepared according to the general Scheme below
Figure imgf000206_0001
Step 1 tert-butyl 4-(2-(3-fluorophenylamιno)-6-(pyrιdιn-2-yl)quιnazolιn-7-yloxy)piperιdιne- 1-carboxylate To the reaction mixture of tert-butyl 4-(2-(3-fluorophenylammo)-6-
(tnfluoromethylsulfonyloxy)quinazolin-7-yloxy)pipendine-l-carboxylate (30 mg, 0 058 mmol) m 0 5 ml of DMF was added Pd(dppi)2Cl2 (9 5 mg, 0 0116 mmol), 2- (tπbutylstannyl)pyπdine (66 mg, 0 174 mmol) and last add TEA (0 021 ml, 0 145 mmol) This reaction mixture was stirred at 1050C for 1 hours or microwaved at 1200C for 800 seconds until done by LCMS The crude reaction mixture with product, tert-butyl 4-(2-(3- fluorophenylammo)-6-(pyπdin-2-yl)qmnazolm-7-yloxy)pipeπdine-l-carboxylate was use m the next step without purification ES/MS m/z 516(MH+)
Step 2 N-(3-fluorophenyl)- 7-(pιperiώn-4-yloxy)-6-(pyndιn-2-yl)quιnazolιn-2-amιne To the crude reaction mixture of, tert-butyl 4-(2-(3-fluorophenylarnino)-6-(ρyπdm-3- yl)quinazohn-7-yloxy)pipeπdme- 1-carboxylate (0 058 mmol) was added 4M HCl in Dioxane (3 0 ml, 12 0 mmol) The reaction mixture was stirred at room temperature for 1 hours or until done by LCMS The crude reaction mixture was concentrate, about 1 ml of DMF was added, filtered, purified on prep HPLC and lyophihzed to give, N-(3- fluorophenyl)-7-(pipendm-4-yloxy)-6-(pyπdm-2-yl)quinazohn-2-amine as TFA salt (4 6 mg) ES/MS m/z 416(MH+) Example 920: (R)-l-(2-(3-fluorophenyIamino)-7-(piperidin-4-yloxy)quinazoIin-6- yl)pyrrolidin-3-ol
The subject compound was prepared according to the general Scheme below
Figure imgf000207_0001
Step 1 (R)-tert-butyl 4-(2-(3-fluorophenylamιno)-6-(3-hydroxypyrrolιdιn-l-yl)quιnazolιn-7- yloxy)pipendine-l-carboxylate
To the reaction mixture OfPd(OAc)2 (9 5 mg, O Ol 16 mmol ) and BINAP (10 8 mg, O 0174 mmol) add O 5 ml of dioxane and stir for 3-5 minutes at room temperature To this reaction mixture add, tert-butyl 4-(2-(3-fluorophenylamino)-6- (tπfluoromethylsulfonyloxy)qumazolin-7-yloxy)pipeπdme-l-carboxylate (30 mg, O 058 mmol), (R)-pyrrolidin-3-ol (20 mg, 0232 mmol) and then last add potassium tertbutoxide (19 5 mg, 0 174 mmol) This reaction mixture was stirred at 90°C for 5 hours or until done by LCMS The crude reaction mixture with product, (R)-tert-butyl 4-(2-(3- fluorophenylammo)-6-(3-hydroxypyrrolidin-l-yl)quinazolm-7-yloxy)pipeπdme-l- carboxylate was use in the next step without purification ES/MS mJz 524(MH+)
Step 2 (R)-l-(2-(3-fluorophenylamιno)-7-(pιperιdιn-4-yloxy)qwnazolιn-6-yl)pyrrohdιn-3-ol
To the crude reaction mixture of (R)-tert-butyl 4-(2-(3-fluorophenylammo)-6-(3- hydroxypyrrolidm-l-yl)quinazolm-7-yloxy)pipeπdme-l -carboxylate (0 058 mmol) was added 4M HCl in Dioxane (3 0 ml, 12 0 mmol) The reaction mixture was stirred at room temperature for 1 hours or until done by LCMS The crude reaction mixture was concentrate, about 1 ml of DMF was added (if needed add about 0 2 ml of water), filter, purified on prep HPLC and lyophilized to give, (R)-l-(2-(3-fiuorophenylamino)-7-(piperidin- 4-yloxy)quinazolm-6-yl)pyrrolidin-3-ol as TFA salt (1 1 mg) ES/MS m/z 424(MH+) Example 909: (2-(3-fluorophenylainino)-6-(thiazol-2-yl)quinazolin-7-yl)(piperazin-l- yl)methanone
The subject compound was prepared according to the general Scheme below
Figure imgf000208_0001
Step 1 tert-butyl 4-(2-(3-fluorophenylamιno)-6-(thιazol-2-yl)quιnazolιne-7- carbonyl)pφerazιne-l -carboxylate
To the reaction mixture of 2-(3-fluorophenylamino)-6-(thiazol-2-yl)quinazoline-7- carboxyhc acid (7 mg, 0 019 mmol) in 04 ml of DMF add HATU (18 2 mg, 0 048 mmol), DIPEA (0 014 ml, 0 076 mmol) and stir at room temperature for about 3-5 minutes To the above reaction mixture add tert-butyl piperazine- 1 -carboxylate ( 14 mg, 0 076 mmol) and stir at room temperature for 2 hours or until done by LCMS The crude reaction mixture with product, tert-butyl 4-(2-(3-fluorophenylammo)-6-(thiazol-2-yl)qmnazolme-7- carbonyl)piperazme-l-carboxylate was use in the next step without purification ES/MS m/z 535(MH+)
Step 2 (2~(3-fluorophenylamιno)-6~(thιazol-2-yl)quιnazohn-7-yl)(pιperazιn-l-yl)methanone To the crude reaction mixture of tert-butyl 4-(2-(3-fluorophenylamino)-6-(thiazol-2- yl)quinazolme-7-carbonyl)piperazme-l -carboxylate (0 019 mmol) was added 4M HCl in Dioxane (2 0 ml, 8 0 mmol) The reaction mixture was stirred at room temperature for 1 hours or until done by LCMS The crude reaction mixture was concentrate, about 1 ml of DMF was added, filtered, purified on prep HPLC and lyophilized to give, (2-(3- fluorophenylammo)-6-(thiazol-2-yl)qumazolm-7-yl)(piperazm-l-yl)methanone as TFA salt (2 1 mg) ES/MS m/z 435(MH+)
Example 908: N-(3-fluorophenyl)-7-(piperazin-l-ylmethyl)-6-(thiazol-2-yl)quinazolin-2- aiDine
The subject compound was prepared according to the general Scheme below
Figure imgf000209_0001
Step 1 tert-butyl 4-((2-(3-fluorophenylamιno)-6-(thιazol-2-yl)quιnazohn-7- yl)methyl)pιperazιne-l-carboxylate
To the reaction mixture of 2-(3-fluorophenylammo)-6-(thiazol-2-yl)qumazoline-7- carbaldehyde (12 mg, 0034 mmol) in 0 75 ml of NMP add acetic acid (0 070 ml , 1 02 mmol) and tert-butyl piperazme-1-carboxylate (65 mg, 0 35 mmol) This reaction mixture was stirred at room temperature for about 16 hours To this reaction solution was added sodium tπacetoxy borohydnde (18 mg, 0 085 mmol) and stirred at room temperature 2 hours or until done by LCMS The crude reaction mixture with product, tert-butyl 4-((2-(3- fluorophenylamino)-6-(thiazol-2-yl)qumazolin-7-yl)methyl)piperazine- 1 -carboxylate was use in the next step without purification ES/MS m/z 521 (MH+)
Step 2 N-(3-fluorophenyl)-7-(pιperazιn-l-ylmethyl)-6-(thιazol-2-yl)quιnazohn-2-amιne To the crude reaction mixture of tert-butyl 4-((2-(3-fluorophenylamino)-6-(thiazol-2- yl)qumazolm-7-yl)methyl)piperazine-l -carboxylate (0 034 mmol) was added 4M HCl in Dioxane (4 0 ml, 16 0 mmol) The reaction mixture was stirred at room temperature for 1 hours or until done by LCMS The crude reaction mixture was concentrate, about 1 ml of DMF was added, filtered, purified on prep HPLC and lyophihzed to give, N-(3- fluorophenyl)-7-(piperazm-l-ylmethyl)-6-(thiazol-2-yl)qumazolin-2-amine as TFA salt (1 7 mg) ES/MS m/z 421(MH+)
Examples 1161. 1165-1171. and 1174
The subject compounds were prepared according to the general Scheme below
Figure imgf000210_0001
Step 1
Figure imgf000210_0002
Step 3
Figure imgf000210_0003
Step 1
This reacbon was conducted in a similar manner to that descnbed in Example 9, step 5
Step 2
This reaction was conducted in a similar manner to that descnbed in Example 10, step
Step 3
Boc Amine was dissolved in Dioxane and treated with 4 M HCl/Dioxane (20 eq) Reaction stirred at room temperature for 2 hours Reaction was concentrated to a white solid identified as desired product
Step 4 Method A
Amine was dissolved in DMF and Et3N (3 eq) at room temperature and treated with appropπate acid chloride (1 5 eq) Reaction stirred at room temperature for 10 hours and was directly purified by RPHPLC to yield desired compounds
Method B Amine, HOAT (1 5 eq), HATU (1 5 eq) and Et3N (3 0 eq) were combined in DMF Corresponding carboxylic acid (1 2 eq) was added and reactions stirred at room temperature for 10 hours and was directly purified by RPHPLC to yield desired compounds
Step 5
This reaction was conducted m a similar manner to that descπbed in Example 10, step
Examples 1153-1155. 1157. 1158. 1160. 1162-1164. 1172. and 1173
The subject compounds were prepared according to the general Scheme below
Figure imgf000211_0001
Carboxylic Acid Acid Chloride Step 3
Figure imgf000211_0002
Step 1
This reaction was conducted in a similar manner to that described in Example 9, step
Step 2 This reaction was conducted in a similar manner to that descπbed in Example 10, step
1 Step 3 Method A
Amine was dissolved in DMF and Et3N (3 eq) at room temperature and treated with appropriate acid chloride (1 5 eq) Reactions stirred at room temperature for 10 hours and was directly purified by RPHPLC to yield desired compounds
Method B
Amine, HOAT (1 5 eq), HATU (1 5 eq) and Et3N (3 0 eq) were combmed in DMF Corresponding carboxyhc acid (1 2 eq) was added and reactions stirred at room temp for 10 hours and was directly purified by RPHPLC to yield desired compounds
Step 4
This reaction was conducted in a similar manner to that descnbed in Example 10, step
Examples 1156 and 1159
The subject compounds were prepared according to the general Scheme below
Figure imgf000212_0001
Step 1
Chloπde and potassium phthalamide (1 5 eq) were combined in DMF and heated at 120 0C for 10 minutes m the microwave Reaction was concentrated and purified on silica with a 0 to 100% EtOAc/Hexane gradient to provide desired compound as a white solid
Step 2
This reaction was conducted in a similar manner to that descπbed in Example 459, step 1
Step 3
This reaction was conducted in a similar manner to that descπbed in Example 9, step
Step 4
This reaction was conducted in a similar manner to that described in Example 10, step
Step 5 This reaction was conducted in a similar manner to that described in Example 10, step
2
Example 1175
The subject compound was prepared according to the general Scheme below
Figure imgf000213_0001
Amine (from Example 1153 or 1154) and formaldehyde (5 0 eq of 37% aq Solution) were suspended in CH2CI2 at room temperature Sodium tπacetoxyborohydπde was added at once and reaction stirred for 10 hours After this time, reaction was quenched by addition of water followed by concentration and purification by RPHPLC Purified fractions were combined and treated as per Example 10, step 2 to yield desired compound
Example 1176
The subject compound was prepared according to the general Scheme below
Figure imgf000214_0001
Amine (from Example 1161 or 1165) and formaldehyde (5 0 eq of 37% aq Solution) were suspended m CH2CI2 at room temperature Sodium tπacetoxyborohydπde was added at once and reaction stirred for 10 hours After this time, reaction was quenched by addition of water followed by concentration and punfication by RPHPLC Punfied fractions were combined and treated as per Example 10, step 2 to yield desired compound
Example 1151
The subject compound was prepared according to the general Scheme below
Figure imgf000215_0001
Step 1
Nitro and SnCl2-(H2θ)2 (10 eq) were combined in a solution of isopropanol and 12 N HCl Reaction was heated at 1100C for 2 hours and was concentrated to 25% original volume Resulting suspension was dissolved in a 3 1 mix of EtOAc CH2CI2 and slowly neutralized with NaHCCh (sat aq ) to pH 7 Resulting mixture was filtered through a Celite plug and the organic layers were separated The aqueous layer was extracted 3x with CH2CI2 and the combined organics were dπed and concentrated to provide 5 7 g of yellow solid which was used without further purification
Step 2
To a solution of amine in DMSO was added NaCN (2 0 eq) at room temperature Reaciton stirred for 1 hour and was quenched with water and extracted 2x with EtOAc Combined organics were dπed over MgSθ4 and concentrated to a yellow oil Silica gel purification with a 0 to 80% gradient provided the desired product as a white solid
Step 3
This reaction was conducted in a similar manner to that described in Example 469, step 2
Step 4 This reaction was conducted in a similar manner to that descπbed in Example 9, step
Step 5 This conversion was achieved in a similar manner to that descπbed in Example 10, step 1 and step 2
Example 1177
The subject compound was prepared according to the general Scheme below
Figure imgf000216_0001
Nitnle (from Example 1151) was treated with IN NaOH (10 eq) in microwave at 120 0C for 10 minutes Reaction was purified directly by RPHPLC to provide desired product
Example 1178
The subject compound was prepared according to the general Scheme below
Figure imgf000216_0002
Nitnle (from Example 1151) was treated with IN NaOH (10 eq) in sealed glass bomb at 1100C for 12 hours Reaction was cooled to room temperature and concentrated to 20% original volume IN HCl was added to pH 7 and resulting yellow solid was collected and dried to provide desired product
Examples 1179-1184
The subject compound was prepared according to the general Scheme below
Figure imgf000217_0001
Step 1 This reaction was conducted in a similar manner to that descπbed in Example 10, step
1 using acid from Example 1178
Step 2
Acid, HOAT (1 5 eq), HATU (1 5 eq) and Et3N (3 0 eq) were combined in DMF Corresponding amine was added and reactions stirred at room temp for 10 hours and was directly purified by RPHPLC to yield desired compounds
Step 3
This reaction was conducted in a similar manner to that descπbed in Example 10, step
Example 1150 The subject compound was prepared according to the general Scheme below
Figure imgf000218_0001
Step 3
Figure imgf000218_0002
Step 1
Amine was suspended in NH4OH and heated at 130 0C for 15 minutes in microwave Reaction was concentrated to a yellow solid which was used without further purification
Step 2
This reaction was conducted in a similar manner to that descπbed in Example 9, step 5
Step 3 This conversion was achieved in a similar manner to that descπbed in Example 10, step 1 and step 2
Examples 1144-1149 and 1152
The subject compounds were prepared using commercially available amines according to the general procedures descπbed in Example 9, step 5 and Example 10, step 1 and step 2 Biological Examples
I. PDKl Kinase Alpha Screen Assay
Reagents/Concentrations The PDKl -4 peptide substrate, biotin-GGGGRTWTLCG- NH2, (SEQ ID NO 1), was purchased from the Tufts University Core Facility The final concentration of PDKl -4 peptide substrate was 50 nM The ATP substrate (adenosme-5'- tπphosphate) was purchased from Roche Diagnostics The final concentration of ATP substrate was lOμM Phospho-(Ser/Thr) PKA substrate antibody was purchased from Cell Signaling Technology The final concentration of antibody was 0 3 mg/mL The Alpha Screen Protein A detection kit containing donor and acceptor beads was purchased from
PerkinElmer Life Sciences The final concentration of both donor and acceptor beads was 25 μg/mL Alpha Screen was used for detection The biotmylated-PDKl-4 peptide was phosphorylated by PDKl kinase using the ATP substrate The biotinylated-PDKl-4 peptide substrate was bound to the streptavidin coated donor bead The antibody was bound to the protein A coated acceptor bead The antibody bound to the phosphorylated form of the biotmylated PDK-I peptide substrate, bringing the donor and acceptor beads mto close proximity Laser irradiation of the donor bead at 680nm generated a flow of short-lived singlet oxygen molecules When the donor and acceptor beads were in close proximity, the reactive oxygen generated by the irradiation of the donor beads initiated a luminescence/fluorescence cascade in the acceptor beads This process led to a highly amplified signal with output in the 530-620 nm range Assays were earned out in 50 niM Tns, pH=7 5, 10 mM MgCl2, 0 1% BSA, 001% Tween-20, 2 mM dithiolthreitol, 2 5% dimethyl sulfoxide Reactions were stopped by adding 50 mM Tns, pH=7 5, 90 mM EDTA, 0 1% BSA, 001% Tween-20 Procedure To 10 μL of PDK1-4 peptide, 0 5 μl of test compound in dimethyl sulfoxide was added PDKl kinase and ATP were mixed, and 10 μL of the PDKl kinase/ATP mix was added to start the reaction The reaction was allowed to proceed for 3- 18 hours The reactions were then stopped by adding 10 μL of the EDTA-contaimng stop buffer Beads were mixed with antibody, and 25 μL of the bead/antibody mix was then added to the stopped reactions Plates were incubated at room temperature overnight to allow for detection development before being read The assay was run in a 384-well format plate Results As shown in Table 1 herein, of the Example compounds in the table, 140 compounds demonstrated ICso's of less than 25 μm in the above screen, and of those, 131 compounds demonstrated ICso's of less than 5 μm
II. CDKl (CDC2) Kinase Inhibition In Vitro Screen Assay
Reagents/Concentrations Human full length Cdkl is purchased from Upstate (# 14- 450) as a co-purification with Cyclin B The final enzyme concentration in the assay is 0 8 nM Histone Hl peptide substrate is purchased from Research Genetics The peptide, with the sequence IcBiOtIn-GGCGPKTPKKAKKL[CONH2], (SEQ ID NO 2), is used in the assay at a final concentration 0 5 μM The ATP substrate (Adenosine-5 '-triphosphate) was purchased from Roche Diagnostics The final concentration of ATP substrate is 1 μM P33 γ- ATP is purchased from NEN The biotinylated peptide substrate is phosphorylated by Cdkl/Cyclm B enzyme, in the presence of varying concentrations of compounds, using the ATP substrate A fraction of ATP in the reaction is radiolabeled to provide a detectable phosphorylation signal The phosphorylation reaction is stopped with the addition of 25 mM EDTA The solutions are then transferred to White BioBmd Streptavidin Coated Assay plates, purchased from Thermo Electron Corporation After washing, Microscint 20 scintillation fluid, purchased from Perkin Elmer, is added to each well and counts per minute (cpm) is measured using a Packard TopCount Microscmtillation Counter The highest cpms measured indicates the maximum phosphorylation of the substrate possible under the assay conditions Reactions run without enzyme present give cpms indicative of complete inhibition of the enzyme Each concentration of compound produced a measurable percent inhibition from the maximum signal based on these values Assays were earned out in 50 mM Tπs-HCl pH7 5, 10 mM MgCl2, 1 mM DTT, 1 mM EGTA, 25 mM β-glycerol phosphate, 1 mM NaF, 0 01% BSA/PBS, 0 5 μM peptide substrate, and 0 8 nM Cdkl
Procedure Reaction Buffer (100 μL) containing 50 mM Tns-HCl pH7 5, 10 mM MgCl2, 0 01% BSA/PBS, 1 5 mM DTT, 1 5 mM EGTA, 37 5 mM β-glycerol phosphate, 1 5 mM NaF, 0 75 μM peptide substrate, and 1 2 nM Cdkl was distributed to each well 100% inhibition control wells contain no Cdkl The compounds to be tested were added to wells m desired 1 OX concentrations with 10% DMSO, 50 mM Tns-HCl pH7 5, 10 mM MgCl2, and 0 01% BSA/PBS The reactions were initiated by adding 15 μL of ATP concentrated at 10 μM, with P33 γ-ATP at < 10 nM as label The reactions were allowed to continue for four hours at room temperature with shaking Streptavidm coated plates were blocked for one hour with 1 % BSA in PBS EDTA (100 μL, 50 mM) was added to each streptavidm well An aliquot (100 μL) of each assay solution was transferred to the corresponding streptavidm well contaimng EDTA The capture of radiolabeled substrate was then earned out by shaking the plate at room temperature for one hour After binding the wells were washed 4 times with PBS, 200 μL Microscmt 20 was added to each well, and cpms were measured The assay was run m a 96-well format
Results Many of the compounds listed in Table 1 were screened according the method above, and exhibited an IC50 value of less than or equal to 25 μM, with respect to inhibition of Cdkl Additionally, many of the compounds exhibited an IC50 of less than 10 μM, or less than 1 μM, or less than 0 1 μM
III. CDK2 Kinase Inhibition In Vitro Screen Assay
Reagents/Concentrations Human full length Cdk2 was purchased from Upstate (# 14-407) as a co-purification with Cyclin A The final enzyme concentration in the assay was 5 nM Histone Hl peptide substrate was purchased from Research Genetics The peptide, with the sequence lcBiotm-GGCGPKTPKKAKKL[CONH2], (SEQ ID NO 2), was used in the assay at a final concentration 0 5 μM The ATP substrate (adenosine-5'-tnphosphate) was purchased from Roche Diagnostics The final concentration of ATP substrate was 1 μM P33 γ-ATP was purchased from NEN The biotmylated peptide substrate was phosphorylated by Cdk2/Cyclm A enzyme, in the presence of varying concentrations of compounds, using the ATP substrate A fraction of ATP in the reaction was radiolabeled to provide a detectable phosphorylation signal The phosphorylation reaction was stopped by the addition of 25 mM EDTA The solutions were then transferred to White BioBind Streptavidm Coated Assay plates, purchased from Thermo Electron Corporation After washing, Microscmt 20 scintillation fluid, purchased from Perkin Elmer, was added to each well and counts per mmute (cpm) were measured using a Packard TopCount Microscmtillation Counter The highest cpms measured indicate the maximum phosphorylation of the substrate possible under the assay conditions Reactions run without enzyme present gave cpms indicative of complete inhibition of the enzyme Each concentration of compound produced a measurable percent inhibition from the maximum signal based on these values Assays were earned out in 50 mM Tns-HCl pH7 5, 10 mM MgCl2, 1 mM DTT, 1 mM EGTA, 25 mM β-glycerol phosphate, 1 mM NaF, 0 01% BSA/PBS, 0 5 μM peptide substrate, and 5 nM Cdkl Procedure Reaction Buffer (100 μL) containing 50 mM Tπs-HCl pH7 5, 10 mM MgCl2, 0 01% BSA/PBS, 1 5 mM DTT, 1 5 mM EGTA, 37 5 mM β-glycerol phosphate, 1 5 mM NaF, 075 μM peptide substrate, and 7 5 nM Cdk2 was distπbuted to each well 100% inhibition control wells contain no Cdk2 The compounds to be tested were added to wells in desired 1OX concentrations with 10% DMSO, 50 mM Tns-HCl pH7 5, 10 mM MgCl2, and 0 01% BSA/PBS The reactions were initiated by adding 15 μL of ATP concentrated at 10 μM, with P33 γ-ATP at < 10 nM as label The reactions were allowed to proceed for four hours at room temperature with shaking Streptavidin coated plates were blocked for one hour with 1% BSA in PBS EDTA (100 μL, 50 mM) was added to each streptavidin well An aliquot (100 μL) of each assay solution was transferred to corresponding streptavidin wells containing EDTA The radiolabeled substrate was captured by shaking at the plate at room temperature for one hour After binding, the wells were washed 4 times with PBS, 200 μL Microscint 20 was added to each well, and cpms were measured The assay was run in a 96-well format plate Results Many of the compounds listed in Table 1 were screened according the method above, and exhibited an IC50 value of less than or equal to 25 μM, with respect to inhibition of Cdk2 Additionally, many of the compounds exhibited an IC50 of less than 10 μM, or less than 1 μM, or less than 0 1 μM IC50 values for additional compounds are provided in Tables 2 and 3
IV. CeU Proliferation Assay Protocol: A2780 of PC-3 CeU Line
A2780 or PC-3 cells were seeded at 1000 cells/well in 100 μL/well (10 000 cells/mL) growth media in 96-well plates Cells were allowed to adhere to the bottom of plates for 3-5 hours in a 37 0C 5% CO2 incubator Compounds were dissolved in DMSO and then transferred to the cell plates The cells were incubated with the compounds for 3 days in a 37 °C 5% CO2 mcubator The growth medium containing the compounds was then removed from the cells and fresh medium was added, followed by 100 μL of Cell Titer GIo assay reagent (Promega) This mixture was shaken for 1 minute and then incubated without shaking for 10 minutes Activity determinations for the compounds were made by detection on a Trilux Instrument Of the Example compounds in Table 1, 101 compounds demonstrated IC5o's of less than 10 μm and of those, 87 compounds demonstrated ICso's of less than 5 μm
V. CeU ProUferation Assay Protocol: PC-3 CeU Line PC-3 cells were seeded at 1000 cells/well in 100 μL/well (10 000 cells/mL) along with growth media into black-walled, clear bottom 96-well plates The cells were allowed to adhere to the bottom of the plate for 3-5 hours in a 37 0C 5% CO2 mcubator
Test compounds were diluted to 50Ox in DMSO The DMSO solutions of six of the compounds were transferred to the cells in the 96 well round bottom plate, column 2, row B- F
A 1 3 serial dilution of each compound was earned out The serial dilution composed addmg 20 μL of DMSO to the wells containing the compounds and doing a 1 3 dilution across the plate from columns 2-10 Column 11 contained only DMSO The seπal dilution was earned out using a BioMek 2000 protocol "CP Senal Dilution using 250 μL tips" or "Proliferation Compound" (if using 20 μL tips)
To a 96 deep well block, columns 2-11 rows B-F, was transferred 500 μL of growth medium Using the FX protocol "HH_CellAssay_2μL to 500 μL", 2 μL of compound from each cell of the compound plate was transferred to the corresponding cell in the 96 deep well block containing 500 μL of growth medium The instrument was programmed to dilute the compound in growth medium and then transfer 100 μL of that mixture to cell plates containing cells
The cell plates, to which test compounds had been added, were incubated for 3 days at 37 °C Following the incubation, the medium was removed and replaced with fresh medium Cell Titer GIo (100 μL) was added to each well and the plate was shaken for 1 mmute and then incubated without shaking for 10 minutes The plates were then read using a Tnlux instrument
VI. The pAktT30S ECL Assay Protocol On Day 1, PC-3 cells were seeded at 15,000 cells/well in 100 μL/well (10 000 cells/mL) growth media into black-walled, clear bottom, poly-L-lysine coated plates The cells were incubated overnight in a 37 0C, 5% CO2 mcubator
On Day 2, a MSD ECL plate was blocked for two hours with 150 μL per well of 3%
MSD blocker A Test compounds were diluted to 500x in DMSO and then were subjected to further senal dilution using a BioMek 2000 instrument DMSO diluted compounds were then diluted into growth media and then added to the cell plates The cell plates incubated with compounds for six hours in a 37 °C, 5% CO2 incubator after which the growth medium was removed and 55 μl of MSD lysis buffer was added to cell plates on ice The plates were lysed on ice for five minutes followed by 15 minutes of vigorous shaking on a plate shaker at 4 0C The blocked MSD assay plates were washed twice with Ix MSD wash buffer followed by the addition of cell lysate as follows 30 μl of cell lysate was added to the pAkt308 plates and 13μl of lysate + 12μl lysis buffer was added to the tAkt plates The plates were then sealed and shaken at 4 °C overnight
On Day 3, the MSD plates were washed four times with Ix MSD wash buffer then, 25 μl/well of MSD SULFO-TAG antibodies diluted to 1OnM final concentration in 1% blocker A buffer was added to the antibody diluent which was added to assay plates The plates were then sealed and incubated at RT for 1 5 hour The plates were then washed twice with Ix MSD wash buffer followed by the addition of 150μl/well of 1 5x MSD read buffer The plates were read immediately after the addition of read buffer using a Tnlux instrument
Of the Example compounds in Table 1, 62 compounds demonstrated ICso's of less than 10 μm and of those, 57 compounds demonstrated ICso's of less than 5 μm Specific IC50 values for representative compounds are also provided in Tables 2 and 3 (see Figures 1 and 2)
The contents of each of the patents, patent applications and journal articles cited above are hereby incorporated by reference herein and for all purposes as if fully set forth in their entireties
A number of embodiments of the invention have been described Nevertheless, it will be understood that various modifications may be made without departing from the spmt and scope of the invention Accordingly, other embodiments are within the scope of the following claims

Claims

WHAT IS CLAIMED IS:
1 A compound of Formula I
Figure imgf000225_0001
I or a pharmaceutically acceptable salt, ester, or tautomer thereof, wherein Ar is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, R1 is H, Cu alkyl, halo, cyano, rutro, CF3, lmidazolyl, thiazolyl, oxazolyl, or amino, R2 is selected from the group consisting of H, alkoxy, substituted alkoxy, alkyl, substituted alkyl, CN, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, and halo,
R3 is selected from the group consisting of H, halo, CN, carboxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, cycloalkyloxy, substituted cycloalkyloxy, heterocyclylalkyloxy, substituted heterocyclylalkyloxy, heteroaryloxy, substituted heteroaryloxy, heteroarylalkyloxy, substituted heteroarylalkyloxy, arylalkyloxy, substituted arylalkyloxy, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroarylalkyl, substituted heteroarylalkyl, heterocyclylalkyl, and substituted heterocyclylalkyl,
L is a covalent bond, carbonyl, carbonylammo, ammocarbonyl, -O-, -S-, -SO-, -SO2-, -NH-, Ci-3 alkyl, substituted Ci 3 alkyl, C2 3 alkenyl, C2 3 alkynyl or an alkyl interrupted with -O-, -S-, -SO-, or -SO2-,
A1 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted ammo, ammocarbonyl, aminothiocarbonyl, ammocarbonylamino, aminotmocarbonylamino, aminocarbonyloxy, ammosulfonyl, ammosulfonyloxy, aminosulfonylammo, amidmo, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, mtro, SO3H, sulfonyl, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, substituted alkylthio, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl, with the provisos a) when R1, R2, and R3 are each H and L is a covalent bond, then A1 is other than aryl or substituted aryl, b) when R1, R2, and R3 are each H, L is a covalent bond, and A1 is Br, substituted phenyl, or substituted pyndmyl, then Ar is other than phenyl, phenyl substituted with piperazinyl or heterocyclylalkyloxy, or pyndmyl, c) when R1, R2, and R3 are each H, L is a covalent bond, and A1 is hydroxy or alkoxy, then Ar is other than phenyl substituted with one or more alkyl or halo, and d) when R1, R2, and R3 are each H and L is O, then A1 is other than pyndmyl or substituted pyndinyl
2 The compound according to claim 1 , or pharmaceutically acceptable salt, ester, or tautomer thereof, wherein L is a covalent bond
3 The compound according to claim 1 , or pharmaceutically acceptable salt, ester, or tautomer thereof, wherein L is carbonyl
4 The compound according to claim 1, or pharmaceutically acceptable salt, ester, or tautomer thereof, wherem L is -NH-
5 The compound according to claim 1, or pharmaceutically acceptable salt, ester, or tautomer thereof, wherein L is aminocarbonyl or carbonylarmno
6 The compound according to claim 1, or pharmaceutically acceptable salt, ester, or tautomer thereof, wherein L is -O-
7 The compound according to any of claims 1 -6, or pharmaceutically acceptable salt, ester, or tautomer thereof, wherein A1 is alkyl
8 The compound according to any of claims 1 -6, or pharmaceutically acceptable salt, ester, or tautomer thereof, wherem A1 is alkynyl
9 The compound according to claim 8, or pharmaceutically acceptable salt, ester, or tautomer thereof, wherem A1 IS ethynyl, propynyl, phenylethynyl or pyπdylethynyl 10 The compound according to any of claims 1 -6, or pharmaceutically acceptable salt, ester, or tautomer thereof, wherein A1 is aryl or substituted aryl
11 The compound according to any of claims 1 -6, or pharmaceutically acceptable salt, ester, or tautomer thereof, wherein A1 is substituted phenyl
12 The compound according to any of claims 1-6, or pharmaceutically acceptable salt, ester, or tautomer thereof, wherein A1 is heteroaryl or substituted heteroaryl
13 The compound according to claim 12, or pharmaceutically acceptable salt, ester, or tautomer thereof, wherein said heteroaryl or substituted heteroaryl is selected from the group consisting of pyπdyl, pyrazolyl, thiazolyl, pyπmidyl, pyπdazmyl, oxazolyl, isoxazolyl, substituted pyπdyl, substituted pyrazolyl, substituted thiazolyl, substituted pyπmidyl, substituted pyπdazmyl, substituted oxazolyl and substituted isoxazolyl
14 The compound according to any of claims 1-6, or pharmaceutically acceptable salt, ester, or tautomer thereof, wherein A1 is heterocyclyl or substituted heterocyclyl
15 The compound according to claim 14, or pharmaceutically acceptable salt, ester, or tautomer thereof, wherein said heterocyclyl or substituted heterocyclyl is selected from the group consisting of pipeπdmyl, piperazinyl, pyrrohdmyl, tetrahydrofuranyl, tetrahydrothiophenyl, morpholinyl, thiomorpholmo, substituted pipeπdinyl, substituted piperazinyl, substituted pyrrohdmyl, substituted tetrahydrofuranyl, substituted tetrahydrothiophenyl, substituted morpholinyl and substituted thiomorpholmo
16 The compound according to claim 2, or pharmaceutically acceptable salt, ester, or tautomer thereof, wherein A1 is halo
17 The compound according to claim 2, or pharmaceutically acceptable salt, ester, or tautomer thereof, wherein A1 is cyano
18 The compound according to any of claims 1 - 17, or pharmaceutically acceptable salt, ester, or tautomer thereof, wherem R1 is H or halo 19 The compound according to claim 18, or pharmaceutically acceptable salt, ester, or tautomer thereof, wherein R2 and R3 are independently selected from the group consisting of H, halo and alkσxy
20 The compound according to claim 19, or pharmaceutically acceptable salt, ester, or r ttaauuttoommeerr tthheerreeooff,, wwhh<erein R2 and R3 are independently selected from the group consisting of H and methoxy
21 The compound according to claim 20, or pharmaceutically acceptable salt, ester, or tautomer thereof, wherein at least one of R2 and R3 is H
22 The compound according to claim 19, or pharmaceutically acceptable salt, ester, or tautomer thereof, wherem R2 and R3 are both H
23 The compound of any of claims 1 - 17, or pharmaceutically acceptable salt, ester, or tautomer thereof, wherein one of R2 and R3 is H and the other of R2 and R3 is alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, cycloalkyloxy, substituted cycloalkyloxy, heterocyclylalkyloxy, substituted heterocyclylalkyloxy, heteroaryloxy, substituted heteroaryloxy, heteroarylalkyloxy, substituted heteroarylalkyloxy, arylalkyloxy, or substituted arylalkyloxy,
24 The compound according to any of claims 1-23, or pharmaceutically acceptable salt, ester, or tautomer thereof, wherein Ar is substituted aryl or substituted heteroaryl
25 The compound according to claim 24, or pharmaceutically acceptable salt, ester, or tautomer thereof, wherein Ar is aryl, substituted by 1 , 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, amino, substituted ammo, ammocarbonyl, aminothiocarbonyl, aminocarbonylammo, aminothiocarbonylammo, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylammo, amidino, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)ammo, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guamdmo, substituted guanidino, halo, hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, mtro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, and alkylthio, wherein the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heterocyclyl, and heteroaryl moieties contained withm any of the listed substituted aryl groups are optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkenyl, alkynyl, alkoxy, acyl, acylammo, acyloxy, amino, substituted amino, ammocarbonyl, ammothiocarbonyl, aminocarbonylammo, ammothiocarbonylammo, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, ammosulfonylammo, amidmo, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)ammo, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guanidino, guanidmo, halo, hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, mtro, SO3H, sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and alkylthio
26 The compound according to claim 25, or pharmaceutically acceptable salt, ester, or tautomer thereof, wherein Ar is aryl substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of aminosulfonyl, ammocarbonyl, aryl, heteroaryl, heterocyclyl, ammo, substituted amino, alkyl, halo, and cyano, wherein the alkyl, aryl, and heteroaryl moieties contained within any of the listed substituted aryl groups are optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkenyl, alkynyl, alkoxy, acyl, acylammo, acyloxy, amino, substituted amino, aminocarbonyl, ammothiocarbonyl, aminocarbonylammo, ammothiocarbonylammo, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, ammosulfonylammo, amidino, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guamdmo, guanidino, halo, hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, mtro, SO3H, sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and alkylthio
27 The compound according to claim 25, or pharmaceutically acceptable salt, ester, or tautomer thereof, wherein Ar is substituted phenyl 28 The compound according to claim 24, or pharmaceutically acceptable salt, ester, or tautomer thereof, wherein Ar is heteroaryl, substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, amino, substituted ammo, ammocarbonyl, ammothiocarbonyl, ammocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, ammosulfonyloxy, ammosulfonylammo, amidino, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)ammo, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guamdino, substituted guamdmo, halo, hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, and alkylthio, wherein the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heterocyclyl, and heteroaryl moieties contained within any of the listed substituted aryl groups are optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, ammothiocarbonyl, ammocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, ammosulfonyloxy, ammosulfonylammo, amidino, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)ammo, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guamdmo, guamdmo, halo, hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, nitro, SO3H, sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and alkylthio
29 The compound according to claim 28, or pharmaceutically acceptable salt, ester, or tautomer thereof, wherein Ar is heteroaryl substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of aminosulfonyl, ammocarbonyl, aryl, heteroaryl, heterocyclyl, ammo, substituted amino, alkyl, halo, and cyano, wherein the alkyl, aryl, and heteroaryl moieties contained within any of the listed substituted aryl groups are optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, ammo, substituted amino, aminocarbonyl, ammothiocarbonyl, ammocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, ammosulfonyloxy, ammosulfonylammo, amidino, aryl, aryloxy, arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkenyl, cycloalkenyloxy, cycloalkenylthio, guamdmo, guanidmo, halo, hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, nitro, SO3H, sulfonyl, sulfonyloxy, sulfonylammo, thioacyl, thiol, alkylthio, and alkylthio
30 The compound according to claim 29, or pharmaceutically acceptable salt, ester, or tautomer thereof, wherein Ar is selected from the group consisting of substituted pyπdyl, substituted pyrazolyl, substituted thiazolyl, substituted pyrimidyl, substituted pyπdazinyl, substituted oxazolyl and substituted isoxazolyl
31 A compound according claim 1 , or pharmaceutically acceptable salt, ester, or tautomer thereof, wherein the Formula I compound is a compound according to one of Formulae II- VII
Figure imgf000231_0001
wherein Rp is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted ammo, ammocarbonyl, aminothiocarbonyl, ammocarbonylatmno, aminothiocarbonylammo, aminocarbonyloxy, aminosulfonyl, ammosulfonyloxy, ammosulfonylammo, amidino, aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guamdmo, substituted guanidmo, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, mtro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylammo, thioacyl, thiol, alkylthio, and substituted alkylthio,
RA is selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl and substituted heterocyclyl,
Het is selected from the group consisting of heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl, and x is 1, 2, 3, 4 or 5
32 The compound of claim 27, or pharmaceutically acceptable salt, ester, or tautomer thereof, wherein said substituted phenyl is substituted by 1, 2 or 3 groups that are not attached to said phenyl ortho to the NH of formula I
33 A compound according to claim 1 selected from the group consisting of 4-(6-bromo-8-methoxyquinazolm-2-ylamino)benzenesulfonarmde, 4-(6-emynyl-8-methoxyqmnazolin-2-ylammo)benzenesulfonamide, 4-(6-ethyl-8-methoxyquinazolm-2-ylamino)benzenesulfonamide, 4-(6-cyano-8-methoxyquinazolm-2-ylamino)benzenesulfonamide, 4-(8-methoxy-6-methylquinazolin-2-ylammo)benzenesulfonamide, ΛL(3-(6-bromo-8-chloroquinazolin-2-ylammo)-5-((dimethylammo)methyl)phenyl)- acetamide, iV-(3-(8-chloro-6-ethynylqumazolin-2-ylamino)-5-((dimethylamino)methyl)phenyl)- acetamide,
4-(8-bromo-6-(tπfluoromethyl)qumazolm-2-ylammo)benzenesulfonamide,
4-(6-bromoqumazolm-2-ylammo)benzenesulfonamide,
4-(6-ethynylqumazolm-2-ylammo)benzenesulfonamide,
4-(6-bromoquinazolm-2-ylammo)-iV-isopropylbenzamide, iV-isopropyl-4-(6-(thiazol-2-yl)qumazolm-2-ylammo)benzamide,
4-(6-cyanoquinazolm-2-ylamino)-iV-isopropylbenzamide,
7V (3-(6-bromo-5-chloro-8-methoxyqumazolm-2-ylamino)-5-((dimethylamino)- methyl)phenyl)acetamide,
4-(8-bromo-6-fluoroqumazolm-2-ylammo)benzenesulfonarmde, iV-(3-(6-bromoqumazolm-2-ylamino)-5-(l-methyl-6-oxo-l,6-dihydropyndin-3- yl)phenyl)acetamide,
Λf-(3-(6-ethynylqmnazohn-2-ylammo)-5-(l-methyl-6-oxo-l,6-dihydropyndm-3- yl)phenyl)acetamide, methyl 2-(4-sulfamoylphenylamino)qumazoline-6-carboxylate,
2-(4-sulfamoylphenylammo)quinazolme-6-carboxyhc acid,
4-(6-(4-methylpiperazine-l-carbonyl)qumazolm-2-ylammo)beiLzenesulfonamide,
4-(6-(l-isobutyl-lH-pyrazol-4-yl)qmnazolin-2-ylamino)benzenesulfonamide,
(4-(5-chloro-6-ethynylqumazolin-2-ylammo)phenyl)(morpholmo)methanone,
6-bromo-5-fluoro-7V-(4-morpholmophenyl)-qumazolm-2-amine,
6-ethynyl-5-fluoro-Λ'-(4-morpholinophenyl)-quinazolin-2-amme, iV-(3-(6-bromo-5-fluoroquinazolin-2-ylammo)-5-(morpholinomethyl)-phenyl)- acetamide,
ΛL(3-(5-fluoro-6-(thiazol-2-yl)quinazohn-2-ylamino)-5-(morpholinomethyl)phenyl)- acetamide,
4-(6-(thiazol-2-yl)qumazolin-2-ylamino)benzenesulfonamide,
5-chloro-iV-(4-morpholinophenyl)-6-(thiazol-2-yl)qumazolin-2-amme,
Λ?-(3-(6-bromoquinazolm-2-ylammo)-5-(morρholinomethyl)ρhenyl)acetamide,
N-
(3-(6-(lH-pyrazol-4-yl)qumazolm-2-ylamino)-5-(moφholmoinethyl)phenyl)- acetamide, iV-(3-(6-bromoqumazolm-2-ylammo)-5-iodophenyl)acetamide, iV-(3-(6-bromoqumazolm-2-ylammo)-5-(pyndin-3-yl)phenyl)acetamide, iV-(3-(pyndin-3-yl)-5-(6-(pyndm-3-yl)qmnazolin-2-ylanuno)phenyl)acetamide,
Λ^(3-(6-ethynylquinazolm-2-ylamino)-5-(pyπdin-3-yl)phenyl)acetamide,
4-(6,7-dimethoxyquinazohn-2-ylamino)benzenesulfonamide,
4-(6-methoxyquinazolin-2-ylammo)benzamide,
7V-methyl-2-(4-sulfamoylphenylamino)quinazolme-6-carboxamide,
A^-(I -methylpipeπdin-4-yl)-2-(4-sulfamoylphenylamino)qmnazolme-6-carboxamide,
4-(6-(4-isopropylpiperazme-l-carbonyl)quinazolin-2-ylammo)benzenesulfonamide,
Λr-isopropyl-2-(4-sulfamoylphenylamino)qmnazolme-6-carboxamide,
4-(6-(pyrrolidme- 1 -carbonyl)qumazolm-2-ylamino)benzenesulfonamide,
2-(4-sulfamoylphenylamino)quinazolme-6-carboxamide,
7V-cyclopropyl-2-(4-sulfamoylphenylammo)qvunazolme-6-carboxamide, 4-(6-(2-fluoropyπdm-3-yl)qumazolm-2-ylammo)beπzenesulfonamide, 4-(6-(2-(4-methylpiperazm-l-yl)pyndm-4-yl)quinazolm-2-ylammo)benzene- sulfonamide, iV-(3-benzarmdophenyl)-2-(4-sulfamoylphenylamino)-quinazoline-6-carboxamide,
4-(6-bromo-7-methoxyqumazolin-2-ylamino)benzenesulfonamide,
6-bromo-7-methoxy-Λ'-(4-(morpholmosulfonyl)phenyl)-qumazolm-2-amine,
4-(6-ethynyl-7-methoxyqmnazolm-2-ylarnmo)benzenesulfonamide,
6-ethynyl-7-methoxy-iV-(4-(moφholmosulfonyl)phenyl)-qumazolin-2-amme,
6-ethynyl-7^-(3-morpholmophenyl)quinazolin-2-atmne,
4-(8-methoxy-6-(phenylethynyl)qumazolin-2-ylammo)benzenesulfonamide,
4-(8-methoxy-6-(pyπdin-3-ylethynyl)qumazolm-2-ylamino)benzenesulfonamide,
4-(6-methylquinazohn-2-ylammo)benzenesulfonamide,
4-(7-methoxy-6-(phenylethynyl)quinazolm-2-ylammo)benzenesulfonamide,
4-(6-(l-methyl-lH-pyrazol-4-yl)qmnazolm-2-ylamino)benzenesulfonamide,
6-ethynyl-7V-(4-morpholmophenyl)qmnazolm-2-amme,
4-(6-ethynylqmnazolm-2-ylamino)benzamide,
3-(6-ethynylqumazolm-2-ylamino)benzamide,
3-(6-ethynylquinazolm-2-ylamino)benzenesulfonamide, iV-(3-(6-ethynylquinazolin-2-ylammo)phenyl)methanesulfonamide,
4-(8-methoxy-6-(l-methyl-lH-pyrazol-4-yl)qmnazolm-2-ylammo)benzene- sulfonamide,
4-(8-methoxy-6-(thiazol-2-yl)quinazolin-2-ylammo)benzenesulfonamide,
4-(8-methoxy-6-(pyπdin-2-ylethynyl)quinazolin-2-ylamino)benzenesulfonamide,
4-(6-(3-hydroxy-3-methylbut-l-ynyl)-8-methoxyqumazolin-2-ylamino)benzene- sulfonamide,
4-(6-(3-amino-3-methylbut-l-ynyl)-8-methoxyqumazolin-2-ylammo)benzene- sulfonamide,
4-(6-(lH-pyrazol-3-yl)qumazolm-2-ylamino)benzenesulfonamide, 7V-(2-(4-sulfamoylphenylamino)qumazolm-6-yl)acetamide, 6-ethynyl-7-methoxy-iV-(4-morpholinophenyl)qumazolm-2-amme, 6-ethynyl-8-methoxy-iV-(4-morpholinophenyl)qumazolin-2-amuie, iV-(3-((dimethylammo)methyl)phenyl)-6-ethynylqumazolm-2-amme, 4-(6-ethynylquinazolin-2-ylammo)-Λ'-isopropylbenzamide, 4-(6-ethynyl-7-methoxyquinazolm-2-ylamino)-iV-isoρropylbenzamide, (4-(6-ethynyl-7-methoxyquinazolin-2-ylammo)phenyl)(morphohno)methanone,
4-(6-(thiazol-2-yl)qumazolin-2-ylamino)benzamide,
2-(4-morpholmophenylammo)quinazoline-6-carborutπle,
64>romo-N-(4-morphohnophenyl)qumazolm-2-amme,
4-(6-cyanoqmnazolin-2-ylammo)benzamide,
4-(6-bromoqumazolm-2-ylammo)benz amide,
6-ethynyl-8-memoxy-ΛH3-morpholinophenyl)qmnazohn-2-amme,
(4-(6-ethynylquinazohn-2-ylamino)phenyl)(moφholmo)methanone, iV-(3-((diπiethylamino)methyl)-4-morpholmophenyl)-6-ethynylquinazolin-2-amine, iV-(3-((dimethylammo)methyl)-5-(6-ethynylqumazolm-2-ylammo)phenyl)acetamide,
JV-(3-((dimethylamino)methyl)-5-(6-(thiazol-2-yl)qumazolm-2-ylamino)phenyl)- acetamide,
JV-(3-((dimethylamino)methyl)-5-(6-ethynyl-7-methoxyquinazolm-2-ylammo)- phenyl) acetamide, iV-(3-((dimethylamino)methyl)-5-(6-ethynyl-8-methoxyqmnazolm-2-ylamino)- phenyl) acetamide, iV-(3-((dimethylammo)methyl)-5-(8-methoxy-6-(thiazol-2-yl)quinazolin-2-ylamino)- phenyl) acetamide,
7V-(3-(5-chloro-6-ethynyl-8-methoxyqmnazolm-2-ylamino)-5-((dimethylamino)- methyl)phenyl)acetamide,
4-(6-bromo-5-chloro-8-methoxyqmnazolm-2-ylamino)-7V-isopropylbenzamide,
7V-(3-(5-chloro-6-ethynylqumazolin-2-ylamino)-5-((dimethylammo)methyl)-phenyl)- acetamide,
7V-(3-(5-chloro-6-(thiazol-2-yl)quinazolm-2-ylamino)-5-((dimethylamino)methyl)- phenyl)acetamide, iV-(3-((dimethylammo)methyl)-5-(6-(pynmidm-5-yl)qumazolm-2-ylammo)phenyl)- acetamide,
7V-(3-((dimethylammo)methyl)-5-(6-(2-methoxypyridm-3-yl)qmnazolin-2-ylamino)- phenyl)acetamide,
7V-(3-((dimethylammo)methyl)-5-(8-methoxy-6-(2-methoxypyndin-3-yl)qumazolin-2- ylamino)phenyl)acetamide, iV-(3-((dimethylammo)methyl)-5-(8-methoxy-6-(ρyrimidin-5-yl)qmnazolm-2- ylamino)phenyl)acetamide, iV-(4-(lH-tetrazol-5-yl)phenyl)-6-ethynyl-7-methoxyqumazolin-2-amme, JV-(4-( 1 H-tetrazol- 1 -yl)phenyl)-6-ethynyl-7-methoxyquinazolin-2-amme,
N-(3 -( 1 H-tetrazol-5-yl)phenyl)-6-ethynyl-7-methoxyquinazohn-2-amme,
5-chloro-6-ethynyl-Λ'-(4-moφholinophenyl)qumazolm-2-amme,
7V-(4-moφholinoρhenyl)-6-(thiazol-2-yl)qumazolm-2-amme,
5-chloro-6-ethynyl-8-methoxy-iV-(4-morpholinophenyl)quinazohn-2-amine,
(4-(6-bromo-7-methoxyquinazolin-2-ylamino)-2-chlorophenyl)(moφholmo)- methanone,
ΛL(3-(lH-tetrazol-l-yl)phenyl)-6-ethynyl-7-methoxyquinazolin-2-amme, (2-chloro-4-(7-methoxy-6-(thiazol-2-yl)qumazolin-2-ylammo)phenyl)(morphohno)- methanone, iV;iV'-(5-(6-ethynylqmnazolm-2-ylammo)-l,3-phenylene)diacetamide,
4-(5-chloro-6-ethynylqmnazolin-2-ylamino)-Λ'-isopropylbenzamide,
4-(5-chloro-6-ethynylquinazohn-2-ylammo)-Λ''-cyclopropylbenzatmde,
4-(5-chloro-6-(thiazol-2-yl)quinazolin-2-ylamino)-7V-isopropylbenzamide, jV-(3-((dimethylammo)methyl)-5-(6-methoxyqiunazolin-2-ylamino)phenyl)acetamide,
N-(3-((dimethylamino)methyl)-5-(8-methoxy-6-(6-methoxypyrazm-2-yl)quinazolin-
2-ylammo)ρhenyl)acetamide,
N-(3-(6-(2-amino-4-methoxypynmidiii-5-yl)-8-methoxyqumazolm-2-ylamino)-5-
((dimethylamino)methyl)-phenyl)acetamide,
N-(3-(lH-tetrazol-l-yl)phenyl)-7-methoxy-6-(thiazol-2-yl)qumazolin-2-amme, (4-(5-chloro-6-ethynyl-8-methoxyqumazolm-2-ylammo)phenyl)(morpholino)- methanone,
4-(5-chloro-6-ethynyl-8-methoxyquinazolm-2-ylammo)-N-isopropylbenzamide, 5-cbloro-8-methoxy-N-(4-morpholinophenyl)-6-(thiazol-2-yl)qmnazolm-2-amine, 6-bromo-5-chloro-8-methoxy-N-(4-morpholinophenyl)quinazolin-2-amme, (4-(5-chloro-8-methoxy-6-(thiazol-2-yl)qumazolin-2-ylamino)phenyl)-(morpholino)- methanone,
(4-(6-bromo-5-chloro-8-methoxyqumazolm-2-ylamino)phenyl)-(moφholmo)- methanone,
4-(5-chloro-8-methoxy-6-(thiazol-2-yl)qumazolm-2-ylamino)-N-isopropylbenzamide, (2-chloro-4-(6-ethynyl-7-methoxyqumazolm-2-ylamino)phenyl)(moφholmo)- methanone,
5-chloro-6-ethynyl-N-(3-moφhohnophenyl)qumazolin-2-amine, N-(3-((dimethylammo)methyl)-5-(7-methoxy-6-(thiazol-2-yl)qumazolm-2-ylamino)- phenyl) acetamide,
5-(6-bromoqumazolin-2-ylamino)-2-morpholinobenzamide, 5-(6-ethynylquinazolm-2-ylammo)-2-moφholmobenzamide, N-(3-(6-ethynylqmnazolm-2-ylammo)-5-(morpholinomethyl)phenyl)acetamide, N-(3-(pyrrohdm-l-ylmethyl)-5-(6-(thiazol-2-yl)qumazolm-2-ylamino)phenyl)- acetamide,
N-(3-(6-ethynylqumazolm-2-ylamino)-5-(pyiτolidm-l-ylmethyl)phenyl)acetamide, N-(3-(6-bromo-8-chloroqumazolin-2-ylammo)-5-(morpholmomethyl)-phenyl)- acetamide,
N-(3-(8-chloro-6-ethynylqumazolin-2-ylamino)-5-(morpholmomethyl)-phenyl)- acetamide,
N,N'-(5-(5-chloro-6-ethynylqumazolin-2-ylammo)-l,3-phenylene)diacetamide, N-(6-chloro- 1 H-indazol-4-yl)-6-ethynylqmnazolin-2-amine, 6-ethynyl-N-(6-fluoro- 1 H-indazol-4-yl)qumazolin-2-amine,
N-(3-(morpholmomethyl)-5-(6-(thiazol-2-yl)qmnazolm-2-ylammo)phenyl)acetamide, 7-methoxy-N-(4-morpholmophenyl)-6-(thiazol-2-yl)quiπazolin-2-amine, N-(3-(6-bromo-8-fluoroqumazolm-2-ylamino)-5-((dimethylammo)methyl)-phenyl)- acetamide,
N-(3-(6-(isoxazol-4-yl)qumazohn-2-ylamino)-5-(morpholmomethyl)phenyl)- acetamide,
N-(3-(aminomethyl)-5-(6-ethynylquinazolm-2-ylamino)phenyl)acetamide,
6-ethynyl-N-phenylqumazolin-2-amine,
N-(3-((dimethylammo)methyl)-5-(6-ethyπyl-8-fluoroqmnazolm-2-ylammo)phenyl)- acetamide,
N-(3-(7-methoxy-6-(thiazol-2-yl)qumazolm-2-ylamino)-5-(morpholinomethyl)- phenyl)-acetamide,
N-(3-(6-ethynylquinazolm-2-ylamino)-5-(ρiρerazm-l-ylmethyl)phenyl)acetaimde,
N-(3-(6-ethynylqumazolm-2-ylamino)-5-(morphobnomethyl)phenyl)-isobutyramide,
^(S-Cό-ethynylquinazolm^-ylammoJ-S-^orpholinomethy^pheny^methane- sulfonamide,
6-bromo-N-(3-(morpholmomethyl)-5-(lH-tetrazol-5-yl)phenyl)quinazolm-2-amine, N-(3-(6-bromoquinazolm-2-ylammo)-5-(morpholmomethyl)phenyl)acetamide, N-(3-(6-ethynylqmnazolm-2-ylammo)-5-(pyndm-4-yl)phenyl)acetamide, N-(3-(6-bromoquinazohn-2-ylammo)-5-((dimethylamino)methyl)phenyl)acetamide, N-(3 -((dimethylamino)methyl)-5-(6-(prop- 1 -ynyl)qumazolm-2-ylammo)phenyl)- acetamide,
6-ethynyl-N-(3-(morpholinomethyl)-5-(lH-tetrazol-5-yl)phenyl)qumazolm-2-amme,
7-methoxy-N-(4-morpholinophenyl)-6-(lH-pyrazol-4-yl)qumazohn-2-amine,
3-(6-bromoquinazolin-2-ylamino)-5-(morpholinomethyl)benzomtπle,
3-(6-ethynylqumazolm-2-ylamino)-5-(morpholinomethyl)benzomtπle,
N-(3-(6-bromoqumazolm-2-ylammo)-5-(lH-pyrazol-4-yl)phenyl)acetamide,
6-bromo-N-(3-methoxy-5-(5-methyl-lH-tetrazol-l-yl)phenyl)quinazolm-2-amine,
6-bromo-N-(3-methoxy-5-(lH-tetrazol-l-yl)phenyl)qumazolm-2-amine,
6-ethynyl-N-(3-methoxy-5-(5-methyl-lH-tetrazol-l-yl)phenyl)quinazolin-2-amine,
6-ethynyl-N-(3-morpholino-5-(pyndm-4-yl)phenyl)qumazolm-2-amine,
6-ethynyl-N-(3-morphohno-5-(lH-pyrazol-4-yl)phenyl)qumazolm-2-amme,
6-ethynyl-N-(3-morpholmo-5-(pyπdm-3-yl)phenyl)qumazolm-2-amme,
6-ethynyl-N-(3-(3-fluoropyndm-4-yl)-5-morpholmophenyl)qumazolin-2-amine,
N-(3-(6-ethynyl-5-fluoroquinazolin-2-ylammo)-5-(morpholinomethyl)-phenyl)- acetamide,
N-(3-(6-ethynyl-5-fluoroqumazolin-2-ylammo)-5-(morphohnomethyl)-phenyl)- methanesulfonamide,
3-(6-bromoqumazolm-2-ylammo)-5-(moφholinomethyl)benzamide, N-(3-(6-ethynylquinazolm-2-ylamino)-5-(lH-pyrazol-4-yl)phenyl)acetamide, N-(3-(6-ethynylqumazolm-2-ylamino)-5-(pyπimdm-5-yl)phenyl)acetamide, methyl 3-(6-ethynylqumazolin-2-ylammo)-5-(morpholinomethyl)phenylcarbamate, methyl 3-(6-bromoqmnazohn-2-ylamino)-5-(morpholmomethyl)phenylcarbamate, N-(4-morphohnophenyl)-5,6-di(thiazol-2-yl)quinazolin-2-amme, 8-methoxy-N-(4-morpholinophenyl)-5,6-di(thiazol-2-yl)quinazohn-2-amine, (4-(8-methoxy-5,6-di(thiazol-2-yl)qmnazolm-2-ylamino)phenyl)(moφhohno)- methanone,
4-(5,6-di(thiazol-2-yl)qumazolin-2-ylammo)-N-isopropylbenzamide, 6-ethynyl-7-methoxy-N-(3-methoxy-5-(5-methyl-lH-tetrazol-l-yl)phenyl)quinazolin-
2-amme,
6,7-dimethoxy-N-(4-moφholmophenyl)-quinazolm-2-amine, N-(3-(6,7-dimethoxyquinazolin-2-ylammo)-5-(morpholinomethyl)-phenyl)acetamide, N-(3-(7-methoxy-6-(lH-pyrazol-4-yl)qmnazolin-2-ylammo)-5-(morpholinomethyl)- phenyl)acetamide, and
N-(3-(7-methoxy-6-(lH-pyrazol-4-yl)quinazohn-2-ylamino)-5-(lH-pyrazol-4- yl)phenyl)acetamide, or a pharmaceutically acceptable salt, ester, or tautomer of one of these compounds
34 The compound of claim 1 , or pharmaceutically acceptable salt, ester, or tautomer thereof, which is selected from the compounds in Table 2 (Figure 1)
35 The compound of claim 1 , or pharmaceutically acceptable salt, ester, or tautomer thereof, which is selected from the compounds in Table 3 (Figure 2)
36 A pharmaceutical composition comprising a pharmaceutically acceptable earner and at least one compound according to any one of the previous claims, or pharmaceutically acceptable salt, ester, or tautomer thereof
37 A method of inhibiting PDKl or a PDKl variant in a patient comprising administering to said patient, a therapeutically effective amount of a compound of any one of claim 1 to 31, or pharmaceutically acceptable salt, ester, or tautomer thereof
38 The method of claim 37, which composes a method of inhibiting PDKl
39 The method of claim 37, which compnses a method of inhibiting a PDKl variant
40 The method of claim 37 wherein said PDKl variant is PDK1T354M or pDK1D527E
41 A method of treating a disease characteπzed by abnormal cellular proliferation in a patient comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1 to 35, or pharmaceutically acceptable salt, ester, or tautomer thereof 42 The method of claim 41 , wherein the abnormal cellular proliferation is mediated by PDKl
43 The method of claim 41 , wherein the disease is a cancer
44 The method of claim 43, wherein the cancer is selected from the group consisting of lung cancer, bronchial cancer, prostate cancer, breast cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, thyroid cancer, liver cancer, intrahepatic bile duct cancer, hepatocellular cancer, gastπc cancer, glioma/glioblastoma, endometrial cancer, melanoma, kidney cancer, renal pelvic cancer, urinary bladder cancer, uteπne corpus cancer, uteπne cervical cancer, ovaπan cancer, multiple myeloma, esophageal cancer, acute myelogenous leukemia, chrome myelogenous leukemia, lymphocytic leukemia, myeloid leukemia, brain cancer, oral cavity cancer, and pharyngeal cancer, laryngeal cancer, small intestinal cancer, non-Hodgkin lymphoma, and villous colon adenoma
45 The method of claim 44, wherein the cancer is selected from the group consisting of cancers of the prostate, lung, colon, and breast
46 The method of claim 41 , wherein the disease is a non-cancer proliferative disorder
47 The method of claim 46, wherein the disease is selected from the group consisting of neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis, proliferative diabetic retinopathy, hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, angiogenesis and endotoxic shock
48 A method of inhibiting the tumor growth m a patient, the method compπsing administering to said patient a therapeutically effective amount of a compound of any one of claims 1 to 31 , or pharmaceutically acceptable salt, ester, or tautomer thereof
49 The method of claim 48, wherein said tumor is characteπzed by elevated receptor tyrosine kinases, Ras, PI3K, PDKl, AKT, RSK, PKC, 70S6K, or SGK activity 50 A method of treating cancer in a patient, the method compnsing administering to said patient a therapeutically effective amount of a compound of any one of claims 1 to 31, or pharmaceutically acceptable salt, ester, or tautomer thereof
51 The method of claim 50 wherein said cancer is characteπzed by increased activity of PDKl
52 The method of claim 49 wherein said cancer is characteπzed by activity of a PDKl variant
53 The method of claim 52 wherein said PDKl variant is PDK1T354M or pDK1D527E
PCT/US2007/088392 2006-12-22 2007-12-20 Quinazolines for pdk1 inhibition WO2008079988A2 (en)

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