INHIBITORS OF POLO-LIKE KINASES

This application claims priority to commonly-owned United States Provisional Patent Application Serial No 60/80331 3, filed May 26, 2006

FIELD OF THE INVENTION

This invention pertains to compounds that inhibit PIk 1, compositions containing the compounds and methods of treating diseases using the compounds,

BACKGROUND OF THE INVENTION Polo-like kinases (Plk's) are important in mitotic progression, and are theiefoie important for cell proliferation For example, Plkl is essential for the proper function of bipolar spindles and chromosomal segregation during metaphase of cell division Plkl depletion causes a defect in the attachment between the mitotic spindles and centrosomes, causing these cells to accumulate during mitosis then die. Because inhibition of Plkl causes mitotic arrest, inhibitors of Plkl have the potential to be cytotoxic agents that are useful for treatment of diseases of cellular proliferation, such as, for example, cancer

SUMMARY OF THE INVENTION

One embodiment of this invention, therefore, comprises compounds which inhibit polo-like kinases, the compounds having formula (I)

(D, and therapeutically acceptable salts, prodrugs and salts of prodrugs thereof, wherein

X ¹ is X ² , OX ² , SX ² , S(O)X ² , SO ₂ X ² or N(A ¹ XB ¹ );

X ² is X ³ , X ⁴ , X ⁵ or X ⁶ ;

X is phenyl which is unfused or fused with benzene, heteroarene or X ; X is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

A A δ 4λ

X is heteroaryl which is unfused or fused with benzene, heteioarene or X ; X is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

X is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloallcenyl, each of which is unfused 01 fused with benzene, heteroarene or X ; X is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

X is alkyl, alkenyl or alkynyl, each of which is un substituted or substituted with phenyl, furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl, 1,2,5-oxadiazoIyl, oxazolyl, pyiazinyl, pyrazolyl, pyridazinyl, pyiimidinyl, pyrτolyl, 1,2,4-thiadiazolyl, thiazolyl, thiophenyl, triazinyl or 1,2,3-triazolyl;

A ¹ and B ¹ are independently selected H, R ¹ , C(O)R \ C(O)OR ¹ , C(O)NHR ¹ ,

C(O)N(R ¹ ) ₂ , SO ₂ NHR ¹ or SO ₂ N(R ¹ ) ₂ ;

R ^" is phenyl which is unfused or fused with benzene, heteroarene or R ^" ; R ^" is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R is heteroaryl which is unfused or fused with benzene, heteroarene or R ; R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of

4A 4A which is unfused or fused with benzene, heteroarene or R ; R is cycloalkane, cycloalkene, heteiocycloalkane or heterocycloalkene;

R is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R ⁶ , OR ⁶ , C(O)OR ⁶ , C(O)NH ₂ , C(O)NHR ⁶ , C(O)N(R ⁶ ) ₂ , NHC(O)R ⁶ , NR ⁶ C(O)R ⁶ , OH, (O), CN, NH ₂ , NHR ⁶ , N(R ⁶ ) ₂ , F, Cl, Br or I;

R ⁶ is R ⁷ , R ⁸ or R ⁹ ;

R is phenyl which is unfused or fused with benzene, heteroarene or R ; R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R is heteroaryl which is unfused or fused with benzene, heteroarene or R ; R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R ; R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

C ¹ is H, R ¹⁰ , C(O)R ¹⁰ , C(O)OR ¹⁰ , C(O)NHR ¹⁰ , C(O)N(R ¹⁰ ) ₂ , SO ₂ NHR ¹⁰ oτ SO ₂ N(R ^l0 ) ₂ ;

R ^{l 0} is R", R ^l2 , R ¹³ or R ¹⁴ ;

R is phenyl which is unfused or fused with benzene, heteroarene or R ; R is cycloalkane, cycloalkene, heteiocycloalkane oi heterocycloalkeiie;

R ^" is heteroaryl which is unfused or fused with benzene, heteroarene or R ; R ~ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R is cycloalkyl, cycloalkenyl, hetetocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteioarene or R ; R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R is alkyl, alkcnyl or alkynyl, each of which is unsubstituted or substituted with

1 _Iλ I J λ I dA one or two or three of independently selected R , OR , C(O)OR , C(O)NH ₂ , C(0)NHR ^!4A , C(O)N(R ^!4A ) ₂ , NHC(0)R ^14A , C(0)R ^14A , OH, CN, NH ₂ , NHR ^14A , N(R ^!4A ) ₂ , F, Cl, Br oi I; _n !4λ • „ 15 _n \6 „ 17

R is R , R or R ;

R is phenyl which is unfused or fused with benzene, heteroarene or R ; R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R is heteroaryl which is unfused or fused with benzene, heteroarene oi R ; R is cycloalkane, cycloalkene, helerocycloalkane or heterocycloalkene;

R is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of

17A ! 7A which is unfused or fused with benzene, heteroarene oi R ; R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

D is R , R or R ;

R is pyrimidinyl which is unfused or fused with benzene, heteroaiene or R and unsubstituted oi substituted with one or two or three of independently selected CN,

N NOO ₂₂ ,, FF,, CCll,, BBrr oorr II;; R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R is pyridinyi which is υnfused or fused with benzene, heteroarene or R and substituted with OR ² ', SR ²¹ , SO ₂ R ²¹ or NHR ² '; R ^19A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R ^" is furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyiidazinyl, pyrimidinyl, pyrrol yl, 1,2,4-thiadiazolyl, Ihiazolyl, thiophenyl, tiiazinyl or 1,2,3-triazolyl, each of which is unfused or fused with benzene or heteroaiyl and substituted with R , OR ^"" , SR ^" , SO ₂ R ² ', NHR ²¹ Or N(CH ₃ )R ²¹ ; τ,2l . „ 22 _Ώ 23 _π 24 _π 25

R is R , R , R or R ;

R ^" is phenyl which is unfused or fused with benzene, heteroarene or R ^"" ; R ^"" is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R ^" is heteroaryl which is unfused or fused with benzene, heteroarene or R ^" ;

⁷ 3A

R ^" is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R ^" is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R ^{" ?} 4A ; R ^" ^4A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R ^" is allcyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or thiee of independently selected R ²⁶ , OR ²⁶ , C(O)OR ²⁶ , C(O)NH ₂ , C(O)NHR ²⁶ , C(O)N(R ²⁶ ) ₂ , NHC(O)R ²⁶ , NR ²⁶ C(O)R ²⁶ , OH, CN, NH ₂ , NHR ²⁶ , N(R ²⁶ ) ₂ , F, Cl, Br or I;

_Ώ 26 . _Ώ 27 _O 28 _n 29

R is R , R or R ;

R ^" is phenyl which is unfused or fused with benzene, heteroarene or R ; R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R ^" is heteroaryl which is unfused oi fused with benzene, heteroarene or R ; R ^" is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R ^" ^9A ; R 29A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

each foregoing cyclic moiety is independently uπsubstituted, further unsubstituted, substituted or further substituted with one or two or three or four or five of independently selected R ³⁰ , OR ³⁰ , SR ³⁰ , S(O)R ³⁰ , SO ₂ R ³⁰ , C(O)R ³⁰ , CO(O)R ³⁰ , OC(O)R ³⁰ , OC(O)OR ³⁰ , NH ₂ , NHR ³⁰ , N(R ³⁰ ) ₂ , C(O)NH ₂ , C(O)NHR ³⁰ , C(O)N(R ³⁰ ) ₂ , SO ₂ NH ₂ , SO ₂ NHR ³⁰ , NHSO ₂ R ³⁰ , N(R ³⁰ )SO ₂ R ³ °, SO ₂ N(R ³⁰ ),, CF ₃ , CF ₂ CF ₃ , C(O)H, CN, C(O)OH ₅ (O), OH, NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I;

„30 ■ _T1 J I „ 32 - 11 ^34

R is R , R , R or R ;

R is phenyl which is unfused or fused with benzene, heteroarene or R ; R is cycloalkane, cycloallcene, heterocycloalkane or heterocycloalkene;

R ^" is heteroaryl which is unfused or fused with benzene, heteroarene or R ^" ; R ~ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocloalkenyl, each of

33A 33A which is unfused or fused with benzene, heteroarene or R ; R is cycloalkane, cycloalkene, heteiocycloalkane or heterocycloalkene;

R is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R ³⁵ , OR ³⁵ , SR ³⁵ , C(O)OR ³⁵ , NH ₂ , NHR ³⁵ , OH, N(R ³⁵ ) ₂ , C(O)NH ₂ , C(O)NHR ³⁵ , C(O)N(R ³⁵ ) ₂ , NHC(O)R ³⁵ , N(R ³⁵ )C(O)R ³⁵ , F, Cl, Br or I;

R ³⁵ is R ³⁶ , R ³⁷ , R ³⁸ or R ³⁹ ;

R ' is phenyl which is unfused or fused with benzene, heteroarene or R ; R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R is heteroaryl which is unfused or fused with benzene, heteroarene or R ;

R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocloalkenyl, each of which is unfused or fused with benzene, heteroarene or R ; R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

the moieties represented by R ^" and R ^" are independently unsubstituted or substituted with one, two, three four or five of independently substituted R , OR , C(O)OR ³⁹ , NH ₂ , NFIR ³⁹ , N(R ³⁹ ) ₂ , C(O)NH ₂ , C(O)NHR ³⁹ , C(O)N(R ³⁹ ) ₂ , NHC(O)R ³⁹ , N(R ³⁹ )C(O)R ³⁹ , SO ₂ NH ₂ , SO ₂ NHR ³⁹ , SO ₂ N(R ³⁹ ) ₂ , (O), CN, F, Cl, Br or I; and

R is alkyl, alkenyl or alkyiiyl, each of which is unsubstituted or substituted with phenyl, furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl, 1 ,2,5-oxadiazoIyl, oxazolyl, pyiazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, 1,2,4-thiadiazolyl, thiazolyi, thiophenyl, triazinyl or 1,2,3-triazolyI.

Another embodiment comprises compounds having formula (I), and therapeutically acceptable salts, prodrugs and salts of prodαigs thereof, wherein

X ¹ Is X^ SX ² Or N(A ¹ XB ¹ );

X ² is X ³ , X ⁴ , X ⁵ or X ⁶ ;

X is phenyl which is unfused or fused with benzene or heteroarene;

X is heteroaryl which is unfused or fused with benzene or heteroarene;

X is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene or heteroarene;

X is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with phenyl, futanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyπolyl, 1,2,4-thiadiazolyl, thiazolyi, thiophenyl, triazinyl or 1 ,2,3-triazolyl;

A ¹ and B ¹ are independently selected H, R ¹ , C(O)R ¹ , C(O)OR ¹ , C(O)NHR ¹ , C(O)N(R ^! ) ₂ , SO ₂ NtIR ¹ or SO ₂ N(R') ₂ ;

R ¹ is R ² , R ³ , R ⁴ or R ⁵ ;

R~ is phenyl which is unfused or fused with benzene or ¹ heteroarene;

R is heteroaryl which is unfused or fused with benzene or heteroarene;

R 4 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene or heteroarene;

R is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R ⁶ , OH, (O) ₅ CN, NH ₂ , NHR ⁶ , N(R ⁶ ) ₂ , F, Cl, Br or I;

R ⁶ is R ⁷ , R ⁸ O ₁ R ⁹ ;

R is phenyl which is unfused or fused with benzene 01 heteroarene;

R is heteroaiyl which is unfused or Fused with benzene or heteroaiene;

R is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene or heteroarene;

C ¹ is H;

^l . „ 18 „ 19 „20

D is R , R or R ;

R is pyrimidinyl which is unfused or fused with benzene or heteroarene and unsubstituted or substituted with one or two or thiee of independently selected CN, NO?, F, Cl, Br or I;

R is pyridinyl which is unfused or fused with benzene or heteroarene;

R is fuianyl, imidazoϊyl, isothiazoiyl, isoxazolyl, 1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyπolyl, 1,2,4-thiadiazolyl, thiazolyl, thiophenyl, triazinyl or 1,2,3-triazolyl, each of which is unfused or fused with benzene or heteroaryl and substituted withNHR ^" or N(CH^)R ^" ;

„2! . „22 „23 _π 24 „25

R is R , R , R or R ;

R ^~ is phenyl which is unfused or fused with benzene, heteroarene or R ^~" ; R ^" is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R ^" is heteioaiyl which is unfused or fused with benzene or heteroarene;

R ^" is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene or heteroarene;

R ^" is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R ^" ;

„26 . „27 „28 _τ ,29

R is R , R or R ;

R ^" is phenyl which is unfused or fused with benzene or heteroarene;

R ^" is heteioaryl which is unfused or fused with benzene 01 heteioarene;

R ^" is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene or heteroarene;

each foregoing cyclic moiety is independently unsubstituted, further unsubstituted, substituted or further substituted with one or two or thiee or four or five of independently selected R ³⁰ , OR ³⁰ , C(O)R ³⁰ , NH _2l NHR ³⁰ , N(R ³⁰ ) ₂ , C(O)NH ₂ , C(O)NHR ³⁰ , C(O)N(R ³⁰ J ₂ , SO ₂ NH ₂ , SO ₂ NHR ³⁰ , NHSO ₂ R ³⁰ , N(R ³⁰ )SO ₂ R ³ °, SO ₂ N(R ³⁰ ) ₂ , CF ₃ , CF ₂ CF ₃ , C(O)H, CN, C(O)OH, (O), OH, NO ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I;

R is R , R , R or R ;

R is phenyl which is unfused or fused with benzene, heteroarene or R ; R is cycloalkane, cycloalkene, heteiocycloalkane or heterocydoalkeπe;

R ^" is heteroaryl which is unfused or fused with benzene, heteroarene or R ^" ;

R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R is cycloalkyl, cycloalkenyl, heterocycloalkyl oi heterocloalkenyl, each of

33A 33A which is unfused or fused with benzene, heteroarene or R ; R is cycloalkane, cycloalkene, heterocycioalkane oi heterocycloalkene;

R is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R ³⁵ , OR ³⁵ , SR ³⁵ , C(O)OR ³⁵ , NH ₂ , NHR ³⁵ , OH ₅ N(R ³⁵ ) ₂ , C(O)NH ₂ , C(O)NHR ³⁵ , C(O)N(R ³⁵ ) ₂ , NHC(O)R ³⁵ , N(R ³⁵ )C(O)R ³⁵ , F, Cl, Br or I; _n 35 • _O 3ό „37 _π 38 _n 39

R is R , R , R or R ;

R is phenyl which is unfused or fused with benzene, heteroarene or R ; R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R is heteroaryl which is unfused or fused with benzene, heteroarene or R ; R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

38

R is cycloalkyl, cycloalkenyl, helerocycloalkyl or heterocloalkenyl, each of which is unfυsed or fused with benzene, heteroaiene or R ; R is cycloalkane, cycloalkene, heteiocycloalkaπe or heterocycloalkene;

the moieties iepresented by R ^" and R are independently unsubstituted or substituted with one, two, three four oi five of independently substituted R , OR , C(O)OR ³⁹ , NH ₂ , NHR ³⁹ , N(R ³⁹ ) ₂ , C(O)NH ₂ , C(O)NHR ³⁹ , C(O)N(R ³⁹ ),, NHC(O)R ³⁹ , N(R ³⁹ )C(O)R ³⁹ , SO ₂ NH ₂ , SO ₂ NHR ³⁹ , SO ₂ N(R ³⁹ ) ₂ , (O), CN, ¥, Cl, Br or I; and

R is alky], alkenyl oi alkynyl, each of which is unsubstituted or substituted with phenyl, furanyl, imidazolyl, isothiazolyl, isoxazoly], 1 ,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyiimidinyl, pyrrolyl, 1 ,2,4-thiadiazolyl, thiazolyl, thiophenyl, triazinyl or 1,2,3-triazolyϊ

Still another embodiment comprises compounds having formula (I), and therapeutically acceptable salts, prodrugs and salts of piodrugs thereof, wherein

X ¹ Is X^ SX ² Or N(A ¹ XB ¹ );

X ² is X ⁵ or X ⁶ ;

X is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;

X is alkyl, alkenyl oi alkynyl, each of which is unsubstituted or substituted with phenyl, furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, oxazolyl, pyiazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, 1 ,2,4-thiadiazolyl, thiazolyl, thiophenyl, triazinyl oi 1,2,3-triazolyl;

A and B are independently selected R ;

R ¹ is R ² , R ³ , R ⁴ or R ⁵ ;

R is phenyl which is unfυsed or fused with benzene;

R is heteroaryl which is unfυsed or fused with benzene;

R is cycloalkyl, cycloalkenyl, heterocycloalkyl or heteiocycloalkenyl, each of which is unfused or fused with benzene;

R is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R ⁶ , OH, (O) ₁ CN ₅ NH ₂ , NHR ⁶ , N(R ⁶ ) _2ϊ F, Cl, Br or I;

R ⁶ is R ⁷ , R ⁸ or R ⁹ ;

R is phenyl which is imfused or fused with benzene;

R is heteroaryl which is υnfused or fused with benzene;

R is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene;

C ¹ is H;

D is R , R or R ;

R is pyrimidinyl which is unfused or fused with benzene and unsubstituted or substituted with one or two or three of independently selected CN, NO?, F, Cl, Br or I;

R is pyridinyl which is unfused or fused with benzene;

R ^" is fuianyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyI, 1,2,5-oxadiazoIyl, oxazolyl, pyrazinyl, pyrazolyl, pyiidazinyl, pyiimidinyl, pyrrolyl, 1,2,4-thiadiazoIyl, thiazolyl, thiophenyl, triazinyl or 1,2,3-triazolyl, each of which is unfused or fused with benzene or heteroaryl and substituted withNHR ^" or N(CHj)R ^" ;

„2! - „22 „23 „24 „25

R is R , R , R or R ;

22 2^A 22A R is phenyl which is unfused or fused with benzene, heteroarene or R ^" ; R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R ^" is heteroaryl which is unfused or fused with benzene;

R ^" is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene;

R is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R ^" ;

„26 • „ 27 „28 „29

R is R , R or R ;

R ^" is phenyl which is unfused or fused with benzene;

R ^" is heteroaryl which is unfused or fused with benzene;

R ^" is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkeπyl, each of which is unfused or fused with benzene;

each foregoing cyclic moiety is independently uπsubstituted, further unsubstituted, substituted or further substituted with one or two or three or four or five of independently selected R ³⁰ , OR ³⁰ , C(O)R ³⁰ , NH ₂ , N(R ³⁰ ) ₂ , C(O)NHR ³⁰ , C(O)N(R ³⁰ ) ₂ , SO ₂ NH ₂ . NHSO ₂ R ³⁰ , CN, C(O)OH, (O), OH, NO ₂ , CF ₃ , OCFj, F, Cl, Br or I;

R ³⁰ is R ³¹ , R ³² , R ³³ or R ³⁴ ;

R is phenyl which is unfused or fused with benzene;

R ^" is heteroaryl which is unfused or fused with benzene;

R is cycloalkyl, cycloalkenyl, heteiocycloallcyl or heterocloalkenyl, each of which is unfused or fused with benzene;

R is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R , OR , SR , OH ₅ N(R ) ₂ ;

„35 . „36 „37 „38 „39

R is R , R , R or R ;

R is phenyl which is unfused or fused with benzene;

R is heteroaryl which is unfused or fused with benzene;

R is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocloalkenyl, each of which is unfused or fused with benzene;

the moieties represented by R ^" and R ^' are independently unsubstituted or substituted with one, two, three four or five of independently substituted R , OR , N(R ³⁹ ) _2l SO ₂ NH ₂ , (O), CN, F, Cl, Br or I; and

R is alkyl, alkcnyl 01 alkynyl, each of which is unsubstituted or substituted with phenyl, furanyl, imidazoJyl, isothiazolyl, isoxazolyl, 1 ,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyϊ, pyridazinyl, pyrimidinyl, pyrrolyl, 1 ,2,4-thiadiazolyl, thiazolyl, thiophenyl, tiiazinyl or 1,2,3-tiiazolyl

Still another embodiment comprises compositions comprising an excipient and a therapeutically effective amount of a compound having formula (I)

Still another embodiment comprises methods of treating diseases involving ovei expression or umegulation of a protein kinase in a mammal, the methods comprising administering thereto a therapeutically effective amount of a compound having formula (I)

Still another embodiment comprises methods of treating coloiectal cancer, endometrial carcinoma, epithelial ovarian cancer, esophageal carcinoma, hepatoblastoma, malignant lymphoma, melanoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oropharyngeal carcinoma, ovarian carcinoma or squamous cell carcinoma in a mammal, the methods comprising administering thereto a therapeutically effective amount of a compound having foimula (I)

Still anothei embodiment comprises compositions comprising an excipient and a therapeutically effective amount of a compound having formula (I) and a therapeutically effective amount of one or more than one additional therapeutic agent.

Still another embodiment comprises methods of treating diseases involving overexpression or umegulation of a protein kinase in a mammal, the methods comprising administering thereto a therapeutically effective amount of a compound having formula (I) and a therapeutically effective amount of one or more than one additional therapeutic agent

Still another embodiment comprises methods of treating colorectal cancer, endometrial carcinoma, epithelial ovarian cancer, esophageal carcinoma, hepatoblastoma, malignant lymphoma, melanoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oropharyngeal carcinoma, ovarian carcinoma or squamous cell carcinoma in a mammal, the methods comprising administering thereto a therapeutically effective amount of a compound having formula (I) and a therapeutically effective amount of one or more than one additional therapeutic agent

Still another embodiment comprises compounds having foimula (I) which are

(R)-3-(2-(3,4,5-trimethoxyphenyIamino)pyriniidin-4-ylamin o)-4~(l,2,2- tiimethylpiopylamino)cyclobut-3-ene-l ,2-dione,

(R,R)-3-(2-(l-phenylethyIamino)pyiimidin-4-ylamino)-4-(l, 2,2- trimethylpropylamino)cyclobut-3-ene™ 1 ,2-dione,

(R)-3-(2-(4-bromophenylamino)pyrimidin-4-ylamino)-4-(l,2, 2- trimethylpiopylamino)cyclobut-3-ene-l,2-dione,

(R)-3-(2-(beπzo[l,3]dioxol-5~ylamino)pyrimidin-4-ylamino )-4-(l ,2,2- trimethylpropylamino)cyclobut-3-ene-l,2-dione,

(R)-3-(2-(4-trifluoromethoxyphenylamino)pyrimidin-4-ylami no)-4-(l,2,2- trimethylpropylamino)cyclobut-3-ene-l,2-dione,

(R)~3-(2-(3-methylphenylamino)pyrimidin-4-ylamino)-4-(l,2 ,2- trirnethylpiopylamino)cyclobut-3-ene-l,2-dione,

(R)-3-(2-(4-fluoiophenylamino)pyrimidin-4-ylamino)-4-(l ₅ 2,2- trimethylpiopylaniino)cyclobυt-3-ene-l ,2-dione,

(R)-3-(2-(2-isopropylphenylamino)pyiimidin-4-ylamino)-4-( l,2,2' trimethylpropyIamino)cyclobut-3-ene- 1 ,2-dione,

(R)-3-(2-(4-chlorophenylaraino)pyrimidin-4-ylamino)-4-(l,2 _J 2- trimethylpropylamino)cyclobut-3-ene-l,2-dione,

(R)-3-(2-phenylaminopyrimidin-4~ylamino)-4-(l,2,2- trimethylpropylamino)cyclobut-3-ene-l,2-dione,

(R)-3-(2-(naphthalen-2-ylamino)pyτimidin-4-ylaπiino)-4- ( 1,2,2- trimethylpropylamino)cyclobut-3-ene- 1 ,2-dione,

(R)-3-(2-(3-bromo-4-methylphenylamino)pyrimidin-4-ylamino )-4"(l,2,2- trimethylpiopylamino)cyclobut-3-ene-l,2-dione,

(R)-3-(2-(biphenyl-4-ylamino)pyrimidin-4-ylamino)-4-(l,2, 2- tiimethylpropylamino)cyclobut-3-ene-l,2-dionc,

(R)-3-(2-(4-p]ienoxyphenyIamino)pyτimidin-4-ylamino)-4-( l ,2,2- trimethylpropylamino)cyclobut-3-ene-l,2-dione,

(R)-3-(2-(3-phenoxyphenylamino)pyrimidin-4-ylaniino)-4-(l ,2,2- tiiniethyIpropylamino)cycIobut-3-ene-l ,2-dione,

(R)-3-(2-(2,3-dimelhoxyphenylamino)pyrimidin-4-ylamino)-4-(l ,2 _J 2- trimethylpiopylamino)cyclobut-3-ene-l,2-dione,

R)-3-(2-(2,3-dihydrobenzo[l,4]dioxiπ-6-ylamino)pyiimidin -4-ylamino)-4-( 1,2,2- trimethylpropylarnino)cyclobut-3-ene-l,2-dione,

(R)-3-(2-(naphthaIen-l-yϊamino)pyrimidin-4-ylamino)-4-(I ,2,2- tiimethylpropylamino)cyclobut-3-ene-l,2-dione,

R)-3-(2-(2,4~dimethoxyphenylamino)pyrimidin-4-ylamino)-4- (l,2,2" trimethylpropylamino)cyclobut-3-ene- 1 ,2-dione,

(R)'3-(2"(2,5-dimethoxyphenylamino)ρyiimidin-4-ylamino)- 4-(l ,2,2- trimethylpropylamino)cyclobut-3-ene-l ,2-dione,

(R)-3-(2-(biphenyl-3-y!amino)pyrimidin-4-ylamino)~4-( 1,2,2- tiimethylpropylamino)cyclobut-3-ene-l,2-dione,

(R)- 3-(2-(4-methoxyphenylamino)pyrimidin~4-ylamiπo)-4-( 1,2,2- trimethylpropylamino)cyclobut-3-ene-l ,2-dione,

(R)-3-(2-(3-chloiophenylamino)pyiimidin-4-yIaniino)-4-(l, 2,2- trimethylpropylamino)cyclobut~3-ene- 1 ,2-dione,

(R)-3-(2-(3-biomophenylamino)pyrimidin-4-ylarnino)~4-(l,2 ,2- trimetliylpropylamiπo)cyclobut-3-ene-l,2-dione,

(R)-3-(2-(3-isopropoxyphenylamino)pyiimidin-4~ylamino)-4- ( 1,2,2- trimethylpiopylamino)cyclobut-3-ene-l ,2-dione,

(R)-3-(2-(4-morpholin~4-yIphenylamino)pyrimidin-4'ylamino )-4-(l,2,2- trimethylpropylamino)cyclobut- 3-ene- 1 ,2-dione,

(R)-3-(4-(3,4-dioxo-2-(l,2,2-trimethylpropylamino)cyclobut-l - eny]ami]io)pyrimidiii-2-y]amino)beπzonitriIe _J

(R)-3-(2-(3 _J 4-diflυorophenylamino)pyrimidin-4-ylamino)-4-(l,2 _J 2- lrimethylpropylamino)cyclobu£-3-ene- 1 ,2-dione,

(R)-3-{2-(3-chloiO-4-fluoiOphenyIamino)pyrimidin-4-ylamino)- 4~(l _> 2,2- trimethylpropylamino)cyclobut-3-ene-l ,2-dione,

(R)-3-(2-(3"trifluoromethyIphenylamino)pyτimidin-4-ylami no)-4-{l,2,2- trimethylpropylamino)cyclobut-3-ene-l,2-dione,

(R)-3-(2-(9H-fluoren-2-ylamino)pyiimidin-4-ylamino)-4-(l, 2,2- trimethylpropylaraino)cyclobut-3-ene-l,2-dione,

(R)-4 ^I -(4-(3 ₎ 4-dioxo-2-(l,2,2-trimethylpropylamino)cyclobut-l- enylamino)pyrimidin-2-ylamino)biphenyl-4-carbonitrile,

(R)-3-(2-(2'-nielhoxybiphenyI-4-ylamino)pytimidin"4~ylami no)-4-(l,2,2- trimethylpiopylamino)cyclobut-3"ene-l ,2-dione,

(R)-3-(2-(4-imidazol-l-ylphenylaniino)pyrimidin-4--ylamin o)-4-(l,2,2- tτimethylprOpylamino)cyclobut-3-ene- 1 ,2-dione,

(R)-3-(2-(4'-methoxybiphenyl-4-ylamino)pyrimidin-4-ylamin o)-4-(l,2,2- trimethylpropylamino)cyclobut-3-ene-l,2-dione,

(R)-3-(2-(4-dimethyIaminophenylamino)pyiimidin-4-ylamino) -4-(l,2,2- trimethylpropylamino)cyclobut~3-ene-l ,2-dione,

(R)-3-(2-((4-methoxyphenyl)methylamino)pyrimidin-4-ylamin o)~4-(l ,2,2- trimethylpiOpylamino)cyclobut-3-ene- 1 ,2-dione,

(R)-3-(2-(4'-chIorobiρhenyl-4-ylamino)pyiimidin-4-ylamin o)-4-( 1,2,2- trimethylpropylamino)cyclobut-3-ene-l,2-dione,

(R)-3-(2-(4-[ 1 ,2,3]thiadiazol-4-yIphenylamino)pyrimidin-4-ylamino)-4-(l ,2,2- trimethy]propylamino)cyclobut-3-ene-l,2-dione,

(R)-3-(2-(4-thiophen-2-ylphenylamino)pyrimidin-4-ylamino) -4-(l,2,2- trimethyIpropyIamino)cyclobut-3-ene-l ,2-dione,

(R)-3-(2-(benzothiazol-6-ylanimo)pyrimidin-4-ylamino)-4-( l,2,2- trimelhylpropylaιτπno)cyclobut-3-ene-l ,2-dione,

3-tert-butyIamino-4-(2-(9H-fluoren»2-ylamino)pyiimidin-4 -ylamino)cyclobul-3- ene-l,2-dione,

3-tert-butylamino-4-(2-(4-fluoiO-3-methylphenylamino)pyii midin-4- ylamino)cyclobut-3-ene- 1 ,2-dione,

3-(2-(benzothiazol-6-ylamino)pyrimidin-4-ylamino)-4-teit- butylaminocyclobut-3- ene-l ,2-dione,

3-tert~butylaniino-4-(2-(4~[l,2,3]thiadiazol-4-ylphenylam ino)pyrimidin-4- ylamino)cyclobut-3-ene-l,2-dione,

3-tert-butylamino~4-(2-(4-(4-methy]piperazin-l-yl)phenyla mino)pyrimidin-4- ylamino)cyclobut-3-ene-l ,2-dione,

3-tert-butylamino-4-(2-(4-hydroxy-3-methylphenylamino)pyr imidin-4" ylamino)cyclobut-3-ene-l,2-dione,

3~tert-butylamino-4-(2"(indan-5-ylamino)pyrimidin-4-ylami no)cycIobut-3-ene- 1 ,2-dione,

3-tert-butylamino-4-(2-(4-moipholin-4-ylphenylamino)pyrim idin-4- ylamino)cyclobut-3-ene-l,2-dione,

3-teit-buty]amino-4-(2-(4-morpholin-4-ylme(:hylphenylamin o)pyiimidin-4- ylamino)cyclobut-3-ene-l,2-dione,

3~tert-butylamino-4-(2-(naphthalen-2-ylamino)pyrimidin-4- ylamino)cyclobut-3- ene-l,2-dione,

3-(2-(benzo[b]thiophen-5-ylarnino)pyiimidin-4-ylamino)-4- tert- butylarninocyclobut-3-ene-l ,2-dione,

3-tert-butylamino-4-(2-(2 _J 3-dihydiobenzofuran-5-ylamino)pyrimidin-4- ylamino)cyclobut-3-ene- 1 ,2-dione,

3-(2-(benzofuran-5-ylamino)pyrimidin~4"yIamino)-4-tert-bu tylaminocyclobut-3- ene-l,2-dione,

34ert-butylamino-4»(2~(lH-indol-5-ylamino)pyrimidin-4-yl amino)cyclobut-3- ene-l,2-dione,

3-tert-butylaniino-4-(2-(IH-indazol-5-ylamino)pyiiniidin- 4-ylamino)cyclobut-3- ene-l,2-dione,

3-tert-butylamino-4-(2-(l~methyI-lH-indazol-5-ylamino)pyi iniidi]v4- ylamino)cyclobut-3-ene-l ,2-dione,

3-tert-butylamino-4-(2-(4'pyrrOl-l-ylphenyIamino)pyτimid in-4-ylamino)cyclobut- 3-ene-l ,2-dione,

3-tert-butylaraino-4-(2-(4-pyrazol-l-ylphenylamino)pycimi din-4~ ylamino)cyclobut-3-ene-l ,2-dione,

3-tert-butylamino~4-(2-(4-(4,6-dimethoxypyiimidin-2"yl)ph enylamsno)pyτimidin- 4-ylamino)cyclobut-3-ene-l ,2-dione,

3-(2-(l-acetyl-2,3-dihydiO-lH-indol-5-ylamino)pyrimidin-4 -ylamino)-4-tert- butylaminocyclobιtt-3-ene-l,2-dione,

3-tert-butylamino-4-(2-(2,3-dihydro-lH-indol-5-ylamino)py rimidin-4- yIamino)cyclobut-3-ene- 1 ,2-dione,

3-tert~butylamino-4-(2-(9H-carbazol-2-ylamino)pyrimidin-4 -ylamino)cyclobut-3- eπe-1 ,2-dione,

3-tert-butylaniino-4-(2-(9-ethyl-9H-carbazol-2~yIamino)py rimidin-4- ylamino)cyclobut-3-ene-l,2-dione,

3-(2-(benzothiazol-5-ylamino)pyiimidin-4"ylamino)-4-tert- bυtylaminocyclobut-3- ene-l,2-dione,

{R)-3-(2-(4-phenylthiazol-2-ylaniino)pyrimidin-4-ylamino) -4-(l,2,2- trimethylpropylamino)cyclobut-3-ene-l,2-dione,

3-tert-butylamino-4-(2-(4~phenylthJazol-2-ylamino)pyrimid in-4- ylamino)cyclobut-3-ene-l,2-dione,

3-(2-(bipheπyl-4-ylamino)pyrimidin-4-ylainino)-4-tert-bu tylaminocyclobut-3- ene-l,2~dione,

3-(2-(biphenyl-4-ylamino)pyrimidin-4-ylamino)-4-(4- trifluoromethoxyphenylamino)cyclobut-3-ene-l,2-dione,

1 1391 ) 3-(2-{biphenyl-4-ylamino)pyrimidin-4-ylamino)-4-(2,2- diniethylpropylamino)cyclobuK3-ene-l,2-dione,

3-(2~(biphenyI-4-ylamino)pyrimidin-4-ylamino)-4- (cyclopropylraethylamino)cyclobut-3-ene-l,2-dione,

3-(2-(biphenyl-4-ylamino)pyiimidin-4-ylaniino)-4-(2-morph olin-4- ylethylamino)cyclobut-3-ene-l,2-dione,

3~(2~(biphenyl-4-ylamino)pyrimidin-4-yIamino)-4-(l,3- dimelhylbutylamino)cyclobut-3-ene-l,2~dione,

3~(2'(biphenyl-4-ylamino)pyrimidin-4-ylamino)-4»(l,2- dimethylpiopylamino)cycIobut-3-ene-l,2-dione,

3-(2-(biρhenyl-4-ylamino)pyrimidin-4-ylamino)-4-(l-pheny Iethylarnino)cyclobut-

3~ene-l,2-dione,

(S)-3-(2-(biphenyl-4-ylamino)pyrimidin-4-ylamino)-4-{ 1,2,2- triniethylpropylamino)cyclobut-3-ene- 1 ,2-dioiie,

3-(2-(biphenyl-4-ylarnino)pyrimidin-4-ylamino)-4-(l,l- dimethylpiopylamino)cyclobut-3-ene~l,2-dione,

(R)-3-(4-(3A5-trimethoxyphenylamino)-(l,3,5)triazin-2-yla mino)-4-(l,2,2- trimethylpiopylamino)cyclobut-3-ene" 1 ,2-dioπe,

4-(3,4-dioxo-2-(l-phenylethylamino)cyclobut-l-enylamino)-2-( 3,4 _s 5- trimethoxyphenylamino)pyrimidine~5-carbonitrile,

(S)-4-(3,4-dtoxo-2-(l,2,2-trimelhylpιopyIamino)cyclobut- l-enylamino)-2-(3,4,5- trimethoxyphenylamino)pyiimidine-5-carbonitiile,

4-{2-(I ,2-dimethylpropylamino)-3,4-dioxocyclobut-l~enylamino)-2-(3, 4,5- trimethoxyphenylamino)pyτimidine~5-carbonitrile,

3-tert"butylamino-4-(2-(9H-fluoren-2-ylamino)-5-fluoiopyr imidin-4- ylamino)cyclobut-3-ene- 1 ,2-dione,

(R)-3-(3-(biphenyl-4-ylamino)-[ 1 ,2,4]thiadiazol-5-ylamino)-4-(l ,2,2- tiimethylpropylamino)cyclobut-3-ene-l,2-dione,

(S)-3-(3-(biphenyl-4-ylamino)-[l,2,4]thiadiazol-5-ylamino )-4-( 1 ,2,2- trimethylpropylamino)cyclobut-3-ene-l ,2-dione,

3-tert-butylamino-4-(2-(4-iodophenylamino)pyrimidin-4-yla mino)cyclobut-3"ene~ 1,2-dione,

3-tert-butylamino-4-(2-(4-pyridin-4-ylphenylamino)pyrimid in-4- ylamino)cyclobut-3-ene- 1 ,2-dione,

3-tert-butylamino-4-(2-(4-pyridin-3-ylphenylamino)pyrinii din-4» ylamino)cyclobut~3-ene-l ,2-dione,

3-iert-butylamino-4-(2-(4-(lH-pyrazol-4-yl)phenylamino)py rimidin-4- ylamino)cyclobut-3-ene-l,2-dione,

3-tert-bυtylamino-4-(2-(4-ρyrimidin-5-ylphenylamino)pyi 'imidin-4- ylamino)cyclobu(:-3-ene- 1 ,2-dioπe,

3-tert-butylamino-4-(2~(4-(2,4'dimethoxypyiimidin-5-yl)ph enylamino)pyrimidin- 4-ylamino)cyclobut-3-ene-l,2-dione,

3-tert-butylamino-4"(2-(4-(2~methoxy-pyrimidin-5-yl)pheny lamino)pyrimidin-4- ylamino)cyclobut-3-ene-l ,2-dione,

3-(ert-butylamino-4-(2-chloro-5-fluoiopyrimidin-4-ylamiπ o)cyclobut-3-ene-l ,2- dioπe,

3-tert-butylamino-4-(5-fluoiO-2-(4-[l ,2,3]thiadiazol-4~ylphenylamino)pyrimidin- 4-ylamino)cyc3obut-3-ene-l ,2-dione,

3-tert-butylamino-4-(2-chloropyrimidin-4-ylamino)cyclobut -3-ene-l ,2-dione,

3-teit-butylamino-4-(2-(4-(l,2,4-triazol)'l-ylphenylamiπ o)pyiimidin-4- ylamino)cyclobut-3-ene-l,2-dione,

3-tert-butyIamino~4-(2-cyc1ohexylaminopyτimidin-4-ylamin o)cyclobut"3-ene-l,2- dione,

3-tert-butylairtino-4-(2-(4-(2H-pyrazol~3-yl)phenylamino) pyτimidin-4- ylamino)cyclobut-3-ene- 1 ,2-dione,

3-(2-(lH-benzotriazol-5-ylammo)pyrimidin-4-yIamino)-4-ter t- butylaminocyclobut-3-ene-l,2-dione,

3-tert-butylamino-4-(2-{4-thiophen-3-ylphenylamino)pyrimi din-4- ylamino)cyclobut-3-ene- 1 ,2-dione,

3-(2-(lH-benzoiniidazol-5-ylamino)pyrimidin-4~ylamino)-4' tert- butylaminocyclobut-3-eπe-l,2-dione,

3-(2-(l-acetyl-2,3-diliydro-lH-indol-6-ylamino)pyrimidin- 4-ylamino)-4-tert- butylaminocyclobut-3-ene-l,2-dione,

N-(3-(4-(2-tert-butylamino-3,4-dioxocyclobut-l"enylamino) pyrirnidin-2- y]amino)phenyl)methanesulfonamide,

3-tert-butylamino-4-(2-(2-tπfluoromethyl-lH-benzoimidazo l'5- ylamino)pyiimidin-4-ylamino)cyclobut-3-ene-l ,2-dione,

N-(4-(4-(2-tert-butylamino-3,4-dioxocycIobut-l-enylamino) pyiimidin-2- ylammo)phenyl)-4-methylbenzenesulfonamide,

3-tert-butylamino-4-(2-(2-methylbenzothiazol-5-ylamino)py iimidin-4- ylamino)cyclobut-3-ene- 1 ,2-dione,

3-tert-butylamino-4-(2-(4-(morpholine-4-sιιlfonyl)pheny laniino)pyiimidin-4- ylaniino)cyclobut-3~ene-l,2-dione,

3-tert-buty]amino-4-{2~(3~(morpholine-4-sulfonyl)phenylam ino)pyrimidiπ-4- ylamino)cyciobul"3-ene-l ,2-dione,

3-tert-butyIaniino~4-(2-(2~niethyl-3H-benzoiniidazol-5"yI amino)pyrimidin~4- ylamino)cyclobut-3-ene- 1 ,2-dione,

3-tert-butylamino-4-(2-(l-(toluene-4-sulfonyl)-lH-indol-5 -ylaniino)pyiimidin-4» ylammo)cyclobut-3-ene-l,2~dioπe,

3-teit-butylamino-4-(2-(I-methanesulfonyl-2,3-dihydro-lH- indol-5- ylaniino)pyrirnidin-4-ylamino)cyclobut-3-ene-l,2-dione,

3-tert-butylamino-4-(2-(4-pyridin-2-ylpheπylamino)pyrimi din-4- ylamino)cyclobut-3-ene-l,2~dione,

3-tert-butylamino-4-(2-(4-(4-methanesulfoπylpiperazin-l- yl)phenylamino)pyiimidin-4-ylamino)cyclobut-3-ene-l,2-dione,

3-teit-butylamino-4-(2-(3-oxθ"3,4-dihydio-2H-benzo[l,4]o xazin-7- ylamino)pyrimidin-4'yiamino)cyclobut-3-ene-l,2-dione,

3-teit-butylamino-4-(2-(3"pyrrol-l-ylphenylamino)pyrimidi n-4-ylamino)cyclobιιt- 3-ene-l ,2-dione,

3-tert-butyl amino-4-(2 -(2-methylbenzothiazo 1- 6~y lam i no)pyrimi di n-4- ylamino)cyclobut-3-ene-l,2-dione,

3-tert-butylamiπo-4-(2-(4-oxazol-5-ylphenylamiπo)pyiimi din-4- ylamino)cyclobut-3-ene-l,2-dione,

3-teit-butylamino-4-(2-(pyridin-4-ylamino)pyiimidin-4-yla mino)cyclobut-3-ene- 1 ,2-dione,

3 -tert-buty 1 amino-4-(2 -(4- dimethylarai nomethy Iphenyl amino )pyrimi din-4- ylamino)cyclobut-3-ene-l,2-dione,

5-(4-(2-tert-butylamino~3,4-dioxocyclobut-l-enylarnino)py iimidin-2-ylamino)-2- methylisoindole-l,3-dione,

3-teit-butylamino-4-(6-chloiopyrimidin~4-ylamiπo)cyclobu t-3-cne-l,2-dione,

3-tert-butylamino-4-(6-(4-iodophenylamiπo)pyiimidin-4-yl amino)cyclobιιt-3-ene- 1 ,2-dione,

3-cyclopropylamino-4-(2-(4-iodophenylamino)pyiimidin-4-yl amino)cyclobut-3- ene-l ,2-dione,

3-cyclobutylamino-4-(2~(4-iodophenylamino)pyrimidin-4-yla mino)cyclobut-3- ene-l,2-dione,

3-cyclobutylamino-4-(2-(4-pyridin-4~ylphenylamino)pyrimid in-4- ylamino)cyclobut-3-ene-l,2-dione,

4'-(4-(2-teit-butylamino-3,4-dioxocyclobut-l-enylamino)py rimidin-2- ylamino)biphenyl-4-carboxylic acid dimethylamide,

3-tert-butylamino-4-(6-methyl-2-(4~thiophen-3-ylρhenylam ino)pyiimidin-4- ylamino)cyclobut-3-ene-l,2-dione,

3-(4-(2-tert-butylamino-3,4-dioxocyclobut-l-enylamino)pyr imidin-2- ylamino)benzenesulfonamide,

34ert-butylamino-4-(2-(3-metlioxyphenylamino)pyiimidin-4- ylamino)cyclobut-3- ene-l,2-dione,

3-(2~(4-(4-benzylpiperazin-l-yl)phenylamino)pyrimidin-4-y larnino)-4-tert- butylaminocyclobut-3-ene-l,2-dione,

3-tert-butylamino-4-(2-(4-nitrophenylamino)pyiimidin-4-yl amino)cyclobut-3- ene-l,2-dione,

3-tert-butylamino-4-(2-(6-chloτo-5-methylpyridin-3-ylami no)pyiimidin-4- ylamino)cyclobut- 3-ene- 1 ,2-dione,

4-(4-(2-tert~bυtylamino-3,4-dioxocyclobut-l--enylamino)p yi'imidin-2-ylamino)-3- me!;hoxy-N-piperidiπ~4-ylbenzamide,

3-tert-butylamino-4-(pyrimidin-4-ylamino)cyclobut-3~ene-l ,2-dione,

S-3-(2-chloτopyτimidin-4-ylamino)-4»(l~cyclohexylethyl amino)cyclobut-3-ene- 1,2-dione,

R-3-(2-chloropyi ⁱ imidin-4-ylamino)-4-(l -cyclohexylethyIamino)cyclobut-3-ene- 1 ,2-dione,

S-3-(l-cyclohexylethylamino)-4-(2-(4-thiophen-3-ylphenyla mino)pyiimidin-4- ylamino)cyclobut-3-ene-l,2-dione,

(R)-3~(l -cyclohexylethylamino)-4-(2-(4-thiopheπ-3~yIphenylamino)pyr imidin-4- ylamino)cycIobut-3-ene- 1 ,2-dione,

(S)-3-(l-cyclohexylethylamino)-4-(2-(4-(4,6-dimethoxypyri midin-2- yl)phenylamino)pyrimidin-4-ylamino)cyclobut-3-ene-l ,2-dione,

(R)-3-(l-cyclohexylethylamino)-4-(2-(4-(4 _> 6-dimethoxypyrimidin-2- yl)phenylamino)pyrimidin-4-ylamino)cyclobut-3-ene- 1,2-dione,

(S)-3-(l-cyclohexylethylamino)-4-(2-(4~pyridin-4-ylphenyl amino)pyiimidin-4- ylamino)cyclobut-3-ene- 1 ,2-dione,

(R)-3-(l-cyclohexylethylamino)-4"(2-(4-pyridin-4-ylphenyl amino)pyrimidin-4- ylamiπo)cyclobut-3-ene- 1,2-dione,

3-tert-bulylamino-4-(2-(3,4,5,6-tetrahydro-2H-[l,4']bipyr idinyl-4- ylamino)pyiimidin-4-ylamino)cyclobut-3-ene-l,2'dione,

3-tert-butylamino-4-(2-(4-(l-methylpiperidin-4-yl)phenyla mino)pyrimidin-4- ylamino)cyclobut-3-eπe- 1 ,2-dione,

3-(piperidin-4-ylamino)-4-(2-(4-pyridin~4~ylphenylamino)p yτimidin-4- ylamino)cyclobut-3-ene- 1 ,2-dione,

3-(4-(2-tert-butylamino-3,4-dioxocyclobut-l -enylamino)pyiimidin-2-ylamino)-N- (l-methylpiperidin-4-yl)benzamide,

3-(4-(2-tert-butylamino-3,4-dioxocyclobut-l-eπylamino)py iiinidin-2- ylamino)benzoic acid,

3-(4-(2-teit-butylaminθ"3,4-dioxo-cyclobut-l-enylamino)p yiimidin-2-ylamino)- N-cyclohepty]benzamide,

3-(4-(2-tert-butylamino-3,4-dioxo-cycIobut-l-enylamino)py rimidin-2-ylamino)- N~cyclohexylbeπzamide,

3-(4-(2-tei ¹ t-butylamino-3,4-dioxo-cyclobut-l-enylamino)pyiimidin-2-ylam ino)-

N-cyclopentylbenzamide,

3-{4~(2-tert-butylamino-3,4-dioxo-cyclobut-l -enylamino)pyiimidin-2~ylamino)-

N-cyclobutylbenzamide,

3-(4~(2-tert-butylamino~3,4-dioxo-cycIobut-l-enylamino)py rimidin-2-ylamino)-- N-cyclohexyl-4-methoxybenzamide,

3-(4-(2-tert-butyIamino-3,4-dioxo-cyclobut-l-enylamino)py rimidin-2-ylamino)-4- niethoxybenzoic acid,

3-tert-butylamino-4-(2-(quinolin-6-ylamino)pyrimidin-4-yl amino)cyclobut-3-ene- 1 ,2-dione,

(R)-3-(2-(4-fluoro-3-niethylphenylamino)pyiimidin-4-ylami no)-4'(l ,2,2- trimethylpiopylamino)cyclobut-3-ene-l,2-dione,

3-tert-butylamino-4~(5-fluoro-2-(2 ^l -methoxybiphenyl-4~ylamino)pyiimidin-4- ylamino)cyclobut-3~ene-l,2-dione _: ,

N-cyclobutyl-4-((4-((2-((2-hydroxy-l,l-dimethylethyl)amin o)-3,4-dioxocyclobut-l-en- l-yl)amino)pyτimidin-2-y])amiπo)-3-methoxybenzamide,

N»cyclobutyl-3-methoxy-4-((4~((2-((l~methyl-l-phenylethy l)amino)-3,4"dioxocyclobut- 1 -en- 1 -yl)amino)pyπmidin-2-yl)amino)benzamide,

N-cyclobutyl-4-((4-((2-((l,l-dimethylprop-2-yπyl)amino)- 3,4-dioxocyclobut-l-en-l- yl)amino)pyiimidin-2-yI)amino)-3-methoxybenzamide,

4-((4~((2-((l -cyaπo-1 -methylethyl)amino)-3,4-dioxocycIobut- 1 -en- 1 - yl)amino)pyrimidin-2-yl)amino)-N-cyclobutyl-3-methoxybenzami de,

N-cyclobutyl-4-((4-((2-((l-cyclopiopyl-l-methylethyl)amino)- 3,4-dioxocyclobut-l~en-l- yl)amino)pyrimidin-2-y])amino)-3-methoxybenzamide ₅

N-cyclobutyl-4"((4-((2-((l ₇ l-dimethyl-2-morpholin-4-ylethyl)amino)-3,4-dioxocyclobut- 1-en- 1 -yI)amino)pyrimidin-2-yl)amino)-3-methoxybenzamide,

N-cyclobutyl-3-methoxy-4-((4-((2-morpholin-4-yI-3,4-dioxo cyclobut-l»en~l- yl)amino)pyrimidin-2-yl)amino)benzamide,

N-cydobutyl^-^-^-tfl _j l-dimethyl^-oxobutyOamino^^-dioxocyclobut-l-en-l- yI)amino)pyriniidin-2-yl)amino)-3-methoxybenzarnide,

N~cycϊobutyϊ~4-((4-((3,4-dioxo-2-(propylamino)cyclobut- l-en-l-yl)amino)pyiimidin-2- yl)amino)-3-methoxybenzaraide,

4-((4-((2-anilino~3,4-dioxocyclobut-l-en-l-yl)amino)ρyii midin~2-yI)amino)-N- cyclobuty 3 -3 -methoxybenzam i de,

N-cyclobutyl~4-((4-((3,4-dioxo-2-(piopylthio)cyclobut-l~e n~l -yl)amino)pyiimidin-2- yl)amino)-3-methoxybenzamide,

3-((2-( 1 , 1 '-biphenyl-4-ylamino)pyιidin-4--yl)amJno)"4~(tert-butylamin o)cyclobut-3-ene- 1 ,2-dione,

3-(tert-butylamino)-4-((2-((4-pyridin-4-ylphenyl)amino)py iidin-4-yl)amino)cyclobut'3- ene-l^-dione,

4-((4-((2-(tert-butylamino)-3,4-dioxocyclobut-l-en-l-yI)a mino)pyiidin-2-yl)amino)-N- cyclohexyl-3-methoxybenzarnide,

N-cyclopentyl-4-((4-((2-(diethylamino)-3,4-dioxocyclobut~ l-en-l-yl)amino)pyrimidin- 2-yl)amino)-3-methoxybenzamide,

N-cyclopentyl-3-methoxy-4-((4-((2-neopentyl-3,4-dioxocycI obut-l-en-l- yl)amino)pyrimidin-2-yl)amino)benzamide,

N-cyclopenlyl-4-((4-((2-(l-ethyIpropyl)-3,4-dioxocyclobut ~I-en-l-yl)amiπo)pyrimidin- 2-yl)amino)-3-methoxybeπzamide,

N-cyclopentyl-3-methoxy-4-((4-((2-(2-methylpiop"l-enyl)-3 ,4'dioxocyclobut-l-en-l- yl)amino)pyrimidin-2-y])amino)benzaniide,

2-(4-((4-((2-(tert-buty]amino)-3 _J 4-dioxocyclobut~l-en-l-yl)aπiino)pyτimidin-2- yI)amino)phenyl)-N-(l-methyIpiperidin-4-yl)acetamide,

2-(4-((4-((2-(tert-butylamino)-3,4-dioxocyclobut-l-en-l-y I)amino)pyiimidin-2- yl)amino)phenyl)-N-(pyτidin-3~ylmethyl)acetamide,

2'(3-((4-((2-(tert-butylamiπo)-3,4-dioxocyclobuM-en-l-yl )amino)pyrimidJii-2- yl)arnino)phenyI)-N-( 1 -methylpiperidin-4-yl)acetamide,

2-(3-((4-((2-(tert-butylamino)-3,4-dioxocyclobut-l-en-l-y I)amino)pyrimidin-2- ylJaminoJphenyO-N-cyclobutylacetamide,

3-(tert-butylamino)-4-((2-((4-(pyiidin-2-ylethynyl)phenyl )amino)pyrimidin-4- yl)amino)cyclobut~3-ene-l,2-dione,

3-(tert-butylamino)-4-((2-((4-pent-l-ynylphenyl)amino)pyr imidin-4-yl)amino)cyc!obut- 3-ene-l,2-dione,

3-(tert-butylaraino)-4-((2-((4-(3-(diethylamino)piOp-l-yn yl)phenyl)amino)pyrimidin-4- yl)amino)cyclobut-3-ene- 1 ,2-dione,

3-(tert-bιιtylamino)-4-((2-((4-((lE)-4-hydroxybut-l-eny l)phenyl)amino)pyτimidin-4- yl)amino)cyclobut-3-ene-l,2-dione,

3-(tert"butylamino)-4-((2-((4-((E)-2-pyridin-2-ylvinyl)ph enyl)arnino)pyrimidin-4- yl)amino)cyclobut-3-ene- 1 ,2-dioπe,

3-(tei t-butylamino)-4-((2-((4-(( 1 E)-pent- 1 -enyl)pheiiyl)amino)pyrimidin-4- yl)amino)cyclobut-3-ene-l,2-dione,

N-(4-((4-((2-(tert-butylarnino)-3,4-dioxocyclobut-l-en-l- yI)amino)pyrimidin-2- yl)amino)-3-methoxyphenyl)cyclopentanecarboxamide,

3-((2-((4-amino-2-methoxypheπyl)amino)pyrimidin-4-yl)ami no)-4~(tert- butylamino)cyclobut-3-ene- 1 ,2-dione,

6-((4-((2-(tert-bulylamino)-3,4-dioxocyclobut~l-cn-l-yl)a mino)pyrimidin-2-yI)amino)- N-cyclopentylnicotinamide,

4-((4-((2-(teit-butylamino)-3,4-dioxocyclobut-l-en-l-yI)a mino)pyrimidin-2-yl)amino)- N-cyclopentyl-3-fiuorobenzamide,

4-({4-((2-(tert-butylaniino)-3,4-dioxocyclobut-l-en-l-yl) amino)pyiimidin-2- yl)amino)benzoic acid,

4-((4-((2-(tert-butylamino)-3,4-dioxocyclobut-l -en-I -yl)amino)pyrimidin-2-yl)amJno)- N-((lR)-l-(hydioxymethyl)'3-methylbutyl)benzamide,

N-2-(4-((4-((2-(tert-butyIamino)- 3,4-dioxocyclobut- 1 -en- 1 -yI)arnino)pyrimidin-2- yl)amino)benzoyl)-L-leucinamide,

4-((4-((2-(tert-butylamino)-3,4-dioxocycIobut-l-en-l-yI)a mino)pyrimidin-2-yl)amino)- N-((lS)-2-hydroxy-l-phenylethyl)benzamide,

4-((4-((2~(teit~butylamiπo)-3,4-dioxocyclobut-l-en-l-yl) amino)pyiimidin-2-yl)amino)- N-(3-ethoxypropyl)benzamide,

4-((4-((2-(tert~butylamino)- 3,4-dioxocyclobut- 1 ™en- 1 -yl)amiπo)pyrimidin-2-yl)amino)- N-(3-(methylthio)propyl)benzamide,

4-((4-((2-(tert-butylamino)-3,4-dioxocyclobut-l-en-l-yl)a mino)pyrimidin-2-yl)amino)- N-(4-(dimethylamino)bυtyl)benzamide,

4-((4-((2-(tert-butylamino)-3,4-dioxocyclobut-l-en-l-yl)a mino)pyrimidin-2-yl)amino)- N-(2-p3ienoxyethyl)benzaniide,

4-((4-((2-(tert-butylamino)-3 ₁ 4-dioxocyclobut-l-en-l-yl)amino)pyrimidin-2-yl)amino)- N-(3-(2-oxopyrτoIidin-l-yl)propyl)benzaniide,

4-((4-((2-(tert-butyiarnino)-3 _J 4-dioxocyclobut-l-cn-l-yl)amino)pyrirnidin-2-yI)amino)- N-(2-(5-methoxy"lH-indol-3-yl)ethyl)benzamide,

4-((4-((2-(tert-butylamino)-3,4-dioxocyclobut-l~en-l-yl)a niino)pyrimidiπ-2-yl)amino)- N-(3,4-difluoiobenzyl)benzamide,

4-({4-((2-(tert-butylamiπo)-3,4-dioxocyclobuH-en-l-yl)am ino)pyrimidiii"2-yl)amino)- N-((l S)-I -(I -naphthyl)ethyl)bcnzamide,

N-(2-(4-(aminosulfony])phenyI)ethyl)-4-((4-((2-(tert-buty larnino)-3,4~dioxocyclobut-l- en-1 -yl)amino)pyrimidin~2-yl)amino)benzamide,

4-((4-{(2-{teit~buiylamino)-3,4-dioxocyclobut-l-en-l-yl)a mino)pyriniidin-2-yl)amino)- N-(pyridin-2-ylmethyl)benzamide,

4-((4-((2-(tert-butyIarnino)-3,4-dioxocycJobut-l-en-l-yl) amino)pyrimidin-2-yl)amino)- N-(2-(lH-imidazol-4-yl)ethyl)benzamide,

4-((4-((2-(teit-butylamino)-3,4-dioxocyclobut-l-en-l-yl)a mino)pyiimidin-2-yl)aiiiino)- N-(2-morpholin-4-ylethyl)benzamide,

4-((4-((2-(tert-butylamino)-3 ₎ 4-dioxocyclobut-l-en-l-yl)amino)pyrimidin-2-yl)ainino)- 3-methoxybenzoic acid,

4-((4-((2-(tert-butylamino)-3,4-dioxocyclobut-l-en-l-yl)a mino)pyrimidin-2-yl)amino)- N-(4-(dimethylamino)cyclohexyl)-3-methoxybenzaiτiide,

4-((4-((2-(tert-bυtylamino)-3,4-dioxocyclobut-l-eπ-l-yl )amino)ρyrimidin-2-yl)amino)- N-(l ,l-dm"tethyl-2-morpholin-4-ylethyl)-3-melhoxybenzamide,

4-((4-((2-(teit~butylamino)-3,4-dioxocyclobut-l-en-l-yl)a mino)pyrimidin-2-yl)amino)- N-(l-ethyIpiperidin-3-yl)"3-methoxybenzamide,

4-((4-((2-(tert-butylamino)-3,4-dioxocyclobut-l-en-l-yl)a mino)pyτimidin-2-yl)amino)- N-cyclobutyl-3-(tπfluoromethoxy)benzamide and

4-((6-((2-(tert-butylamino)-3,4-dioxocyclobut-l-en-l-yl)a mino)-9H-purin-2-yl)amino)- N-cyclobutyl-3-methoxybenzamide

DETAILED DESCRIPTION OF THE INVENTION Variable moieties of compounds herein aie represented by identifiers (capital letters with numerical and/or alphabetical superscripts) and may be specifically embodied

It is meant to be understood that pioper valences are maintained foi all moieties and combinations theieof, that monovalent moieties having moie than one atom are attached tluough their left ends.

It is also meant to be understood that a specific embodiment of a vaiiable moiety may be the same or different as another specific embodiment having the same identifier

The term "cyclic moiety," as used herein, means benzene, cycloalkane, cycloalkyl, cycloalkene, cycloalkenyl, heteroarene, heteroaiyl, heteiocycloalkane, heterocycloalkyl, heterocycloalkeπe, heterocycloalkenyl, phenyl, spiroalkyl, spiroalkenyl, spiroheteroalkyl and spiroheteroalkenyl.

The term "cycloalkane," as used herein, means C ₃ -cycloalkane, C ₄ -cycloalkane, Cs-cycloalkaπe and C ₆ -cycloalkane

The term "cycloalkyl," as used herein, means C ₃ -cycloalkyl, C^cycloalkyl, Cs-cycloalkyl, Cg-cycloalkyl, C ₇ -cycIoalkyl and Cg-cycloalkyl.

The term "cycloalkene," as used herein, means C ₄ -cycloalkene, Cg-cycloalkene, Cg-cycloalkene, C ₇ -cycloalkene, and Cg-cycloalkene

The term "cycloalkenyl," as used herein, means C ₄ -cycloalkenyl, Cs-cycloalkenyl, Ce-cycloalkenyl, C ₇ -cycloalkenyI, and Cg-cycloalkenyl

The term "heteroarene," as used herein, means furan, imidazole, isothiazole, isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyiazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazine and 1 ,2,3-triazole

The term "heteroaryl," as used herein, means furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1 ,2,4-oxadiazoyl, 1,3,4-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetiazolyl, 1,3,4-thiadiazolyl, thiazolyl, thiophenyl, 1 ,3,5-tτiazinyl and 1,2,3-triazolyl

The term "heterocycloalkane," as used herein, means cycloalkane having one or two or three CH? moieties replaced with independently selected O, S, S(O), SO ₂ or NH and one or two CH moieties unreplaced or replaced with N and also means cycloalkane having one or two or three CH? moieties unreplaced or replaced with independently selected O, S, S(O), SO? 01 NH and one or two CH moieties replaced with N The term "heteiocycloalkane," as used herein, also means the saturated part of indoline

The term "heteiocycloalkyl," as used herein, means cycloalkyl having one or two or thiee CH ₂ moieties replaced with independently selected O, S, S(O), SO ₂ or NH and one or two CH moieties iirueplaccd or replaced with N and also means cycloalkyl having one or two or three CH ₂ moieties unreplaced or replaced with independently selected O, S, S(O), SO? or NH and one or two CH moieties replaced with N

The teim "heteiocycloalkene," as used herein, means cycloalkene having one or two 01 three CH ₂ moieties replaced with independently selected O, S, S(O), SO ₂ or NH and one or two CH moieties unreplaced or replaced with N and also means cycloalkene having one or two or three CH ₂ moieties unreplaced or replaced with independently selected O, S, S(O), SO ₂ or NH and one or two CH moieties replaced with N

The term "heterocycloalkcnyl," as used herein, means cycϊoalkenyl having one or two or three CH? moieties replaced with independently selected O, S, S(O), SO ₂ or NH and one or two CH moieties unreplaced or replaced with N and also means cycloalkenyl having one or two or three CH ₂ moieties unreplaced 01 replaced with independently selected O, S, S(O), SO ₂ or NH and one or two CH moieties replaced with N

The term "alkenyl," as used herein, means C ₂ -alkenyl, C ₃ -alkenyl, C ₄ -alkenyl, C ₅ -alkenyl and C<j-alkenyl,

The term "alkyl," as used herein, means C[-alkyl, C ₂ -alkyl, C ₃ -alkyl, C ₄ -aϊkyl, Cs-alky] and C _fr alkyl.

The term "alkynyl," as used herein, means C ₂ -alkynyl, C ₃ -alkynyl, Gφ-alkynyl,

Cs-alkynyl and Cβ-alkynyl

The term "C ₂ -alkenyl," as used herein, means ethenyl (vinyl).

The term "C^-alkenyl," as used herein, means 1-propen-l-yl, l-propen-2-yl

(isopropenyl) and l-propen-3-yl (allyl)

The term "Gφ-alkenyl," as used heiein, means l-buten-l~yl, l-buten-2-yl, 1,3- butadien-1-yl, l,3-butadien-2-y], 2-buten-l-yl, 2-buten-2-yl, 3-buten-l-yl, 3-buten-2-yl, 2-methyl- 1-propen-l-yl and 2-methyl-2-propen-l-yl

The term "Cs-alkenyl," as used herein, means 2 -methylene- 3-buten-l-yl, 2-methylenebut-l-yl, 2-methyI-l-buten-l-yl, 2-methyl- 1,3-butadien-l-yl, 2-methyl-2- butcn-1-yl, 2-methyl-3-buten-l-yl, 2-rnethyl-3-buten-2-yl, 3-methyM-buten-l-yl, 3-methyl- l-buten-2-yl, 3-methyl-l ,3-butadien-l-yl, 3-methyl-l,3-butadien-2-yI, 3-

methyl-2-buten-l-yl, 3-methyl-2-buten-2-yl, 3~methyI-3-buten-l-yl, 3-methyl-3-buten-2- yl, ] -penten-l-yl, l-penteπ-2-yl, l-penten-3-yl, 1,3-pentadien-l-yl, l,3-penta-dien-2-yl, l ,3-pentadien-3-yI, 1 ,4-pentadien-l-yl, 1 ,4-pentadien-2-yl, l,4-pentadien-3-yl, 2-penten- 1-yl, 2-penten-2-yl, 2-penten-3-yl, 2,4-pentadien-l-yl, 2,4-peπtadien-2-yϊ, 3-penten-l-yl, 3-peiiten-2-yI, 4-penteπ-l-y! and 4-penten-2-yI.

The term "Q-alkenyl," as used herein, means 2,2-dimethyI-3-buten-l-yl, 2,3-dimethyl-l-buten-l-yl, 2,3-dimethyl-l,3-butadien-l-yi, 2,3-dimethy]-2-buten-I-yl, 2,3-dimethyl-3-buten-l-yl, 2,3-dimethyl-3-buten-2-yl, 3,3-dimethyl-l-buten-l-yl, 3,3-dimethyl-l -buten-2-y], 2-ethenyl-l ,3-butadien-l -yl, 2-ethenyl-2-buteπ-l -yl, 2-ethyl- 1-buten-l -yl, 2-ethyl-l ,3-butadien-l-yl, 2-ethyl-2-buten-l-yl, 2-ethyl-3-buten-l-yI, 1- hexen-1-yl, l-hexen-2-yl, l-hexen-3-yl, 1 ,3-hexadien-l-yl, l,3-hexadien-2-yl, 1,3- hexadien-3-yI, 1,3,5-hexatrien-l-yl, l,3,5-hexatrien-2-yl, l,3,5-hexatrien-3-yl, 1,4- hexadien-1-yl, l,4-heχadien-2-yl, 1 ,4-hexadien-3-yl, 1,5-hexadien-l-yl, l,5-hexadien-2- yl, l,5~hexadien-3-yl, 2-hexen-l-yI, 2-hexen-2-yl, 2-hexen-3-yI, 2,4-hexadien-l-yl, 2,4- hexadien-2-yl, 2,4-hexadien-3-yl, 2,5-hexadien-l-yl, 2,5-hexadien-2-yl, 2,5-hexadien-3- yl, 3-hexen-l-yl, 3-hexen-2-yl, 3-hexen-3-yl, 3,5-hexadien-l-yl, 3,5-hexadien-2-yl, 3,5- hexadien-3-yl. 4-hexen-l-yl, 4-hexen-2-yl, 4-hexen-3-yl, 5-hexeπ-l-yJ, 5-hexen-2-yl, 5- hexen-3-yl, 2-methylene-3-methyl-3-buten-l-yl, 2-methylene-3-methylbut-l-yl, 2- methylene-3-penten-l-yl, 2-methyIene-4-penten-l-yl, 2-methylenepent-l-yl, 2- methylenepent-3-yl, 3-methylene-l-penten-l-yl, 3-methyIene-l-penteπ-2-yl, 3- methylenepenM-yl, 3 -m ethylene- 1,4-pentadi en- 1-yl, 3-methylene-l,4-pentadien-2-yl, 3- methylene-pent-2-yl, 2-methyl-l-penten-l-yl, 2-methyl- l-penten-3-yl, 2-methyl- 1,3- pentadien-l-yl, 2-methyl-l,3-pentadien-3-yI, 2-methyl-l,4-pentadien-l-yl, 2-methyl-l,4- pentadien-3-yl, 2-methyl-2-penten-l-yl, 2-methyl-2-penten-3-yl, 2-methyl-2,4-pentadien- 1-yl, 2-methyl-2,4-pentadien-3-yl, 2-methyl-3-penten-l-yl, 2-methyl-3-penten-2-yl, 2- methyl-3~penten-3-yI, 2-methyl-4-penten-l~yl, 2-methyl-4-penten-2-yl, 2-methyl-4- penten-3-yl, 3-methyl-l-penten-l-yI, 3 -methyl- 1 -penten-2-yl, 3-methyl- 1,3-pentadien-l- yl, 3-methyl- 1 ,3-pentadien-2-yl, 3-methyl- 1 ,4-peπtadien- 1 -yl, 3-methyl- ϊ ,4-pentadien-2- yl, 3-methyl-2-penten-l -yl, 3-rnethyl-2-penten-2-yl, 3-methyl-2,4-pentadien- 1 -yl, 3- methyl-3-penten-l-yl, 3-methyl-3-penten-2-yl, 3-methyl-4-penten-l-yl, 3-methyl-4- penten-2-yl, 3-methyl-4-penten-3-yl, 4-methyl-l-ρenten-l-yl, 4-methyl-l -penten-2-yl, 4- methyl- l-penten-3-yl, 4-methyl-l, 3-pentadien-l-yl, 4-methyl-l, 3-pentadien-2-yl, 4- methyl-l,3-pentadien-3-yl, 4-methyl-l, 4-pentadien-l-yI, 4-methyl-l,4-pentadien-2-yl, A- methyl- 1 ,4-pentadien-3-yl, 4-methylene-2-penten-3-yl, 4-methyl-2-penten-l-yl, 4- methyl-2-penten-2-yl, 4-methyl-2-penten-3-yl, 4-melhyl-2,4-pentadien-l-yl, 4-methyl- 2,4-pentadien-2-yl, 4-methyl-3-penten-l-yl, 4-methyl-3-penteπ-2-yl, 4-methyl-3-penten- 3-yl, 4-methyl-4-penten- 1 -yl and 4-methyl-4-penten-2-yl.

The term "Cj-alkyl," as used herein, means methyl

The teim "C?-alkyl," as used herein, means ethyl.

The term "C^-alkyl," as used heiein, means piop~l-yl and prop-2-yl (isopropyl)

The term "C ₄ -alkyl," as used heiein, means but-l-yl, but-2-yl, 2-methylprop-l-yl and 2-methylprop-2-yl (tert-butyl).

The term "Cs-alkyl," as used herein, means 2,2-dimethylprop-l-yl (neo-pentyl), 2-rnethy]but-l~yl, 2-methyJbut-2-yl, 3»methylbut-l-yl, 3-methylbut-2-yl, pent-l-yj, pent-2-yl and pent-3-yl.

The term "Cc-alkyl," as used herein, means 2,2-dimethylbut-l-yl, 2,3-dimethylbut-l-yl, 2,3-dimethylbut-2-yI, 3,3-dimethylbuM-yl, 3,3-dimethylbut-2-yl, 2-ethylbut-l-yl, hex-l-yl, hex-2-yl, hex-3-yl, 2-methylρent-l-yl, 2-methylpent-2-yl, 2-methylpent-3-yl, 3-methylpent-l-yl, 3-methylpent-2-yl, 3-methylpent-3-yl, 4-methylpent-l-yl and 4-methylpent-2-yl.

The teim "Ci-alkynyl," as used herein, means ethynyl (acetylenyl).

The term "Cj-alkynyl," as used herein, means 1-piopyπ-l-yl and 2-propyn-l-yl (propargyl)

The term "Cψ-alkynyl," as used herein, means 1-butyn-l-yl, l,3~butadiyn-l-yl, 2-butyn-l-yl, 3-butyn-l-yl and 3-butyn-2-yl

The term "Cs-alkynyl," as used herein, means 2-methyl-3-butyn-l-yl, 2-methyl-3- butyn-2-yl, 3-methyI-l-butyn-l-yI, 1 ,3-pentadiyn-l-yl, 1,4-pentadiyn-l-yl, 1,4- pentadiyn-3-yl, 2,4-pentadiyn-l-yl, l-pentyn-l-yl, l-pentyn-3-yl, 2-pentyn-l-yl, 3- pentyn-1-yl, 3-pentyn-2-yl, 4-pentyn-l-y! and 4-pentyn-2-yl

The term "C^-alkynyl," as used herein, means 2,2-dimethyl-3-butyn~l-yl, 3,3-dimethyl-l-butyn~l-yl, 2-ethyl-3-butyn-l~yl, 2-ethynyl-3-butyn-l-yl, l~hexyn-l-yl, 1 -hexyii-3-yl, 1,3-hexadiyn-l-yl, 1,3,5-hexatriyn-l-yl, 1,4-hexadiyn-l-yl, 1,4-hexadiyn- 3-yl, 1,5-hexadiyn-l-yl, l,5-hexadiyn-3-yl, 2-hexyn-l-yl, 2,5-hexadiyn-l-yl, 3-hexyn-l- yl, 3-hexyn-2-yl, 3,5-hexadiyii-2-yl, 4-hexyn-l-yl, 4-hexyπ-2-yl, 4-hexyn-3-yl, 5-hexyπ- 1-yl, 5-hexyn-2-yl, 5-hexyn-3-yl, 2-methyI-3-pentyn-l-yl, 2-methyl-3-pentyn-2-yl, 2- melhyl-4-pentyn-l-yl, 2-methyl-4-pentyn-2-yI, 2-methyl-4-pentyn-3~yl, 3 -methyl- 1- pentyn-1-yU 3-methyl-4-pentyn-l-yl, 3-methyl-4-pentyn-2-yl, 3 -methyl- 1,4-pentadiyn-l -

yl, 3-methyl-l,4-pentadiyn-3-yl, 3-methyl-4-pentyn-l-yl, 3-methyl-4-pentyn-3-yl, A- methy]-]-pentyn-l-yl and 4-methyl-2-pentyn-l-yl

The term "C ₄ -cycloalkane," as used herein, means cyctobutane.

The term "Cs-cycloalkane," as used herein, means cyclopentane and the saturated part of fluorene

The term "C<;-cycloalkane," as used herein, means cyclohexane.

The term "C ₄ -cycloalkene," as used herein, means cyclobutene and 1 ,3-cyclobutadiene

The term "Cs-cycloalkene," as used herein, means cyclopentene and 1,3-cyclopentadiene.

The term "Ce-cycloalkene," as used herein, means cyclohexene, 1,3-cyclohexadiene and 1,4-cyclohexadiene.

The term "C ₇ -cycloalkene," as used herein, means cycloheptene and 1,3- cycloheptadiene.

The term "Cs-cycloalkene," as used herein, means cyclooctene, 1,3- cyclooctadiene, 1 ,4-cyclooctadiene, 1 ,5-cyclooctadiene, 1 ,3,5-cyclooctatriene and 1 ,3,6- cyclooctatiiene

The term "C ₇ -cycIoalkane," as used herein, means cycloheptane.

The term "Cs-cycloalkane," as used herein, means cyclooctane.

The term "C ₃ -cyc.0alken.yl," as used herein, means cycloprop-1-en-l-yl and cycloprop-2-en- 1 -yl .

The term "Crcycloalkenyl," as used herein, means cyclobut-1-en-l-yl and cyclobut-2-en-l-yl.

The term "Cs-cycloalkenyl," as used herein, means cyclopent-l-en-l-yl, cyclopent-2-en-l-yl, cyclopent-3-en-l-yl and cyclopenta-l,3-dien-l~yl,

The teim "Cc-cycloalkenyl," as used heiein, means cyclohex-l-en-l-yl, cyclohex- 2-en-l-yl, cycIohcx-3-en-l-yl, cyclohexa-l,3-dien-l-yl, cyclohexa-l,4-dien-l-yl, cyclohexa-l,5-dien-l-yl, cyclohexa-2,4-dien-l-yl and cyclohexa~2,5-dien-l-yl

The term "0 ₇ -cycloaIkenyI," as used herein, means bicyclo[2 2 ϊ]hept-2-en-l-yl, bicyc!o[2 2.1]hept-2-en-2-yl, bicyclo[2 2 l]hept-2-en-5-yl, bicycIo[2,2.1]hept-2-en-7-yl, bicyclo[2 2J]hepta-2,5-dien-ϊ-yl, bicyclo[2.2 l]hepta-2,5-dien-2-yl, bicyclo[2 2 l]hepta- 2,5-dien-7-yI, cyclohept-1-en-l -yl, cyclohept-2-en-l-yl, cyclohept-3-en-l-yl, cyclohept- 4-en-l-yI, cyclohepta-1, 3~dien-l-yl, cyclohepta-I ,4-dien~l-yl, cyclohepta-l ,5-dien-l-yl, cydohepta-1 ,6-dien-l -yl, cyclohepta-2,4-dien-l -yl, cyc]ohepta-2,5-dien-l -yl, cyclohepta- 2,6-dien-l-yl, cyclohepta-3,5-dien-l-yl, cyclohepta-l,3,5-trien-l-yl, cyclohepta-1, 3,6- trien-1-yl, cyclohepta-1 , 4,6-trien-l-yl and cyclohepta-2,4,6-trien-l-yl

The term "Cg-cycloalkenyl," as used heiein, means bicyclo[2 2 2]ocl-2-en-l-yl, bicyclo[2 2.2]oct-2-en-2-yl, bicyclo[2,2 2]oct-2-en-5-yl, bicyclo[2.2 2]oct-2-en-7-yl, bicyclo[2 2 2]octa-2,5-dien-l-yl, bicyclo[2 2 2]octa-2,5-dien-2-yl, bicyclo[2.2 2]octa~2,5- dien-7-yl, bicyclo[2,2 2]octa-2,5,7-trien-l-yl, bicyclo[2.2 2]octa-2,5,7-trien-2-yl cyclooct-1-en-l-yl, cyclooct-2-en-l-yl, cyclooct-3-eπ-l-yI, cyclooct-4-en-l-yl, cycloocta- 1,3-dien-l-yl, cycloocta-l ,4-dien-l-yl, cycloocta-l ,5-dien-l-yl, cycloocta-l,6-dien-l-yl, cyclooctal,7-dien-l-yl, cyc!oocta-2,4-dien-l-yl, cycloocta-2,5-dien-l-yl, cycloocta-2,6- dien-1-yl, cycloocta-2,7-dien-l-yl, cycIoocta-3,5-dien-l-yl, cycloocta-3,6-dien-l-yl, cycloocta-l,3,5-trien-l-yl, cycloocta-l ,3,7-tτien-l-yl, cycloocta-l^β-tiien-l-yl, cycloocta-l,4,7-trien-l-yl, cycloocta-I ^J-trien-l-yl, cycloocta-2,4,6-trien-l-yl, cycloocta-2,4,7-trien-l-yl, cycloocta-2,5,7-lrien-l-yl and cycloocta- 1 ,3 ,5 ,7-tetraen- 1 -yl .

The term "C ₃ -cycloalkyl," as used herein, means cycloprop-1-yl

The term "C ₄ -cycloalkyl," as used herein, means cyclobut-1 -yl

The term "Cs-cycloalkyl," as used herein, means cyclopent-1 -yl

The teim "Cβ-cycloalkyl," as used herein, means cyclohex-1-yl

Compounds of this invention may contain asymmetrically substituted carbon atoms in the R or S configuration, wherein the terms "R" and "S" are as defined in Pure Appl Chem. (1976) 45, 13-10 Compounds having asymmetrically substituted carbon atoms with equal amounts of R and S configurations are iacemic at those atoms Atoms having excess of one configuration ovei the other are assigned the configuration in excess, preferably an excess of about 85%-90%, more preferably an excess of about

95%-99%, and still more preferably an excess greater than about 99% Accordingly, this invention is meant to embrace racemic mixtures and relative and absolute diasteieoisomers of the compounds thereof

Compounds of this invention may also contain carbon-carbon double bonds oi carbon-nitrogen double bonds in the Z or E configuration, in which the term "Z" represents the larger two substituents on the same side of a caibon-carbon or carbon-nitrogen double bond and the term "E" represents the larger two substituents on opposite sides of a carbon-carbon or carbon-nitrogen double bond The compounds of this invention may also exist as a mixture of "Z" and "E" isomers.

Compounds of this invention may also exist as tautomeis or equilibrium mixtures thereof wherein a proton of a compound shifts fiom one atom to another Examples of tautomers include, but are not limited to, keto-enol, phenol-keto, oxime-nitroso, nitro-aci, imine-enamine and the like.

Compounds of this invention containing NH, C(O)OH, OH or SH moieties may have attached thereto prodrug-forming moieties. The prodrug-forming moieties are removed by metabolic processes and release the compounds having the freed NH, C(O)OH, OH or SH in vivo Prodrugs are useful for adjusting such pharmacokinetic properties of the compounds as solubility and/or hydrophobicity, absorption in the gastrointestinal tract, bioavailability, tissue penetration, and rate of clearance

Metabolites of compounds having formula (I) produced by in vitro or in vivo metabolic processes, may also have utility for treating diseases associated with over expression or unregulation of a kinase

Certain precursor compounds which may be metabolized in vitio or in vivo to form compounds having formula (I) may also have utility for ti eating diseases associated with overexpression oi uniegulation of a kinase

Compounds having formula (I) may also be radiolabeled with a radioactive isotope such as a radioactive isotope of carbon (i.e. C), hydrogen (i e H), nitrogen (i.e. N), phosphorus (i e ^" P), sulfur (i e S)or iodide (i e ^" I). Radioactive isotopes may be incorporated into the compounds having formula (II) by ieacting the same and a radioactive derivitizing agent or by incorporating a radiolabeled intermediate into their syntheses The radiolabeled compounds of formula (II) are useful for both prognostic and diagnostic applications as well as for in vivo and in vitro imaging

Compounds having formula (I) may exist as acid addition salts, basic addition salts or zwitterions Salts of compounds having formula (I) aie prepaied during their isolation or following their purification Acid addition salts aie those derived fiom the ieaction of a compound having formula (I) with acid Accoidingly, salts including the acetate, adipate, alginate, bicaibonate, citrate, aspaitate, beπzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphoiate, camphoisufonate, digluconate, formate, fumarate, glyceiophosphate, glutamate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactobionate, lactate, maleate, rnesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate, picrate, propionate, succinate, tartrate, thiocyanate, trichloroacetic, trifluoroacetic, paia-toluenesuifonate and undecanoate salts of the compounds having foimula (I) are meant to be embraced by this invention Basic addition salts of compounds are those deπ ^' ved from the reaction of the compounds having formula (I) with the bicaibonate, carbonate, hydroxide or phosphate of cations such as lithium, sodium, potassium, calcium and magnesium

Compounds having formula (I) may be administered, for example, bucally, ophthalmically, orally, osmotically, parenterally (intramuscularly, intraperintoneally intiasternally, intravenously, subcutaneously), rectally, topically, transdermal Iy, vaginally and intiaarterially as well as by intraarticular injection, infusion, and placement in the body, such as, for example, the vasculature by means of, for example, a stent

Therapeutically effective amounts of a compound having formula (I) depend on recipient of treatment, disease treated and severity thereof, composition comprising it, time of administration, route of administration, duration of treatment, potency, rate of clearance and whether or not another drug is co-administered The amount of a compound having formula (I) used to make a composition to be administered daily to a mammal in a single dose or in divided doses is from about 0 03 to about 200 mg/kg body weight Single dose compositions contain these amounts or a combination of submultiples thereof

Compounds having formula (I) may be administered with or without an excipient Excipients include, but are not limited to, encapsulators and additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents, mixtures thereof and the like

Excipients foi pieparation of compositions compiising a compound having formula (I) to be administeied oialjy include, but are not limited to, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomeis, castoi oil, cellulose, cellulose acetate, cocoa butter, com staich, com oil, cottonseed oil, cross-povidone, diglyceiides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethyl celluose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethyl cellulose, sodium phosphate salts, sodium lauryj sulfate, sodium sorbitol, soybean oil, stearic acids, stearyl fumaiate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water, mixtures thereof and the like Excipients for preparation of compositions comprising a compound having formula (I) to be administered ophthalmically or orally include, but are not limited to, 1 ,3-butylene glycol, castor oil, corn oil, cottonseed oil, ethanol, fatty acid esters of sorbitan, germ oil, gioundnut oil, glycerol, isopiopanol, olive oil, polyethylene glycols, propylene glycol, sesame oil, water, mixtures thereof and the like. Excipients for preparation of compositions comprising a compound having formula (I) to be administered osmotically include, but are not limited to, chlorofiuorohydrocaibons, ethanol, water, mixtures thereof and the like. Excipients for preparation of compositions comprising a compound having formula (I) to be administered parenterally include, but are not limited to, 1,3- butanediol, castor oil, coin oil, cottonseed oil, dextiose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, U S.P or isotonic sodium chloride solution, water, mixtures thereof and the like. Excipients for preparation of compositions comprising a compound having formula (1) to be administeied rectally or vaginally include, but arc not limited to, cocoa butter, polyethylene glycol, wax, mixtures thereof and the like

This invention also comprises combination therapeutic methods of treating disease conditions involving polo-like kinases, such as cancer, in a patient comprising administering thereto a therapeutically effective amount of a pharmaceutical composition comprising a compound having formula (I) and a therapeutically effective amount of one or more than one additional therapeutic agents and/or ionizing radiation

The combination therapeutic methods include administering compositions of a compound having formula (I) and one or more than one additional therapeutic agents or ionizing radiation to a patient using any desired dosing and/oi scheduling regimen

Compounds having formula (I) may be administered with one or more than one additional therapeutic agents, wherein the additional theiapeutic agents include ionizing

radiation or chemotherapeutic agents, wherein chemotherapeυlic agents include, but are not limited to, carboplatin, cisplatiπ, cyclophosphamide, dacarbazine, dexamethasone, docetaxel, doxorubicin, etoposide, fludarabine, irinotecan, CHOP (C: Cytoxan® (cyclophosphamide); H: Adriamycin® (hydioxydoxombicin); O: Vincristine (Oncovin©); P: prednisone), paclitaxel, rapamycin, Rituxin® (rituximab), vinciistine and the like

Compounds having formula (I) are also expected to be useful as chemotherapeutic agents in combination with therapeutic agents that include, but are not limited to, angiogenesis inhibitors, antiproliferative agents, kinase inhibitors, receptor tyrosine kinase inhibitors, aurora kinase inhibitors, other polo-like kinase inhibitors, bcr-abl kinase inhibitors, growth factor inhibitors, COX-2 inhibitors, non-steroidal antiinflammatory drugs (NSAIDS), antimitotic agents, alkylating agents, antimetabolites, intercalating antibiotics, platinum containing agents, growth factor inhibitors, ionizing radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologic response modifiers, immunologicals, antibodies, hormonal therapies, retinoids/deltoids plant alkaloids, proteasome inhibitors, HSP-90 inhibitors, histone deacetylase inhibitors (HDAC) inhibitors, purine analogs, pyrimidine analogs, MEK inhibitors, CDK inhibitors, ErbB2 receptor inhibitors, mTOR inhibitors as well as other antitumor agents.

Angiogenesis inhibitors include, but are not limited to, EGFR inhibitors, PDGFR inhibitors, VEGFR inhibitors, TIE2 inhibitors, IGFlR inhibitors, matrix metalloproteinase 2 (MMP-2) inhibitors, matrix metalloproteinase-9 (MMP-9) inhibitors, thrombospondin analogs and the like,

Examples of EGFR inhibitors include, but are not limited to, Iressa (gefitinib), Tarceva (erlotinib or OSI-774), Erbitux (cetuximab), EMD-7200, ABX-EGF, HR3, IgA antibodies, TP-38 (IVAX), EGFR fusion protein, EGF-vaccine, anti-EGFr immunoliposomes, Tykerb (lapatinib) and the like.

Examples of PDGFR inhibitors include, but are not limited to, CP-673,451, CP-868596 and the like.

Examples of VEGFR inhibitors include, but are not limited to, Avastin (bevacizumab). Sutent (sunitinib, SUl 1248), Nexavar (sorafenib. BAY43-9006),

CP-547,632, axitinib (AG13736), Zactima (vandetanib, ZD-6474), AEE788, AZD-2171, VEGF trap, Valalaπib (PTK-787, ZK-222584), Macugeπ, JM862, Pazopanib (GW786034), ABT-869, angiozyme and the like.

Examples of thrombospondin analogs include, but are not limited to, TSP-I , ABT-510, ABT-567, ABT-898 and the like

Examples of auiora kinase inhibitors include, but are not limited to, VX-680, AZD- 1152, MLN-8054 and the like

An example of another polo-like kinase inhibitor includes, but is not limited to BI-2536 and the like

Examples of bcr-abl kinase inhibitors include, but are not limited to, Gleevec

(imatinib), Dasatinib (BMS354825) and the like

Examples of platinum containing agents includes, but are not limited to, cisplatin, Paraplatin (carboplatin), eptaplatin, lobaplatin, nedaplatin, Eloxatin (oxaliplatin), satrap latin and the like

Examples of mTOR inhibitors includes, but are not limited to, CCI-779, rapamycin, temsirolimus, everolimus, RADOOl, AP-23573 and the like

Examples of HSP-90 inliibitois includes, but are not limited to, geldanamycin, radicicol, 17- AAG, KOS-953, 17-DMAG, CNF-101, CNF-1010, 17-AAG-nab, NCS-683664, Mycograb, CNF-2024, PU3, PU24FC1, VER49009, 1PI-504, SNX-2112, STA-9090 and the like

Examples of histone deacetylase inhibitors (HDAC) includes, but are not limited to, Suberoylam ^' lide hydroxamic acid (SAHA), MS-275, Valproic acid, TSA, LAQ-824, Trapoxiπ, Depsipeptide and the like.

Examples of MEK inhibitors include, but are not limited to, PD325901, ARRY-142886, ARRY-438162, PD98059 and the like

Examples of CDK inhibitors include, but are not limited to, flavopyridol, MCS-5A, CVT-2584, seliciclib (CYC-202, R-roscovitine), ZK-304709, PHA-690509, BMM 040, GPC-286199, BMS-387,032, PD0332991, AZD-5438 and the like

Examples of useful COX-2 inhibitors include, but are not limited to, CELEBREX™ (celecoxib), parecoxib, deiacoxib, ABT-963, MK-663 (etoricoxib), COX-189 Lumiracoxib), BMS347070, RS 57067, NS-398, Bextia (valdecoxib), paracoxib, Vioxx (rofecoxib), SD-8381, 4-Methyl-2-(3,4-dimethylphenyl)-l-(4-

sulfamoyl-phenyl-lH-pyπole, T-614, 1TE-522, S-2474, SVT-2016, CT-3, SC-58125, Aicoxia (etoiicoxib) and the like

Examples of non-steroidal anti-inflammatory drugs (NSAIDs) include, but are not limited to, Saisalate (Amigesic), Difϊunisal (Dolobid), Ibuprofen (Motrin), Ketoprofen (Omdis), Nabumetone (Relafen), Piroxicam (Feldene), Naproxen (Aleve, Naprosyn), Diclofenac (Voltaren), Indornethacin (Indocin), Sulindac (Clinoril), Tolmetin (Tolectin), Etodolac (Lodine), Ketorolac (Toradol), Oxapiozin (Daypro) and the like.

Exambles of ErbB2 receptor inhibitois include, but are not limited to, CP-724-

714, CI-1033 (canertinib), Herceptin (trastuzumab), Omitarg (2C4, petuzumab), TAK-165, GW-5720ϊ6 (Ionafamib), GW-282974, EKB-569, PI-166, dHER2 (HER2 Vaccine), APC8024 (HER2 Vaccine), anti-HER/2neu bispecific antibody, B7 her2IgG3, AS HER2 trifunctional bispecfic antibodies, mAB AR-209, mAB 2B- 1 and the like

Examples of alkylating agents include, but are not limited to, nitrogen mustard N~oxide, cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, melphalan, busulfan, mitobronitol, carboquone, thiotepa _? ranimustine, nimustine, Cloretazine (VNP 40101M) ₃ temozolornide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, carmustine, estiamustine, fotemustine, glufosfamide, KW-2170, mafosfamide, mitolactol, carmustine (BCNU), lomustine (CCNU), Busulfan, Treosulfan, Decaibazine, Temozolomide and the like

Examples of antimetabolites include but are not limited to, methotrexate, 6-mercaptopuiine riboside, meicaptopurine, 5-fluorouracil (5-FU) alone or in combination with leucovorin, tegafur, UFT, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-I, Alimta (premetrexed disodium, LY231514, MTA), Gemzar (gemeitabine, EH Lilly), fludarabine, 5-azacitidine, capecitabine, cladribine, clofarabiπe, decitabine, eflorπi thine, ethnylcytidine, cytosine arabinoside, hydroxyurea, TS-I , melphalan, nelarabme, nolatrexed, ocfosate, disodium premetrexed, pentostatin, pelitrexol, taltitrexed, triapine, trimetrexate, vidarabine, mycophenolic acid, tiazofurin, Ribavirin, EICAR, hydroxyurea, deferoxamine and the like

Examples of antibiotics include intercalating antibiotics but are not limited to, aclambicin, actinomycin D, amrubicin, annamycin, adriarnycin, bleomycin, daunorubicin, doxombicin, elsamitrucin, epirbucin, glaibuicin, idarubicin, mitomycin C, nemorubicin, neocaizinosta.in, peplomycin, pirarubicin, rcbeccaniyciπ, stimalamer, streptozocin, valrubicin, zinostatin, combinations thereof and the like

Examples of topoisomerase inhibiting agents include, but are not limited to, one oi moie agents selected fiom the group consisting of aclambicin, amonafide, belotecan, camptothecin, 10-hydioxycamptothecin, 9-amϊnocamptothecin, Amsacrine, Cardioxane (Dexrazoxine), diflomotecan, irinotecan HCL (Camptosar), edotecarin, epirubicin (Ellence), etoposide, exatecan, Becatecarin, gimatecan, lurtoiecan, orathecin (Supergen), BN-80915, mitoxantrone, phatbucin, pixantrone, lubitecan, sobuzoxane, SN-38, tafluposide, topotecan and the like

Examples of antibodies include, but are not limited to, Rituximab, Cetuximab, Bevacizumab, Trastuzimab, specific CD40 antibodies and specific IGFlR antibodies, chTNT-1/B, Denosumab, Panoiex (Edrecolomab), Rencarex (WX G250), Zanolirnumab, Lintuzumab Ticilimumab and the like.

Examples of hormonal therapies include, but are not limited to, exemestane (Aiomasin), leuprolide acetate, Buseielin, Cetrorelix, Deslorelin, Vantas, anastrozole (Arimidex), fosrelin (Zoladex), goserelin, Degarelix, doxercalcifeiol, fadrozole, formestane, tamoxifen citrate (tamoxifen), Arzoxifene, Casodex, Abarelix, Trelstar, finasteride, fulvestrant, toremifene, raloxifene, Trilostane (Modrastane, Desopan), lasofoxifene, letiozole, flutamide, bicalutamide, megesterol, mifepristone, πilutamide, dexamethasone, predisone, other glucocorticoids and the like.

Examples of retinoids / deltoids include, but are not limited to, seocalcitol (EB 1089, CB 1093), lexacalcitiol (KH 1060), fenretinide, Panietin (aliretinoin), Atragen, Bexaiotene, LGD- 1550 and the like.

Examples of plant alkaloids include, but are not limited to, vincristine, vinblastine, vindesine, vinorelbine and the like

Examples of proteasome inhibitors include, but are not limited to, bortezomib (Velcade), MG 132, NPI-0052, PR-171 and the like

Examples of immunologicals include, but are not limited to, interferons and numerous other immune enhancing agents. Interferons include interferon alpha, interferon alpha-2a, interferon alpha- 2b, interferon beta, interferon gamma- Ia, interferon gamma- Ib (Actimmune), or interferon gamma-nl and combinations thereof. Other agents include Alfaferone (Leukocyte alpha interferon, Cliferon), filgrastim, lentinan, sizofϊlan, TheraCys, ubenimex, WF-IO, aldesleukin, alemtuzumab, BAM-002, decarbazine, daclizumab, denileukin, gemtuzumab ozogamicin, ibritumomab, imiquimod, leπograstim, lentinan, melanoma vaccine (Corixa), molgramostim, Onco VAC-CL, sargaramostim, tasonerππn, tecleukin, thymalasin, tositumomab, Virulizin, Z-100,

epratuzumab, mitumomab, oregovomab, pemtumomab (Y-muHMFGl), Provenge (Dendreon), CTLA4 (cytotoxic lymphocyte antigen 4) antibodies, agents capable of blocking CTLA4 such as MDX-010 and the like.

Examples of biological response modifiers ate agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth, or differentiation of tissue cells to direct them to have anti-tumor activity. Such agents include krestin, lentinan, sizofiran, picibanil PF-3512676 (CpG-8954)., ubenimex and the like,

Examples of pyrimidine analogs include, but are not limited to, 5-Fluorouracil, Floxuridine, Doxifluridine, Ratitrexed, cytarabine (ara C), Cytosine arabinoside, Fludarabine, triacetyluridine Troxacitabine (Troxatyl), Gemcitabine and the like.

Examples of purine analogs include but are not limited to, Mercaptopurine, thioguanine and the like.

Examples of antimitotic agents include, but are not limited to, N-(2-((4- hydroxyphenyl)amino)pyiidin-3"yl)-4-methoxybenzenesulfoπami de, paclitaxel, docetaxel, epothilone D (KOS-862), PNU100940 (109881), Batabulin, Ixabepilone (BMS 247550), Patupilone, XRP-9881, Vinflunine, ZK-EPO and the like.

Compounds of the present invention are also intended to be used as a radiosensitizer that enhances the efficacy of radiotherapy. Examples of radiotherapy include but are not limited to, external beam radiotherapy (XBRT), or teletherapy, brachtherapy or sealed source radiotherapy, unsealed source radiotherapy and the like

Additionally, compounds having formula (I) may be combined with other antitumor agents selected from the following agents, Genasense, Panitumumab, Zevalin, Bexxar (Corixa), Arglabin, Abarelix, Alimta, EPO906, discodermolide, Neovastat, enzastaurin, Combrestatin A4P, ZD-6126, AVE-8062, DMXAA, Thymitaq, Temodar, Revlimid, Cypat, Histerelin, Plenaizis, Atrasentan, Celeuk (celmoleuldn), Satraplatin, thalomide (Thalidomide), theratope, Temilifene, ABI-007, Evista, Atamestane, Xyotax, Targretin, Triazone, Aposyn, Nevastat, Ceplene, Lanreotide, Aredia (pamidronic acid), Orathecin, Virulizin, Gastrimmune, DX-8951f, Mepact (Liposome muramyl tripeptide phophatidylethanolamine, Junovan), Dimericine (Liposome T4 endonuclase V), Onconase, BEC2, Xcytrin, CeaVac, NewTrexin, OvaRex, Osidem, Advexiπ, RSRl 3 (efaproxiral, Cotara, NBI-3001 (IL-4), Canvaxin, GMK vaccine, PEG Interferon A, Taxoprexin, gene therapy agents such as TNFeiade (GeneVac) or GVAX, Inter feron- alpha, Interferon-gamma, Gardasil, Eniluracil (GW 776C85), Lonafamib, ABT-100,

Tumor necrosis factor, Lovastatin, stauiospoiine, dactinomycin, zombicin, Bosentaπ, OncoVAX, Cervarix, Cintredekin besudolox (IL-13-PE38, IL-13-PE38QQR, Interleukiπ 13-pseudomonas exotoxin), Oncophage (HSPPC 96), Phenoxodiol (NV 06), IGN 101, PANVAC (CEA, MUC-I vaccinia), ampligen, ibaπdroπic acid, miltefosine, L-asparaginase, piocarbazine, Trabectedin (ET- 743, Ecteinascidiπ 743, Yondeiis), 5,10-methylenetetrahydrofolate, hydroxycaibamide, pegaspargase, pentostatin, tazarotne, TransMID 107R (KSB 311), Trisenox, Telcyta, tretinoin, acitretin, Zometa (zolendronic acid), Pandimex (Aglycon protopanaxadiol, PBD-2131), Talabostat (PTlOO), Tesmilifene, Tetrandrine, halofuginone, rebimastat, removab, squalamine, ukraiπ, paditaxel, Zinecard, Vitaxin and the like.

To determine the binding of compounds having formula (I) to a repiesentative protein kinase, the following in vitro kinase assay was used:

Recombinant GST-PIkI(I -331) was expressed using the FastBac bacculovirus expression system (GIBCO BRL, Gaithersburg, MD) and purified using glutathione (GST) affinity chromatogiaphy Kinase reactions were conducted using InM Plkl , 5μM γ- P-ATP (2mCi/μmol), 2μM biotinylated peptides substiate biotin-ahx- AKMETT FYDDALNASFLPSEKKIC-amide (SEQ, ID- 1), and various concentrations of inhibitor in kinase buffer (25mM Hepes pH 7,5, ImM DTT, 1OmM MgCl ₂ lOOμM Na ₃ VO ₄ 0 075mg/mL Triton X-100) for 30min at ambient temperature prior to stopping the reaction with 50 mM EDTA Stopped reactions weie transferred to streptavidin-coated FlashPlates, the plates washed, and scintillation counted on a TopCount plate reader. Ki values of repiesentative examples (μM) in are shown in TABLE 1.

TABLE l

The data from these assays demonstrate the utility of compounds having formula (I) as PIk 1 inhibitors Compounds having foimula (I) are therefore expected to have utility in treatment of diseases during which PIk 1 is expressed.

Diseases involving overexpiession or unregulation of Plkl include, but are not limited to, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocaicinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocyte), acute t-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myleogeneous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial

cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleυkemia, esophageal cancer, estrogen-ieceptoi positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, folliculai lymphoma, genu cell testicular cancer, glioma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellulai cancer, hormone insensitive prostate cancer, leiomyosarcoma, Iiposarcoma, lung cancer, lymphagioendotheliosarcoma, Iymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, non-small cell lung cancer, ohgodendroglioma, oral cancer, oropharyngeal carcinoma, osteogenic saicoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer, Wilms' tumor and the like

It is also expected that compounds having formula (I) would inhibit the growth of cells derived fiom a cancer or neoplasm such as bieast cancer (including estrogen- receptor positive breast cancer), colorectal cancer, endometrial cancer, lung cancer (including small cell lung cancer), lymphoma (including follicular or Diffuse Large B-cell), lymphoma (including non-Hodgkin's lymphoma), neuroblastoma, ovarian cancer, prostate cancer (including homione-insensitive prostate cancer) and testicular cancer (including genu cell testicular cancer)

It is also expected that compounds having formula (I) would inhibit the growth of cells derived fiom a pediatric cancer or neoplasm such as embryonal rhabdomyosarcoma, pediatric acute lymphoblastic leukemia, pediatric acute myelogenous leukemia, pediatric alveolar rhabdomyosarcoma, pediatric anaplastic ependymoma, pediatric anaplastic large cell lymphoma, pediatric anaplastic medulloblastoma, pediatric atypical teratoid/rhabdoid tumor of the central nervous syatem, pediatric biphenotypic acute leukemia, pediatric Burkitts lymphoma, pediatric cancers of Ewing's family of tumors such as primitive neuroectodermal rumors, pediatric diffuse anaplastic Wilm's tumor, pediatric favorable histology Wilm's tumor, pediatric glioblastoma, pediatric medulloblastoma, pediatric neuroblastoma, pediatric neiπoblastoma-derived myelocytomatosis, pediatric pre-B-cell cancers (such as leukemia), pediatric psteosarcoma, pediatric rhabdoid kidney tumor,

pediatric rhabdomyosarcoma, and pediatric T-cel! cancers such as lymphoma and skin cancer.

For example, involvement of Plkl in non-small cell lung cancer is reported in Oncogene 14, 543-9 (1997)

Involvement of Plkl in colorectal cancer is reported in Cancer Science 94, 148-52 (2003)

Involvement of Plkl in hepatoblastoma is repoited in Oncogene 23, 5901-11 (2004) Involvement of Plkl in endometrial carcinoma is reported in Cancer Letters- 169,

41-9 (2001).

Involvement of Plkl in ovarian carcinoma is reported in British Journal of Cancer 90, 815-21 (2004)

Involvement of Plkl in squamous cell carcinomas is reported in Cancer Research 59, 2794-7 (1999).

Involvement of Plkl in oropharyngeal carcinomas is reported in International Journal of Oncology 15, 687-92 (1999).

Involvement of Plkl in esophageal carcinoma is reported in Internationa] Journal of Oncology 15, 687-92 (1999) Involvement of Plkl in melanomas is reported in JAMA 283, 479-80 (2000)

Involvement of Plkl in malignant lymphoma of the thyroid is reported in Anticancer research 24, 259-63 (2004).

Involvement of Plkl in non-Hodgkin ^! s lymphomas is reported in Leukemia & Lymphoma 46, 225-31 (2005) Involvement of Plkl in epithelial ovarian cancer is reported in Journal of Clinical

Oncology 15, 199-206, (1997).

Compounds having formula (I) may be made by synthetic chemical processes, examples of which are shown hereinbelow. It is meant to be understood that the order of the steps in the processes may be varied, that reagents, solvents and reaction conditions may be substituted for those specifically mentioned, and that vulnerable moieties may be protected and deprotected, as necessary

Protecting groups for C(O)OH moieties include, but are not limited to, acetoxymethyl, ally!, benzoylmethyl, benzyl, benzyl oxymethyl, tert-butyl, tert-butyldiphenylsilyl, diphenylmethyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl, diphenylmethylsilyl, ethyl, para-methoxybenzyl, methoxymethyl, methoxyethoxym ethyl, methyl, methyl thiomethyl, naphthyl, para-nitrobenzyl, phenyl, n- propyl, 2,2,2-trichloroethyl, triethylsilyl, 2-(tiimethylsiIyl)ethyl, 2- (trirnethylsilyl)ethoxymethyl, triphenylmethyl and the like

Protecting groups for C(O) and C(O)H moieties include, but are not limited to, 1,3-dioxylketal, dielhylketal, dimethylketal, 1,3-dithianylkelaI, O-meihyloxime, O-phenyloxime and the like.

Protecting groups for NH moieties include, but are not limited to, acetyl, alanyl, benzoyl, benzyl (phenylmethyl), benzylidene, benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), 3,4-dimethoxybenzyloxycarbonyl, diphenylmethyϊ, diphenylphosphoryl, formyl, methanesulfonyl, para-methoxybenzyloxycarbonyl, phenylacety], phthaloyl, succinyl, trichloroethoxycarbonyl, tiiethylsilyl, trifluoroacetyl, trirnethylsilyl, triphenylmethyl, triphenylsilyl, para-toluenesυlfonyl and the like

Protecting groups for OH and SH moieties include, but are not limited to, acetyl, allyl, allyloxycarbonyl, benzyloxycarbonyl (Cbz), benzoyl, benzyl, tert-butyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, 3,4-dimethoxybenzyl,

3,4-dimethoxybenzyloxycarbonyl, l,l-dimethyl-2-propenyl, diphenylrnethyl, formyl, methanesulfonyl, methoxyacetyl, 4-methoxybenzyloxycarbonyl, para-methoxybenzyl, methoxycarbonyl, methyl, para-toluenesulfonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-trichloroethyl, triethylsilyl, trifluoroacetyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-trimethylsilylethyl, triphenylmethyl, 2-(triphenylphosphonio)ethoxycarbonyl and the like.

The following abbreviations have the meanings indicated, ADDP means l,l'-(azodicarbonyl)dipiperidine; AD-mix-β means a mixture of (DHQD) ₂ PHAL, K ₃ Fe(CN) ₆ , K ₂ CO ₃ and K ₂ SO ₄ ); AIBN means 2,2'-azobis(2- methylpropionitrile); 9-BBN means 9-borabicyclo[33, l]nonane; Cp means cyclopentadiene; (DHQD) ₂ PHAL means hydroquinidine 1 ,4-phthalazinediyl diethyl ether; DBU means l,8-diazabicyclo[5.4.0]undec-7-ene; DIBAL means diisobutylaluminum hydride; DIEA means diisopropyϊethylamiπe; DMAP means N,N-dimethylaminopyiidine; DME means 1,2-dimethoxyethane; DMF means

N,N-dimethylformarnide; dmpe means l ,2-bis(dimethylphosphino)ethane; DMSO means dimethylsulfoxide; dppa means diphenylphosphoryl azide; dppb means 1,4- bis(diρhenylphosphino)butane; dppe means 1 ,2-bis(diρhenylphosphino)ethane; dppf means l,r-bis(diphenylphosphino)feπocene; dppm means 1,1- bis(diphenylphosphino)methane; EDAC means l-(3-dimethylaminoρropyl)-3- ethylcarbodiimide; Fmoc means fluorenylmethoxycarbonyl; HATU means O-(7- azabenzotriazo3-l-yl)-N,N'N'N'-tetramethyluronium hexafluorophosphate; HMPA means hexamethylphosphoramide; IPA means isopropyl alcohol; LDA means lithium diisopropylamide; LHMDS means lithium bis(hexamethyldisilylamide); MP-BH ₃ means macroporas triethylammonium methylpolystyrene cyanoborohydride; LAH means

lithium aluminum hydiide; NCS means N-chlorosuccinimide; PyBOP means benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate; TDA-I means tris(2~(2-methoxyethoxy)ethyl)amine; TEA means triethylamiπe; TFA means trifluoioacetic acid; THF means tetiahydrofuran; NCS means N-chlorosuccinimide; NMM means N-methylmorpholiπe; NlVlP means N-methylpyrio3idine and PPh ₃ means triphenylphosphine

SCHEME 1

(D (2)

As shown in Scheme 1, 3,4-dielhoxycyclobut-3-ene-l,2-dione can be reacted with compounds having formula H?N-A to provide compounds having formula ( 1 ). Compounds having formula (1) can be converted to compounds having formula (2) by reacting the former, an alkoxide base and compounds having formula H?N-D to provide compounds having formula (2) Conversion of 1, 3,4-diethoxycyclobut-3-ene-l,2-dione to compounds having formula (1) is usually conducted in solvents such as methanol, ethanol or tert-butanol at about 25°C over about 24 hours Conversion of compounds having formula (1 ) to compounds having formula (2) is usually conducted in solvents such as DMSO at about 50 ⁰ C to 100°C over about 24 hours.

SCHEME 2

(3)

As shown in Scheme 2, 3,4~diethoxycyclobut-3-ene-l,2-dione can be reacted with ammonia in methanol to provide compounds having formula (3) The reaction is typically conducted at about 25°C to about 50 ⁰ C over about 24 hours. Compounds having formula (3) can be reacted with the appropriately functionalized compounds having formula ClC(O)R ¹ , ClC(O)OR ¹ , ClC(O)NHR ¹ , CIC(O)N(R ¹ ) ₂ , ClSO ₂ NHR ¹ or ClSO ₂ N(R ) ₂ , with or without a base, to provide compounds having formula (I) Examples of bases include, but are not limited to TEA, DIEA and the like The degree of reactivity of the amino moieties can be determined by the molar ratios of the reactaπts, the temperatures at which the reactions are conducted, and whether or not a promoter such as DMAP is used.

The size, length and natuie of substitution of R ^"" and R can be tailored according to the nature of substituents on the proximal ring Rings having a desϊied substitution pattern may be purchased or derivatized by means well-known in the ait Accordingly, the following examples are presented to provide specifics of what is believed to be the most useful and readily undei stood description of piocedures and conceptual aspects of this invention

EXAMPLE 1

A mixture of 3,4-diethoxycyclobut-3-ene-l,2-dione (1 9 g) and 1,2- dimethylpropylamine (0 87 g) in ethanol (10 mL) was stirred at ambient temperature overnight. The mixture was concentrated, and 15:1 pentane/ether was added. The solid was collected, washed with 15:1 pentane/ether and dried. H NMR (DMSOd ₆ ) δ 0 83 (d, J=8 Hz, 6H), 1 16 (d, 1=8 Hz, 3H), 1.38 (m, 3H), 1 67 (m, IH), 3,42-3 82 (m, IH), 4,63 (m, 2H), 8 55-8 75 (m, IH).

EXAMPLE 2

This example was prepared as described in EXAMPLE 1 using 1,3- dimethylbutylamine in place of 1,2-dimethylpropylamine H NMR (DMSOd ₆ ) δ 0 83 (d, J=8 Hz, 6H), 1 16 (d, 1=8 Hz, 3H), 1.22 (m, IH), 1 35 (m, 3H), 1.44 (m, IH), 1 54 (m, IH), 3 65-4.10 (m, IH), 4 63 (m, 2H), 8.42-8 64 (m, IH)

EXAMPLE 3

This example was prepared as described in EXAMPLE 1 using (R)-1, 2,2- trimethylpiopylamine in place of 1,2-dimethylpropylamine H NMR (CDCI ₃ ) δ 0 93 (s, 9H), 1 22 (d, J=8 Hz, 3H), 1 47 (m, 3H), 3 57 (m, IH), 4 80 (m, 2H), 5 58 (m, IH)

EXAMPLE 4

This example was prepared as described in EXAMPLE 1 using (S)- 1,2,2- trimethylpropylamine in place of 1,2-dimethylpropylamine. H NMR (DMSOd ₆ ) 8 0 84 (s, 9H), 1 12 (d, J=8 Hz, 3H), 1.38 (m, 3H), 3.42-3 92 (m, IH), 4 63 (m, 2H), 8 47-8.67 (m, IH)

EXAMPLE 5

This example was prepared as described in EXAMPLE 1 using 1,1- dimethylpropylamine in place of 1,2-dimethylpropylamine H NMR (DMSOd ₆ ) δ 0.80 (t, J=8 Hz, 3H), 1 24 (s, 6H), 1.38 (m, 3H), 1 62 (m, 2H), 4 70 (m, 2H), 8 47-8 57 (m, IH)

EXAMPLE 6

This example was prepared as described in EXAMPLE 1 using tert-butyJamine in place of 1 ,2-dimethylpropylamine. ¹ H NMR (DMSOd ₆ ) δ 1.32 (s, 9H), 1.38 (t, .1=10 Hz, 3H), 4.70 (m, 2H), 8.66 (d, ,1=7 Hz, IH).

EXAMPLE 7

This example was prepared as described in EXAMPLE 1 using 2,2- dimethylpropylamine in place of 1 ,2-dimethylpropylamine..

EXAMPLE S

This example was prepared as described in EXAMPLE 1 using cyclopropylrnethylamine in place of 1 ,2-dimethylpropylamine.

EXAMPLE 9 This example was prepared as described in EXAMPLE 1 using 2-morpholin-4-yl- ethylamine in place of 1 ,2-dimethylpropylamine.

EXAMPLE 10

This example was prepared as described in EXAMPLE 1 using 1 - phenylethylamine in place of 1 ,2-dimethylpropylamine.

EXAMPLE 11

A mixture of 3,4-diethoxycyclobut-3-ene-l,2-dione (1.7 g) and 4-trifluoromethoxyphenyIamine (1 05 g) was stirred at ambient temperature for 3 days. 1 :5 ethyl acetate/hex ane was added, and the solid was collected, washed with 1 :5 ethyl acetate/hexane and dried. ¹ H NMR (DMSOd ₆ ) δ 1.40 (t, J=8 Hz, 3H), 4.77 (q, J=8 Hz, 2H), 7.40 (d, .1=8 Hz ₅ 2H), 7.50 (d, J=8 Hz, 2H), 10.87 (s, IH),

EXAMPLE 12A To 4-aminopyrimidine-2-thiol (0,254 g) was added water (3 mL), ammonium hydroxide (3 mL), tetrahydrofuran (20 mL) and 2M iodomethane in tert-butyl methyl ether (3 mL). The mixture was stiπed at ambient temperature for 1.5 hours and concentrated. Ethyl acetate and water was added, and the organic phase was separated, dried over magnesium sulfate, filtered and concentrated. H NMR (CDCI ₃ ) δ 2.50 (s, 3H), 4.90 (br s, 2H), 6.16 (d, .1=6 Hz, IH), 8.05 (d, 1=6 Hz, IH).

EXAMPLE 12B

A mixture of EXAMPLE 3 (1.57 g), EXAMPLE 12A (1.48 g), N,N'- dimethylformamide (100 mL) and sodium ethoxide (21% (w/w) in ethanol, 3 mL) was heated at reflux overnight. The mixture was concentrated, water was added and

concentrated hydrochloric acid was added to adjust the pH to -2 The solution was filtered, and the solid was dried. ¹ H NMR (DMSOd ₆ ) δ 0.95 <s, 9H), 1 22 (d, J=8 Hz, 3H), 2 50 (s, 3H), 4.08 (m, IH), 7 12 (m, IH), 8,17 (d, J=IO Hz, IH), 8.41 (d, J=6 Hz, IH), 1 1 01 (br s, IH).

EXAMPLE 12C

A mixture of Oxone (14.2 g) in water (100 mL) was added slowly to a solution of EXAMPLE 12B (2.03 g) in methanol (120 mL). The mixture was stirred at ambient temperature overnight and partially concentrated. The solution was filtered and the solid washed with water and ethanol and dried. ¹ H NMR (DMSO-d _ό ) δ 0.95 (s, 9FI), 1 .22 (d, J=8 Hz, 3H), 3.40 (s, 3H), 4.22 (m, IH), 7 49 (m, IH), 8.34 (d, J=IO Hz, IH), 8,70 (d, J=6 Hz, IH), 1 1.60 (br s, IH).

EXAMPLE 12D A mixture of EXAMPLE 12C (15 mg), 3,4,5-trimethoxyphenylamine (18.3 mg), and p-toluenesulfonic acid in tetrahydrofuran (0 5 mL) was heated at 88 ⁰ C overnight The mixture was purified by preparative HPLC on a C8 column using a gradient of 10% to 100% acetonitrile/water containing 0.1% trifliioroacetic acid to give the desired product as the trifluoroacetate salt. ¹ H NMR (DMSOd ₆ ) δ 0.88 (s, 9H), 1.09 (d, .1=8 Hz, 3H), 3.64 (s, 3H), 3.77 (s, 6H), 3.97 (m, IH) ₁ 6.97 (s, 2H), 7,28 (d, J=6 Hz, IH), 7,91 (d, J=IO Hz, IH), 8.28 (d, J=6 Hz, IH), 9.27 (s, IH), 10..39 (br s, IH).

EXAMPLE 13

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 12D using (R)-I -phenylethylamine in place of 3,4,5-trimethoxyphenylamine. ¹ H NMR (DMSO-d ₆ ) δ 0 90 (s, 9H), 1.19 (d, J=8 Hz, 3H), 1 ,48 (d, J=8 Hz, 3H), 3.99 (m, IH), 5.22 (m, IH), 7 20 (m, 2H), 7 38 (m, 4H), 8.04 (d, J=IO Hz, IH), 8 17 (d, J=6 Hz, IH), 10.56 (br s, IH).

EXAMPLE 14

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 12D using 4-bromophenylamine in place of 3,4,5-trimethoxyphenylamine. ^! H NMR (DMSO-d ₆ ) δ 0.88 (s, 9H), 1.16 (d, J=8 Hz, 3H), 4,00 (m, IH), 7.40 (d, J=6 Hz, IH) ₁ 7.48 (d _f J=8 Hz _; 2H), 7.66 (d, J=8 Hz, 2H), 7,96 (d, J=IO Hz, IH), 8.32 (d, J=6 Hz, IH), 9.51 (s, IH), 10,26 (br s, IH).

EXAMPLE 15

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 12D using benzo[l,3]dioxol-5-ylamine in place of 3,4,5- trimethoxyphenylamine ¹ H NMR (DMSOd ₆ ) δ 0.88 (s, 9H), 1 16 (d, J=8 Hz, 3H), 3 98

(m, IH), 5,98 (s, 2H), 6.87 (d, J=8 Hz, IH), 7.00 (d, J-8 Hz, IH), 7.31 (s, IH), 7 38 (d, J=6 Hz ₃ IH), 8,00 (d, J=IO Hz, IH), 8-24 (d, J=ό Hz, IH), 9.43 (s, IH), 10,31 (br s, IH).

EXAMPLE 16 This example as the trifluoroacetate salt was prepared as described in

EXAMPLE 12D using 4-trifluoromethoxyphenyI amine in place of 3,4,5- trimethoxyphenylamine. ¹ H NMR (DMSOd ₆ ) δ 0.89 (s, 9H), 1 17 (d, J=8 Hz, 3H), 3.99 (m, IH), 7.30 (d, .1=8 Hz, 2H) ₃ 7.42 (d, J=6 Hz, IH), 7.77 (d, J=8 Hz, 2H), 7 99 (d, J=IO Hz, IH), 8.34 (d, J=6 Hz, IH), 9.61 (s, IH), 10 30 (br s, IH).

EXAMPLE 17

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 12D using 3-methyϊphenylamine in place of 3,4,5-trimethoxyphenylamine, ¹ H NMR (DMSOd ₆ ) δ 0.88 (s _} 9H), 1 17 (d, J=8 Hz, 3H), 2.28 (s, 3H), 3,99 (m. IH), 6.82 (d, J=8 Hz, IH), 7.20 (t, J=8 Hz, IH), 7.38 (m, 2H), 7.56 (d, J=8 Hz, IH), 8.01 (d, J=IO Hz, IH), 8.30 (d, J=6 Hz, IH), 9,35 (s, IH), 10,32 (br s, IH).

EXAMPLE 18

This example as the trifluoroacetate salt was prepared as described in EXAMPLE I2D using 4-fluorophenylamine in place of 3,4,5-trimethoxyρhenylamine. ¹ H NMR (DMSOd ₆ ) S 0,89 (s, 9H), 1 .17 (d, J=8 Hz, 3H), 3 99 (m, IH), 7.18 (t, J=8 Hz, 2H), 7.42 (d, J=6 Hz, IH), 7.66 (m, 2H), 8 01 (d, J=IO Hz, IH), 8.30 (d, J=6 Hz, IH), 9.50 (s, IH), 10.30 (br s, IH).

EXAMPLE 19

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 12D using 2-isopropylphenylamine in place of 3,4,5-tτimethoxyphenylamine, ¹ H NMR (DMSOd ₆ ) δ 0 88 (s, 9H), 1.17 (d, J=8 Hz, 3H), 1.18 (d, J=8 Hz, 6H), 3.18 (m, IH), 3 98 (m, IH), 7.22 (m, 3H), 7.38 (m, 2H), 8.03 (d, J-IO Hz, IH), 8.20 (d, J=6 Hz, IH), 9.00 (S ₃ IH), 10,28 (br s, IH).

EXAMPLE 20

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 12D using 4-chlorophenylamine in place of 3,4,5-trirnethoxyphenylamine. ¹ H NMR (DMSOd ₆ ) δ 0,88 (s, 9H), 1.11 (d, J=8 Hz, 3H), 3.97 (m, IH), 7,30 (d, J=8 Hz, 2H), 7.37 (d, J=6 Hz, IH), 7,66 (d, J=8 Hz, 2H), 7.95 (d, J=IO Hz, IH), 8.28 (d, J=6 Hz, IH), 9.45 (s, IH), 10.20 (br s, IH).

EXAMPLE 21

This example as the tπ ^' fluoroacetate salt was prepared as described in EXAMPLE 20 using aniline in place of 4-fluoro-3-methylphenylamine. H NMR (DMSOd ₆ ) δ 0,90 (s, 9H), 1 13 (d, .1=7 Hz, 3H), 4.00 (m, IH), 6.98 (m, IH), 7.29 (t, J=8 Hz, 2H), 7.40 (t, J=6 Hz, IH), 8 68 (d, J=8 Hz, 2H), 8 00 (d, J=8 Hz, IH), 8.31 (d, .1=6 Hz, IH), 9.38 (s, IH), 10,25 (s, IH).

EXAMPLE 22

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 20 using 2-naphthylamiπe in place of 4-fluoro-3-methylphenylamine. H NMR (DMSO-d ₆ ) δ 0.90 (s, 9H), 1.13 (d, .1=7 Hz, 3H) ₁ 4.00 (m, IH), 7.38 (m, 2H), 7.45 (t, J=8 Hz, IH), 7.80 (m, 4H), 7.98 (d, J=8 Hz, IH), 8.26 (s, IH), 8.36(d, J=6 Hz, IH), 9.53 (s, IH) ₁ 10.29 (s, IH).

EXAMPLE 23

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 20 using 3-bromo-4-methylphenylamine in place of 4-fluoro-3- methylphenylamine. ¹ H NMR (DMSOd ₆ ) δ 0.90 (s, 9H), 1.13 (d, J=7 Hz, 3H) ₅ 2.29 (s, 3H), 4.00 (m, IH), 7.26 (d, J=8 Hz, IH), 7.36 (d, .1=6 Hz, IH), 7 65 (d, .1=8 Hz, IH), 7,90 (s, 4H), 7.98 (d, J=8 Hz, IH), 8.33 (d, 3=6 Hz, IH), 9.35 (s, IH), 10.25 (s, IH).

EXAMPLE 24

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 20 using 4-aminobiphenyl in place of 4-fluoro-3-methylphenylamine. H NMR (DMSOd ₆ ) δ 0.90 (s, 9H), 1.15 (d, J=7 Hz, 3H), 4.00 (m, IH), 732 (t, J=8 Hz, IH), 7.39 (d, J=6 Hz, IH), 7.45 (t, J=8 Hz, 2H), 7.65 (t, J=8 Hz, 4H), 7 78 (d, J=8 Hz, 2H), 7.98 (d, J=8 Hz, IH), 8.33 (d, .1=6 Hz, IH), 9.52 (s, IH), 10.28 (s, IH).

EXAMPLE 25 This example as the trifluoroacetate salt was prepared as described in

EXAMPLE 20 using 4-phenoxyphenylamine in place of 4-fluoro-3-methylphenylamine. ¹ H NMR (DMSOd ₆ ) δ 0.90 (s, 9H), 1.15 (d, J=7 Hz, 3H), 4,00 (m, IH), 6.99 (I, J=8 Hz, 4H), 7.10 (t, .1=8 Hz, IH), 7,38 (m, 3H), 7.67 (d, .1=8 Hz, 2H), 7.99 (d, J=8 Hz, IH), 8.30 (d, .1=6 Hz, IH), 9.42 (s, IH), 10.26 (s, IH).

EXAMPLE 26

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 20 using 3-phenoxyphenylamine in place of 4-fluoro-3-methylphenylamine. ¹ H NMR (DMSOd ₆ ) δ 0.90 (s, 9H), 1.15 (d, .1=7 Hz, 3H), 4,00 (m, IH) ₅ 6.57 (d, .1=6 Hz,

IH), 7.04 (d, J=8 Hz ₁ 2H), 7.12 (t, J=8 Hz, IH), 7 28 (t, .1=8 Hz, IH), 7.38 (m, 4H), 7.52 (d, J=6 Hz, IH), 7,98 (d, J=8 Hz, IH), 8 30 (d, J=6 Hz, IH), 9λ6 (s, IH), 10,26 (s, IH).

EXAMPLE 27 This example as the lrifluoroacetate salt was prepared as described in

EXAMPLE 20 using 2,3-dirnethoxyphenylamine in place of 4-fluoro-3- methylphenylamine. ¹ H NMR (DMSO-d ₆ ) δ 0.91 (s, 9H), 1 18 (d, .1=7 Hz, 3H), 3.74 (s, 3H), 3.82 (s, 3H), 4.00 (m, IH), 6.75 (d, J=8 Hz, IH), 7.01 (m, IH), 7.26 (d, .1=6 Hz, IH),

7.79 (d, J=8 Hz, IH), 7 88 (s, IH), 8 01 (d, J=8 Hz, IH), 8,31 (d, J=6 Hz, IH), 10.40 (s, IH),

EXAMPLE 28

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 20 using 2,3-dihydιobenzo[l,4]dioxin-6-ylarnine in place of 4-fluoro-3- raethylphenylamine. ' H NMR (DMSOd ₆ ) δ 0.91 (s, 9H), 1.18 (d, J=7 Hz, 3H), 4.00 (m, IH), 4 22 (m, 4H), 6.79 (d, J=8 Hz, IH), 7,03 (d, J=8 Hz, IH), 7,22 (s, IH), 737 (d, J=6 Hz, IH), 8.04 (d, J=8 Hz, IH), 8,26 (d, .1=6 Hz, IH), 932 (s, IH), 1030 (s, IH),

EXAMPLE 29 This example as the trifluoroacetate salt was prepared as described in

EXAMPLE 20 using 1-naphthylamine in place of 4-fluoro-3-methyIplienylamiπe, H NMR (DMSOd ₆ ) δ 0.91 (s, 9H), 1.18 (d, .1=7 Hz, 3H), 4.00 (m, IH), 7,40 (d, .1=6 Hz, IH), 7.52 (m, 3H), 7.65 (d, ,1=8 Hz, IH), 7.82 (d, .1=8 Hz, IH), 7 99 (m, 3H), 8.25 (d, J=6 Hz, IH), 9 50 (s, IH), 10 32 (s, IH)..

EXAMPLE 30

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 20 using 2,4-dimethoxyphenylamine in place of 4-fluoro-3- methylpheπylamine. ¹ H NMR (DMSOd ₆ ) δ 0,91 (s, 9H), 1 18 (d, J=7 Hz, 3H), 3.78 (s, 3H), 3,81 (s, 3H), 4,00 (m, IH), 6.58 (d, 1=6 Hz, IH), 6,70 (s, IH), 7 35 (br s, IH), 7.58 (br s, IH), 8 10 (d, .1=8 Hz, IH) ₅ 8.21 (d, J=6 Hz, IH), 8.70 (br s, IH), 10.67 (s, IH).

EXAMPLE 31

This example as the trifluoioacetate salt was prepared as described in EXAMPLE 20 using 2,5-dimethoxyphenylamine in place of 4-fluoro-3- methylphenylamine ^! H NMR (DMSOd ₆ ) δ 0 91 (s, 9H) ₅ 1.18 (d, J=7 Hz, 3H) ₅ 3.72 (s, 3H), 3,80 (s, 3H), 4.00 (m, IH), 6 81 (d, J=8 Hz, IH), 7.00 (d, J=6 Hz, IH), 7.21 (m, IH),

7.80 (s, IH), 8.06 (d, J=8 Hz, IH) ₅ 8.10 (br s, IH), 8.31 (d, J=6 Hz, IH), 10 69 (s, IH).

EXAMPLE 32

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 20 using 3-aminobiphenyl in place of 4-fluoro-3-methylphenyIamine. H NMR (DMSOd ₆ ) δ 0.90 (s, 9H), 1 ,15 (d, J=7 Hz, 3H), 4.00 (m, IH), 7,28 (d, J=8 Hz, IH), 7 35 (m, 3H), 7.43 (t, J=8 Hz, 2H), 7.63 (d, J=8 Hz ₁ 2H), 7.78 (d, J=8 Hz, IH), 7.85 (s, IH), 7.98 (d, J=8 Hz, IH), 8.33 (d, J=6 Hz, IH), 9 42 (s, IH), 10 29 (s, IH).

EXAMPLE 3i

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 20 using 4-methoxypheπylamine in place of 4-fluoi o-3-methy]phenylamine, ¹ H NMR (DMSO-d ₆ ) δ 0 89 (s, 9H), 1.15 (d, J=7 Hz ₃ 3H), 3.72 (s, 3H), 4.00 (m, IH), 6.91 (d, .7=8 Hz, 2H), 7.35 (d, J=6 Hz, IH), 7.52 (d, J=8 Hz, 2H), 8.00 (d, J=8 Hz, IH), 8.22 (d, J=ό Hz, IH) ₅ 9.20 (s, IH), 10,28 (s, IH).

EXAMPLE 34

This example as the trifiuoroacetate salt was prepared as described in EXAMPLE 20 using 3-chlorophenyIamine in place of 4-fluoro-3-methylphenylamine., ¹ H NMR (DMSOd ₆ ) δ 0,90 (s, 9H). 1.15 (d, 3=7 Hz, 3H), 4.01 (m, IH), 7 00 (d, J=S Hz ₁ IH), 730 (t, J=8 Hz, IH), 7.41 (d, J=6 Hz, IH), 7.68 (d, J=8 Hz, IH), 7.81 (s, IH), 7.98 (d, .1=8 Hz, IH), 8,35 (d, .1=6 Hz, IH), 9.52 (s, IH), 10.28 (s, IH).

EXAMPLE 35

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 20 using 3-bromophenylamine in place of 4-fluoro-3-rnethylphenylamine. ¹ H NMR (DMSOd ₆ ) δ 0.90 (s, 9H), 1.15 (d, J=7 Hz, 3H), 4.01 (m, IH), 7.1 1 (d, J=8 Hz, IH), 7.28 (t, J=8 Hz, IH), 7.39 (d, .1=6 Hz, IH), 7.73 (d, J=8 Hz, IH), 7.91 (s, IH), 7.98 (d, .1=8 Hz, IH), 8.35 (d, J=6 Hz, IH), 9.45 (s, IH), 10.23 (s, IH),

EXAMPLE 36 This example as the trifluoroacetate salt was prepared as described in

EXAMPLE 20 using 3-isopropoxyphenylamine in place of 4-fluoro-3- methylphenylamine. ¹ H NMR (DMSOd ₆ ) δ 0.90 (s, 9H), 1.15 (d, J=7 Hz, 3H), 1.28 (d, J=4 Hz, 6H), 3.98 (m, IH), 4.55 (m. IH), 6.56 (d, .1=8 Hz, IH), 7.18 (m, 2H), 7.30 (d, .1=8 Hz, IH), 7.35 (d, J=6 Hz, IH), 7.98 (d, J=8 Hz, IH), 8.30 (d, J=6 Hz, IH), 9.30 (s, IH), 10.28 (s, IH).

EXAMPLE 37

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 20 using 4-morpholin-4-ylphenylamine in place of 4-fluoro-3- methylphenylamine. ¹ H NMR (DMSO-d ₆ ) δ 0.90 (s, 9H), 1.15 (d, .1=7 Hz, 3H), 3.08 (t,

J=5 Hz, 4H), 3 72 (t, J=5 Hz, 4H), 3.98 (m, IH), 6 93 (d, .1=8 Hz, 2H), 7 38 (d, J=6 Hz, IH), 7,46 (d, J=8 Hz, 2H), 8,00 (d, J=8 Hz, IH), 8 25 (d, 1=6 Hz, IH), 938 (s, IH), 10 38 (s, IH)

EXAMPLE 3$

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 20 using 3~aminobenzonitrile in place of 4-fluoro-3-methylphenylamiπe H NMR (DMSOd ₆ ) δ 0 90 (s, 9H), Ll 5 (d, 3=7 Hz, 3H), 4,00 (m, IH), 7.06 (d, J=8 Hz, IH), 7.32 (t, J=8 Hz, IH), 7.39 (d, .1=6 Hz, IH), 7.75 (s, IH), 7 81 (d, J=8 Hz, IH), 8.00 (d, J=8 Hz, IH), 8 25 (d, J=6 Hz, IH), 9.42 (s, IH), 10.28 {s, IH),

EXAMPLE 39

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 20 using 3,4-difluorophenylamine in place of 4-fluoro-3-methylphenyl amine ¹ H NMR (DMSOd ₆ ) δ 0.90 (s, 9H), 1.18 (d, J=7 Hz, 3H), 4.02 (m, IH), 7.38 (m, IH), 7.42 (m, 2H), 7.88 (m, IH), 7 95 (d, J=8 Hz, IH), 8.35 (d, .1=6 Hz, IH), 9.58 (s, IH), 10,23 (s, IH)

EXAMPLE 40 This example as the trifluσioacetate salt was prepared as described in

EXAMPLE 20 using 3-chioro-4-fluorophenylamine in place of 4-f!uoro-3- methylphenylamine. ¹ H NMR (DMSOd ₆ ) δ 0 90 (s, 9H), 1.15 (d, J=7 Hz, 3H), 4,00 (m, IH), 7.32 (t, J=8 Hz, IH), 740 (d, .1=6 Hz, IH), 7,68 (m, IH), 7 92 (m, 2H), 8,35 (d, 3=6 Hz, IH), 9 43 (s, IH), 10 20 (s, IH).

EXAMPLE 41

This example as the trifluoioacetate salt was prepared as described in EXAMPLE 20 using 3-trifluoromethylpheriylamine in place of 4-fIuoro-3- methylphenylamiπe. ¹ H NMR (DMSOd ₆ ) 8 0.90 (s, 9H), 1.15 (d, 3=7 Hz, 3H), 4.00 (m, IH), 7,28 (d, J=8 Hz ₁ IH), 7.39 (d, J=6 Hz, IH), 7.55 (t, J=8 Hz, IH), 7.98 (m, 2H), 8 08 (d, J=8 Hz, IH), 8.38 (d, .1=6 Hz, IH), 9 56 (s, IH), 10,25 (s, IH),

EXAMPLE 42

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 20 using 9H-fluoren-2-yl amine in place of 4-fluoro-3-methylphenylamine. ¹ H NMR (DMSOd ₆ ) δ 0.90 (s, 9H), 1.15 (d, J=7 Hz, 3H), 3.90 (s, 2H), 4 00 (m, IH), 7.25 (t, .1=8 Hz, IH), 7.35 (m, 2H), 7.55 (d, J=8 Hz, IH), 7 70 (d, .1=8 Hz, IH) ₅ 7,80 (d, J=S Hz, 2H), 7 98 (m, 2H), 8.35 (d, J=6 Hz ₅ IH), 9.42 (s, IH), 10.25 (s, IH).

EXAMPLE 43

A mixture of EXAMPLE 3 (30 mg), 4'-aminobipheny]-4-caiboπitiile (20 nig), tetrahydrofυran (2 mL), and trifiuoroacetic acid (50 μL) was heated to 7O ⁰ C and stiπed overnight The mixture was cooled, concentrated, and the residue purified as described in EXAMPLE 12D to give 6 mg of the title compound as the trifluoroacetate salt. H NMR (DMSOd ₆ ) δ 0.89 (s, 9H), 1 15 (d, 1=7 Hz, 3H), 4 00 (m, IH), 7.43 (d, 3=6 Hz, IH), 7 73 (d, .1=8 Hz, 2H), 7 86 (m, 6H), 8.00 (d, J=8 Hz, IH), 8 38 (d, 3=6 Hz, IH), 9.65 (s, IH), 10.35 (s, IH).

EXAMPLE 44

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 43 using 2'-methoxybiphenyl-4-ylamine in place of 4'-aminobiphenyl-4- caibonitiile ¹ H NMR (DMSO-d ₆ ) δ 0 89 (s, 9H), 1.15 (d, 1=7 Hz, 3H), 3.78 (s, 3H),

4.00 (m, IH), 7-02 (m. IH), 7 11 (d, .1=8 Hz, IH), 7 32 (m, 2H), 7 41 (d, J=6 Hz, IH), 7.45 (d, 1=8 Hz, 2H), 7 70 (d, J=8 Hz, 2H), 8 00 (d, J=8 Hz, IH), 832 (d, J=6 Hz, IH),

9 50 (s, IH), 10 32 (s, IH).

EXAMPLE 45

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 43 using 4-imidazol-l-ylphenylarnine in place of 4'-aminobiphenyl-4- caibonitrile. ¹ H NMR (DMSOd ₆ ) δ 0.90 (s, 9H), 1 ,15 (d, J=7 Hz, 3H), 4.02 (m, IH), 6.75 (d, 1=8 Hz, 2H), 7.52 (d, J=8 Hz, 2H), 7 62 (d, J=6Hz, IH), 7.78 (m, IH), 8 00 (d, .1=8 Hz, IH), 8.36 (s, IH), 8.62 (s, IH), 8 75 (d, J=6Hz, IH) ₅ 10 38 (s, IH), 11.12 (s, IH)

EXAMPLE 46

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 43 using 4'-methoxybiphenyl-4-ylamine in place of 4'-aminobiphenyI-4- carbonitiile ¹ H NMR (DMSOd ₆ ) δ 0.89 (s, 9H), 1.15 (d, .1=7 Hz, 3H), 3 78 (s, 3H),

4.01 (m, IH), 6.99 (d, J-8Hz, 2H), 7 38 (d, 3=6 Hz ₅ IH), 7.48 (dd, J=8Hz, 4H), 7 73 (d, .1=8 Hz, 2H), 8 00 (d, 1=8 Hz, IH), 8 35 (d, J=6 Hz, IH), 9.48 (s, IH), 10.28 (s, IH),

EXAMPLE 47

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 43 using 4-dimethylaminoρhenylamine in place of 4'-aminobiρhenyl-4- carbonitrile ¹ H NMR (DMSOd ₆ ) δ 0.91 (s, 9H), 1.15 (d, J=7 Hz, 3H), 3 00 (s, 6H), 3.99 (m, IH), 7 15 (d, J=8 Hz, 2H), 7.45 (d, J=6 Hz, 2H), 7 55 (d, J=8 Hz, 2H), 8 06 (d, J=8 Hz, IH), 8 30 (d, J=6 Hz, IH), 9.79 (s, IH), 10.52 (s, IH)

EXAMPLE 48

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 43 using 4-methoxyphenylmethylamine in place of 4'-aminobiphenyl-4- carbonitrile. ¹ H NMR (DMSO-(I ₆ ) δ 0.89 (s, 9H) ₁ 1.15 (d, J=7 Hz, 3H), 3 77 (s, 3H), 3.41 (s. 3H) ₁ 4 01 (m, ϊH), 6.97 (m, 2H), 7.24 (m, 3H), 7.85 (m, IH), 7,99 (m, IH), 8.20 (d, J=6 Hz, IH).

EXAMPLE 49

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 43 using 4'-chlorobiphenyI-4-ylamine in place of 4'-aminobiphenyl-4- carbonitrile. ¹ H NMR (DMSO-d ₆ ) δ 0 89 (s, 9H), 1.15 (d, J=7 Hz, 3H), 4.01 (m, IH), 7.40 (d, J=O Hz, IH), 7 48 (d, J=8 Hz, 2H), 7 65 (d, J=8 Hz, 2H), 7.70 (d, .1=8 Hz, 2H), 7.79 (d, J=8 Hz, 2H), 8,00 (d, J=8 Hz, IH), 8.35 (d, 1=6 Hz, IH), 9 53 (s, IH), 10.31 (s, IH).

EXAMPLE 50

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 43 using 4-[l,2,3]thiadiazol-4-yIphenyIamine in place of 4'-aminobiphenyl- 4-carbonitrile. ¹ H NMR (DMSO-d ₆ ) δ 0,89 (s, 9H), 1 15 (d, J-7 Hz, 3H), 4.01 (m, IH), 7.25 (d, J=6 Hz, IH), 7.86 (d, J=8 Hz, 2H), 8.02 (d, J=8 Hz, IH) ₉ 8.09 (d, .1=8 Hz, 2H), 8.35 (d, J=6 Hz, IH), 9.43 (s, IH), 9.69 (s, IH), 10.36 (s, IH)

EXAMPLE 51

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 43 using 4-thiophen-2-ylphenyIamine in place of 4'-aminobiρhenyl-4- carbαnitrile. ¹ H NMR (DMSO-d ₆ ) δ 0.90 (s, 9H), 1 15 (d, .1=7 Hz, 3H), 4.01 (m, IH), 7.15 (m, IH), 7.42 (m, 2H), 7.48 (d, J=6 Hz, IH), 7 58 (d, J=8 Hz, 2H), 7 75 (d, J=8 Hz, 2H), 7.98 (d, .1=8 Hz, IH), 8.35 (d, J=6 Hz, IH), 9 42 (s, IH), 10.26 (s, IH).

EXAMPLE 52

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 43 using 6-aminobenzothiazole in place of 4'-aminobiphenyl-4-carbonitrile. ¹ H NMR (DMSO-d ₆ ) δ 0.90 (s, 9H), 1.12 (d, J=7 Hz, 3H), 3.98 (m, IH), 7 42 (d, J=6 Hz, IH), 7.71 (d, J=8 Hz, IH) ₅ 8.00 (d, ,1=8 Hz, IH), 8.05 (d, J=8 Hz, IH), 8.35 (d, J=6 Hz, IH), 8.58 (s, IH), 9.22 (s, IH), 9 86 (s, IH), 10.46 (s, IH).

EXAMPLE 53A

This example was prepared as described in EXAMPLE 12B using EXAMPLE 6 in place of EXAMPLE 3, ¹ H NMR (DMSO-d ₆ ) δ 1 46 (s, 9H), 2.52 (s, 3H), 7.25 (d, J=IO Hz, IH), 8,42 (d, J=IO Hz, IH), 8.69 (s, IH), 10 96 (s, IH)

EXAMPLE 53B

This example was prepared as desciibed in EXAMPLE 12C using EXAMPLE 53A in place of EXAMPLE 12B ¹ H NMR (DMSOd ₆ ) δ 1 46 (s, 9H), 3 40 (s, 3H), 7 25 (d, J=IO Hz, IH), 8 40 (d, J-IO Hz, IH), 8 60 (s, IH), 1 1 40 (s, IH)

EXAMPLE 53C

A mixture of EXAMPLE 53B (30 mg), 9H-fluoren-2-ylamine (18 mg, 0 11 mmol), tetrahydrofuian (2 mL), and trifluoroacetic acid (50 uL) was heated to 70 ⁰ C and stirred overnight. The mixture was cooled, concentrated and the residue purified as described in EXAMPLE 12D to give 2 mg of the title compound as the trifluoroacetate salt ¹ H NMR (DMSO-d ₆ ) δ 1 35 (s, 9H) ₅ 3.88 (s, 2H), 7 19 (m, 2H), 732 (t, ,1=8 Hz, IH), 7.55 (d, J=8 Hz, IH), 7 70 (d, J=8 Hz, IH), 7.70 (d, J=S Hz, 2H), 7 92 (s, IH), 8 30 (s, IH), 8 35 (d, J=6 Hz, IH), 9 42 (s, IH), 10.48 (s, IH)

EXAMPLE 54 3-tert-butylamino-4-(2-(4-fluoro-3-methylphenylamino)pyiimid in-4-ylamino)cyclobut-3- ene-l,2-dione

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 53C using 4-fluoro-3-methylphenylamine in place of 9H-fluoren-2-ylamine ^! H NMR (DMSOd ₆ ) δ 1 36 (s, 9H), 2 21 (s, 3H), 7 08 (t, J=S Hz, IH), 7 16 (d, J=6 Hz, IH), 7,50 (m, 2H), 8 22 (m, 2H), 9 38 (s, IH), 10 53 (s, IH)

EXAMPLE 55 This example as the trifluoroacetate salt was prepared as described in

EXAMPLE 53C using 6-aminobenzthiazole in place of 9H-fluoren-2-ylamine H NMR (DMSO-de) δ 1 36 (s, 9H), 7.26 (d, J=6 Hz, IH) ₅ 7 71 (d, J= 8 Hz, IH), 8.00 (d, J=8 Hz, IH), 8 25 (s, IH), 835 (d, 1=6 Hz, IH), 8.60 (s, IH), 9 20 (s, IH), 9.68 (s, IH), 10 49 (s, IH).

EXAMPLE 56

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 53C using 4-[l,2,3]thiadiazol-4-ylphenyIamine in place of 9H-fluoren-2- ylamine. ¹ H NMR (DMSOd ₆ ) δ 1 38 (s, 9H) ₅ 7 26 (d, 1=6 Hz, IH), 7.88 (d, J=8 Hz, 2H), 8 08 (d, J=8 Hz, 2H), 8.28 (s, IH), 8.36 (d, J=6 Hz, IH), 9 63 (s, IH), 10.48 (s, IH)

EXAMPLE 57

This example as the trifluoroacetate salt was piepared as described in EXAMPLE 53C using 4-rnethylpiperazin-l-yIphenylamine in place of 9H-fluoren-2- ylamiπe ¹ H NMR (DMSOd ₆ ) δ 1 35 (s, 9H), 2 88 (s, 3H), 2.93 (m, 2H), 3.25 (m, 2H),

3.52 (m, 2H), 3.75 (m, 2H) ₅ 6.95 (d, .1=8 Hz, 2H), 7.09 (d, J=6 Hz, IH), 7.52 (d, J=8 Hz, 2H), 8 25 (d, J=6 Hz, 2H), 9 25 (s, IH) ₇ 10.52 (s, IH),

EXAMPLE 58 This example as the trifiuoroacetate salt was prepared as described in

EXAMPLE 53C using 4-hydroxy-3~methylphenylamine in place of 9H-fluoien-2- ylamine. ¹ H NMR (DMSOd ₆ ) δ 1.35 (s, 9H), 2.10 (s, 3H), 6.76 (d, .1=8 Hz, IH), 7.16 (m, 3H), 8.18 (d, .1=8 Hz, IH), 8.29 (s, IH), 9.1 1 (s, IH), 9 25 (bi s, IH), 10.63 (br s, IH).

EXAMPLE 59

This example as the trifiuoroacetate salt was prepared as described in EXAMPLE 53C using 5-aminoindane in place of 9H-fluoren-2-ylamine. H NMR (DMSOd ₆ ) δ 135 (s, 9H), 2.00 (t, J=8 Hz, 2H), 2.83 (m, 4H), 7. 13 (m, 2H), 7,36 (d, J=8 Hz, IH), 8 28 (m, 2H), 9.11 (s, IH), 9,33 (s, IH), 10 53 (s, IH).

EXAMPLE 60

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 53C using 4-rnorpholin-4-ylphenylamine in place of 9H-fluoren-2-ylamine- ¹ H NMR (DMSOd ₆ ) δ 1 35 (s, 9H), 3.03 (t, J=5 Hz, 4H), 3.72 (t, .1-5 Hz, 4H), 6.88 (d, .1=8 Hz, 2H), 7.18 (d, J=6 Hz, IH), 7.49 (d, J-8 Hz, 2H), 8.25 (d, .1=6 Hz, IH), 8.32 (s, IH), 9.1 1 (S, IH), 10.41 (s, IH).

EXAMPLE 61

This example as the trifiuoroacetate salt was prepared as described in EXAMPLE 53C using 4-moipholin~4-ylmethylphenyIamine in place of 9H-fluoren-2- ylamine ¹ H NMR (DMS0-d ₆ ) δ 1.38 (s, 9H), 3.06 (m, 2H), 3.25 (m, 2H), 3.62 (m, 2H), 3.98 (m, 2H), 4 28 (s, 2H), 7.25 (d, .1=6 Hz, IH), 7.20 (d, .1=8 Hz, 2H), 7.79 (d, J=8 Hz, 2H), 8.30 (s, IH), 8.32 (d, .1=6 Hz, IH), 9,59 (s, IH), 10.49 (s, IH).

EXAMPLE 62

This example as the trifiuoroacetate salt was prepared as described in EXAMPLE 53C using 2-naphthyϊamine in place of 9H-fluoren-2-ylamine. H NMR (DMSOd ₆ ) δ 1.31 (s, 9H), 7.23 (d, .1=6 Hz, IH), 7,39 (t, .1-7 Hz, IH), 7.45 (t, J=7 Hz, IH), 7 75 (d, J=8 Hz, IH), 7,83 (m, 3H), 8 28 (s, IH), 8.38 (d, J=6 Hz, IH), 9.63 (s, IH), 10.55 (s, IH).

EXAMPLE 63

This example as the trifiuoroacetate salt was prepared as described in EXAMPLE 53C using 5-aminobenzo[b]thiophene in place of 9H-fluoren-2-y1amine. H NMR (DMSOd ₆ ) δ 1,32 (s, 9H), 7.20 (d, .1=6 Hz, IH), 7.38 (d, .1=6 Hz, IH), 7.58 (d, .1=8

Hz, IH) ₁ 7 75 (d, 1=6 Hz, IH) ₁ 7 92 (d, J=8 Hz, IH), 8 23 (s, IH), 8 28 (s, IH), 8 32 (d, J=6 Hz, IH), 9 55 (s, IH), 10.53 (s, IH)

EXAMPLE 64 This example as the trifliioroacetate salt was prepared as described in

EXAMPLE 53C using 5-amino-2,3-dihydiobenzofuran in place of 9H-fluoren-2-ylamine ^! H NMR (DMSOd ₆ ) 6 1 38 (s, 9H), 3 26 (t, T=8 Hz, 2H), 4 50 (t, 1=8 Hz, 2H), 6 73 (d, 1=6 Hz, IH), 7 20 (m, IH), 7 28 (d, 1=6 Hz, IH), 7 42 (s, IH), 8 22 (d, 1=6 Hz, IH), 8 32 (s, IH), 9 32 (s, IH), 10 54 (s, IH)

EXAMPLE 65

This example as the trifluoioacetate salt was prepared as described in EXAMPLE 53C using 5-aminobenzofuian in place of 9H-fluoien-2-ylamine H NMR (DMSOd ₆ ) δ 1 32 (s, 9H), 6 92 (s, IH), 7 22 (d, 1=6 Hz, IH), 7 48 (d, 1=6 Hz, IH), 7 55 (d, J=6 Hz, IH), 7 95 (s, IH), 7 99 (s, IH), 8 28 (m, 2H), 9 62 (s, IH), 10 64 (s, IH).

EXAMPLE 66

This example as the trifluoroacetate salt was prepaied as described in EXAMPLE 53C using 5-amino-lH-indole in place of 9H-fluoien-2-ylamine ¹ H NMR (DMSOd ₆ ) δ 1 32 (s, 9H), 6 41 (s, IH), 7 20 (m, 2H), 7 38 (m, 2H), 7 75 (s, IH), 8 21 (d, 1=6 Hz, IH), 8 35 (s, IH), 9 45 (s, IH), 10 64 (s, IH), 11 05 (s, IH)

EXAMPLE 67

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 53C using 5-amino-lH-indazole in place of 9H-fluoien-2-ylamine ^! H NMR (DMSOd ₆ ) δ 1 28 (s, 9H), 7 15(d, 1=6 Hz, IH), 7 26 (d, J-8 Hz, IH), 7 65 (d, 1=8 Hz, IH), 7 93 (s, IH), 8 03 (s, IH), 8 24 (s, IH), 8 33 (d, 1=6 Hz, IH), 9.55 (s, IH), 10 64 (s, IH), 12 78 (s, IH).

EXAMPLE 68

This example as the trifluoroacetate salt was prepaied as described in EXAMPLE 53C using 5-amino-l -methyl- lH-indazole in place of 9H-fIuoren-2-yIamine ¹ H NMR (DMSOd ₆ ) δ 1 28 (s, 9H), 4 05 (s, 3H), 7 25(d, 1=6 Hz, IH), 7 52 (d, 1=8 Hz, IH), 7 65 (d, J=8 Hz _? IH), 7 99 (s, IH), 8 05 (s, IH), 8 28 (d, J=6 Hz, IH), 8 31 (s, IH), 9.60 (s, IH), 10 60 (s, IH)

EXAMPLE 69

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 53C using 4-pyrrol-l-ylphenylamine in place of 9H-fluoren-2-ylamine H NMR (DMSOd ₆ ) δ 1 38 (s, 9H), 6 22 (d, J=5 Hz, 2H), 7 23 (d, 1=6 Hz, IH), 7 28 (d, J=5

Hz, 2H) ₅ 748 (d, J=8 Hz, 2H), 7.78 (d, J=8 Hz, 2H), 828 (s, IH) ₁ 8.33 (d, .1-6 Hz, IH), 9.49 (s, lH), 10 48 (s. IH)

EXAMPLE 70 This example as the trifluoroacetate salt was prepared as described in

EXAMPLE 53C using 4-pyrazol-l-ylphenylamine in place of 9H-fluoren-2-ylamine. H NMR (DMSOd ₆ ) δ 136 (s, 9H), 6.62 (s, IH), 7,35 (d, 3=6 Hz, IH), 7.72 (s, IH), 7.75 (d, .1=8 Hz, IH), 7.80 (d, J=8 Hz, 2H), 8 28 (s, IH), 8 33 (d, J=6 Hz, 2H), 8.39 (s, IH), 9.58 (s, IH), 10,48 (s, IH).

EXAMPLE 71

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 53C using 4 _J 6-dimethoxypyrimidin-2-ylphenyIamine in place of 9H-fluoren- 2-ylamine. ¹ H NMR (DMSOd ₆ ) δ 1.39 (s, 9H), 4.00 (s, 6H), 7.28 (d, J=6 Hz, IH), 7 83 (d, J=8 Hz, 2H), 8 35 (m, 5H), 9.71 (s, IH), 10 45 (s, IH).

EXAMPLE 72

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 53C using l-acetyl-5-amino-2,3-dϊhydro-lH-indole in place of 9H-fluoren-2- ylamine. ¹ H NMR (DMSOd ₆ ) δ 138 (s, 9H), 2.13 (s, 3H), 3 12 (t, J=9 Hz, 2H), 4.06 (t, .7=9 Hz, 2H), 7 20 (d, J=7 Hz ₁ IH), 7 38 (d, J=7 Hz, IH), 7 52 (s, IH), 7.96 (d, J=7 Hz ₁ IH), 828 (m, 2H), 9.38 (s, IH), 10.52 (s, IH)

EXAMPLE 73 This example as the trifluoroacetate salt was prepared as described in

EXAMPLE 53C using 5-amino-2,3-dihydro-lH-indole in place of 9H-fluoren-2-ylamine, ¹ H NMR (DMSOd ₆ ) δ 1 39 (s, 9H) ₃ 3 15 (t, 3=9 Hz, 2H), 3.66 (t, .1=9 Hz, 2H), 722 (d, .1=7 Hz, 2H), 7.58 (d, J=7 Hz, IH), 7.56 (s, IH), 8 30 (d, J=7 Hz, 2H), 9.48 (s, IH), 10.52 (s, IH)

EXAMPLE 74

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 53C using 9H-carbazol-2-ylamine in place of 9H-fluoren-2-ylamine. H NMR (DMSOd ₆ ) δ 1.32 (s, 9H), 7.15 (t, J=8 Hz, IH), 722 (m, IH), 7,32 (t, J=8 Hz, IH), 7 50 (m, 3H), 8,05 (d, J=8 Hz, 2H), 828 (m, 3H), 9.52 (s, IH), 10,62 (s, IH), 1 1.18 (s, IH).

EXAMPLE 75

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 53C using 9-ethyl-9H-carbazoI-2-ylamiπe in place of 9H-flιιoren-2 -ylamine.

¹ H NMR (DMSOd ₆ ) δ 1 30 (s, 9H), 1 32 (t, J=8 Hz, 3H), 4 43 <q, J=8 Hz, 2H), 7 17 (s, IH), 7 18 (t, J=8 Hz, IH), 7 45 (t, J=8 Hz, I H), 7 48 (m, 3H), 8 08 (d, 1=8 Hz, IH), 8.23 (d, 1=8 Hz, IH), 9 30 (m, 2H), 9 58 (s, IH), 10 65 (s, IH)

EXAMPLE 76

This example as the trifluoroacetate salt was piepared as described m EXAMPLE 53C using 5-aminobenzthiazole in place of 9H-fluoien-2-ylamine H NMR (DMSOd ₆ ) δ 1.35 (s, 9H), 7 28 (d, 1=6 Hz, IH), 7 75 (d, .1=8 Hz, IH), 8.05 (d, J=8 Hz, IH), 7 35 (m, 2H), 8 58 (s, IH), 9 35 (s, IH), 9 62 (s, IH), 10 52 (s, IH).

EXAMPLE 77

To 2-amino-4-phenylthiazole (35 mg), in 1 :1 THF/toluene (0 5 mL) was added 0 1 mL of 2M trimethylalumiπum in hexane, and the mixture stirred at 55 ⁰ C for 2 hours EXAMPLE 12C (40 mg) in tetrahydrofuran (0 5 mL) was added and the mixture stirred at 11O ⁰ C overnight The mixture was cooled, quenched with water and the crude product purified as described in EXAMPLE 12D to give 4 mg of the title compound as the trifluoroacetate salt ¹ H NMR (DMSOd ₆ ) δ 0.85 (s, 9H), 1 17 (d, J=8 Hz, 3H), 4.03 (m, IH), 7 20 (d, 1=7 Hz, 2H), 7.26 (s, IH), 7.38 (m, 4H), 7.58 (bi s, IH), 7 82 (m, IH), 8 54 (s, IH), U 39 (s, IH).

EXAMPLE 78

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 77 using EXAMPLE 53B in place of EXAMPLE 12C ^! H NMR (DMSO- d ₆ ) δ 1 38 (s, 9H), 7 20 (d, J=7 Hz, 2H), 7 27 (s, IH), 7 38 (m, 4H), 7 68 (br s, IH), 8 38 (s, IH), 8 58 (d, J=6 Hz, IH), 1 1.29 (s, ϊH)

EXAMPLE 79A

A mixture of 4-aminobiphenyl (1 7 g), EXAMPLE 12A (0 62 g) and concentrated hydrochloric acid (0.06 mL) was heated at 178 ⁰ C overnight After cooling, the crude product was purified by flash chromatography on silica gel using ethyl acetate to provide 0 36 g of the title compound as a yellow solid. ¹ H NMR (DMSOd ₆ ) δ 5 87 (d, 3=6 Hz, IH), 6 55 (br s, 2H), 7 28 (m, IH), 7 42 (t, 1-7 Hz, 2H), 7.52 (d, .1=8 Hz, 2H), 7 62 (d, 1=8 Hz ₃ 2H) ₅ 7 88 (m, 3H), 8 99 (s, IH)

EXAMPLE 79B

A mixture of EXAMPLE 79A (30 mg), EXAMPLE 6 (60 mg), sodium ethoxide (0 1 mL, 21% (w/w) in ethanol) and dimethylsulfoxide (1 2 mL) was heated at 155 ⁰ C overnight After cooling, the mixture was purified as described in EXAMPLE 12D to give 15 mg of the title compound as the trifluoroacetate salt ¹ H NMR (DMSOd ₆ ) δ

1 38 (s, 9H), 7.22 (d, .1=6 Hz, IH), 7 32 (m, IH), 7,42 (t, J=8 Hz, 2H), 7,63 (m, 4H), 777 (d, .1=8 Hz, 2H), 8.30 (s, IH), 8 33 (d, .1=6 Hz, IH), 9 58 (s, IH), 10.57 (s, IH).

EXAMPLE 80 This example as the trifluoroacetale salt was prepared as described in

EXAMPLE 79B using EXAMPLE 11 in place of EXAMPLE 6 ¹ H NMR (DMSOd ₆ ) δ

7 00 (br s, IH), 7.30 (m, 5H), 7 40 (t, J=8 Hz, 2H), 7.56 (m, 4H), 7,72 (d, .1-8 Hz ₃ 2H),

8 37 (d, J=6 Hz, IH), 9 70 (s, IH), 10 20 (br s, IH), 10.96 (s, IH)

EXAMPLE 81

This example as the tri flu oio acetate salt was prepared as described in EXAMPLE 79B using EXAMPLE 7 in place of EXAMPLE 6. ¹ H NMR (DMSOd ₆ ) δ 0.89 (s, 9H), 3.30 (m, 2H), 6.96 (br s, IH), 7.34 (m, IH), 742 (t, J=8 Hz, 2H), 7.66 (m, 6H), 8 20 (m, IH), 8.29 (d, J=6 Hz, IH) ₃ 9 67 (s, IH), 10,82 (s, IH)

EXAMPLE 82

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 79B using EXAMPLE 8 in place of EXAMPLE 6 ¹ H NMR (DMSOd ₆ ) δ 0 17 (m, 2H), 0 39 (m, 2H), 0,95 (m, IH), 3.38 (m, 2H), 6.90 (m, IH) ₅ 7.32 (m, IH), 7.42 (t, J=8 Hz, 2H), 7 62 (m, 4H), 7 73 (d, 1=8 Hz, 2H), 8.10 (m, IH), 8,28 (d, .1=6 Hz, IH), 9.65 (s, lH), 10,82 (s, IH).

EXAMPLE 83

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 79B using EXAMPLE 9 in place of EXAMPLE 6. ¹ H NMR (DMSOd ₆ ) δ 3.10 (m, 2H), 332 (ID, 2H), 3.42 (m, 2H), 3 70 (m, 2H), 3.93 (m, 4H), 6 78 (d, J=6 Hz, IH), 7.36 (m, IH), 7.42 (t, .1=8 Hz, 2H), 7 62 (m, 4H), 7 75 (d, J=8 Hz, 2H), 7.98 (m, IH), 8 28 (d, 3=6 Hz, IH), 9.61 (s, IH), 1 1.02 (s, IH).

EXAMPLE 84

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 79B using EXAMPLE 2 in place of EXAMPLE 6. ¹ H NMR (DMSOd ₆ ) δ 0.81 (d, J=7 Hz, 3H), 0.82 (d, .1=7 Hz, 3H), 1 16 (d, J=7 Hz, 3H), 1 23 (m, IH), 1.40 (m, IH), 1.59 (m, IH), 4.15 (m, IH), 7.16 (m, IH), 732 (m, IH), 7,42 (t, J=8 Hz, 2H), 7 62 (m, 4H), 7.77 (d, .1=8 Hz, 2H), 7 98 (d, J=IO Hz, IH), 8.31 (d, J=6 Hz, IH), 9.57 (s, IH), 10 47 (s, IH).

EXAMPLE 85

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 79B using EXAMPLE 1 in place of EXAMPLE 6 ¹ H NMR (DMSOd ₆ ) δ

0 81 (d, J=7 Hz, 3H), 0 82 (d, 1=7 Hz, 3H), 1 16 (d, .1=7 Hz, 3H), 1 69 (m, IH), 3 96 (m, IH), 7 30 (m, 2H), 7 42 (t, J=8 Hz, 2H), 7 62 (m, 4H), 7 77 (d, J=8 Hz, 2H), 7 99 (d, J=IO Hz, IH) ₅ 8 33 (d, J=6 Hz, IH), 9 58 (s, I H), 10 42 (s, IH)

EXAMPLE 86

This example as the trifluoioacetate salt was prepared as described in EXAMPLE 79B using EXAMPLE 10 in place of EXAMPLE 6 ¹ H NMR (DMSOd ₆ ) δ 1.52 (d, .1=8 Hz, 3H), 5 28 (m, IH), 7 20 (m, IH), 7 35 9M ₅ 6H), 7.45 (t, J=8 Hz, 2H), 7.62 (rn, 4FI), 7.77 (d, .1=8 Hz, 2H), 832 (d, 1=6 Hz, IH)

EXAMPLE 87

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 79B using EXAMPLE 4 in place of EXAMPLE 6 ¹ H NMR (DMSOd ₆ ) δ 0 88 (s, 9H) ₅ 1.35 (d, .1=8 Hz, 3H), 3,99 (m, IH), 7 30 (m, IH), 7 39 (d, J=7 Hz, IH), 7.42 (t, J=8 Hz ₅ 2H), 7.62 (m, 4H), 7.79 (d, .1=8 Hz, 2H), 8 00 (d, J-IO Hz, IH), 8 35 (d, J=6 Hz, IH), 9 57 (s, IH), 10 32 (s, IH)

EXAMPLE 88

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 79B using EXAMPLE 5 in place of EXAMPLE 6 ' H NMR (DMSOd ₆ ) δ 0 80 (t, J=7 Hz, 3H), 1 32 (s, 6H), 1.67 (q, J=7 Hz, 2H), 7 30 (m, 2H), 7 42 (t, J-8 Hz ₅ 2H), 7 62 (m, 4H) ₅ 7 78 (d, J=8 Hz, 2H), 8 20 (s, IH), 8 35 (d, J=6 Hz, IH), 9 60 (s, IH), 10 52 (S ₅ IH)

EXAMPLE 89

This example was prepared as described in EXAMPLE 79A using 3,4,5- trimethoxyphenylamine in place of 4-aminobiphenyI. H NMR (DMSOd ₆ ) δ 3 61 (s, 3H), 3 77 (s, 6H), 5 87 (d, 1=6 Hz, IH), 6.50 (br s, 2H) ₅ 7 20 (s, 2H), 7 82 (d, J=6 Hz, IH), 8 69 (s, IH)

EXAMPLE 90

To 3,5-dichloro~[l,2,4]thiadiazole (0.66 g) was added 0.5 M ammonia in dioxane (20 niL) at 0 ^D C and the mixture stirred at ambient temperature overnight. The mixture was concentrated, 4-aminobiphenyl (1 6 g) added and the mixture heated neat at 150 ⁰ C overnight Purification as described in EXAMPLE 12D gave 56 mg of the title compound as the trifluoioacetate salt ¹ H NMR (DMSOd ₆ ) δ 7.23 (m, IH), 7.41 (m, 4H), 7 52 (t, J=8 Hz, 2H), 7 62 (m, 2H), 7 75 (d, J=S Hz, 2H), 9.55 (s, IH)

EXAMPLE 91

A mixture of 9H-fluoren-2-yIamine (122 mg), 4-amino-2-chloro-5- fluoropyrimidine (54 mg) in n-butanol (1 mL) was heated at 12O ⁰ C overnight. The mixtuie was concentrated and the residue puiified as described in EXAMPLE 12D to give 98 mg of the title compound as the trifluoroacetate salt H NMR (DMSOd ₆ ) δ 3.90 (s, 2H), 7 30 (t, J=7 Hz, IH), 7 39 (t, J=7 Hz, IH), 7.58 (m, 2H), 7.82 (m. 3H), 8JO (d, J=4 Hz, IH), 8^20 (br s, 2H) ₅ 9.82 (s, IH).

EXAMPLE 92 A mixture of 4-iodophenylamine (660 mg), 4-amino-2-chloropyrimidine (400 mg) in n-butanol (4 mL) was heated at 1 15 ⁰ C overnight- The mixture was concentrated and the residue purified by flash chromatography on silica gel using 5:1 ethyl acetate/hexane followed by 5:1 :0 01 ethyl acetate/hexane/triethylamiπe to provide 0 43 g of the title compound as a solid. ¹ H NMR (DMSOd ₆ ) δ 5.92 (d, J=6 Hz, IH), 6.55 (br s, 2H), 7.50 (d, J=8 Hz, 2H), 7 63 (d, J=8 Hz, 2H), 7.82 (d, J=6 Hz, IH), 9.00 (s, IH).

EXAMPLE 93

N-(3,4,5-trimethoxyphenyl)-(l,3,5)triazine-2 _? 4-diamine This compound was purchased from Ryan Scientific, Inc. (U.S.A.)

EXAMPLE 94

A mixture of 2-chloro-5-cyano-6-amino pyrimϊdine (0,1 g), 3,4,5-trimethoxy aniline (0.71 mmol), palladium(II) acetate (1 mol%), 9.9-dimethyI-4,5- bis(diphenylphosphino)xanthene (1.5 mol%) and cesium carbonate (L29 mmol) in dioxane (2 mL) was heated in a microwave at 150 ⁰ C for 20 minutes, cooled, filtered through diatomaceous earth (Celite ^® ) and concentrated.. The concentrate was purified by HPLC on a C18 column with acetonitrile/water/0.1% trifluoroacetic acid, ¹ H NMR (DMSOd ₆ ) δ 9 35 (br s, IH), 8.15 (s, IH), 6.45 (s, 2H), 5,5 (s, 2H), 3.73 (s, 6H), 3.70 (s, 3H).

EXAMPLE 95 (R)-3-(4-(3,4,5-trimethoxyphenylamino)-(l,3,5)triazin-2-ylam ino)-4-(l,2,2- trimethylpropylamino)cycIobut-3-ene- 1 ,2-dione This example as the trifluoroacetate salt was prepared as described in EXAMPLE 79B using EXAMPLE 3 in place of EXAMPLE 6 and EXAMPLE 93 in place of EXAMPLE 79A. ¹ H NMR (DMSOd ₆ ) δ 0 87 (s, 9H), 1.19 (d, J=8 Hz, 3H), 3 62 (s, 3H), 3.79 (s, 6H), 408 (m, IH), 7 10 (s, 2H), 8.08 (s, IH), 8 63 (s, IH), 10.04 (s, IH), 1 1.22 (s, IH).

EXAMPLE 96

This example as the tiifluoroacetate salt was prepared as described in EXAMPLE 79B using EXAMPLE 10 in place of EXAMPLE 6 and EXAMPLE 94 in place of EXAMPLE 79A ¹ H NMR (DMSOd ₆ ) δ 1 30 (m, 3H), 3 61 (s, 3H), 3 64 (s, 6H) ₅ 5.22 (m, IH), 7 02 (s, 2H) ₁ 7 23 (m, IH), 7 30 (m, 4H), 8 06 (d, J=IO Hz, IH), 8 63 (s. IH), 10.00 (s, IH), 11.21 (s, IH).

EXAMPLE 97

This example as the tiifluoroacetate salt was prepared as described in EXAMPLE 79B using EXAMPLE 4 in place of EXAMPLE 6 and EXAMPLE 94 in place of EXAMPLE 79A. ^! H NMR (DMSOd ₆ ) δ 0.85 (s, 9H), 1.09 (d, .1=8 Hz, 3H), 3 60 (s, 3H), 3 64 (s, 6H), 3.98 (m, IH), 7 01 (s, 2H), 7.72 (d, J=IO Hz, IH), 8.64 (s, IH), 9.98 (s, IH), 10.55 (s, IH).

EXAMPLE 98

This example as the trifluoro acetate salt was prepared as described in EXAMPLE 79B using EXAMPLE 1 in place of EXAMPLE 6 and EXAMPLE 94 in place of EXAMPLE 79A, ¹ H NMR (DMS0-d ₆ ) δ 0.80 (m, 6H), 0.98 (m, 3H), 1.60 (m, IH), 3 60 (s, 3H), 3.64 (s, 6H), 3.92 (m, IH), 7.00 (s, 2H), 7 63 (d, J=IO Hz, IH), 8 63 (s, IH), 9.98 (s, IH), 10 80 (s, IH).

EXAMPLE 99

This example as the trifluoro acetate salt was prepared as described in EXAMPLE 79B using EXAMPLE 91 in place of EXAMPLE 79A. ¹ H NMR (DMSO- d ₆ ) δ 1 30 (S ₅ 9H), 3 82 (s, 2H), 7.22 (t, J=7 Hz, IH), 7.32 (t, 1=7 Hz, IH), 7.53 (d, J-7 Hz, IH), 7.61 (d, 1=7 Hz, IH), 7,71 (m, 2H) ₅ 7 84 (s, IH), 8.01 (s, IH), 8 39 (s, IH), 9.52 (s, IH), 10.78 (s, IH)

EXAMPLE 100 This example as the tiifluoroacetate salt was prepared as described in

EXAMPLE 79B using EXAMPLE 3 in place of EXAMPLE 6 and EXAMPLE 90 in place of EXAMPLE 79A ¹ H NMR (DMSOd ₆ ) δ 0.88 (s, 9H), 1.21 (d, J=8 Hz, 3H), 4.02 (m, IH), 7.31 (m, IH), 7.42 (t, J=8 Hz, 2H), 7.62 (m, 4H), 7 71 (d, 1=8 Hz, 2H), 7.91 (d, 1=10 Hz ₁ IH), 9.77 (s, IH), 11 82 (s, IH).

EXAMPLE 101

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 79B using EXAMPLE 4 in place of EXAMPLE 6 and EXAMPLE 90 in place of EXAMPLE 79A ¹ H NMR (DMSOd ₆ ) δ 0.88 (s, 9H), 1.21 (d, J=8 Hz, 3H),

4 02 (m, IH), 7 31 (m, IH), 7 42 (t, 1=8 Hz, 2H), 7 62 (m, 4H) ₁ 7 71 (d, J=8 Hz, 2H), 7 91 (d, J=IO Hz, IH), 9 77 (s, IH), 1 1 82 (s, IH)

EXAMPLE 102 This example as the trifluoroacetate salt was prepared as described in

EXAMPLE 79B using EXAMPLE 92 in place of EXAMPLE 79A ¹ H NMR (DMSO- d ₆ ) δ 1 37 (s, 9H), 7 22 (d, 1=6 Hz, IH), 7 52 (t, 1=8 Hz, 2H), 7.61 (d, J=8 Hz, 2H), 8 23 (s, IH) ₅ 8 31 (d, 1-6 Hz, IH), 9 55 (s, IH), 10 47 (s, IH)

EXAMPLE 103

A mixture of EXAMPLE 102 (14 mg), pyridine-4-boronic acid (5 mg), tetialds(triphenylphosphine)palladium(0) (5 mg), potassium carbonate (26 mg), ethanol (1 mL), benzene (1 ml) and water (100 μL) was healed to lefϊux for 2 hours The mixtuie was cooled and concentrated and the residue purified as described in EXAMPLE 12D to give 2 1 mg of the title compound as the trifluoroacetate salt H

NMR (DMSOd ₆ ) δ 1 38 (s, 9H), 7 31 (d, 1=6 Hz, IH), 7 96 (d, J=8 Hz, 2H), 8 03 (d, J=8 Hz, 2H) ₅ 8 25 (d, J=6 Hz, 2H) ₅ 8 27 (s, IH), 8 40 (d, J=6 Hz, IH), 8 82 (d, 1=6 Hz, 2H), 9 89 (s, IH), 10 56 (s, IH)

EXAMPLE 104

This example as the trifluoroacetate salt was piepared as described in EXAMPLE 103 using ρyridine-3-boronic acid in place of pyridiπe-4-boronic acid H NMR (DMSOd ₆ ) δ 1 38 (s, 9H), 7 25 (d, J=6 Hz, IH), 7 65 (m, IH), 7 72 (d, J=8 Hz, 2H), 7.86 (d, J=S Hz, 2H), 8 28 (m, 2H), 8 35 (d, J-6 Hz, IH), 8 62 (d, J=6 Hz, IH), 8 98 (s, IH), 9 62 (s, IH), 10 52 (s, IH)

EXAMPLE 105

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 103 using lH-pyrazoϊe-4-boronic acid in place of pyridine-4-boronic acid ¹ H NMR (DMSO-d ₆ ) δ 1 36 (s, 9H), 7 12 (d, 1=6 Hz, IH), 7 53 (d, J=8 Hz, 2H), 7 68 (d, J=8 Hz, 2H), 7.98 (s, 2H), 8 28 (m, 2H), 9 48 (s, IH), 10 56 (s, IH)

EXAMPLE 106

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 103 using pyrimidine-5-boronic acid in place of pyridine-4-boronic acid. H NMR (DMSOd ₆ ) δ 1.39 (s, 9H), 7 29 (d, J=6 Hz, IH), 7 78 (d, J=8 Hz, 2H), 7 88 (d, 1=8 Hz, 2H), 8 32 (s, IH), 8 35 (d, J=ό Hz, IH), 9 1 3 (m, 2H), 9 65 (s, IH), 10 56 (s, IH)

EXAMPLE 107

This example as the trifluoioacetate salt was prepaied as described in EXAMPLE 103 using 2,4-dimethoxypyiimidine~5-boronic acid in place of pyridine-4- boronic acid. ¹ H NMR (DMSO-d ₆ ) δ 139 (s, 9H), 3 93 (s, 3H), 3 93 (s, 3H), 7 23 (d, .1=6 Hz, IH), 7 50 (d, 1=8 Hz, 2H), 7 73 (d, J=8 Hz, 2H), 8 32 (s, IH), 8 35 (d, 1-6 Hz, IH), 8.37 (s, IH), 9 56 (s, IH), IO 49 (s, IH)

EXAMPLE 108

This example as the trifluoroacetate salt was piepared as described in EXAMPLE 103 using 2-methoxypyrimidine-5-boronic acid in place of pyridine-4- boronic acid. ¹ H NMR (DMSO-d ₆ ) δ 139 (s, 9H), 3.93 (s, 3H), 7 25 (d, J=6 Hz, IH), 7.46 (d, .1=8 Hz, 2H), 7 63 (d, J=8 Hz, 2H), 830 (s, IH), 8.35 (d, J=6 Hz, IH), 8,91 (s, 2H), 9.56 (s, IH), 10.49 (s, IH).

EXAMPLE 109 A mixture of 4-amino-2-chloro-5-fluoropyritnidine (147 mg), EXAMPLE 6 (280 mg), sodium ethoxide (038 niL, 21% (w/w) in ethanol) and dimethylsulfoxide (4 niL) was heated at 75 ⁰ C overnight After cooling, the mixture was purified by flash chromatography on silica gel using ethyl acetate to provide 0 126 g of the title compound as a solid ¹ H NMR (DMSOd ₆ ) δ 1.42 (s, 9H), 8.20 (s, IH), 8 53 (s, IH), 11.52 (s, IH)

EXAMPLE 110

A mixture of 4-[l,2,3]thiadiazol-4-ylphenylamine (10.7 mg), EXAMPLE 109 (14.8 mg) and n-butanol (0 6 mL) was heated at 1 1O ⁰ C overnight The mixture was cooled and concentrated and the residue purified as described in EXAMPLE 12D to give 3 mg of the title compound as the trifluoroacetate salt ^! H NMR (DMSOd ₆ ) δ 1 31 (s, 9H), 7.81 (s, IHX 7 82 (d, J=8 Hz, 2H), 8.01 (d, J=8 Hz, 2H), 8.40 (s, IH), 9.45 (s, IH), 9.66 (s, IH), 10 80 (s, IH)

EXAMPLE H lA To EXAMPLE 6 (4.9 g) was slowly added 7N ammonia in methanol (120 mL) and the mixture stirred at ambient temperature overnight. The solid was filtered, washed with ether, and dried ¹ H NMR (DMSOd ₆ ) δ 1.38 (s, 9H), 7 52 (s, IH).

EXAMPLE 11 IB A mixture of EXAMPLE U IA (I 85 g), 2,4-dichloiopyiimidine (1.64 g), 60% oily sodium hydride (0.88 g) and N,N'-dimethylformamide (50 mL) was stirred at ambient temperatuie for 3 hours. The mixture was quenched with saturated ammonium chloride and concentrated. The residue was dissolved in 1 :2 methano I/chloroform and the insoluble solid removed The FiHt ate was concentrated and the resulting solid again dissolved in 1:2 methanoi/chloroform and the insoluble product removed. The filtrate

was concentrated and the residue purified by flash chromatography on silica gel using 100:100:0.5 to 100:100:2 chloroform/dichloromethane/methano. to provide 0.7 g of the title compound as a solid. ^S H NMR (DMSO-d ₆ ) δ 1.42 (s, 9H), 7.47 (s, IH), 8.47 (d, T=7 Hz, 1 H), 8.56 (m, 1 H), 1 1.28 (br s, 1 H).

EXAMPLE 111 ALTERNATE

EXAMPLE 11 1 was also prepared by the following alternate procedure: To a cooled solution of 3,4-diethoxycyclobut-3-ene-l,2-dione (3.07 g) and sodium hydride (60% in mineral oil, 0 57 g) in 100 mL tetrahydrofuran was added 4-amino-2- chloropyrimidine (1.84 g) and the mixture stirred at O ⁰ C for I hour and at ambient temperature for 3 days. The mixture was concentrated, water added and the solution washed with 1 :9 ethyl acetate/hexane. To the aqueous mixture was added tert- butylamine (1 .06 g) in 10 mL cold water and the mixture stirred at ambient temperature overnight. The precipitate was filtered, washed with water and dried.

EXAMPLE 1 12

A mixture of 4-[l,2,4]triazol-l-ylphenylamine (24 mg), EXAMPLE 1 11 (21 mg), trifluoroacetic acid (0.06 mL) and 2,2,2-trifluoioethanol (0.6 mL) was heated at 75 ⁰ C overnight. The mixture was concentrated and the residue purified as described in EXAMPLE 12D to give 22 mg of the title compound as the trifluoroacetate salt. H

NMR (DMSOd ₆ ) δ 1 .38 (s, 9H), 7 29 (d, J=6 Hz, IH), 7.77 (t, J=8 Hz, 2H), 7.84 (d, J=8 Hz, 2H), 8,20 (s, IH), 8.30 (br s, IH), 8.37 (d, J=6 Hz, IH), 9.18 (s, IH), 9.69 (s, IH), 10.52 (s, IH).

EXAMPLE 1 13

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 112 using cyclohexylamine in place of 4-[l,2,4]triazol-l-ylphenylamine. H NMR (DMSOd ₆ ) δ 1 .19 (m, IH), 1.29 (m, 4H) ₅ 1,42 (s, 9H), 1.60 (m, IH), 1.72 (m, 2H), 1.87 (m, 2H), 3,80 (m, IH), 7.10 (m, IH), 8 ϊ 7 (d, 1=6 Hz, IH), 839 (br s, IH), 10,82 (br s, IH).

EXAMPLE 1 14

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 112 using 4-(pyrazol-3-yl)phenylamine in place of 4-[l,2,4jtriazol-l- ylphenylamine. ¹ H NMR (DMSOd ₆ ) δ 136 (s, 9H), 6.66 (s, IH) ₃ 7.80 (m, IH), 7.69 (m, 3H), 7.76 (d, J=8 Hz, 2H), 8.28 (s, IH), 8.33 (d, J=6 Hz, 2H), 9,82 (s, IH), 10.68 (s, IH).

EXAMPLE 115

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 1 12 using 5-arnmobenzotriazole in place of 4-[l,2,4]triazol-l-ylphenylamine,

¹ H NMR (DMSOd _n ) δ 1.35 (s, 9H), 7.25 (d, J=6 Hz, IH), 7.55 (d, .1=8 Hz, IH), 7.88 (d, .1=8 Hz, IH), 8,26 (s, IH), 8.32 (s, IH), 8.36 (d, J=ό Hz, IH), 9,70 fs, IH), 10.58 (s, IH)

EXAMPLE 1 16 This example as the trifluoroacetale salt was prepared as described in

EXAMPLE 112 using 4-thiophen-3-ylphenylamine in place of 4-[l,2,4]triazol-l- ylphenylamine. ¹ H NMR (DMSOd ₆ ) δ 138 (s, 9H), 7.21 (d, ,1=6 Hz, IH), 7 52 (d, ]= ^β Hz, IH), 7.62 (m, IH), 7 67 (d, J=8 Hz, 2H), 7.76 (d, J=8 Hz, 2H), 7 77 (s, IH), 8.30 (s, IH), 8.33 (d, J=6 Hz, IH), 9 42 (s, IH), 1043 (s, IH).

EXAMPLE 117

This example as the tiifluoroacetate salt was prepared as described in EXAMPLE 112 using 5-aminobenzimidazoIe in place of 4-[l,2,4]triazol-l- ylphenylamine. ¹ H NMR (DMSOd ₆ ) δ 1 .34 (s, 9H), 7.22 (d, .1=6 Hz, IH) ₅ 7.76 (m, 2H), 8.23 (s, IH), 8.36 (s, IH), 8.37 (d, J=6 Hz, IH), 9.38 (s, IH) ₅ 9.78 (s, IH), 10.60 (s, IH).

EXAMPLE 118

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 112 using l-acetyl~2,3-dihydro-lH-indol-6-yIamine in place of 4- [l,2.4]triazol-l-ylphenylamine ¹ H NMR (DMSOd ₆ ) 6 1 34 (s, 9H), 2.13 (s, 3H), 3 09 (t, J=7 Hz, 2H), 409 (t, J=7 Hz, 2H), 7.13 (m, 2H), 7,32 (d, J=6 Hz, IH), 8.23 (m, 3H), 9.53 (s, IH), 10.62 (S ₅ IH).

EXAMPLE 119 This example as the trifluoroacetate salt was prepared as described in

EXAMPLE 112 using N-(3-arninophenyl)methanesuIfonamide in place of 4- [l,2,4]triazol-l-ylphenylamine. ¹ H NMR (DMSOd ₆ ) 6 1.34 (s, 9H), 2.99 (s, 3H), 6.82 (d, J=6 Hz, IH), 7 15 (m, IH), 7.22 (t, .1=6 Hz, IH), 7.42 (m, 2H), 8,23 (s, IH), 8.25 (d, J=6 Hz, IH), 9.53 (s, IH), 9 73 (s, IH), 10.60 (s, IH),

EXAMPLE 120

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 112 using 5-amino-2-trifluoromethylbenzimidazole in place of 4- [1 ,2,4JtHaZoH -ylphenylamine. ¹ H NMR (DMSOd ₆ ) δ 1.34 (s, 9H), 7.22 (m, IH), 7.50 (d, .1=8 Hz, IH), 7.63 (d, J=8 Hz, IH), 8.17 (s, IH), 8.23 (s, IH), 8.34 (d, .1=6 Hz, IH), 9.72 (s, IH), 10.62 (s, IH),

EXAMPLE 121

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 112 using N-(4-aminophenyl)-4-methylbenzenesuIfonamide in place of 4-

[l,2,4]tiiazol-l-ylphenylamine ¹ H NMR (DMSOd ₆ ) δ 134 (s, 9H), 2,37 (s, 3H), 7.00 (d, .1=8 Hz, 2H), 721 (ra, IH), 7.37 (t, .1=8 Hz, 2H), 7.50 (t, .1=8 Hz, 2H), 7.61 (t, 1-8 Hz, 2H), 8.23 (m, 2H), 9 39 (s, I H), 9.99 (s, IH), 10.41 (s, IH).

EXAMPLE 122

This example as the triflυoroacetate salt was prepared as described in EXAMPLE 112 using 5~amino-2-methylbenzthiazole in place of 4-[l,2,4]triazol-l- ylphenylamine. ¹ H NMR (DMSOd ₆ ) δ 1.35 (s, 9H) ₅ 2,79 (s, 3H), 7.30 (m, IH), 7.61 (d, J=8 Hz, IH), 7,91 (d, .1=8 Hz, IH), 8.27 (m, 2H), 8.29 (s, IH), 9.72 (s, IH), 10.58 (s, IH).

EXAMPLE 123

This example as the trifluoioacetate salt was prepared as described in EXAMPLE 112 using 4-(morpholine~4-sulfonyl)phenylamine in place of 4-[l ,2,4]triazol- 1-ylpheπylamine. ¹ H NMR (DMSOd ₆ ) 6 1.39 (s, 9H) ₅ 2.82 (m, 4H) ₅ 3.62 (m, 4H), 7.32 (m, IH), 7.62 (d, J=8 Hz, 2H), 7.97 (d, J=8 Hz, 2H), 8.27 (s, IH), 8.40 (d, J=6 Hz, IH) ₅ 9.96 (S ₅ IH), 10.57 (s, lH).

EXAMPLE 124

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 112 using 3-(rnorpholine-4-sulfonyl)phenyϊarnine in place of 4-[ 1 ,2,4]triazol- 1-ylphenylamine. ¹ H NMR (DMSOd ₆ ) δ 1.39 (s, 9H) ₅ 2.84 (m, 4H), 3,63 (m, 4H), 7.28 (m, IH) ₅ 7.30 (d, .1-7 Hz, IH), 7.59 (t, J=7 Hz, IH), 7.99 (s, IH), 8.19 (d, J=6 Hz, IH) ₅ 8.27 (s, IH). 8.38 (d, J=6 Hz, IH), 9.72 (s, IH), 10 56 (s, IH),

EXAMPLE 125

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 112 using 5-amino~2-methylbenzimidazole in place of 4-[l,2,4]triazol-l- ylphenylamine. ¹ H NMR (DMSOd ₆ ) δ 1.38 (s, 9H) ₅ 2.78 (s, 3H), 7.22 (d, J=6 Hz ₅ IH) ₅ 7.70 (m, 2H), 8.24 (m, 2H), 8,38 (d, J=6 Hz, IH) ₅ 9.70 (s, IH) ₅ 10.58 (s, IH) ₅ 14.42 (bs, IH).

EXAMPLE 126 This example as the trifluoroacetate salt was prepared as described in EXAMPLE 112 using l-(toluene-4-sulfonyl)-lH-indol-5-ylamine in place of 4-[l,2,4]triazol-l- ylphenylamine. ¹ H NMR (DMSOd ₆ ) δ 1.21 (s, 9H), 2 32 (s, 3H), 6.78 (d, .1-6 Hz, IH), 7.10 (d, J=6 Hz ₅ IH), 7.38 (d, J=S Hz, 2H), 7.47 (d, .1=8 Hz, IH), 7,72 (d, .1=6 Hz, IH), 7.84 (m, 3H), 7,91 (s, IH), 8 17 (s, IH), 8.27 (d, ,1=8 Hz, IH), 9.39 (s, IH), 10.50 (s, IH).

EXAMPLE 127

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 112 using l-methaπesulfonyl-2,3-dihydio-lH-indol-5-ylamine in place of 4- [l,2,4]triazol-l-ylphenylamine. ¹ H NMR (DMS0-d ₆ ) δ 1 .38 (s, 9H), 2.92 (s, 3H), 3 08 (t, .1=8 Hz, 2H), 3 92 (t, .1=8 Hz, 2H), 7.18 (m, 2H), 7 42 (d, J=8 Hz, IH), 7,57 (s, IH), 8.28 (m, 2H), 9 M (s, IH), 10,49 (s, IH).

EXAMPLE 128

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 112 using 4-pyridin-2-ylphenylamine in place of 4-[l,2,4]lriazol-l- ylphenylamine. ¹ H NMR (DMSOd ₆ ) 5 1.32 (s, 9H), 7.20 (d, .1=6 Hz, IH), 738 (t, 3=6 Hz, IH), 7 42 (t, J=O Hz, IH), 7,58 (d, .1=8 Hz, IH), 7.83 (d, J=8 Hz, IH), 7.92 (m, 2H), 8^26 (d, J=8 Hz, 2H), 8.32 (d, 1=6 Hz, IH), 8.65 (d, 1=6 Hz, IH), 9,55 (s, IH), 10.58 (s, IH).

EXAMPLE 129

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 112 using 4-(4-methanesulfonylpiperazin-l-yl)phenylamine in place of 4- [l,2,4]triazol-l-ylphenylamine. ¹ H NMR (DMSOd ₆ ) δ 136 (s, 9H), 2.92 (s, 3H), 3.18 (t, J=6 Hz, 4H), 3.26 (t, 3=6 Hz, 4H), 6.95 (d, .1=8 Hz, 2H), 7.25 (d, 3=6 Hz, IH), 7.48 (d, J=8 Hz, 2H), 8 23 (d, J=6 Hz, IH), 8.28 (s, I H), 9.28 (s, IH), 10.52 (s, IH).

EXAMPLE 130

This example was prepared as described in EXAMPLE 112 using 7-amino-4H- benzo[l,4]oxaziπ-3-one in place of 4-[l,2,4]triazol-l-ylphenylamine. Instead of HPLC purification, crude material was washed with methanol and dried H NMR (DMSOd ₆ ) δ 1.33 (S ₅ 9H), 4,50 (s, 2H), 6.90 (d, J=8 Hz, IH), 7.08 (d, J ^» 8 Hz, IH), 7 25 (d, 3=6 Hz, IH), 7.48 (s _> IH), 8.26 (d, 3=6 Hz, IH), 8.50 (s, IH), 9.75 (s, IH), 10.68 (s, IH), 10-98 (s, IH)..

EXAMPLE 131

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 112 using 3-pyrrol-l-ylphenylamine in place of 4-[l,2,4]triazol-l- ylphenylamiπe. ¹ H NMR (DMSOd ₆ ) 5 1.36 (s, 9H), 6.25 (s, 2H), 7.15 (d, J=8 Hz, IH), 7.22 (d, .1=6 Hz, IH), 7.26 (s, 2H), 738 (t, J=8 Hz, IH), 7.58 (d, .1=8 Hz, IH), 7,82 (s, IH), 8.28 (s, IH), 834 (d, J=6 Hz, IH), 9 55 (s, IH), 10,52 (s, IH),

EXAMPLE 132

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 112 using 6-amino-2-methylbeπzthiazole in place of 4-[l,2,4]triazol-l-

ylphenylamine ¹ H NMR (DMSOd ₆ ) δ 1.37 (s, 9H), 2,78 (s, 3H), 7 26 (d, 1=6 Hz, IH), 7,66 (d, J=8 Hz, IH), 7.81 (d, I=S Hz, IH), 8.28 (s, IH), 8.33 (d, J=6 Hz, IH), 8.46 (s, IH), 9 62 (s, IH), 10.48 (s, IH)

EXAMPLE 133

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 112 using 4- ox azol- 5 -ylphenylamine in place of 4-[l,2,4]triazol-l- ylpheπylamine. ¹ H NMR (DMSOd ₆ ) δ 1.38 (s, 9H), 7,26 (d, J=6 Hz, 1H),7.35 (s, IH), 7.65 (d, J=8 Hz, 2H), 7 81 (d, .1=8 Hz, 2H), 8,25 (s, IH), 8.34 (d, J=6 Hz, IH), 8 .38 (s, IH), 9 59 (s, IH), 10.46 (s, IH)

EXAMPLE 134

This example as the tiifluoroacetate salt was prepared as described in EXAMPLE 112 using 4-aminopyridine in place of 4-[l,2,4]triazol-l-ylphenylamine, H NMR (DMSOd ₆ ) δ 1.42 (s, 9H), 7.00 (d, .1=8 Hz, 2H),7.55 (br.s, IH), 8.18 (s, IH), 8 71 (d, J=6 Hz, IH), 8.95 (s, 2H), 9,25 (d, .1-8 Hz, 2H) _S 11.08 (s, IH),

EXAMPLE 135

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 112 using 4-(dimethylaminomethyl)phenylamine in place of 4-[l,2,4]triazol- 1 -ylphenylamine. ¹ H NMR (DMSO-d ₆ ) δ 1 39 (s, 9H), 2.73 (s, 6H), 4,20 (s, 2H), 7.23 (d, J=6 Hz, IH), 7.39 (d, J=8 Hz, 2H), 7,78 (d, J=8 Hz, 2H), 8.25 (s, IH), 8.33 (d, J=6 Hz, IH), 9 58 (s, IH), 10.48 (s, IH).

EXAMPLE 136

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 112 using 5-ammo-2-melhylisoindole-l ,3-dione in place of 4-[l,2,4]triazol- 1 -ylphenylamine, ¹ H NMR (DMSOd ₆ ) δ 140 (s, 9H) _S 3,02 (s, 3H), 7.38 (d, .1=6 Hz, IH), 7.78 (d, J-8 Hz, IH), 8.10 (d, J=8 Hz, IH), 8 23 (s, IH), 8 30 (s, IH), 8 42 (d, J=6 Hz, IH), 10.08 (s, IH), 10,53 (s, IH).

EXAMPLE 137

A mixture of EXAMPLE 11 IA (168 mg), 4,6-dichloropyrimidine (157 g), 60% oily sodium hydride (0.80 g) and N,N ^f -dirnethylformamide (7 mL) was stirred at ambient temperature for 4 hours. The mixture was quenched with ice and the mixture concentrated The residue was purified by flash chromatography on silica gel using 100:100:1 chJoroform/dichlorornethane /methanol to provide 160 mg of the title compound as a solid. ¹ H NMR (DMSOd ₆ ) δ 1.42 (s, 9H), 7,78 (s, IH), 8.69 (s, IH), 8.78 (br s, IH), l l ,10 (s, IH),

EXAMPLE 138

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 1 12 using 4-iodoaniline in place of 4-[l ,2,4]triazol-l-ylphenylamine and EXAMPLE 137 in place of EXAMPLE 11 IB ¹ H NMR (DMSOd ₆ ) δ 1.42 (s, 9H), 6 Jl (s, IH), 7 47 (t, J=8 Hz, 2H), 7,62 (d, J=8 Hz, 2H), 8,40 (s, IH), 9 48 (s, IH), 9 80 (s, IH), 10 82 (s, IH).

EXAMPLE 139

This example was prepared as described in EXAMPLE 1 1 1 -2 using cyclopropylamine in place of tert-butylamine MS (ESI): m/z 265 (M+H)

EXAMPLE 140 3-(2-chIoropyrimidin-4-ylamino)-4-cyclobutyIaminocyclobut-3- ene-I,2-dione

This example was prepared as described in EXAMPLE 11 1-2 using cyclobutylamine in place of tert-butylamine

EXAMPLE 141

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 112 using 4-iodoaniline in place of 4-[l,2,4]triazol-l-ylphenylamine and EXAMPLE 139 in place of EXAMPLE 111. ¹ H NMR (DMSOd ₆ ) δ 049 (m, 2H), 0.65 (m, 2H) ₁ 2.98 (m, IH), 6 88 (d, 1=6 Hz, IH), 7.48 (d, J=8 Hz, 2H), 7.61 (d, J= 8 Hz, 2H), 6 89 (d, J=6 Hz, IH), 8.25 (d, J=6 Hz, IH), 9,58 (s, IH), 10,60 (s, IH)

EXAMPLE 142 This example as the trifluoroacetate salt was prepared as described in

EXAMPLE 112 using 4-iodoaniline in place of 4-[l,2,4]triazol-l-ylphenylamine and EXAMPLE 140 in place of EXAMPLE 111. ¹ H NMR (DMSOd ₆ ) δ 1.59 (m, 2H), 1.90 (m. 2H), 2.18 (m, 2H), 4.42 (in, IH), 6.95 (d, J=6 Hz, IH), 748 (d, J=8 Hz, 2H), 7.61 (d, J=8 Hz, 2H), 8.08 (d, J=6 Hz, IH), 8.28 (d, J=6 Hz, IH), 9-55 (s, IH), 10,60 (s, IH).

EXAMPLE 143

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 112 using 4-pyridin-4-ylpheny-amine in place of 4-[l,2,4]triazol-l- ylphenylamine and EXAMPLE 140 in place of EXAMPLE 1 11, ¹ H NMR (DMSOd ₆ ) δ 1.55 (m, 2H), 1.85 (m, 2H), 2.38 (m, 2H), 4.55 (m, IH), 7.01 (d, J=6 Hz, IH), 7.82 (d, J=8 Hz, 2H), 7.92 (d, J=8 Hz, 2H), 830 (d, J=6 Hz, IH), 8,33 (d, .1=6 Hz, 2H), 846 (d, J=6 Hz, IH), 8 75 (d, J=6 Hz, 2H), 9 82 (s, IH), 10.63 (s, IH).

EXAMPLE 144

This example as the trifluoroacetate salt was prepared as desciibed in EXAMPLE 103 using 4-(N,N-dimethylaminocarbonyl)phenylboiOπic acid in place of pyiidine-4-boronic acid. ¹ H NMR (DMSOd ₆ ) δ 1.38 (s, 9H), 2,98 (s, 6H), 7.23 (d, .1-6 Hz, IH), 748 (d, .1=8 Hz, 2H) ₃ 7 66 (m, 4H), 7.82 (d, J=8 H ₂ , 2H), 8 29 (s, IH), 8 33 (d, .1=6 Hz, IH), 9 60 (s, IH), 10.53 (s, IH).

EXAMPLE 145 A

This example was prepared as described in EXAMPLE 111-2 using 4-amino-2- chloro-6-methylpyrimidine in place of 4-amino-2-chloropyrimidiπe. H NMR (DMSO- d ₆ ) δ 1 43 (s, 9H), 2 37 (s, 3H), 7,27 (s, IH), 8.60 (s, IH), 11 28 (br s, IH).

EXAMPLE 145B

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 112 using 4-thiophen-3-ylρhenylamine in place of 4-[l,2,4]triazol-l- ylphenylamine and EXAMPLE 145A in place of EXAMPLE 111. ¹ H NMR (DMSOd ₆ ) δ 1.38 (s, 9H), 2 31 (s, 3H), 7.03 (s, IH), 7.52 (d, J=4 Hz, IH), 7.61 (m, IH), 7.63 (d, J=S Hz, 2H), 7 76 (d, J=8 Hz, 2H), 7,77 (s, IH), 8 27 (s, IH), 9.46 (s, IH), 10 45 (s, IH)

EXAMPLE 146

EXAMPLE 53B (141 mg), 3-aminobenzenesulfonamide (157 mg), and trϊfluoroacetic acid (0.016 mL) were heated in 1 mL 2,2,2-trifluoroethanol for 6 hours The mixture was cooled and concentrated and the residue purified by HPLC using a gradient of 10/90 to 90/10 acetonitrile/0.1% trifluoroacetic acid in water to provide the title compound as the trifluoroacetate salt. ¹ H NMR (DMSOd ₆ ) δ 10.50 (br s, IH), 9 64 (br s, IH), 8.33 (m, 2H), 8.10 (br t, IH), 7.98 (m, 2H), 7 43 (m, 2H), 7 28 (m, 3H), 1.39 (s, 9H).

EXAMPLE 147

This example was prepared as described in EXAMPLE 146 using m-anisidine (188 mg) in place of 3-aminobenzenesulfonamide to give a yellow solid H NMR

(DMSOd ₆ ) 5 10.48 (br, IH), 9 35 (br s, IH), 8 30 (d, IH), 8.27 (br s, IH), 7 32 (t, IH), 7.21 (m, 3H), 6.53 (m, IH) ₁ 3.72 (s, 3H) ₅ 1.34 (s, 9H).

EXAMPLE 148 This example as the trifluoroacetate salt was prepared as described in

EXAMPLE 146 using 4-(4-benzylpiperazin-lyl)phenylamine (326 mg) in place of 3- aminobenzenesulfonamide to give a yellow solid. H NMR (DMSOd ₆ ) δ 10 52 (br s, IH), 9 27 (br s, IH), 8 25 (s, IH), 8,23 (s, IH), 7.52 (m 7H), 7.08 (br d, IH), 6 93 (d, 2H), 4.41 (br s, 2H), 3 71 (m, 2H), 3.41 (m, 2H), 3..19 (m, 2H), 2 91 (m, 2H), 1.33 (s, 9H).

EXAMPLE 149

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 146 using 4-nitroaniline (167 mg) in place of 3-aminobenzenesulfonamide to give a yellow solid ¹ H NMR (DMSOd ₀ ) δ 10.52 (s, IH), 10 19 (s, IH), 8 42 (d, IH), 8.26 (br s, IH), 8 18 (d, 2H), 7 95 (d, 2H), 7 40 (d,lH), 1 39 (s, 9H).

EXAMPLE 150

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 146 using 5-amino-2-chloro-picoline (209 mg) in place of 3- aminobenzenesulfonamide to give a yellow solid H NMR (DMSOd ₆ ) δ 10,43 (br s, IH), 9 64(s, IH), 8.63 (d, IH), 8.36 (d, IH), 8.25 (br s, IH), 8.04 (d, IH), 734 (d, IH), 2.32 (s, 3H), 139 (s, 9H).

EXAMPLE 151 A 4-amino-3-methoxybenzoic acid (250 mg) and l,r-carbonyldiimidazole (248 mg) were stirted in 5 mL acetonitrile for 1 hour. 4-Amino-l-methylpipeiidine (205 mg) in 4 niL acetonitrile was added and the mixture iefluxed for 4 houis The mixture was cooled, concentrated, and partitioned between dichlorom ethane and water , The organic phase was washed with 10% aqueous sodium hydroxide and brine, dried over magnesium sulfate and concentrated. ¹ H NMR (DMSOd ₆ ) δ 7.75 (br d, IH), 7 29 (m, 2H), 6.58 (d, IH), 5.19 (s, 2H), 3.80 (s, 3H), 3 68 (m, IH), 2.74 (m, 2H), 2.15 (s, 3H), 1.91 (m, 2H) ₅ 1.71 (m, 2H), 1.54 (m, 2H).

EXAMPLE 15 IB EXAMPLE 1 11 (161 mg), EXAMPLE 151 A (150 mg), palladium (II) acetate (6 mg), 4,5-bis(diphenylphosphino)-9,9-dimelhy]χanthene (5 mg), and cesium carbonate (372 mg) in 2 5 mL dioxane were heated at 160"C for 40 minutes in a microwave The mixture was concentrated and the residue purified HPLC using a gradient of 10/90 to 90/10 acetonitrile/0, 1 % trϊfluoroacetic acid in water to give the title compound as a trifluoracetate salt ¹ H NMR (DMSOd ₆ ) δ 10,70 (br s, IH), 8.27 (br s, IH), 8.21 (d, IH), 7.94 (d, IH), 735 (s, IH), 7.32 (s, IH), 7,20 (br s, IH), 6.74 (d, IH), 4 51 (m, 2H), 4,11 (m, IH), 3.83 (s, 3H), 3 16 (br t, 2H), 1 ,90 (m, 2H), 1 53 (m, 2H), 1.42 (s, 9H), 1 35 (m, 2H).

EXAMPLE 152

A mixture of 4-aminopyrimidine (101.5 mg) and EXAMPLE 6 (101.6 mg) in N,N'-dimethylformamide (4 mL) was treated with a solution of 21% sodium ethoxide in ethanol (0.2 mL) and heated at 140°C overnight. The solvent was removed and the residue purified by flash chromatography on silica gel using 20:1 to 10:1 dichloromethane/methanol to provide the title compound (57 8 mg, 46%). H NMR

(DMSOd ₆ ) δ 11 00 (s, IH), 9 01 (s, IH), 8.80 (s, IH), 8 57 (d, 1=6 Hz, IH), 7.54 (d, J=6 Hz, I H), 1 45 (s, 9H)

EXAMPLE 153 A solution of 3,4-diethoxy-3-cyc1obutene-l,2-dione (3 07 g) in telrahydrofuran

(50 mL) was treated with sodium hydride (60% in mineral oil, 570 mg) The mixture was cooled to 0 ⁰ C, and 4-amino-2-chloropyrimidine (1 84 g) was added in small portions. After 1 hour the reaction was warmed to ambient temperature and stiπed overnight The solvent was removed and the residue taken up in water and washed with 9:1 hexane/ethyl acetate. The aqueous solution was cooled to 0 ⁰ C and treated dropwise with neat S-α- methylbenzylamiπe (2 J mL). After 1 hour the reaction was warmed to ambient temperature and stiπed for 3 days The precipitate was collected, washed with methanol, and dried to provide the title compound as a tan solid (3.14 g, 66%) H NMR (DMSO d ₆ ) δ 11 37 (bs, IH), 8 42 (d, J=5 8 Hz, IH), 8 03 (d, J=9.5 Hz, IH), 7 27 (bs, IH), 4.05- 4 09 (m, IH), 1 60-1 82 (m, 6H), 1 38-1.45 (m, IH), 1 23 (d, 1=6 8 Hz, 3H), 0.954 16 (m, 4H)

EXAMPLE 154

This example was prepared as described in EXAMPLE 153 using R-α- methylbenzylamine in place of S-α-methylbenzylamine. H NMR (DMSOdβ) δ 1 1 37 (bs, IH), 8 42 (d, 1=5 8 Hz, IH), 8 03 (d, 1=9 5 Hz, IH), 7 27 (bs, IH) ₇ 4 05-4 09 (m, IH), 1 60-1.82 (m, 6H), 1.38-1 45 (m, IH), 1 23 (d, T=6 8 Hz, 3H), 0 95-1 16 (m, 4H)

EXAMPLE 155 A mixture of 4-(Thiophen-3-yl)aniline (55 3 mg) and EXAMPLE 153 (99 6 mg) were heated at 100 ⁰ C in n-butanol (3 mL) overnight The precipitate was collected and rinsed with hot n-butanol followed by hexane to provide the title compound (78 4 mg, 53%). ¹ H NMR (DMSOd ₆ ) δ 10 73 (s, IH), 9.80 (s, IH), 8.31 (d, 1=6 Hz ₅ IH), 8.20 (d, J=9 Hz, IH), 7.75-7.80 (m, IH), 7 68-7.71 (m, 4H), 7.53-7 64 (m, 2H), 7.34 (d, J=SA Hz, IH), 1 65-1 70 (m, 6H), 1 18-1 33 (m, 2H), 1 14 (d, 1=6.4 Hz, 3H), 0 86-1 00 (m, 4H).

EXAMPLE 156

This example was prepared as described in EXAMPLE 155 using EXAMPLE 154 in place of EXAMPLE 153 ¹ H NMR (DMSOd ₆ ) δ 10 73 (s, IH), 9.80 (s, IH), 8 31 (d, J=6 Hz, IH), 8 20 (d, 1=9 Hz, IH), 7.75-7.80 (m, IH), 7 68-7.71 (m, 4H), 7 53-7 64 (m, 2H), 7.34 (d, J=5.4 Hz, IH), 1 65-1 70 (m, 6H), 1 18-1 33 (m, 2H), 1 14 (d, J = 6 4 Hz, 3H), 0 86-1.00 (m, 4H)

EXAMPLE 157

This example was prepared as described in EXAMPLE 155 using 4-(4,6- diinethoxypyrimidin-2-yl)phenylamiπe in place of 4-(thiophen-3-yl)aniline. H NMR (DMSOd ₆ ) δ 10.57 (s, IH), 9.83 (s, IH), 8-36 (d, .1=5 8 Hz, IH), 8.33 (d, .1=8.8 Hz ₁ 2H), 8.15 (d, .1=6.1 Hz, IH), 7,85 (d, .1=8.8 Hz, 2H), 7.36 (d, J=5.8 Hz, IH), 6,1 1 (s, IH), 3 99 (s, 6H), 1 ,54-1.75 (m, 6H), 1.21-1.34 (m, 2H), 1.16 (d, .1=6 8 Hz, 3H), 0.88-1 .10 (m, 4H).

EXAMPLE 158

This example was prepared as described in EXAMPLE 156 using 4-(4,6- dimethoxypyrimidin-2-yI)phenylarnine in place of 4-(thiophen-3-yl)aniline. H NMR

(DMSOd ₆ ) δ 10.57 (s, IH), 9.83 (s, IH), 8.36 (d, .1=5.8 Hz, IH), 8.33 (d, J=S S Hz, 2H),

8 15 (d, .1=6.1 Hz, IH), 7.85 (d, J=S-S Hz, 2H), 7.36 (d, .1=5.8 Hz, IH), 6.11 (s, IH), 3.99

(s, 6H), 1 .54-1.75 (m, 6H), 1,21-1.34 (m, 2H), 1 .16 (d, J-6..8 Hz, 3H), 0.88-1.10 (m, 4H).

EXAMPLE 159

A mixture of EXAMPLE 153 (69.2 rag), 4~pyridin-4-ylphenylamine (37.8 mg), palladium (II) acetate (3.0 mg), 4 _s 5-bis(diphenylphosphiiio)-9,9-dirnethylxanthene (9.6 mg), cesium carbonate (141.6 mg) and dioxane (2.5 ml) were heated in a microwave at 16O ⁰ C for 40 minutes. The solvent was removed and the residue purified by flash chromatography using 20: 1 dichloromethane/methanol. Further purification by reverse phase HPLC afforded the title compound (12.8 mg, 13%). ¹ H NMR (DMSOd ₆ ) δ 10.40 (s, IH), 9.84 (s, IH), 8.81 (d, J=6.8 Hz, 2H), 8.38 (d, J=5.8 Hz, IH), 8.24 (d, J=6.8 Hz, 2H), 7.94-8,04 (m, 5H), 734 (d, J=5.8 Hz, IH) ₁ 1..55-1 .75 (m, 6H), 1.27-1.36 (m, 2H), 1.17 (d, J=6.8 Hz, 3H), 0.87-1.12 (m, 4H).

EXAMPLE 160

This example was prepared as described in EXAMPLE 159 using EXAMPLE 154 in place of EXAMPLE 153. ¹ H NMR (DMSOd ₆ ) δ 10.40 (s, IH), 9.84 (s, IH), 8.81 (d, J=6.8 Hz, 2H), 8.38 (d, 1=5.8 Hz, IH), 8.24 (d, J-6.8 Hz, 2H), 7.94-8.04 (m, 5H), 7.34 (d, J = 5.8 Hz, IH), 1.55-1.75 (m, 6H), 1.27-1.36 (m, 2H), 1.17 (d, J=6.8 Hz, 3H), 0.87-1.12 (m, 4H).

EXAMPLE 161 A

A solution of 3,4-diethoxy-3-cyclobutene-l,2-dione (10.3 mL) in tetrahydrofuran (200 mL) was treated with sodium hydride (60% dispersion in mineral oil, 2.16 g). The mixture was cooled to O ⁰ C, and 4-amino-2-chloropyrimidine (7,00 g) was added in small portions. After 1 hour the reaction was wanned to ambient temperature and stirred for 3 days The solvent was removed and the residue was taken up in water and washed with 9:1 hexane/ethyl acetate. The aqueous solution was cooled to 0 ⁰ C and treated dropwise with neat t-butylamine (5.8 mL). The mixture was warmed to ambient temperature and

after 1 day, additional t-butylamine (1 2 mL) was added The mixture was stirred at ambient temperature for another 2 days and the precipitate was collected and washed with water, tiiturated in methanol, filteied, and rinsed with methanol The solid was collected, vigorously shaken in water for 10 minutes, filtered, washed with additional water, and dried to provide the title compound (6 09 g, 40%)

EXAMPLE 161 B

A mixture of 4-(4-aminopiperidino)pyridine dihydrochloride (90 1 mg), EXAMPLE 161 A (100 0 mg), potassium carbonate (147 1 mg), and n-butanol (3 0 mL) was heated at 100 ⁰ C overnight The solvent was removed and the residue purified by reveise phase HPLC to provide the title compound (54.6 mg, 36%) H NMR (DMSO- d ₆ ) δ 1 1 12 (s, IH), 9 37 (d, .1-8.1 Hz, 2H), 8.72 (d, J=5 8 Hz, IH), 8 24 (s, IH), 7,97 (bs, 2H), 7 48 (d, 1=8 1 Hz, 2H), 4 41-4 49 (m, 2H), 3-37-3 45 (m, 4H), 2 07-2 20 (m, 2H), 1 57-1 62 (m, IH), 1.44 (s, 9H)

EXAMPLE 162

A mixture of EXAMPLE 161 A (101 4 mg), 4-(l-methylpiperidin-4-yl)- phenylamine (76.1 mg), palladium(II) acetate (3 6 mg), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (13 0 mg), cesium carbonate (238.2 mg), and dioxane (4.5 ml) were heated in a microwave at 160°C for 40 minutes. The solvent was removed and the residue purified by reverse phase HPLC to provide the title compound as the trifluoroacetate salt ¹ H NMR (DMSOd ₆ ) δ 9 28 (s, IH), 8.27 (d, .1-8 5 Hz, 2H), 7 56 (d, 1=8 5 Hz, 2H), 7 1 1-7.16 (m, 4H), 2 88-2 95 (m, 2H), 2 26 (s, 3H), 2 02-2 10 (m, 2H), 1.60-1.73 (m, 3H), 1.33 (s, 9H), 1 13-1.20 (m, 2H)

EXAMPLE 163 A

A solution of 3,4-diethoxy-3-cyclobutene-l,2-dione (2 21 g) in tetrahydrofuran (35 mL) was treated with sodium hydride (60% in mineral oil, 0.040 g) The mixture was cooled to 0°C and 4-amino-2-chioropvrimidine (1 29 g) was added in portions. The reaction was warmed to ambient temperature, stirred for 3 days and concentrated The residue was taken up in water and washed with 9:1 hexane/ethyl acetate The aqueous solution was cooled to O ⁰ C and t-butyl 4-aminopiperidine-l-caiboxylate (2 01 g) added in poitions The mixture was warmed to ambient temperature, stirred for 3 days, and the resulting precipitate collected, washed with water and dried

EXAMPLE 163B

A mixture of EXAMPLE 163A (298.8 mg), 4-pyridin-4-yl-phenylamine (124.9 mg), palladium(II) acetate (7 7 mg), 4,5-bis(diphenylphosphino)~9,9-dimethylxanthene (25 6 mg), cesium carbonate (0.46 g), and dioxane (5 mL) were heated in a microwave at 16O ⁰ C for 40 minutes The solvent was removed and the residue purified by flash

chioniatography on silica gel using 15% methanol/dichloromethane to provide the title compound (141 6 mg, 36%) as a tan powder

EXAMPLE 163C A suspension of EXAMPLE 163B (140 9 mg) in dichloromethane (5 niL) and methanol (0.2 mL) was treated with tiifluoroacetic acid (5 niL) and stilted at ambient temperature overnight The solvent was removed and the residue tiiturated with methanol/dichloromethane and purified by reverse phase HPLC to provide the title compound (45.2 mg) ¹ H NMR (DMSOd ₆ ) δ 9 61 (s, IH), 8 59 (d, J=4.5 Hz, 2H), 8.32 (d, J=5 4 Hz, IH), 8.10-8.20 (bs, IH), 7.87 (d, J=8.8 Hz, 2H), 7 77 (d, J=8.8 Hz, 2H), 7.68 (d, J=4 5 Hz, 2H), 7 18 (d, 1=5.4 Hz, IH), 3 85-3 94 (bs, IH), 2 87-2.97 (m, 4H), 1 77-1.84 (m, 2H), 1 29-1 42 (m, 2H)

EXAMPLE 164A A mixture of EXAMPLE 161 A (400 mg) and 3-aniinobenzoic acid (201 mg) in n- butanol (10 mL) was heated at 100-115 ⁰ C overnight. The ptecipitate was collected, washed with hexane and dr ied

EXAMPLE 164B A solution of EXAMPLE 164A (75.0 mg), 4-amiiio-l-methylpiperidine (25.7 mg) and 4-dimethylaminopyridine (27 7 mg) in N,N'-dimethyIformamide (2 mL) was treated with 1 -rnethyl-4-aminopiperidine (0 25 mL) and l-ethyl-3-(3'- dimethylaminopropyl)carbodiimide (41.9 mg) The mixture was stirred at ambient temperature for 1 day, additional l-methyl-4-aminopiperidine was added and the mixtuie stiired overnight. The solvent was removed and the residue purified by reverse phase HPLC to provide the title compound (50 9 mg). ¹ H NMR (DMSOd ₆ ) δ 10 54 (s, IH), 9.50 (s, IH), 8.40 (d, J=7.5 Hz, IH), 8 32 (d, J=5.7 Hz, IH), 8 26 (s, IH) ₃ 8 05 (s, IH), 7.85 (d, 1=8.8 Hz, IH), 7 35-7.46 (m, 2H), 7.18 (d, J=5 7 Hz, IH), 3.42-3 51 (m, 2H), 3 04-3 15 (m, 2H), 2 78 (s, 3H), 1.94-2.05 (m, 3H), 1 674 82 (m, 2H), 1.34 (s, 9H)

EXAMPLE 165

This example was prepared as described in EXAMPLE 164B using cycloheptylamine in place of l-methyl-4-aminopiperidine H NMR (DMSOd ₆ ) δ 10 55 (s, IH), 9 51 (s, IH), 8.31 (d, J=5.4 Hz, IH), 8.26 (s, IH) ₅ 8.12 (d, J=8.1 Hz, IH) ₅ 8.01 (s, IH), 7 80 (d, .1=8,1 Hz, IH), 7 44 (d, J=7.8 Hz, IH), 7 33-7 38 (in, IH), 7.20 (d, J=5.8 Hz, IH), 1 77-1.88 (m, 4H), 1 37-1.70 (m, 9H), 1 33 (s, 9H)

EXAMPLE 166

This example was prepared as described in EXAMPLE 164B using cyclohexylamine in place of l-methyl-4-aminopiperidine H NMR (DMSOd ₆ ) δ 10 56

(s, IH), 9.54 (S ₁ IH), 8 31 (d, 1=5.8 Hz, IH) ₃ 8.26 (s, IH), 8 09 (d, J=7,8 Hz, IH), 8 01 (s, IH), 7 82 (d, J=7 8 Hz, IH), 7 45 (d, ϊ=7.8 Hz, IH), 7 33-7 38 (m, IH), 7.21 (d, J=5 8 Hz, IH), 1 68-1 85 (m, 4H), 1 56-1 65 (m, IH), 1 33 (s, 9H) 1 10-1 30 (m, 6H).

EXAMPLE 167

This example was prepaied as described in EXAMPLE 164B using cyclopentylamine in place of l-methyl-4-aminopiperidine. H NMR (DMSOd ₆ ) δ 10 53 (s, IH), 9 49 (s, IH), 8.31 (d, 1=5.4 Hz, IH), 8.26 (s, IH), 8 17 (d, .1=7.1 Hz, IH), 8 02 (s, IH), 7.82 (d, 1=8 8 Hz, IH), 7 44 (d, 1=7.5 Hz ₅ IH), 7 21-7.38 (m, IH), 7 20 (d, J=5.8 Hz, IH), 4 16-4 25 (m, IH) 1.81-1.91 (m, 2H), 1 64-1 70 (m, 2H), 1.47-1 57 (m, 4H) 1 33 (s, 9H).

EXAMPLE 168

This example was prepared as described in EXAMPLE 164B using cyclobutylamine in place of 1 -methyl-4-aminopiperidine H NMR (DMSOd ₆ ) δ 10 54 (s, IH), 9.51 (s, IH), 8.50 (d, .1=7.8 Hz, IH), 8.31 (d, .1=5 8 Hz, IH), 8.27 (s, IH), 8 02 (s, IH), 7 83 (d, J=8 1 Hz, IH), 7.46 (d, J = 7.8 Hz, IH), 7 34-7 39 (m, IH), 7 22 (d, J=5 8 Hz, IH), 4 34-4,44 (m, IH) 2 15-2 25 (m, 2H), 1.99-2 09 (m, 2H), 1.62-1 Jl (m, 2H) I 34 (s, 9H)

EXAMPLE 169A

This example was prepaied as described in EXAMPLE 164A using 3-amino-4- methoxybenzoic acid in place of 3-aminobenzoic acid

EXAMPLE 169B

A mixture of EXAMPLE 169A (41.1 mg) and O-(benzotriazol-l-yl)-N,N,N',N ^f - tetramethyluronium tetrafluoroborate (33.8 mg) in dichloromethane (1 mL) was treated with NjN-diisopropylethylamiπe (0 04 mL) and stirred foi 30 minutes Cyclohexylamine (0.03 mL) was added and the mixture stirred at ambient temperature overnight The solvent was removed and the residue purified by reverse phase HPLC to provide the title compound (5.9 mg). ¹ H NMR (DMSOd ₆ ) δ 10 62 (s, IH), 8 47 (d, T=2.0 Hz, IH), 8 42 (s, IH), 8 29 (d, J=5 8 Hz, IH), 7 96-8 03 (m, 2H), 7.58 (dd, J=8 5, 2.0 Hz, IH), 7 05- 7.10 (m, 2H), 3.87 (s, 3H), 3 68-3,77 (m, IH), 1.67-1 85 (m, 4H), 1 55-1.65 (m, 2H), 1 40 (s, 9H), 1 24-1.37 (m, 4H).

EXAMPLE 170

A mixture of 6-ammoquiπoIine (29 mg), EXAMPLE 1 1 1 (56 mg), cesium carbonate (1.30 mg), palladium (II) acetate (2 mg), 4,5-bis(diphenyIphosρhino)-9,9~ dimethylxanthene (9 mg) and dioxane (1.2 mL) was heated at 16O ⁰ C for 40 minutes by microwave The residue was purified as described in EXAMPLE 12D to give 75 mg of

the title compound as the trifluoroacetale salt: ¹ H NMR (DMSOd ₆ ) δ 1 38 (s, 9H), 7 31 (d, 1=6 Hz, IH), 7 76 (dd, J=6, 8 Hz, IH), 8 OS (d, J=8 Hz, IH), 8 15 (d, J=8 Hz, IH), 8 24 (s, IH), 842 (d, .1=6 Hz, IH), 8 60 (s, IH), 8 63 (d, J=8 Hz, IH), 8 92 (d, 1=4 Hz, IH), 10 OO (s, IH), 10 57 (s, IH)

EXAMPLE 171

A mixture of EXAMPLE 3 (30 mg), 4-fluoro-3-methylphenylamine (12 5 mg), toluene (2 rnL), and p-toluenesulfonic acid {1 5 mg) was heated to 86 ⁰ C and stirred overnight The mixture was cooled, concentrated and the residue purified as described in EXAMPLE 12D to give 10,3 mg of the title compound as the trifluoroacetate salt, H NMR (DMSOd ₆ ) δ 0,90 (s, 9H), 1 15 (d, 1=7 Hz, 3H), 2.21 (s, 3H), 4,00 (in, IH), 7.08 (t, J=8 Hz, IH), 7 32 (d, J=6 Hz, IH), 7 45 (d, 1=8 Hz, IH), 7,55 (t, .1=8 Hz, IH), 7.95 (d, .1=8 Hz, IH), 8.30 (d, .1=6 Hz, IH), 9.18 (s, IH), 10.18 (s, IH)

EXAMPLE 172

This example as the trifluoroacetate salt was prepared as described in EXAMPLE 109 using 2'-methoxybiphenyl-4-ylamine in place of 4-[l,2,3]thiadiazol-4- ylphenylamine ¹ H NMR (DMSOd ₆ ) δ 1.30 (s, 9H), 3.76 (s, 3H), 7 00 (t, J=7 Hz, IH), 7.12 (d, J=7 Hz, IH), 7.24 (d, .1=7 Hz, IH), 7 31 (t, J=7 Hz, IH), 7.35 (d, 1=8 Hz, 2H) ₅ 7 66 (d, T=8 Hz, 2H), 7 81 (s, IH), 8 38 (s, IH), 9.48 (s, IH), 10.82 (s, IH)

EXAMPLE 173 A

This example was prepared as described in EXAMPLE 161 A by substituting 2-amino-2-methylpiopan-l-ol for tert-butylamine

EXAMPLE 173B

A mixture of EXAMPLE 173 A (27 mg), 4-amino-N-cyclobutyl-3- methoxybenzamide (20 mg) and para-toluenesulfonic acid monohydrate in THF was stiixed at 72°C overnight, cooled and concent, ated. The concentrate was purified by reverse phase HPLC ¹ H NMR (DMSOd ₆ ) δ 1 40 (s, 6H), 1 59-1,76 (m, 2H), 1 96-2 14 (m, 2H), 2 16-2.31 (m, 2H), 3.50 (s, 2H), 3 90 (s, 3H), 4.43 (m, IH), 5,64 (s, brd, IH), 6.90 (d, J=5.1Hz, IH), 7.41-7.54 (m, 2H), 8,13 (m, IH), 8 27 (d, J=5.8Hz, IH), 8 41 (s, IH), 8.49 (d, J=7 5Hz, IH), 9.10 (s, IH), 10.91 (s, IH).

EXAMPLE 174A

This example was prepared as described in EXAMPLE 161 A by substituting 2-phenyIpropan-2-amine for tert-butylamine

EXAMPLE 174B

This example was prepared as described in EXAMPLE 173B by substituting EXAMPLE 174A for EXAMPLE 173A ¹ H NMR (DMSOd ₆ ) 6 1 59-1 75 (m, 2H), 1.81 (s, 6H), 1 98-2 31 (ni, 4H), 3 85 (s, 3H), 442 (m, IH), 7 1 1-7 29 (m, 2H), 7 35 {t, .1=7 6Hz, 2H), 7 42-7.56 (m, 4H), 7 89 (s, IH), 8 30-8 41 (m, 2H), 8 46 (d, J=7 5Hz, IH), 8 75 (s, IH), 10.75 (s, IH)

EXAMPLE 175 A

This example was prepared as described in EXAMPLE 161 A by substituting 2-methylbut-3-yπ-2-amine for tert-butylamine.

EXAMPLE 175B

This example was prepared as described in EXAMPLE 173B by substituting EXAMPLE 175A for EXAMPLE 173A. ¹ H NMR (DMS0-d ₆ ) 8 1.61-1.71 (m, 2H), 1.73 (s, 6H), 1 98-2.30 (m, 4H), 3 93 (s, 3H), 4.43 (m, IH), 7,16 (d, J=5,4Hz, IH), 7.44-7 53 (m, 3H), 7 98 (s, IH), 8 26-8 40 (m, 2H), 8 47 (d, J=7 IHz, IH), 8 67 (s, IH), 10.71 (s, IH).

EXAMPLE 176 A This example was prepared as described in EXAMPLE 161A by substituting

2-amiπo-2-methylpropanenitriIe for tert-butylamine

EXAMPLE 176B

This example was prepared as described in EXAMPLE 173B by substituting EXAMPLE 176A for EXAMPLE 173A ¹ H NMR (DMSOd ₆ ) 6 1 61-1 73 (m, 2H), 1 85 (s, 6H), 1 99-2.14 (m. 2H), 2 16-2.28 (m, 2H), 3 91 (s, 3H), 4 42 (m, IH), 6 98 (d, J-5.5Hz, IH), 7 47-7,52 (m, 2 H,) 8.12 (s, IH), 8 32 (d, J-8.3Hz, IH), 8,37 (d, 1=5 5Hz, IH), 8 45 (d, .1=7 4Hz, IH), 8 61 (s, IH), 10 94 (s, IH)

EXAMPLE 177 A

This example was prepared as described in EXAMPLE 161A by substituting 2-cyclopropylpropan-2-amme for tert-butylamine

EXAMPLE 177B This example was piepared as described in EXAMPLE 173B by substituting

EXAMPLE 177A for EXAMPLE 173 A ¹ H NMR (DMSOd ₆ ) δ 0.34-0 48 (m, 3H), 1 32 (s, 6H), 1.31-1 40 (m, 2H), 1 59-1.75 (m, 2H), 1 99-2 29 (m, 4H) ₅ 3 91 (s, 3H), 4 42 (m, IH), 7 20 (d, J-5.8HZ, IH), 7.46-7 55 (m, 2H), 7 89 (s, IH), 8 30-8 40 (m, 2H), 8 42-8 52 (m, 2H), 10 73 (s, lH)

EXAMPLE 178 A

This example was prepared as described in EXAMPLE 161 A by substituting 2-melhyl-I -morpholinopropan-2-amine for tert-butyl amine,

EXAMPLE 178B

This example was prepared as described in EXAMPLE 162 by substituting EXAMPLE 178A for EXAMPLE 161 A and 4-amino-N-cyclobuty]-3-methoxybenzamide for 4-(l-methylpiperidin-4-y!)phenylamine. ¹ H NMR (CD ₃ OD) δ 1 62 (s, 6H), 1.73-1 85 (m, 2 H, 2 07-2,19 (m, 2H), 2.29-2 41 (m, 2H), 3.36 (brs, 4H), 3,72 (brs, 2H), 3 88 (brs, 4H), 3.99 (s, 3H), 4.50 (m, IH), 6.93 (brs _r IH), 7 47-7.55 (m, 2H), 8.33 (d, J=5.8Hz, IH), 8 44 (d, J-8,5Hz, IH),

EXAMPLE 179A

This example was prepared as described in EXAMPLE 161 A by substituting morpholine for tert-butylamine

EXAMPLE 179B

This example was prepared as described in EXAMPLE 162 by substituting EXAMPLE 179A for EXAMPLE 161 A and 4-amino-N-cyclobutyl-3-methoxybenzamide for 4-(l -methylpiperidin-4-yl)phenyIamine. ¹ H NMR (CD ₃ OD) δ 1 JO-1.88 (m, 2H) ₅

2.04-2,23 (m, 2H) ₁ 2.28-2.46 (m, 2H), 3,43-3 88 (m, 8H, brd), 4.00 (s, 3H), 4.50 (m, IH), 6.62 (d, J=6.8Hz, IH), 7 47 (dd, .1-8.5, 1 JHz, IH), 7.57 (d, J=I JHz, IH), 8 04-8.20 (m, 2H).

EXAMPLE 180A

This example was prepared as described in EXAMPLE 161 A by substituting 4- amino-4-methylpentan-2-one hydrogenoxylate and sodium bicarbonate (2.1 equiv) for tert-butylamine.

EXAMPLE 180B

This example was prepared as described in EXAMPLE 173B by substituting EXAMPLE 180A for EXAMPLE 173 A. ¹ H NMR (DMSO-d ₆ ) δ 1 49 (s, 6H), 1.62-1 76 (m, 2H), 2.00-2.15 (m, 5H), 2 17-2 28 (m, 2H), 3.04 (s, 2H), 3.90 (s, 3H) 4.43 (m, IH), 7.07 (s, IH), 7.44J 56 (m, 2H) ₁ 8.13 (s, IH), 8 31-8A3 (m, 2H), 8.48 (d, J=7.3Hz, IH), 8.62 (s, IH), 10 85 (s, IH)-

EXAMPLE 181 A

This example was prepared as described in EXAMPLE 161 A by substituting propylamine for tert-butylamine.

EXAMPLE 181 B

This example was prepared as described in EXAMPLE 173B by substituting EXAMPLE 181 A for EXAMPLE 173 A. ¹ H NMR (DMSOd ₆ ) 6 0 88 (t, J=7.3Hz, 3H), 1.45-1.58 (m, 2H), 1.61-1 .71 (m, 2H), 1.99-2.13 (m. 2H), 2.18-2.29 (m, 2H), 3.43-3.52 (m, 2H), 3 90 (s, 3H), 4.42 (m, IH), 6.79 (d, T-5.2Hz, IH), 7 46-7 54 (m, 2H), 7.99 (t, J=6.4Hz, IH), 8.13 (d, J=8.2Hz, IH), 8.26 (d, J-5.5Hz, IH), 8.32 (s, IH), 8.51 (d, J=7.6Hz, IH), 10.84 (s, IH).

EXAMPLE 182A This example was prepared as described in EXAMPLE 161 A by substituting aniline for lert-butylamine.

EXAMPLE 182B

This example was prepared as described in EXAMPLE 173B by substituting EXAMPLE 182A for EXAMPLE 173A. ^! H NMR (DMSOd ₆ ) δ 1.59-1.78 (m, 2H), 2.01- 2.14 (m, 2H), 2.16-2.29 (m, 2H), 3,91 (s, 3H), 4,41 (m, IH), 7.04 (s, IH), 7.12 (t, J=7.2Hz, IH), 7.33-7.44 (m, 4H), 7.45-7.51 (m, 2H), 8.18 (s, IH), 8 29 (d, J=8.5Hz, IH), 8.38 (d, J=5.5Hz, IH), 8.44 (d, J=7.3Hz, IH), 10.28 (s, IH), 10.98 (s, IH).

EXAMPLE 183 A

A mixture of EXAMPLE 161 A (0.63 mmol), sodium sulfide hydrate (70 mg) and propylbromide (227 mg) in water (2 mL) and THF (1 mL) was stiired at ambient temperature for 1 day, diluted with ethyl acetate, washed with brine and dried, filtered and concentrated.

EXAMPLE 183B

This example was prepared as described in EXAMPLE 162 by substituting EXAMPLE 183A for EXAMPLE 161 A and 4-amiπo-N-cyclobutyl-3-methoxybenzamide for 4-(l-methylpiperidin-4-yl)phenylamine. ¹ H NMR (DMSOd ₆ ) <5 1.05 (t, .1=7.4Hz, 3H), 1.61-1 .72 (m, 2H), 1.72-1.79 (m, 2H), 2.02-2.14 (m, 2H), 2. 17-2.28 (m, 2H), 3.47 (t, J=7.2Hz, 2H), 3.96 (s, 3H), 4.42 (m, IH), 6 69 (d, J=5.5Hz, IH), 7.49-7.55 (m, 2H), 8,0.3 (s, IH), 8.42 (d, J=5.5Hz, IH), 8.46 (d, J=8.9Hz, IH), 8.50 (d, J=7.7Hz, IH), U .76 (s, IH).

EXAMPLE 184A

A mixture of 4-amino-2-bromo-pyridirie (213 mg), EXAMPLE 6 (100 mg) and 21 wt% sodium ethoxide in ethaπol (03 mL) in dimethylsulfoxide (3 mL) was heated at 155 ⁰ C under microwave conditions for 20 minutes and concentrated. The concentrate was purified by reverse phase HPLC on a RPl 8 prep cartridge with 0.1% trifluoroacetic

acid/water/acetonitiile. ¹ H NMR (DMSO-d ₆ ) δ 1.43 (s, 9H), 7.33 (dd, .1-5.7, 2 OHz, IH), 7.86 (d, J=I.8Hz, IH), 8.04 (s, IH), 8,20 (d, J=5.8Hz, IH), 10.03 (s, IH).

EXAMPLE 184B A mixture of EXAMPLE 184A (50 mg), biphenyl-4-amine (31.3 mg), palladium(ll) acetate (2 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7.8 mg) and cesium carbonate (98 mg) in dioxane (2 mL) at 16O ⁰ C was stirred for 80 minutes under microwave conditions and concentrated. The concentrate was purified by reverse phase HPLC. ¹ H NMR (DMSO-d ₆ ) δ 1.43 (s, 9H), 7 01 (s, IH), 7.13 (d, J=5.2Hz, IH), 7.35 (t, J=7.3Hz, IH), 7,47 (t, J=7.6Hz, 2H), 7.57 (d, J=8.2Hz, 2H), 7.68 (d, J=7.0Hz, 2H), 7.71 (d, J=8.5Hz, 2H), 8.00 (d, J=6.4Hz, IH), 8.12 (s, IH), 9,88 (s, IH), 10.22 (s, IH).

EXAMPLE 185 This example was prepared as described in EXAMPLE 184 by substituting 4-

(pyridin-4-yl)aniliπe for biphenyl-4-amine. ¹ H NMR (DMSOd ₆ ) δ 1.11-1.61 (m, 9H), 7.04 (s, IH), 7.06-7.12 (m, IH), 7.85 (d, J=7.9Hz, 2H), 8.01 (d, J=8.8Hz, 2H), 8.08 (s, IH), 8.11 (d, J=6.1Hz, IH), 8,19 (d, J=4.9Hz, 2H), 8.78 (d, J=6 IHz, 2H), 9,75 (s, IH), 9.99 (s, IH).

EXAMPLE 186

This example was prepared as described in EXAMPLE 184 by substituting 4- amino-N-cyciohexyl-3-methoxybenzamide for biphenyl-4-amine. H NMR (DMSO-d ₆ ) δ 1.06-1.21 (m, IH), 1.24-1.39 (m, 4H) ₃ 1.43 (s, 9H), 1 .58-1.67 (m, IH), 1.69-1.80 (m, 2H), 1.80-1.91 (m, 2H), 3.70-3,85 (m, IH), 3 89 (s, 3H), 7.04 (d, J=O .9Hz, IH), 7.12 (dd, J=6.3, UHz, IH), 7.54 (d, J=S OHz, IH), 7.58 (m, IH), 7.57-7.60 (m, IH), 7.95 (d, J=6.7Hz, IH), 8.16 (s, IH), 8.18 (d, J=7.7Hz, IH), 9.55 (s, IH), 10..31 (s, IH).

EXAMPLE 187A A mixture of 4-amino-3-methoxybenzoic acid (0.93g), cyclopentylamine

(0.64 mL), HATU (2.5 g) and TEA (0.90 mL) in DMF (20 mL) was stirred at ambient temperature for 3 days and diluted with water and ethyl acetate. The extract was washed with brine and dried (Na ₂ SO ₄ ), filtered and concentrated. The concentrate was purified by flash column chromatography on silica gel with 45:55 hexanes/ethyl acetate. H NMR (DMSOd ₆ ) δ 1.51 (m, 4H), 1.68 (m, 2H), 1.85 (m, 2H), 3.80 (s, 3H) ₅ 4.18 (m, IH), 5.18 (s, 2H), 6.59 (d, J=8Hz, IH), 7.28 (m, 2H), 7.81 (br d, .1-7Hz, IH),

EXAMPLE 187B

To a solution of 2-amino-4-chϊoropyrimidine (0.23 g) and 3,4-diethoxycyclobut- 3-ene-l ,2-dione (0.35 g) in THF (5 mL) at ambient temperature was added 95% oily

sodium hydride (55 mg), The mixture was stirred overnight, treated with diethylamine (0.14 g), stirred overnight, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 15:85 hexane/ethyl acetate. H NMR (DMSOd ₆ ) δ 1.18 (m, 6H), 3.55 (m, 2H), 3.75 (rn, 2H), 7.05 (d, J=6Hz, IH), 8.40 (d, J=6Hz, IH), 10.75 (brs, IH)

EXAMPLE 187C

To a solution of EXAMPLE 187A (34 mg) and EXAMPLE 187B (40 mg) in dioxane (0.5 mL) was added paia-toluenesulfonic acid monohydrate (25 mg). The mixture was stirred at 70 ⁰ C overnight and concentrated. The concentrate was puiifϊed by reverse phase HPLC. ¹ H NMR (DMSOd ₆ ) δ 1.16 (m, 6H) ₅ 1 ,64 (m, 4H), 1.71 (m, 2H), L90 (m, 2H), 3.83 (s, 3H), 4.23 (m, IH), 6.61 (d, J=6Hz, IH), 7.45 (dd, J=8Hz, 2Hz, IH), 7.51 (d, J=2Hz, IH), 8.18 (d, J=7Hz, IH), 8.24 (d, J=7Hz, IH), 8.26 (d, J= 7Hz, IH), 8 46 (brs, IH), 10.49 (brs, IH).

EXAMPLE 188A

To a solution of ^" 3,4-diethoxycyclobut-3-ene-l,2-dione (1.2 g) in THF (20 mL) at 0 ⁰ C was added IM solution neopentylmagnesium bromide in diethyl ether (9 mL), The mixture was stirred at O ⁰ C for 10 minutes and at ambient temperature for 20 minutes, treated with 6M hydrochloric acid (25 mL) and extracted with diethyl ether. The extract was washed with brine and dried (Na ₂ SO ₄ ), filtered and concentrated. The concentrate was flash chromatographed in silica gel with 93:7 hexane/ethyl acetate. H NMR (CDCl ₃ ) δ 1.02 (s, 9H), 1.48 (t, J=7Hz, 3H), 2.49 (s, 2H), 4.81 (q, J=7Hz, 2H).

EXAMPLE 188B

To a solution of 2~amino-4-chloropyrimidine (0.13 g) and EXAMPLE 188A (0.19 g) in THF (2 5 mL) was added 95% sodium hydride (28 mg). The mixture was stirred at ambient temperature overnight and concentrated. The concentrate was flash chromatographed in silica gel with 6:4 hexanes/ethyl acetate. H NMR (DMSO-dg) δ 0..94 (s, 9H), 2.97 (s, 2H), 7.53 (d, J=6Hz, IH), 8 63 (d, J=6Hz, IH), 1 1.98 (brs, IH).

EXAMPLE 188C

This example was prepared as described in EXAMPLE 187C by substituting EXAMPLE 188B for EXAMPLE 187B. ¹ H NMR (DMSOd ₆ ) δ 0.92 (s, 9H), 1.54 (m, 4H), 1 71 (m, 2H), 1.90 (m, 2H), 2.86 (s, 2H), 3.83 (s, 3H), 4.23 (m, IH), 6 97 (d, J=6Hz, IH), 7.51 (m, 2H), 8 07 (s, IH), 8 16 (d, J=7Hz, IH), 8.28 (d, J=9Hz, IH), 8.44 (d, J=6Hz, IH), 1 1.44 (s, IH).

EXAMPLE 189A

This example was piepared as described in EXAMPLE 188A by substituting penlyI-3-magnesium bromide fot neopentylmagnesium bromide H NMR (DMSOd ₆ ) δ 0 85 (t, l=7Hz, 6H), 1 38 (t, J=7Hz, 3H), 1 62 (m, 4H), 2 82 (m, IH), 4 73 (q, J=7Hz, 2H)

EXAMPLE 189B

This example was prepared as described in EXAMPLE 188B, by substituting EXAMPLE 189A for EXAMPLE 188 A.

EXAMPLE 189C

This example was prepared as described in EXAMPLE 187C by substituting EXAMPLE 189B for EXAMPLE 187B This example precipitated out of the reaction mixture and was isolated by filtration. ¹ H NMR (DMSOd ₆ ) δ 0 86 (t, 1-7Hz, 6H), 1.54 (m, 4H), 1 71 (m, 6H), 1.91 (m, 2H), 2 29 (s, 3H), 3.29 (m, IH), 4.24 (m, IH), 7.03 (d, J=6Hz, IH), 7 11 (d, J=SHz ₅ 2H), 7 47 (d, J=8Hz, 2H), 7.54 (m, 2H), 8 19 (d, J=7Hz, IH), 8 27 (d, J=9Hz, IH), 8.28 (bra, IH), 8.45 (d, J=6Hz, IH), 11 52 (s, IH)

EXAMPLE 190A A solution of 1.7M tert-butyl lithium in pentane (4.6 ml) was added to THF

(20 mL) at -78 ⁰ C, followed by l-bromo-2-methyl-ϊ-propene (0 53 g). The mixture was stirred for 30 minutes, treated with 3,4-diethoxycyclobut-3-ene-l,2-dione (0.52 g) in THF (30 niL), stirred for 40 minutes, treated with irifliioroacetic anhydride (1 4 g), stiπed for 10 minutes, treated with water (10 mL) and extracted with diethyl ether The extract was washed with brine and dried (Na ₂ SO ₄ ), filtered and concentrated. The concentrate was flash chromatographed in silica gel with 93:7 hexane/ethyl acetate. H NMR (DMSOd ₆ ) δ 1 40 (t, J=7Hz, 3H) ₅ 1.99 (d, J=IHz, 3H), 2 14 (s, 3H), 4.77 (q, J=7Hz, 2H) ₅ 6 05 (m, IH)

EXAMPLE 190B

This example was prepared as described in EXAMPLE 188B by substituting EXAMPLE 190A for EXAMPLE 188A ¹ H NMR (DMSOd ₆ ) a 2 02 (s, 3H), 2.18 (s, 3H), 6 73 (s, IH), 7.65 (d, J=6Hz, IH), 8 63 (d, J=6Hz, IH), 11 92 (brs, IH),

EXAMPLE 190C

A mixture of EXAMPLE 190B (30 mg), EXAMPLE 187A (26 rag), palladium(II) acetate (3 8 mg), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (13 7 mg) and cesium carbonate (85 mg) in dioxane (1 8 mL) was heated in a microwave reactor at

(R)

ISO ⁰ C for 10 minutes, filtered through diatomaceous earth (Celite ) and concentrated The concentrate was purified by reverse phase HPLC. H NMR (DMSOd ₆ ) θ 1.54 (m,

4H), 1.71 (m, 2H), 1 91 (m, 2H), 1 99 (s, 3H), 2 18 (s, 3H), 3 95 (s, 3H), 4 23 (ra, IH), 6 62 (s, IH), 7,06 (d, J=6Hz, IH), 7 51 (m, 2H), 7 98 (s, IH), 8 15 (d, J=7Hz, IH), 8 41 (d, J=9Hz, IH), 8 45 (d, J=OHz, IH), 1 1 -40 (s, IH)

EXAMPLE 191 A

This example was prepared as described in EXAMPLE 12D by substituting methyl 2-(4-aminophenyl)acetate for 3,4,5-trimethoxyphenylamine and EXAMPLE 161 A for EXAMPLE 12C ^! H NMR (DMSOd ₆ ) δ 10.46 (s, IH), 9.32 (s, IH), 8 25-8 31 (m, 2H), 7 67 (dd, .1=8 1, 1 4Hz, IH), 7 46 (t, J=LSHz, IH), 7 24 (t, J-8.0HZ, IH), 7 17 (bs, IH), 6 87 (d, J=7 8Hz, IH), 3.63 (s, 2H), 3,61 (s, 3H), 1 36 (s, 9H).

EXAMPLE 19 IB

To a solution of EXAMPLE 191 A (417 mg) in THF/water (15 mL) was added lithium hydroxide (85 mg) The mixture was stirred at ambient temperature for 30 minutes, neutralized with IM hydrochloric acid and partitioned between ethyl acetate and water. The extract was washed with brine and dried (MgSO ₄ ), filtered and concentrated. ¹ H NMR (DMSOd ₆ ) δ 1038 (bs, IH), 9 30 (s, IH), 8.29-8 35 (m, 2H), 7.65 (dd, J=8.0, 1 2Hz, IH), 7.46 (t, I=I 7Hz, IH), 7 17-7 25 (m, 2H), 6 84-6.88 (m, IH), 3.50 (s, 2H), 137 (s, 9H).

EXAMPLE 191 C

This example was prepared as described in EXAMPLE 187A by substituting EXAMPLE 191 B for 4-amino-3-methoxybenzoic acid and l-methylpipeiidin-4-amine for cyclopentylamine ¹ H NMR (DMSO-d ₆ ) δ 10.55 (s, IH), 9 42 (s, IH), 8 29 (m, 2H), 8.22 (d, 3=7 3Hz, IH), 7.59 (d, J=7 9Hz, IH), 7.45 (rn, IH) ₃ 7 17-7.24 (m, 2H), 6.88 (d, J=7.6Hz, IH), 3.71-3 77 (m, IH), 3.36-3 43 (m, 4H), 2 99-3.12 (m, 2H), 2,75 (d, J=4.6Hz, 2H), 1 84-1.97 (m, 3H), 1.54-1 62 (m, 2H), 1.35 (s, 9H)

EXAMPLE 192

This example was prepared as described in EXAMPLE 191 C by substituting pyridin-3-ylmethanamine for l-methyIpiperidin-4-amine H NMR (DMSO-dg) δ 10 52 (s, IH), 9 40 (s, IH), 8 66 (t, J=6.1Hz, IH), 8,60 (s, 2H), 8 29 (m, 2H), 7.97 (d, J=7 9Hz, IH), 7 59-7.63 (m, 2H), 7.48 (s, IH), 7,23 (t, J=7.8Hz, IH), 7 18 (m, IH), 6 91 (d, J=7.6Hz, IH), 4.36 (d, J=6 IHz, 2H), 3.17 (s, 2H), 1 35 (s, 9H).

EXAMPLE 193 A

This example was prepared as described in EXAMPLE 12D by substituting methyl 2-(3-aminophenyl)acetate for 3,4,5-trimethoxyphenylamine and EXAMPLE 161 A for EXAMPLE 12C.

EXAMPLE 193B

This example was prepared as described in EXAMPLE 191 C by substituting EXAMPLE 193 A for EXAMPLE 191 B. ¹ H NMR (DMSOd ₆ ) δ 10.51 (s, IH), 9.34 (s, IH), 8.29 (m, 2H), 8 21 (d, J=7 5Hz, IH), 7.59 (d, J=8.1Hz, IH), 7.46 (m, IH), 7.16-7.24 (m, 2H), 6.86-6.91 (m. IH), 3.69-3.76 (m, IH), 3.40-3.44 (m, 2H), 3.36 (s, 3H) ₅ 2.97- 3 08 (m, 2H), 2.75 (d, J-4.7Hz, 2H), 1.82-1,98 (m, 2H), 1.50-1 .65 (m, 2H), 1.36 (s, 9H).

EXAMPLE 194 This example was prepared as described in EXAMPLE 191 C by substituting cyclobutylamine for l-methylpiperidin-4-amine and EXAMPLE 193 A for EXAMPLE 191B. ¹ H NMR (DMSOd ₆ ) 8 10.48 (s, IH) ₁ 9 33 (s, IH), 8.26-8.30 (m, 3H), 7 59 (dd, J=8.0, 1..5Hz, IH), 7.42 (m, IH), 7.16-7,23 (m, 2H), 6.87 (d, J=7.5Hz, IH), 4.08-4.22 (m, IH), 3 17 (s, 2H), 2.07-2.17 (m, 2H), 1.81-1.94 (m, 2H), 1.54-1 66 (m, 2H), 136 (s, 9H).

EXAMPLE 195

A mixture of EXAMPLE 102 (30 mg), 2-ethynylpyridine (19,6 rag), copper(I) iodide (12 mg), TEA (45 μh), and 1,1'- bis(diphenylphospliino)ferrocene]dichloropalladiurn(II) (5.3 mg) in DMF (1.5 niL) was heated at 90 ⁰ C for 4 hours, cooled, treated with water and extracted with ethyl acetate. The extract was dried (MgSO ₄ ), filtered and concentrated. The concentrate was purified by reverse phase HPLC with acetonitrile/water/0.1% trifluoroacetic acid. H NMR (DMSOd ₆ ) δ 10.49 (s, IH), 9 7 (s, IH), 9.34 (s, IH), 8.56 (s, IH), 8.36 (d, .1=5.4Hz, IH), 8 3 (s, IH), 7.94-7.98 (m, IH), 7 81 (d, J=8.8Hz, 2H), 7,52 (d, J=8.8Hz, 2H), 7.46 (dd, J=7.6Hz, 49Hz, IH), 7,31 (d, J-5.8Hz, IH), 1 .40 (s, 9H).

EXAMPLE 196

This example was prepared as described in EXAMPLE 195 by substituting pent- 1-yne for 2-ethynylpyridine. ¹ H NMR (CD ₃ OD) δ 8.19 (d, J=6.1Hz, IH), 7.52 (d,

J=8.54Hz, 2H), 7,34 (d, .1-8.5Hz, 2H), 7.1 (s, IH), 2,38 (t, J=6.9Hz, 2H), 1.59-1.64 (m, 2H), 1.38 (s, 9H), 1 05 (t, .1=7 5Hz, 3H).

EXAMPLE 197 A mixture of EXAMPLE 102 (60 mg), N,N-diethylproρ-2-yn-l -amine (90 μL), copper(I) iodide (1,2 mg), dichlorobis(triphenylphosphine) palladium(II) (9.1 mg) and triphenylphosphine (1.7 mg) in THF (2 mL) was heated at 90 ⁰ C for 4 hours, cooled and concentrated. The concentrate was purified by reverse phase HPLC. H NMR (DMSO-d ₆ ) δ 10,55 (s, IH), 9,83 (s, IH), 9.7 (s, IH), 9.35 (d, J=5.5Hz, IH), 8.29 (s, IH),

7.79 (d, J=8.6Hz, 2H) ₃ 7,46 (d, ,1=8.9Hz, 2H), 726 (d, .1-5.5Hz, IH), 4.36 (d, J=4.6Hz, 2H), 3.23-3.28 (m, 4H) ₁ 1.37 (s, 9H), 1.26 (t, J=7.2Hz, 6H)

EXAMPLE 198 A mixture of EXAMPLE 102 (60 mg), but-3-en-l-ol (13 μL), pailadium(II) acetate (1 .5 mg), tris-ortho-tolylphosphine (4 mg) and TEA (22 μL) in DMF (2 niL) was heated in a microwave at HO ⁰ C for 10 minutes, cooled, treated with water and extracted with ethyl acetate. The extract was washed with brine and dried (MgSO ₄ ), filtered and concentrated. The concentrate was purified by HPLC. ¹ H NMR (DMSOd ₆ ) δ 10.48 (s, IH), 9.46 (s, IH), 8.31 (s, IH), 8.29-8.30 (m, 2H), 7.6 (d, J-8.5Hz, 2H), 7.31 (d,

J=8.5Hz, 2H), 7 22 (d, J=5.8Hz, IH), 6.37 (d, J=15.9Hz, IH), 6.13-6.19 (m, IH), 3.49- 3.53 (m. 2H), 2.30-2.34 (m, 2H), 1.37 (s, IH).

EXAMPLE 199 This example was prepared as described in EXAMPLE 198 by substituting 2- vinylpyridine for but-3-en-l-ol and triturating the product with methanol. H NMR (DMSOd ₆ ) δ 10.8 (s, IH), 9 58 (s, IH), 8.54 (dd, J=4.9Hz, 1.5Hz, IH), 8.33 (d, ,1-5.4Hz, IH), 8.29 (s, IH), 7.73-7.76 (m, 3H), 7.58-7.61 (m, 3H), 7.49 (d, J- 7.8Hz, IH), 7 21 (m, 3H), 137 (s, 9H).

EXAMPLE 200

This example was prepared as described in EXAMPLE 199 by substituting pent- 1-ene for 2-vinylpyridine and purifying the product by HPLC. ¹ H NMR (DMSOd ₆ ) δ 10.46 (s, IH), 9 39 (s, IH), 8,29-8.30 (m, 2H), 7,62 (d, J=8.όHz, 2H), 7.31 (d, J=8.6Hz, 2H), 7.19 (d, J-5.8Hz, IH), 6.34 (d, J=16.0Hz, IH), 6.12-6.19 (m, IH), 2.12-2.19 (m, 2H), 1.42-1.48 (m, 2H), 1.36 (s, 9H), 0.92 (t, J=7.4Hz, 3H).

EXAMPLE 20 IA

A mixture of EXAMPLE 161 A (140 mg), 2-methoxy- 4-nitroanilme (93 mg), palladium(II) acetate (8.9 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (34.7 mg) and cesium carbonate (325.8 mg) in dioxane (3.5 mL) was heated in a microwave at 160 ⁰ C for 40 minutes, cooled and filtered. The filtrate was suspended in 5% methanol in dichloromethane/water and filtered.

EXAMPLE 20 IB

A mixture of EXAMPLE 201 A (800 mg) and tin(II) chloride dihydrate (2.1 mg) in 15:1 DMF/water was stirred at 50 ⁰ C for 6.5 hours, treated with sodium bicarbonate and brine, and extracted with ethyl acetate. The extract was washed with water and dried (MgSO ₄ ), filtered and concentrated. The concentrate was triturated with methanol. H NMR (DMSO-de) δ 10,40 (s, IH), 8.48 (s, IH), 8.15 (d, .1=5.4Hz ₁ IH), 7.66 (s, IH), 7.34

(d, J=8.1Hz, IH), 7 0 (d, .1=5 IHz, IH), 6 29 (d, J=2 4Hz ₃ IH), 6.14 (dd, J=8.5Hz, 2,4Hz, IH) ₁ 4.95 (s, 2H), 3.68 (s, 3H).

EXAMPLE 201C A mixture of EXAMPLE 201B (60 mg), HATU (71.6 mg), TEA (26 μL) and cyclopentanecarboxamide (20.4 μL) in DMF was stirred at ambient temperature for 4.3 hours and extracted with ethyl acetate. The concentrate was washed with water and brine and dried (MgSO ₄ ), filtered and concentrated. The concentrate was triturated with methanol and purified by HPLC. ¹ H NMR (DMSO-d ₆ ) δ 10.58 (s, IH), 9.85 (s, IH), 8 46 (s, IH), 8.25 (d, J=5.4Hz, IH), 7.87 (d, J=8.1Hz, IH), 7.51 (d, J=2.0Hz, IH), 7.10 (dd, J=8.6Hz, 2.2Hz, 2H), 3 ,78 (s, 3H), 2.70-2.81 (m, IH), 1.80-1.87 (m, 2H), 1.63-1.75 (m, 4H), 1.53-1.58 (m, 2H), 1.4.3 (s, 9H).

EXAMPLE 202A A mixture of 6-aminonicolinic acid (1.0 g) in DMF (43 mL), cyclopeiitanamine

(1.07 mL), HOBt-hydrate (1.46 g), EDCI (2.07 g) and TEA (1.5 mL) in dichloiomethane (43 mL) was stirred at ambient temperature for 20 hours and filtered. The filtrate was washed with aqueous sodium bicarbonate and water.

EXAMPLE 202B

A mixture of EXAMPLE 161 A (35 mg), EXAMPLE 202A (28 mg), palladium(II) acetate (2.2 mg), 4,5-bis(diphenylphosphino)-9,9-dirnethylxanthene (8.7 mg), and cesium carbonate (81.3 mg) in dioxane (L5 mL) was heated in a microwave at 16O ⁰ C for 40 minutes and purified by reverse phase HPLC with acetonitriIe/water/0.1% trifluoroacetic acid. ¹ H NMR (DMSOd ₆ ) δ 10 71 (s, IH), 8.76 (d, J=2.4Hz, IH), 8.45 (d, J=5.8Hz, IH), 8.42 (s, IH), 8.37 (d, J=7.1Hz, IH), 8 26 (dd, J=8.8Hz, 2.03Hz, IH), 8.04 (d, J=9.2Hz, IH), 7.35 (d, J=9,2Hz, IH), 4.2-4,27 (m, IH), 1.86-1.93 (m, 2H), 1.68-1.72 (m, 2H), 1 .53-1.59 (m, 4H), 1.41 (s, 9H).

EXAMPLE 203A

To a solution of 4-amino-3-fluorobenzoic acid (0.50 g) in THF (40 mL) was added cyclopentanamine (0.478 ml), HOBt-hydrate (0.653), EDCI (0.926 g) and TEA

(0.673 mL). The mixture was stirred at ambient temperature for 6 hours and concentrated.

The concentrate was treated with water and extracted with ethyl acetate. The extract was washed with aqueous sodium bicarbonate and brine and dried (MgSC* ₄ ), filtered and concentrated. The concentrate was triturated with ethyl acetate/hexane.

EXAMPLE 203B

This example was prepared as described in EXAMPLE 202B by substituting EXAMPLE 203 A for EXAMPLE 202 A. ¹ H NMR (DMSOd ₆ ) 6 10.51 (s, IH), 9.08 (s,

IH), 8.37 (s, IH), 8.32 (d, J=5.8Hz, IH), 8.25 <d, ,1=7.1 Hz, IH), 7.94 (t, .1=8. IHz, IH), 7,67-7.76 (m, 2H), 7.28 (d, J=S-SHz ₅ IH), 4.18-4.25 (m, IH), 1.84-1.93 (m, 2H), 1.66- 1.71 (m, 2H), 1.49-1.58 (m, 4H), 1 39 (s, 9H).

EXAMPLE 204

EXAMPLE 161 A (2 g) and 4-aminobenzoic acid (1.5 g) were refluxed in 2,2,2- trifluoroethanol (30 niL) for 24 hours, The mixture was cooled and Filtered. The filtrate was washed with methanol and diethyl ether. ¹ H NMR (DMSOd ₆ ) δ 10.52 (brs, IH), 9.79 (s, IH), 8 37 (d, IH), 8.31 (s, IH), 7.85 (dd, 4H), 7 30 (d, IH), 1 68 (s, 9H).

EXAMPLE 205

A solution of 0.07M EXAMPLE 204 in DMA (0,7 mL) was treated with 0,07M O-(benzotriazol-l-yl)-N,N,N',N'-tetramethylιιronium tetrafluoroborate in DMA (0.7 mL), 0.2M (R)-2-amino-2-methyl-pentan-l-ol in DMA (0.3 mL) and 0.2M DIEA in DMA 0.7 mL), shaken at 80 ⁰ C for 4 hours, passed through a 1 g Si-Carbonate cartridge with methanol and concentrated. The concentrate was puiified by reverse phase HPLC H NMR (DMSOd ₆ ) B 8,33 (d, IH), 7.83 (d, 2H), 7.71 (d, 2H), 7.27 (br d, IH), 4.06 (m, IH), 3.40 (m, 2H), 1.61 (m, IH), 1.39 (m, 2H), 1 ,35 (s, 9H), 0,87 (m, 6H),

EXAMPLE 206

This example was prepared as described in EXAMPLE 205 by substituting (S)-2- amino-4-methylpentanamide for (R)-2-amino-2-methyl-pentan~l-ol.. H NMR (DMSO-d ₆ ) δ 8.34 (d IH), 7,88 (d, 2H), 7,75 (d, 2H), 7.28 br d (IH), 4.45 (m, IH), 1.66 (m, 2H), 1.56 (m, IH), 1.35 (s, 9H), 0.90 (dd, 6H)

EXAMPLE 207

This example was prepared as described in EXAMPLE 205 by substituting (S)-2- arnino-2-phenylethanol for (R)-2-amino-2-methyl-pentan-l-ol. H NMR (DMSOd ₆ ) δ 8.34 (d IH), 7.88 (d, 2H), 7.75 (d, 2H), 7.33 (m, 6H), 5.07 (m, IH), 3,71 (m, 2H), 1 ,35 (s, 9H).

EXAMPLE 208

This example was prepared as described in EXAMPLE 205 by substituting 3- ethoxypropan-1 -amine for (R)-2-amiπo-2-methyl-pentan-l-ol. H NMR (DMSO-dβ) δ 8.34 (d IH), 7.82 (d, 2H), 7.73 (d, 2H), 7.28 (br d, IH), 3.42 (m, 4H), 3.31 (t, 2H), 1.76 (m, 2H), 1 .35 (s, 9H), U l (t, 3H).

EXAMPLE 209

This example was prepared as described in EXAMPLE 205 by substituting 3- (methylthio)propan-l -amine for (R)-2-amino-2~methyl-pentan-l-ol. H NMR

(DMSOd ₆ ) δ 8 34 (d IH), 7.82 (d, 2H), 7.74 (d, 2H), 727 fbr d, IH), 334 (I, 2H), 2 51 (t, 2H), 2 06 (s, 3H), 1.79 (m, 2H), 1.35 (s, 9H),

EXAMPLE 210 This example was prepared as described in EXAMPLE 205 by substituting.

N ,N -dimethylbutane~l,4-diamine for (R)-2-amino-2-methyl-pentan-l-ol. H NMR (DMSOd ₆ ) δ 8.34 (d IH), 7.78 (dd, 4H), 7.24 (br d, IH), 3.30 (t, 2H), 3.08 (t, 2H), 2.78 (s, 3H), 1.65 (m, 2H), 1.57 (m, 2H), 1.36 (s, 9H).

EXAMPLE 211

This example was prepared as described in EXAMPLE 205 by substituting 2- phenoxyethanamine for (R)-2-amino-2-methyl-pentan-I-ol. ¹ H NMR (DMSOd ₆ ) δ 8.34 (d IH), 7.85 (d, 2H), 7.74 (d, 2H), 7.30 (m, 3H), 6.96(m, 3H), 4.11 (t, 2H), 3 ,64 (t, 2H), 1.35 (s, 9H).

EXAMPLE 212

This example was prepared as described in EXAMPLE 205 by substituting l-(3- aminopropyl)pyrrolidin-2-one for (R)-2-amino-2-rnethyl-peπtan- 1-oL H NMR (DMSOd ₆ ) δ 8.34 (d IH), 7 82 (d, 2H), 7 75 (d, 2H), 7.29 (br d, IH), 3.37 (t, 2H) ₅ 3.34 (m, 4H), 2 26 (t, 2H), 1 94 (m, 2H), 1.71 (m, 2H), 1.36 (s, 9H).

EXAMPLE 213

This example was prepared as described in EXAMPLE 205 by substituting 2-(5- methoxy-1 H-indo!-3-yl)ethanamine for (R)-2-amino-2-methyl-pentan- 1 -ol. H NMR (DMSO-d ₆ ) δ 8 34 (d IH), 7 78 (dd, 4H), 7 25 (d, 2H), 7.14 (s, IH), 7.07 (d, IH), 6.73 (dd, IH), 3,5.3 (t, 2H), 2.93 (t, 2H), 131 (s, 9H),

EXAMPLE 214

This example was prepared as described in EXAMPLE 205 by substituting (3,4- difluoropheny!)methanamine for (R)-2-amino-2-methyl-pentan-l-ol. H NMR

(DMSOd ₆ ) δ 8 34 (d IH), 7,86 (d, 2H), 7.76 (d, 2H), 7.27 (m, 4H), 4.45 (s, 2H), 1 ,35 (s, 9H).

EXAMPLE 215 This example was prepared as described in EXAMPLE 205 by substituting (S)-I-

(naphthalen-l-yl)ethanamine for (R)-2-amino-2-methyl-pentan-l-ol. H NMR (DMSOd ₆ ) δ 8.34 (d IH), 8.20 (d, IH), 7.95 (d, IH), 7 87 (d, 2H), 7 84 (d, IH), 7.75 (d, 2H), 7.57 (m, 4H), 7.22 (br d, IH), 5.95 (m, IH), 1 ,62 (d, 3H), 1.35 (s, 9H).

EXAMPLE 216

This example was prepared as described in EXAMPLE 205 by substituting 4-(2- aminoethyl)benzenesulfonamide foi (R)-2-amino-2-methyl-pentan-l-oϊ H NMR (DMSOd ₆ ) δ 8 34 (d IH), 7 76 (m, 6H), 7.45 (d, 2H), 7.26 (br d, IH) ₁ 3 53 (t, 2H), 2 94 (t, 2H), 1 36 (s, 9H)

EXAMPLE 217

A solution of 0 06M EXAMPLE 204 in DMA (0.8 mL) was tieated with 0 06M O-(benzotria2θl-l-yl)-N,N,N',N'-tetiamethyluronium tetraflυoroborate in DMA (0.8 ml-), 0.2M pyridin-2-ylmethanamine in DMA (0.3 mL), and 0.2M DIEA in DMA (0.8 mL), shaken at 80 ⁰ C for 4 hours, passed through a Ig Si-Carbonate cartridge with methanol and concentrated The concentrate was purified by reverse phase HPLC. H NMR (DMSO-d ₆ ) δ 8 7 (d IH), 8.40 (td, IH), 8 35 (d, IH), 7.87 (m, 6H), 7.25 (br d, IH), 4 78 (s, 2H), 1 37 (s, 9H)

EXAMPLE 218

This example was prepared as described in EXAMPLE 217 by substituting 2- (lH-imidazol-4-yl)ethanamine for pyτidin-2-ylmethanamine H NMR (DMSOd ₆ ) 5 8.93 (d, IH), 8 34 (d, IH), 7,76 (m, 4H), 7.41 (s, IH), 7 22 (br d, IH), 3.57 (t, 2H), 2.93 (t, 2H), 1 35 (s, 9H)

EXAMPLE 219

This example was prepared as described in EXAMPLE 217 by substituting 2- morpholinoethanamine for ρyridin-2-ylmethanamine H NMR (DMSOd ₆ ) δ 8 35 (d, IH), 7 81 (m, 4H), 7 24 (br d, IH), 4 00 (m, 2H), 3.66 (m, 4H), 3 54 (m, 2H), 3-32 (t, 2H) 3.15 (m, 2H), 1 37 (s, 9H)

EXAMPLE 220

EXAMPLE 161 A (3 02 g) and 4-amino-3-methoxybenzoic acid (2.7 g) were lefluxed in 2,2,2-trifluoioethanol (30 mL) for 24 hours The mixture was cooled and filtered, and the filtrate was washed with methanol and diethyl ether. H NMR (DMSOd ₆ ) δ 10 70 (brs, IH), 8.44 (d, IH), 8.42 (s, IH), 8 37 (d, IH), 7 98 (s, IH), 7 59 (dd, IH), 7.52 (d, IH), 7 19 (d, IH), 3 93 (s, 3H), 1 45 (s, 9H)

EXAMPLE 221

A solution of EXAMPLE 220 (99 mg), HATU (1 19 mg) and diisopropylethyϊamine (0 08 mL) in DMF (1 mL) was stirred at ambient temperature for 0 5 hours N ,N -dimethylcyclohexane-l,4-diamine (44 mg) was added, and the mixture was stirred for 24 hours and concentrated The concentiate was purified by reverse phase HPLC with acetonitrile/water/0.1 % trifluoroacetic acid. ' H NMR (DMSOd ₆ ) δ 10 80

(bis, IH), 9 45 (brs, IH), 8 32 (m, 4H) ₅ 7 50 (m, 2H), 7 18 (br d, IH), 3 93 (d, 3H), 3 18 (m, IH), 2.76 (d, 6H), 2 02 (m, 3H), 1 81 (m, 3H), 1 59 (m, 3H), 1 43 (s, 9H)

EXAMPLE 222 This example was prepaied as described in EXAMPLE 221 by substituting 2- methyl-l-morpholinopropan-2-amine foi N ,N -dimethylcyclohexane-l^-diamine H NMR (DMSOd ₆ ) δ 10 78 (brs, IH), 8 36 (m, 3H), 8 14 (d, IH), 8-06 (d, I H), 7 53 (m, 2H), 7 16 (br d, IH), 3 93 (m, 5H), 3 80 (m, 2H), 3 67 (m, 2H) ₅ 3 48 (m, 2H), 3 20 (m, 2H), 1 50 (S ₅ 6H), 1 44 (s, 9H)

EXAMPLE 223

This example was prepared as described in EXAMPLE 221 by substituting 1- ethyIpiperidin-3 -amine for N ,N -dimethylcyclohexane-l^-diamine H NMR (DMSOd ₆ ) δ 10 82 (bis, IH), 9 58 (bis, IH), 8.46 (m, 2H), 8 38 (m, 2H), 8 10 (brs, IH), 7 52 (m, IH), 7 18 (m, IH), 3 93 (s, 3H), 3.51 (m, 2H), 3 17 (m. 2H), 2 74 (m, 2H), 1 96 (m, 2H), 1.71 (m, 3H), 1 44 (s, 9H) ₅ 1 24 (t, 3H)

EXAMPLE 224

A mixture of EXAMPLE 161A (511 mg) and 4-amino-3- (trifluoromethoxy)benzoic acid (610 mg) in 2,2,2-trifluoroethanoI (20 ml) was refluxed for 24 hours, cooled and chromatographed by reverse phase HPLC with acetonitriIe/water/0.1% trifluoroacetic acid ¹ H NMR (DMSOd ₆ ) δ 10 62 (brs, IH), 9 20 (brs, IH), 8 38 (d, IH), 8 28 (brs, IH), 8 22 (d, IH), 7 91 (dd, IH), 7.84 (m, IH), 7 36 (br d, IH), 1 36 (s, 9H)

EXAMPLE 225

This example was prepared as described in EXAMPLE 221 by substituting EXAMPLE 224 (21 mg) for EXAMPLE 220 and cyclobutylamine (8 mg) for N ¹ JSF ¹ - dimethylcyclohexane-l,4-diamine ¹ H NMR (DMSOd ₆ ) δ 10 61 (brs, IH), 9 17 (s, IH), 8 69 (d, IH), 8 34 (m, 2H), 8 08 (d, IH), 7 90 (m, 2H) ₅ 7 35 (br d, IH) ₅ 4 42 (m, IH), 2 23 (m, 2H), 2 06 (m, 2H), 1 68 (m, 2H) ₅ 1.36 (s, 9H).

EXAMPLE 226A

A mixture of 2 _J 6-dichloro-9H~purine (0 567 g), benzyl bromide (1.03 g) and potassium carbonate (1 38 g) in DMF (10 mL) at ambient temperatuie was stirred overnight and partitioned between ethyl acetate and water The extract was washed with brine and dried (MgSO^, filtered, and concentrated The concentrate was purified by flash chromatography on silica gel with 2:3 ethyl acetate/hex ane H NMR (DMSO-dg) δ 8.86 (s, IH), 7.31-7 37 (m, 5H), 5 51 (s, 2H)

EXAMPLE 226B

A mixture of EXAMPLE 226A (0280 g), 3-amino-4-(teit-butylamino)cyclobut- 3-ene-l,2-dione (0.170 g) and potassium carbonate (0 138 g) in 2-piopanol (10 mL) was heated at reflux for 2 hours, cooled and concentiated The concentrate was partitioned between ethyl acetate and watei, and the extract was separated, washed with biine and dried (MgSO ₄ ), filtered, and concentrated The concentrate was purified by flash chromatography on silica gel with 2:3 ethyl acetate/hexane H NMR (DMSOd ₆ ) 5 11 71 (s, IH), 8 60(s, IH), 8 56 (s, IH), 739-7 39 (m, 5H), 5 44 (s, 2H), 1.47 (s, 9H)

EXAMPLE 226C

A mixture of EXAMPLE 226B (0 082 g), 4-amino-N-cyclobutyl-3- methoxybenzamide (0,049 g), palladium(II) acetate (4,5 mg), 9,9-dimethyl-4,5- bis(diphenyiphosphino)xanthene (17 4 mg) and cesium carbonate (0 078 g) in dioxane (2 mL) was heated under microwave conditions at 150 ⁰ C for 10 minutes The mixture was flash chromatographed on silica gel with 100:1 ethyl acetate/methanoL H NMR (DMSOd ₆ ) δ 11 1 1 (s, IH) ₅ 8 56 (d, J=8 2Hz, IH), 8 48 (d, J=7.3Hz, IH) ₅ 8 38 (s, IH), 8 31 (s ₅ IH), 7 79 (s, IH), 7 49-7.54 (m, 2H), 7 38-7 44 (m, 4H), 7 30-7.33 (m, IH), 5.43 (s, 2H), 4.41-4.44 (m, IH), 3 94 (s, 3H), 2 21-2 25 (m, 2H), 2 06-2 12 (m, 2H), 1 66-1 71 (m, 2H), 1 45 (s, 9H).

EXAMPLE 226D

A mixture of EXAMPLE 226C (45 mg), 10% palladium on carbon (10 mg) and palladium(II) chloride (10 mg) in 37% hydrochloric acid (0.5 mL) and methanol (5 mL) was stirred overnight under 1 atmosphere of hydrogen, filtered and concentrated. The concentrate was purified by leverse phase HPLC on a Ci g column with acetonitrile/water/0.1% trifluoroacetic acid ¹ H NMR (DMSOd ₆ ) δ 1 1 06 (s, IH), 8 61 (d, 1=8 9Hz, IH), 8 47 (d, J=7.7Hz, IH), 8 43 (s, IH), 8 24 (s, IH), 7.76 (s, IH), 7 50- 7 52 (m, 2H), 2 19-2.28 (m, 2H), 2 06-2.1 1 (m, 2H), 1 63-1 72 (m, 2H), 1 47 (s, 9H)

The foregoing is meant to illustrate the invention but not to limit it. Variations and changes obvious to one skilled in the art are intended to be within the scope of the invention as defined in the claims.