BENZODIAZEPINES AS FAK INHIBITORS FOR THE TREATMENT OF

CANCER

FIELD OF THE INVENTION

This invention pertains to compounds which inhibit the activity of focal adhesion kinase (FAK), methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.

BACKGROUND OF THE INVENTION

Tyrosine kinases play a critical role in signal transduction for several cellular functions including cell proliferation, carcinogenesis, apoptosis, and cell differentiation. Inhibitors of these enzymes are useful for the treatment or prevention of proliferative diseases which are dependent of these enzymes.

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase involved in integrin-mediated signal transduction pathways. FAK co-localizes with integrins in focal contact sites. FAK activation and its tyrosine phosphorylation have been shown in many cell types to be dependent on integrins binding to their extracellular ligands. Results from several studies support the hypothesis that FAK inhibitors could be useful in cancer treatment. For example, FAK-deficient cells migrate poorly in response to chemotactic signals and over-expression of C-terminal domain of FAK blocks cell spreading as well as chemotactic migration (Sieg et al, J. Cell Science, 1999, 1 12, 2677-2691 ; Richardson A. and Parsons T., Cell, 1997, 97, 221 -231 ). In addition, studies have demonstrated that an increase in FAK mRNA levels accompanied invasive transformation of tumors and attenuation of the expression of FAK (through the use of antisense oligonucleotides) induces apoptosis in tumor cells (Xu et al, Cell Growth Differ. 1996, 4, 413-418). FAK has been reported to be over-expressed in prostate, breast, thyroid, colon and lung cancers. The level of expression of FAK is directly correlated with tumors demonstrating the most aggressive phenorype.

Accordingly, a need exists for additional selective inhibitors of certain receptor and non-receptor tyrosine kinases, useful in the treatment of abnormal cell growth, such as cancer. The present invention provides novel pyrrolopyrimidines that are selective inhibitors of focal adhesion kinase. Such compounds can be used to treat subjects suffering from cancer, and can further expand the range of treatment options available for such subjects.

SUMMARY OF THE INVENTION

One embodiment of this invention, therefore, pertains to compounds or therapeutically acceptable salts, prodrugs or salts of prodrugs thereof, which are useful as inhibitors of focal adhesion kinase (FA ), the compounds having Formula (I)

wherein

X is CR ^10A or N;

A is NR ⁿ S0 ₂ R ^{, 2} or S0 ₂ NR ⁿ R ¹² ;

R ^{1 1} is hydrogen or alkyl;

R ¹² is alkyl, alkenyl, alkynyl, or R ^{1 A} ; wherein the alkyl, alkenyl, or alkynyl are unsubstituted or substituted with one or more F, CI, Br, or I;

R ^12A is cycloalkyl;

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , and R ^I0A are independently selected from the group consisting of hydrogen, R ¹³ , OR ¹³ , SR ¹³ , S(0)R ¹³ , S0 ₂ R ¹³ , C(0)R ¹³ , CO(0)R ¹³ , OC(0)R ¹³ , OC(0)OR ¹³ , NH ₂ , NHR ¹³ , N(R ^{, 3} ) ₂ , NHC(0)R ¹³ , NR ¹³ C(0)R ¹³ , NHS(0) ₂ R ¹³ , NR ¹³ S(0) ₂ R ¹³ , NHC(0)OR ¹³ , NR ¹³ C(0)OR ¹³ , NHC(0)NH ₂ , NHC(0)NHR ¹³ ,

NHC(0)N(R ^{l 3} ) ₂ , NR ¹³ C(0)NHR ¹³ , NR ^l C(0)N(R ¹³ ) ₂ , C(0)NH ₂ , C(0)NHR ¹³ ,

C(0)N(R ^l3 ) ₂ , C(0)NHOH, C(0)NHOR ¹³ , C(0)NHS0 ₂ R ¹³ , C(0)NR ^l3 S0 ₂ R ¹³ , S0 ₂ NH ₂ , S0 ₂ NHR ¹³ , S0 ₂ N(R ^{l 3} ) ₂ , C(0)H, C(0)OH, C(N)NH ₂ , C(N)NHR ¹³ , C(N)N(R ^{I 3} ) ₂ , CNOH, CNOCH3, OH, (O), CN, N ₃ , N0 ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, CI, Br and I;

each R ¹³ is independently R ¹⁴ , R ¹⁵ , R ¹⁶ , or R ¹⁷ ;

R ¹⁴ is aryl;

R ¹⁵ is heteroaryl; R ¹⁶ is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;

17

R is alkyl, alkenyl, or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R ¹⁸ , OR ¹⁸ , SR ¹⁸ , S(0)R ¹⁸ , S0 ₂ R ¹⁸ , C(0)R ¹⁸ , CO(0)R ¹⁸ , OC(0)R ¹⁸ , OC(0)OR ¹⁸ , NH ₂ , NHR ¹⁸ , N(R ¹⁸ ) ₂ , NHC(0)R ¹⁸ , NR ¹⁸ C(0)R ¹⁸ , NHS(0) ₂ R ¹⁸ , NR ¹⁸ S(0) ₂ R ¹⁸ , NHC(0)OR ¹⁸ , NR ¹⁸ C(0)OR ¹⁸ ,

NHC(0)NH ₂ , NHC(0)NHR ¹⁸ , NHC(0)N(R ¹⁸ ) ₂ , NR ¹⁸ C(0)NHR ¹⁸ , NR ^{l 8} C(0)N(R ¹⁸ ) ₂ , C(0)NH ₂ , C(0)NH ¹⁸ , C(0)N(R ¹⁸ ) ₂ , C(0)NHOH, C(0)NHOR ¹⁸ , C(0)NHS0 ₂ R ¹⁸ , C(0)NR ¹⁸ S0 ₂ R ¹⁸ , S0 ₂ NH ₂ , S0 ₂ NHR ¹⁸ , S0 ₂ N(R ¹⁸ ) ₂ , C(0)H, C(0)OH, C(N)NH ₂ , C(N)NHR ¹⁸ , C(N)N(R ¹⁸ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , N0 ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, CI, Br, or I;

each R ¹⁸ is independently R ¹⁹ , R ²⁰ , R ²¹ or R ²² ;

R ¹⁹ is aryl;

R ²⁰ is heteroaryl;

21

R is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;

22

R is alkyl, alkenyl or alkenyl, each of which is unsubstituted or substituted with one or two or three of independently selected R ²³ , OR ²³ , SR ²³ , S(0)R ²³ , S0 ₂ R ²³ , C(0)R ²³ , CO(0)R ²³ , OC(0)R ²³ , OC(0)OR ²³ , NH ₂ , NHR ²³ , N(R ²³ ) ₂ , NHC(0)R ²³ , NR ²³ C(0)R ²³ , NHS(0) ₂ R ²³ , NR ³ S(0) ₂ R ²³ , NHC(0)OR ²³ , NR ²³ C(0)OR ²³ ,

NHC(0)NH ₂ , NHC(0)NHR ²³ , NHC(0)N(R ²³ ) ₂ , NR ²³ C(0)NHR ²³ , NR ²³ C(0)N(R ²³ ) ₂ , C(0)NH ₂ , C(0)NHR ²³ , C(0)N(R ²³ ) ₂ , C(0)NHOH, C(0)NHOR ²³ , C(0)NHS0 ₂ R ²³ , C(0)NR ²³ S0 ₂ R ²³ , S0 ₂ NH ₂ , S0 ₂ NHR ²³ , S0 ₂ N(R ²³ ) ₂ , C(0)H, C(0)OH, C(N)NH ₂ , C(N)NHR ²³ , C(N)N(R ²³ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , N0 ₂ , CF ₃ , CF ₂ CF ₃ ,

OCF3, OCF ₂ CF ₃ , F, CI, Br or I substituents;

23

eeaacchh RR iiss iinnddeeppeennddeennttllyy aallkkyyll,, aallkkeenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;

wherein the moieties represented by R ¹⁴ , R ¹⁵ , R ¹⁶ , R ^18A , R ¹⁹ , R ²⁰ , and R ²¹ are independently unsubstituted or substituted with one or two or three or four of independently selected R ²⁴ , OR ²⁴ , SR ²⁴ , S(0)R ²⁴ , S0 ₂ R ²⁴ , C(0)R ²⁴ , CO(0)R ²⁴ , OC(0)R ²⁴ , OC(0)OR ²⁴ , NH ₂ , NHR ²⁴ , N(R ²⁴ ) ₂ , NHC(0)R ²⁴ , NR ²⁴ C(0)R ²⁴ ,

NHS(0) ₂ R ²⁴ , NR ²⁴ S(0) ₂ R ²⁴ , NHC(0)OR ²⁴ , NR ²⁴ C(0)OR ²⁴ , NHC(0)NH ₂ ,

NHC(0)NHR ²⁴ , NHC(0)N(R ²⁴ ) ₂ , NR ²⁴ C(0)NHR ²⁴ , NR ²⁴ C(0)N(R ²⁴ ) ₂ , C(0)NH ₂ , C(0)NHR ²⁴ , C(0)N(R ²⁴ ) ₂ , C(0)NHOH, C(0)NHOR ²⁴ , C(0)NHS0 ₂ R ²⁴ ,

C(0)NR ²⁴ S0 ₂ R ²⁴ , S0 ₂ NH ₂ , S0 ₂ NHR ²⁴ , S0 ₂ N(R ²⁴ ) ₂ , C(0)H, C(0)OH, C(N)NH ₂ , C(N)NHR ²⁴ , C(N)N(R ²⁴ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , N0 ₂ , CF ₃ , CF ₂ CF ₃ , OCF3, OCF ₂ CF ₃ , F, CI, Br or I;

each R ²⁴ is independently R ²⁵ , R ²⁶ , R ²⁷ or R ²⁸ ;

25

R is aryl;

R ²⁶ is heteroaryl;

27

R is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;

28

R is alkyl, alkenyl or alkenyl, each of which is unsubstituted or substituted with one or two or three of independently selected R ²⁹ , OR ²⁹ , SR ²⁹ , S(0)R ²⁹ , S0 ₂ R ²⁹ , C(0)R ²⁹ , CO(0)R ²⁹ , OC(0)R ²⁹ , OC(0)OR ²⁹ , NH ₂ , NHR ²⁹ , N(R ²⁹ ) ₂ , NHC(0)R ²⁹ , NR ²⁹ C(0)R ²⁹ , NHS(0) ₂ R ²⁹ , NR ²⁹ S(0) ₂ R ²⁹ , NHC(0)OR ²⁹ , NR ²⁹ C(0)OR ²⁹ ,

NHC(0)NH ₂ , NHC(0)NHR ²⁹ , NHC(0)N(R ²⁹ ) ₂ , NR ²⁹ C(0)NHR ²⁹ , NR ²⁹ C(0)N(R ²⁹ ) ₂ , C(0)NH ₂ , C(0)NHR ²⁹ , C(0)N(R ²⁹ ) ₂ , C(0)NHOH, C(0)NHOR ²⁹ , C(0)NHS0 ₂ R ²⁹ , C(0)NR ²⁹ S0 ₂ R ²⁹ , S0 ₂ NH ₂ , S0 ₂ NHR ²⁹ , S0 ₂ N(R ²⁹ ) ₂ , C(0)H, C(0)OH, C(N)NH ₂ , C(N)NHR ²⁹ , C(N)N(R ²⁹ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , N0 ₂ , CF ₃ , CF ₂ CF ₃ ,

OCF ₃ , OCF ₂ CF ₃ , F, CI, Br or I;

29

each R is independently alkyl, alkenyl, alkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; and

25 26 27

the moieties represented by R , R , and R independently are unsubstituted or substituted with one or two or three or four of independently selected alkyl, alkenyl, alkynyl, NH ₂ , C(0)NH ₂ , C(0)NHOH, S0 ₂ NH ₂ , CF ₃ , CF ₂ CF ₃ , C(0)H, C(0)OH, C(N)NH ₂ , OH, (O), CN, N ₃ , N0 ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, CI, Br or I. In one embodiment of formula (I), X is CR ^I0A orN; and A isNR"S0 ₂ R ¹² .

In another embodiment of formula (I), X is CR ^,0A orN; A is NR ⁿ S0 ₂ R ¹² ; and R ¹¹ isalkyl.

In another embodiment of formula (I), X is CR ^10A orN; A is NR ⁿ S0 ₂ R ¹² ; R" is alkyl; and R ¹² is alkyl.

In another embodiment of formula (I), X is CR ^I0A or N; A is NR ¹ 'S0 ₂ R ¹² ; R ¹¹ is alkyl; R ¹² is alkyl; and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , and R ^,0A are hydrogen.

In another embodiment of formula (I), X is CR ^10A or N; A is NR ⁿ S0 ₂ R ¹² ; R ¹¹ is alkyl; R ¹² is alkyl; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , and R ^10A are hydrogen.

In another embodiment of formula (I), X is CR ^10A or N; A is NR ⁿ S02R ¹ ; R ¹¹ is alkyl; R ¹² is alkyl; and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ⁹ , R ^!0 , and R ^10A are hydrogen.

Still another embodiment pertains to compounds having Formula (I), which are N-[2-(l l-oxo-10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepin-3- yl)phenyl]methanesulfonamide;

N-methy l-N-[2-( 11 -oxo- 10, 11 -dihydro-5H-dibenzo[b,e][ 1 ,4]diazepin-3- yl)phenyl]methanesulfonamide;

N-[3-(4-methylpiperazin-l-yl)propyl]-3-{2-[(methylsulfonyl)a mino]phenyl}-l 1-oxo- 10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepine-8-carboxamide;

N-methyl-N-[3-(l l-oxo-10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepin-3-yl)pyridin-2- yl]methanesulfonamide;

N-{2-[l l-oxo-8-(3,4,5-trimethoxyphenyl)-10,ll-dihydro-5H-dibenzo[b, e][l,4]diazepin- 3-yl]phenyl} methanesulfonamide;

N-[3-(8-amino-l l-oxo-10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepin-3-yl)pyridin-2-yl]- N-methylmethanesulfonamide;

3-{2-[(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepine-8-carboxamide;

N-methyl-2-( 11 -oxo- 10, 11 -dihydro-5H-dibenzo[b,e][l ,4]diazepin-3- yl)benzenesulfonamide;

N-ethyl-N-[2-(ll-oxo-10,ll-dihydro-5H-dibenzo[b,e][l,4]diaze pin-3- yl)phenyl]methanesulfonamide; N-methyl-N-[4-methyl-2-(l l-oxo-10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepin-3- yl)phenyl]methanesulfonamide;

N-methyl-N-[3-methyl-2-(l l-oxo-10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepin-3- yl)phenyl]methanesulfonamide;

N-(3-{2-[methyl(methylsulfonyl)amino]pyridin-3-yl}- 11 -oxo- 10, 11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-8-yl)acetamide;

N-methy l-N-[5-methy l-2-( 11 -oxo- 10,11 -dihydro-5H-dibenzo[b,e] [ 1 ,4]diazepin-3- yl)phenyl]methanesulforiamide;

tert-butyl 3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-7-ylcarbamate;

N-[3-(4-methylpiperidin-l-yl)propyl]-3-{2-[(methylsulfonyl)a mino]phenyl}-l l-oxo- 10,11 -dihydro-5H-dibenzo[b,e][ 1 ,4]diazepine-8-carboxamide;

N-(l-methylpiperidin-4-yl)-3-{2-[(methylsulfonyl)amino]ph enyl}-l l-oxo-10,11-dihydro- 5H-dibenzo[b,e][l,4]diazepine-8-carboxamide;

N-[3-(2-methylpiperidin-l-yl)propyl]-3-{2-[(methylsulfonyl)a mino]phenyl}-l l-oxo- 10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepine-8-carboxamide;

N-[2-(4-methylpiperazin-l-yl)ethyl]-3-{2-[(methylsulfonyl )amino]phenyl}-l 1-oxo- 10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepine-8-carboxamide;

3-{2-[(methylsulfonyl)amino]phenyl}-l l-oxo-N-(2-pyridin-4-ylethyl)-10,l 1-dihydro- 5H-dibenzo[b,e][l,4]diazepine-8-carboxamide;

N-(2-methoxyethyl)-3-{2-[(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepine-8-carboxamide;

N-(4-hydroxybutyl)-3-{2-[(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepine-8-carboxamide;

N-[3-( 1 H-imidazol- 1 -yl)propy l]-3-{2-[(methy lsulfonyl)amino]phenyl }- 11 -oxo- 10, 11- dihydro-5H-dibenzo[b,e][l,4]diazepine-8-carboxamide;

3-{2-[(methylsulfonyl)amino]phenyl}- -(2-moφholin-4-ylethyl)-l l-oxo-10,11-dihydro- 5H-dibenzo[b,e][l,4]diazepine-8-carboxamide;

3- {2-[(methylsulfonyl)amino]phenyl}- 11 -oxo-N-(pyridin-3-ylmethyl)- 10, 11 -dihydro-5H- dibenzo[b,e][l,4]diazepine-8-carboxamide; 3- {2-[(methy lsulfonyl)amino]phenyl } - 11 -oxo-N-(pyridin-4-y Imethyl)- 10,11 -dihydro-5H- dibenzo[b,e][l,4]diazepine-8-carboxamide;

3-{2-[(methylsulfonyl)amino]phenyl}-N-(3-moφholin-4-ylpr opyl)-l l-oxo-10,11- dihydro-5H-dibenzo[b,e][l,4]diazepine-8-carboxamide;

3-{2-[(methylsulfonyl)amino]phenyl}-l l-oxo-N-(pyridin-2-ylmethyl)-10,l l-dihydro-5H- dibenzo[b,e][l,4]diazepine-8-carboxamide;

3-{2-[(methylsulfonyl)amino]phenyl}-l l-oxo-N-(3-pyrrolidin-l-ylpropyl)-10,l 1- dihydro-5H-dibenzo[b,e][l ,4]diazepine-8-carboxamide;

3- {2-[(methylsulfonyl)amino]phenyl}- 11 -oxo-N-(2-pyridin-3-ylethyl)- 10, 11 -dihydro- 5H-dibenzo[b,e][l,4]diazepine-8-carboxamide;

3-{2-[(methylsulfonyl)amino]phenyl}-l l-oxo-N-(2-pyridin-2-ylethyl)-10,l 1-dihydro- 5 H-d ibenzo[b,e] [ 1 ,4]d iazepine-8-carboxam ide;

3-{2-[(methylsulfonyl)amino]phenyl}-l l-oxo-N-(2-pyrrolidin-l-ylethyl)-10,l 1-dihydro- 5H-dibenzo[b,e][l,4]diazepine-8-carboxamide;

N-[2-(dimethylamino)ethyl]-3-{2-[(methylsulfonyl)amino]pheny l}-l l-oxo-10,11- dihydro-5H-dibenzo[b,e][l,4]diazepine-8-carboxamide;

3-{2-[(methylsulfonyl)amino]phenyl}-l l-oxo-N-[3-(2-oxopyrrolidin-l-yl)propyl]-10,l 1- dihydro-5H-d ibenzo[6,e] [ 1 ,4]diazepine-8-carboxamide;

3-{2-[(methylsulfonyl)amino]phenyl}-l l-oxo-N-(2-piperidin-l-ylethyl)-10,l 1-dihydro- 5H-dibenzo[b,e][l,4]diazepine-8-carboxamide;

N-[2-(lH-imidazol-4-yl)ethyl]-3-{2-[(methylsulfonyl)amino]ph enyl}-l l-oxo-10,11- dihydro-5H-dibenzo[b,e][l,4]diazepine-8-carboxamide;

3-{2-[(methylsulfonyl)amino]phenyl}-l l-oxo-N-(4-pyrrolidin-l-ylbutyl)-10,l 1-dihydro- 5 H-d ibenzo[b,e] [ 1 ,4]d iazepine-8-carboxam ide;

3-{2-[(methylsulfonyl)amino]phenyl}-l l-oxo-N-(tetrahydrofuran-3-ylmethyl)-10,l 1- dihydro-5H-dibenzo[b,e][l,4]diazepine-8-carboxamide;

N-methyl-N-[2-(l l-oxo-10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepin-3- yl)phenyl]ethanesulfonamide;

methyl 3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepine-8-carboxylate; 3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepine-8-carboxylic acid;

N-isopropy!-N-[2-(l l-oxo-10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepin-3- yl)phenyl]methanesulfonamide;

N-butyl-N-[2-( 11 -oxo- 10, 11 -dihydro-5H-dibenzo[b,e][ 1 ,4]diazepin-3- yl)phenyl]methanesulfonamide;

N-[2-( 11 -oxo- 10, 11 -dihydro-5H-dibenzo[b,e][ 1 ,4]diazepin-3-y l)pheny 1]-N- propylmethanesulfonamide;

N-isobutyl-N-[2-(l l-oxo-10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepin-3- yl)phenyl]methanesulfonamide;

3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepine-7-carboxamide;

3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepine-8-carboxamide;

3-{2-[methyl(methylsulfonyl)amino]phenyl}-N-(l-methylpiperid in-4-yI)-l l-oxo-10,11- dihydro-5H-dibenzo[b,e][l,4]diazepine-8-carboxamide;

3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-N-(pyrimidin-4-ylmethyl)-10,l 1- dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide;

3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-N-(4-pyrrolidin-l-ylbutyl)-10,l 1- dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide;

3-{2-[methyl(methylsulfonyl)amino]phenyl}-N-[3-(4-methylpipe ridin-l-yl)propyl]-l 1- oxo-10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide;

3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-N-(tetrahydrofuran-3-ylmethyl)- 10, 11 -dihydro-5H-dibenzo[b,e][ 1 ,4]diazepine-7-carboxamide;

3-{2-[methyl(methylsulfonyl)amino]phenyl}-N-(3-moφholin-4-y lpro yl)-l l-oxo-10,11- dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide;

3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-N-(2-pyridin-2-ylethyl)-10, 11- dihydro-5H-dibenzo[b,e][l ,4]diazepine-7-carboxamide;

3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-N-(2-piperidin-l-ylethyl)-10,l 1- dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide; 3-{2-[methyl(methylsulfonyl)amino]phen l}-l l-oxo-N-(2-pyrrolidin-l-ylethyl)-10,l 1- dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide;

N-[2-(dimethylamino)ethyl]-3-{2-[methyl(methylsulfonyl)am ino]phenyl}-l l-oxo-10,11- dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide;

3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-N-(2-pyridin-4-ylethyl)-10,l 1- dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide;

3-{2-[methyl(methylsulfonyl)arnino]phenyl}-N-[3-(2-methylpip eridin-l-yl)propyI]-l 1- oxo-10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide;

3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-N-(2-pyridin-3-ylethyl)-10,l 1- dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide;

3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-N-(pyridin-3-ylmethyl)-10,l 1- dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide;

N-[2-(lH-imidazol-4-yl)ethyl]-3-{2-[methyl(methylsulfony] )amino]phenyl}-l l-oxo- 10,11 -dihydro-5H-dibenzo[b,e][ 1 ,4]diazepine-7-carboxamide;

3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-N-(3-pyrrolidin-l-ylpropyl)-10,l 1- dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide;

N-[3-(diethy lamino)propyl]-3-{2-[methyl(methylsulfonyl)amino]phenyl }- 11 -oxo- 10, 11 - dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide;

N-[3-(dimethylamino)propyl]-3-{2-[methyl(methylsulfonyl)amin o]phenyl}-l l-oxo- 10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide;

N-[3-(lH-imidazol-l-yl)propyl]-3-{2-[methyl(methylsulfonyl)a mino]phenyl}-l l-oxo- 10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide;

N-(3-methoxypropyl)-3-{2-[methyl(methylsulfonyl)amino]phe nyl}-l l-oxo-10,11- dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide;

3- {2-[methyl(methylsulfony])amino]phenyl} -N-(2-morpholin-4-ylethy 1)- 11 -oxo- 10, 11 - dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide;

N-(3-hydroxypropyl)-3-{2-[methyl(methylsulfonyl)amino]phenyl }-l l-oxo-10,11- dihydro-5H-dibenzo[b,e][l ,4]diazepine-7-carboxamide;

3-{2-[methyI(methyIsuIfonyl)amino]phenyI}-l l-oxo-N-(pyridin-2-ylmethyl)-10,l I- dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide; N-(2-methoxyethyl)-3- {2-[methyl(methy lsulfony l)amino]pheny I } - 11 -oxo- 10,11 -dihydro- 5H-dibenzo[b,e][l,4]diazepine-7-carboxamide;

3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-N-[3-(2-oxopyrrolidin-l-yl)propyl]- 10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide;

N-[2-(diethylamino)ethyl]-3-{2-[methyl(methylsulfonyl)amino] phenyl}-l 1 -oxo- 10,11- dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide;

N-(4-hydroxybutyl)-3-{2-[methyl(methylsulfonyl)amino]phenyl} -l 1 -oxo- 10,11-dihydro- 5H-dibenzo[b,e][l,4]diazepine-7-carboxamide;

3-{2-[methyl(methylsulfonyl)amino]phenyl}-N-[2-(4-methylpipe razin-l-yl)ethyl]-l 1- oxo-10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide;

3-{2-[methyl(methylsulfonyl)amino]phenyl}-N-(l-methylpiperid in-4-yl)-l 1 -oxo- 10,11- dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide;

3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-N-(3-piperidin-l-ylpropyl)-10,l 1- dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide;

3-{2-[methyl(methylsulfonyl)amino]phenyl}-N-[3-(4-methylpipe razin-l-yl)propyl]-l 1- oxo-10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide;

N-methyl-N-{2-[ 11 -oxo-8-(pyrrolidin-l-ylcarbonyl)- 10,11 -dihydro-5H- dibenzo[b,e][l ,4]diazepin-3-yl]phenyl}methanesulfonamide;

N-methyl-N-{2-[l l-oxo-8-(piperidin-l-ylcarbonyl)-10,l l-dihydro-5H- dibenzo[b,e][l,4]diazepin-3-yl]phenyl}methanesulfonamide;

N-(3- {2-[methy l(methylsulfonyl)amino]pheny 1 }- 11 -oxo- 10, 11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-8-yl)acetamide;

3-{2-[methyl(methylsulfonyl)amino]phenyl}-N-[3-(4-methylp iperazin-l-yl)propyl]-l 1- oxo- 10, 11 -dihydro-5H-dibenzo[b,e][l ,4]diazepine-8-carboxamide;

N-methyl-N-(2- { 8-[(4-methylpiperidin- 1 -yl)carbony I]- 11 -oxo- 10,11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-3-yl}phenyl)methanesulfonamide;

N-{2-[8-({4-[2-(dimethylamino)ethyl]piperazin-l-yl}carbonyl) -l 1 -oxo- 10,11-dihydro- 5H-dibenzo[b,e][l,4]diazepin-3-yl]phenyl}-N-methylmethanesul fonamide;

N-[2-(8- { [4-(dimethy lamino)piperidin- 1 -y l]carbonyl } - 11 -oxo- 10,11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-3-yl)phenyl]-N-methylmethanesulfon amide; 3-{2-[methyl(methylsulfonyl)amino]phenyl} - 11 -oxo-N-(2-pyrrolidin- 1 -ylethyl)- 10, II- dihydro-5H-dibenzo[b,e][l,4]diazepine-8-carboxamide;

N-methyl-N-(2-{8-[(3-methylpiperidin-l-yl)carbonyl]-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-3-yl}phenyl)methanesulfonamide;

N-(cyclohexylmethyl)-3-{2-[methyl(methylsulfonyl)amino]ph enyl}-l l-oxo-10,11- dihydro-5H-dibenzo[b,e][l,4]diazepine-8-carboxamide;

3-{2-[rnethyl(methylsulfonyl)amino]phenyl}-N-(4-{[(5-methyl- l,3,4-thiadiazol-2- yl)amino]sulfonyl}phenyl)-l l-oxo-10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepine-8- carboxamide;

3- {2-[methyl(methylsulfonyl)amino]phenyl}- 11 -oxo-N-pyridin-4-yl- 10,11 -dihydro-5H- dibenzo[b,e][l,4]diazepine-8-carboxamide;

N-(2-hydroxyethyl)-3-{2-[methyl(triethylsulfonyl)amino]pheny l}-l l-oxo-10,11-dihydro- 5H-dibenzo[b,e][l,4]diazepine-8-carboxamide;

N-(3-hydroxypropyl)-3-{2-[methyl(methylsulfonyl)amino]phenyl }- 11 -oxo- 10, 11 - dihydro-5H-dibenzo[b,e][l,4]diazepine-8-carboxamide;

3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-N-(pyridin-3-ylmethyl)-10,l 1- dihydro-5H-dibenzo[b,e][l,4]diazepine-8-carboxamide;

3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-N-pyridin-3-yl-10,l l-dihydro-5H- dibenzo[b,e][l,4]diazepine-8-carboxamide;

1 -[(3- {2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-8-yl)carbony]]piperidine-3-carboxa mide;

l-[(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-8-yl)carbonyl]piperidine-4-carboxa mide;

N-methyl-N- {2-[8-(mo holin-4-ylcarbonyl)- 11 -oxo- 10, 11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-3-yl]phenyl}methanesulfonamide;

N-(3-methoxypropyl)-3-{2-[methyl(methylsulfonyl)amino]phenyl }-l l-oxo-10,11- dihydro-5H-dibenzo[b,e][l,4]diazepine-8-carboxamide;

N-methyl-N-(2-{8-[(4-methylpiperazin-l-yl)carbonyl]-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-3-yl}phenyl)methanesulfonamide;

3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-N-[3-(2-oxopyrrolidin-l-yl)propyl]- 10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepine-8-carboxamide; N-(4-hydroxybutyl)-3-{2-[methyl(methylsulfonyl)amino]phenyl} - 1 1 -oxo- 10, 1 1 -dihydro- 5 H-d ibenzo[b,e] [ 1 ,4]d iazepine-8-carboxam ide;

N-methy l-N-(2- { 8-[(2-methy lpiperidin- 1 -yl)carbony 1]- 1 1 -oxo- 10,1 1 -dihydro-5H- dibenzo[b,e][l ,4]diazepin-3-yl}phenyI)methanesulfonamide;

N-(4-methylcyclohexyl)-3- {2-[methy l(methy lsulfony l)amino]pheny 1 } - 1 1 -oxo- 10, 1 1- dihydro-5H-d ibenzo[b,e] [ 1 ,4]d iazepine-8-carboxam ide;

N-methy l-N-[2-(l l-oxo-10,1 l-dihydro-5H-dibenzo[b,e][l ,4]diazepin-3- yl)phenyl]cyclopropanesulfonamide;

N-methyl-N-{2-[ 1 1 -oxo-8-(3,4,5-trimethoxyphenyl)- 10, 1 1 -dihydro-5H- dibenzo[b,e][l ,4]diazepin-3-yl]phenyl} methanesulfonamide;

N-[2-(7-amino- l l-oxo-10,1 l -dihydro-5H-dibenzo[b,e][l ,4]diazepin-3-yl)phenyl]-N- methylmethanesulfonamide;

N-[2-(8-amino- 1 1 -oxo- 10, 1 1 -dihydro-5H-dibenzo[b,e][ 1 ,4]diazepin-3-yl)pheny l]-N- methylmethanesulfonamide;

1 -methyl-N-(3-{2-[methyl(methylsulfonyl)amino]phenyl} - 1 1 -oxo- 10, 1 1 -dihydro-5 H- dibenzo[b,e][l ,4]diazepin-7-yl)piperidine-4-carboxamide;

l -methyl-N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo- 10, 1 l -dihydro-5H- dibenzo[b,e][l ,4]diazepin-8-yl)piperidine-4-carboxamide;

N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l -oxo-10, 1 l -dihydro-5H- dibenzo[b,e][l ,4]diazepin-7-yl)acetamide;

N-methy l-N-[2-(l l-oxo- 10,1 l -dihydro-5H-dibenzo[b,e][l ,4]diazepin-3- yl)phenyl]propane-l-sulfonamide;

N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l -oxo-10, 1 1 -dihydro-5H- dibenzo[b,e][ l ,4]diazepin-8-yl)-4-(2-oxopyrrolidin- l-yl)butanamide;

N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo- 10, 1 1 -dihydro-5H- dibenzo[b,e][l ,4]diazepin-8-yl)-l H-pyrazole-4-carboxamide;

N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l -oxo- 10,1 l-dihydro-5H- dibenzo[b,e][l ,4]diazepin-8-yl)-3-pyridin-2-ylpropanamide;

N-(3-{2-[methyi(methylsulfonyI)amino]phenyl}- l l-oxo- 10, 1 l -dihydro-5H- dibenzo[b,e][l ,4]diazepin-8-yl)- l H-pyrazole-3-carboxamide; 3-methoxy-N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-8-yl)propanamide;

3,4,5-trimethoxy-N-(3-{2-[methyl(methylsulfonyl)amino]phenyl }-l l-oxo-10,11-dihydro- 5H-dibenzo[b,e][l,4]diazepin-8-yl)benzamide;

N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-8-yl)-3-(4-methylpiperazin-l-yl)pr opanamide;

N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-8-yl)-3-(2,3,4-trimethoxyphenyl)pr opanamide;

N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-8-yl)-2-(4-methy]piperazin-l-yI)ac etamide;

N'-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-8-yl)cyclopropane-l,l-dicarboxamid e;

N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-8-yl)-5-oxoprolinamide;

N-(3-{2-[methyl(methylsulfonyl)amino]phenyI}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-8-yl)nicotinamide;

N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-8-yl)pyridine-2-carboxamide;

l-acetyl-N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-8-yl)piperidine-4-carboxamide;

N-(3- {2-[methyl(methylsulfonyl)amino]phenyl}- 11 -oxo- 10, 11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-8-yl)-2-(3,4,5-trimethoxyphenyl)ac etamide;

N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-7-yl)-4-(2-oxopyrrolidin-l-yl)buta namide;

N-(3- {2-[methyl(methylsulfony l)amino]phenyl}- 11 -oxo- 10, 11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-7-yl)-lH-pyrazole-4-carboxamide;

N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-7-yl)-lH-pyrazole-3-carboxamide;

N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-7-yl)-2-pyridin-2-ylacetamide; 3-methoxy-N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-7-yl)propanamide;

3,4,5-trimethoxy-N-(3-{2-[methyl(methylsuifonyl)amino]phenyl }-l l-oxo-10,11-dihydro- 5H-dibenzo[b,e][l,4]diazepin-7-yl)benzamide;

N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-7-yl)-3-(4-methylpiperazin-l-yl)pr opanamide;

N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-7-yl)-2-pyridin-3-ylacetamide;

N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-7-yl)-3-(2,3,4-trimethoxyphenyl)pr opanamide;

N-(3- {2-[methyl(methylsulfonyl)amino]phenyl}- 11 -oxo- 10, 11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-7-yl)-3-pyrrolidin-l-ylpropanamide ;

N-(3- {2-[methyl(methylsulfonyl)amino]phenyl }- 11 -oxo- 10, 11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-7-yl)-2-(4-methylpiperazin-l-yl)ac etamide;

N'-(3-{2-[methyl(methylsulfonyl)amino]phenyl}- 11 -oxo- 10, 11 -dihydro-5H- dibenzo[b,e][l ,4]diazepin-7-yl)cyclopropane- 1 , 1 -dicarboxamide;

N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-7-yl)-lH-pyrrole-2-carboxamide;

N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-7-yl)-5-oxoprolinamide;

N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-7-yl)-3-piperidin-l-ylpropanamide;

N-(3- {2-[methyl(methy lsulfonyl)amino]phenyl}- 11 -oxo- 10, 11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-7-yl)nicotinamide;

N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-7-yl)pyridine-2-carboxamide;

l-acetyl-N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-7-yl)piperidine-4-carboxamide;

N-(3-{2-[methyl(methyIsulfonyI)amino]phenyl}-l I -oxo- 10,1 l-dihydro-5H- dibenzo[b,e] [ 1 ,4]diazepin-7-y l)-2-pyrrolidin- 1 -ylacetamide; N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l 1 -oxo- 10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-7-yl)-2-(3,4,5-trimethoxyphenyl)ac etamide;

N ,N ² -dimethyI-N ^l -(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l 1 -oxo- 10,11-dihydro-

5H-dibenzo[b,e][l,4]diazepin-7-yl)glycinamide;

N-[2-(l l-oxo-10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepin-3- yl)phenyl]ethanesulfonamide;

l,l,l-trifluoro-N-methyl-N-[2-(l l-oxo-10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepin-3- yl)phenyl]methanesulfonamide;

N-methyl-N-[2-(l l-oxo-10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepin-3- yl)phenyl]butane-l-sulfonamide;

N-methyI-N-[2-(l l-oxo-10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepin-3- yl)phenyl]propane-2-sulfonamide;

N,2-dimethyl-N-[2-(l l-oxo-10,1 l-dihydro-5H-dibenzo[b,e][l, 4]diazepin-3- yl)phenyl]propane-l -sulfonamide;

N,N-dimethyl-3-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,11-dihydro- 5H-dibenzo[b,e][l,4]diazepin-7-yl)benzamide; -methyl-N-(2-{7-[4-(mo holin-4- ylmethyl)phenyl]-l l-oxo-10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepin-3- yl}phenyl)methanesulfonamide;N-methyl-N-[2-(7-{4-[(4-methylp iperazin-l- yl)carbonyl]phenyl}-l l-oxo-10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepin-3- yl)phenyl]methanesulfonamide;N,N-dimethyl-4-(3-{2- [methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-7-yl)benzamide;N-[2-(dimethylamino )ethyl]-4-(3-{2- [methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-8-yl)benzamide;N-methyl-N-[2-(7-{3 -[(4-methylpiperazin-l- yl)carbonyl]phenyl}-l l-oxo-10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepin-3- yl)phenyl]methanesulfonamide;N-methyl-N- {2-[7-( 1 -methyl- 1 H-pyrazol-4-yl)- 11 -oxo- 10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepin-3-yl]phenyl}methanesu lfonamide;

N-methyl-N-[2-(8- {3-[(4-methylpiperazin- 1 -yl)carbonyl]phenyl}- 11 -oxo- 10, 11 -dihydro- 5H-dibenzo[b,e][l,4]diazepin-3-yl)phenyl]methanesulfonamide; N-methyl-N-[2-(l 1-oxo- 8-quinolin-3-yl-10,l l-dihydro-5H-dibenzo[b,e][l,4]diazepin-3- yl)phenyl]methanesulfonamide;N-(2-{8-[3-(dimethylamino)pheny l]-l l-oxo-10,11- dihydro-5H-dibenzo[b,e][l,4]dia2epin-3-yl}phenyl)-N-methylme thanesulfonamide;N-{2- [8-(l ,3-benzodioxol-5-yl)- 1 1 -oxo- 10, 1 1 -dihydro-5H-dibenzo[b,e][ 1 ,4]diazepin-3- yl]phenyl}-N-methylmethanesulfonamide;N-methyl-N-(2-{ 1 l-oxo-8-[4- (trifluoromethoxy)phenyl]-10,l l -dihydro-5H-dibenzo[b,e][l ,4]diazepin-3- yl}phenyl)methanesulfonamide; and N-[5-nitro-2-(l l-oxo-10,1 l -dihydro-5H- dibenzo[b,e][l,4]diazepin-3-yl)phenyl]methanesulfonamide; or a pharmaceutically acceptable salt thereof.

Another embodiment pertains to a composition for treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer or spleen cancer, said composition comprising an excipient and a therapeutically effective amount of a compound of Formula (I).

Another embodiment pertains to a method of treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer or spleen cancer in a patient, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula (1).

Another embodiment pertains to a method of treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer or spleen cancer in a patient, said method comprising administering to the patient therapeutically effective amount of the compound of Formula (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.

DETAILED DESCRIPTION OF THE INVENTION

Variable moieties herein are represented by identifiers (capital letters with numerical and/or alphabetical superscripts) and may be specifically embodied.

It is meant to be understood that proper valences are maintained for all moieties and combinations thereof, that monovalent moieties having more than one atom are drawn from left to right and are attached through their left ends, and that divalent moieties are also drawn from left to right.

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

The term "alkenyl" as used herein, means a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3- butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl- l-heptenyl, and 3-decenyl.

The term "alkyl" as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3- dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

The term "alkynyl" as used herein, means a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited to, acetylenyl, 1 -propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

The term "aryl," as used herein, means phenyl, a bicyclic aryl or a tricyclic aryl. The bicyclic aryl is naphthyl, or a phenyl fused to a cycloalkyl, or a phenyl fused to a cycloalkenyl, or a phenyl fused to a monocyclic heteroaryl ring as defined herein, or a phenyl fused to a monocyclic heterocycle as defined herein. The bicyclic aryl of the present invention must be attached to the parent molecular moiety through any available carbon atom contained within the phenyl ring. Representative examples of the bicyclic aryl include, but are not limited to, 2,3-dihydro-l ,4-benzodioxin-5-yl, 2,3-dihydro- l ,4- benzodioxin-6-yl, 3,4-dihydro-2H-l ,5-benzodioxepin-6-yl, dihydroinden l, indenyl, indol-4-yl, naphthyl, dihydronaphthalenyl, and tetrahydronaphthalenyl. The tricyclic aryl is anthracene or phenanthrene, or a bicyclic aryl fused to a cycloalkyl, or a bicyclic aryl fused to a cycloalkenyl, or a bicyclic aryl fused to a phenyl. The tricyclic aryl is attached to the parent molecular moiety through any carbon atom contained within the tricyclic aryl. Representative examples of tricyclic aryl ring include, but are not limited to, azulenyl, dihydroanthracenyl, fluorenyl, and tetrahydrophenanthrenyl.

The term "cycloalkenyl" as used herein, means a monocyclic, bicyclic, tricyclic, spirocyclic, or bridged ring system containing from 3 to 12 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens.

Representative examples of monocyclic ring systems include, but are not limited to, 2- cyclohexen- l-yl, 3-cyclohexen- l -yl, 2,4-cyclohexadien-l-yl and 3-cyclopenten-l-yl.

Bicyclic ring systems are exemplified by a monocyclic cycloalkenyl ring system which is fused to another monocyclic cycloalkyl ring as defined herein, a monocyclic aryl ring as defined herein, a monocyclic heterocycle as defined herein or a monocyclic heteroaryl as defined herein. The bicyclic ring systems of the present invention must be appended to the parent molecular moiety through an available carbon atom within the cycloalkenyl ring. Representative examples of bicyclic ring systems include, but are not limited to, 4,5-dihydro-benzo[l ,2,5]oxadiazole, 3a, 4, 5, 6, 7, 7a-hexahydro- IH-indenyI, 1 , 2, 3, 4, 5, 6-hexahydro-pentalenyl, 1 , 2, 3, 4, 4a, 5, 6, 8a-octahydro-pentalenyl.

The term "cycloalkyl" as used herein, means a monocyclic, bicyclic, tricyclic, spirocyclic, or bridged ring system containing a saturated cyclic hydrocarbon group containing from 3 to 12 carbon atoms. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl groups of the present invention are exemplified by a monocyclic cycloalkyl ring fused to another monocyclic cycloalkyl ring, or a monocyclic cycloalkyl ring fused cycloalkenyl, or a monocyclic cycloalkyl ring fused to a phenyl ring, or a monocyclic cycloalkyl ring fused to a monocyclic heteroaryl ring as defined herein, or a monocyclic cycloalkyl ring fused to a monocyclic heterocycle as defined herein. The bicyclic cycloalkyl ring systems of the present invention must be appended to the parent molecular moiety through an available carbon atom within the monocycloalkyl ring.

The term "heteroaryl," as used herein, means a monocyclic heteroaryl, a bicyclic heteroaryl, or a tricyclic heteroaryl. The monocyclic heteroaryl is a 5 or 6 membered ring containing at least one heteroatom independently selected from O, N, or S. The 5 membered ring contains two double bonds may contain one, two, three or four heteroatoms. The 6 membered ring contains three double bonds may contain one, two, three or four heteroatoms. The 5 or 6 membered heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heteroaryl. Representative examples of monocyclic heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazoly!, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl. The bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a monocyclic aryl ring as defined herein, a monocyclic cycloalkyl ring as defined herein, a monocyclic cycloalkenyl ring as defined herein, another monocyclic heteroaryl or a monocyclic heterocycle ring as defined herein. The bicyclic heteroaryl ring systems of the present invention must be appended to the parent molecular moiety through an available carbon atom within the heteroaryl ring. The bicyclic heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the bicyclic heteroaryl. Representative examples of bicyclic heteroaryl include, but are not limited to, benzofuranyl, benzoxadiazolyl, 1 ,3-benzothiazolyl, benzimidazolyl, benzodioxolyl, benzothiophenyl, chromenyl, cinnolinyl, furopyridine, indolyl, indazolyl, isoindolyl, isoquinolinyl, naphthyridinyl, oxazolopyridine, quinolinyl, thienopyridine and thienopyridinyl.

The term "heterocycle" or "heterocyclic" as used herein, refers to a monocyclic, bicyclic, tricyclic, spirocyclic, or bridged ring system that contains at least one heteroatom. The monocyclic heterocycle is a 3, 4, 5, 6 or 7 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S.

The 3 or 4 membered ring contains 1 heteroatom selected from the group consisting of O, N and S. The 5 membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The 6 or 7 membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S. The monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle. Representative examples of monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1 ,3-dioxanyl, 1 ,3-dioxolanyl, 1,3-dithiolanyl, 1 ,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, isoindoline-l ,3-dione, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl,

thiomorpholinyl, 1 ,1 -dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclic heterocycle of the present invention is defined as a monocyclic heterocycle fused to a phenyl group, a cycloalkylgroup as defined herein, a cycloalkenyl group as defined herein, another monocyclic heterocycle group as defined herein, or a spirocyclic ring wherein one carbon atom of the monocyclic heterocycle is bridged by two ends of an alkylene chain. The bicyclic heterocycle of the present invention is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocyclic ring. Representative examples of bicyclic heterocycle include, but are not limited to, 1,3-benzodioxolyl, 1 ,3-benzodithiolyl, 2,3-dihydro- l,4- benzodioxinyl, 2,3-dihydro- l -benzofuranyl, 2,3-dihydro-l-benzothienyl, 3,4-dihydro- lH- isochromen-4-yl, 2,3-dihydro- lH-indolyl, succinmimidyl, and

1 ,2,3,4-tetrahydroquinolinyl. The tricyclic heterocycle is a bicyclic heterocycle fused to a phenyl, or a bicyclic heterocycle fused to a cycloalkyl, or a bicyclic heterocycle fused to a cycloalkenyl, or a bicyclic heterocycle fused to a monocyclic heterocycle. The tricyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the tricyclic heterocycle. Representative examples of tricyclic heterocycle include, but are not limited to, 2,3,4,4a,9,9a-hexahydro- lH-carbazolyl, 5a,6,7,8,9,9a-hexahydrodibenzo[b,d]furanyl, and 5a,6,7, 8,9,9a- hexahydrodibenzo[b,d]thienyl.

The term "heterocycloalkyl," as used herein, means a monocyclic, bicyclic, tricyclic, spirocyclic, or bridged heterocycle, as defined herein, wherein the 5 membered ring contains zero double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S, and the 6 or 7 membered ring contains zero double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S.

The term "heterocycloalkenyl," as used herein, means a monocyclic, bicyclic, tricyclic, spirocyclic, or bridged heterocycle, as defined herein, wherein the 5 membered ring contains one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S, and the 6 or 7 membered ring contains one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S.

The term "phenyl," as used herein, means a monovalent radical formed by removal of a hydrogen atom from benzene.

The term "spiroalkyl," as used herein, means a spirocyclic cycloalkyl as defined herein.

The term, "spirocyclic," as used herein, means a ring system wherein one atom is common to two different rings.

The term, "bridged," as used herein, means a ring system wherein the rings share at least two common non-adjacent atoms.

The term "NH protecting group," as used herein, means trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, para-nitrobenzylcarbonyl,

ortho-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-amyloxycarbonyl,

tert-butoxycarbonyl, para-methoxy benzyloxycarbonyl, 3,4-dimethoxybenzyl- oxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 2-furfuryl-oxycarbonyl,

diphenylmethoxycarbonyl, 1 ,1 -dimethylpropoxy-carbonyl, isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl, 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl, benzyl, diphenylmethyl, triphenylmethyl, 2-nitrophenylthio, methanesulfonyl, para- toluenesulfonyl, Ν,Ν-dimethylaminomethylene, benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-l-naphthyl-methylene, 3-hydroxy-4- pyridylmethylene, cyclohexylidene, 2-ethoxycarbonylcyclohexylidene,

2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3,3-dimethyl-5-oxycyclo- hexylidene, diphenylphosphoryl, dibenzylphosphoryl, 5-methyI-2-oxo-2H- l ,3-dioxol-4- yl-methyl, trimethylsilyl, triethylsilyl, and triphenylsilyl. The term "C(0)OH protecting group," as used herein, means methyl, ethyl, n-propyl, isopropyl, 1 ,1 -dimethylpropyl, n-butyl, tert-butyl, phenyl, naphthyl, benzyl, diphenylmethyl, triphenylmethyl, para-nitrobenzyl, para-methoxybenzyl, bis(para- methoxyphenyl)methyl, acetylmethyl, benzoylmethyl, para-nitrobenzoylmethyl, para-bromobenzoylmethyl, para-methanesulfonylbenzoylmethyl, 2-tetrahydropyranyl

2- tetrahydrofuranyl, 2,2,2-trichloro-ethyl, 2-(trimethylsilyl)ethyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, phthalimidomethyl, succinimidomethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl,

methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl,

methylthiomethyl, 2-methylthioethyl, phenylthiomethyl, l , l -dimethyl-2-propenyl,

3- methyl-3-butenyl, allyl, trimethylsilyl, triethylsilyl, triisopropylsilyl,

diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, and tert-butylmethoxyphenylsilyl.

The term "OH or SH protecting group," as used herein, means

benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,

4- methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1 , 1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl,

2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,

2-(phenylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphonio)ethoxycarbonyl,

2-furfuryloxycarbonyl, 1 -adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl,

5- benzylthiocarbonyl, 4-ethoxy-l-naphthyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl, benzoyl, methyl, tert-butyl, 2,2,2-trichloroethyl,

2-trimethylsilylethyl, l , l -dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl (phenylmethyl), para-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, triphenylmethyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl,

methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl,

2,2,2-trichloro-ethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, 1 -ethoxyethyl, methanesulfonyl, para-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, and tert-butylmethoxyphenylsilyl.

Compounds

Geometric isomers may exist in the present compounds. Compounds of this invention may contain carbon-carbon double bonds or carbon-nitrogen double bonds in the E or Z configuration, wherein the term "E" represents higher order substituents on opposite sides of the carbon-carbon or carbon-nitrogen double bond and the term "Z" represents higher order substituents on the same side of the carbon-carbon or carbon- nitrogen double bond as determined by the Cahn-Ingold-Prelog Priority Rules. The compounds of this invention may also exist as a mixture of "E" and "Z" isomers.

Substituents around a cycloalkyl or heterocycloalkyl are designated as being of cis or trans configuration. Furthermore, the invention contemplates the various isomers and mixtures thereof resulting from the disposal of substituents around an adamantane ring system. Two substituents around a single ring within an adamantane ring system are designated as being of Z or E relative configuration. For examples, see C. D. Jones, M. Kaselj, R. N. Salvatore, W. J. le Noble J. Org. Chem. 1998, 63, 2758-2760.

Compounds of this invention may contain asymmetrically substituted carbon atoms in the R or S configuration, in which the terms "R" and "S" are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13- 10. Compounds having asymmetrically substituted carbon atoms with equal amounts of R and S configurations are racemic at those carbon atoms. Atoms with an excess of one configuration over the other are assigned the configuration present in the higher amount, 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 includes racemic mixtures, relative and absolute

stereoisomers, and mixtures of relative and absolute stereoisomers.

Compounds of this invention containing NH, C(0)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 hydroxyl, amino or carboxylic acid 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.

Compounds of this invention can exist in an isotopic form containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most abundantly found in nature. Isotopes of atoms such as hydrogen, carbon,

2 3 phosphorous, sulfur fluorine, chlorine, and iodine include, but are not limited to, H, H, ^l C, ³² P, ³⁵ S, ^l8 F, ³⁶ C1, and ^l25 I, respectively. Compounds that contain other isotopes of these and/or other atoms are within the scope of this invention. Compounds containing tritium ( ³ H) and ¹⁴ C radioisotopes are preferred in general for their ease in preparation and detectability for radiolabeled compounds. Isotopically labeled compounds of this invention can be prepared by the general methods well known to persons having ordinary skill in the art. Such isotopically labeled compounds can be conveniently prepared by carrying out the procedures disclosed in the Examples and Schemes herein by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

Suitable groups for A, X, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ in compounds of Formula (I) are independently selected. The described embodiments of the present invention may be combined. Such combination is contemplated and within the scope of the present invention. For example, it is contemplated that embodiments for any of A, X, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ can be combined with embodiments defined for any other of A, X, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ .

One embodiment of this invention, therefore, pertains to compounds or therapeutically acceptable salts, prodrugs or salts of prodrugs thereof, which are inhibitors of focal adhesion kinase (FAK), the compounds having Formula (I)

(I)

wherein

X is CR ^{I UA} or N; A is NR ¹ 'S0 ₂ R ¹² or S0 ₂ NR ⁿ R ¹² ;

R ⁿ is hydrogen or alkyl;

R ¹² is alkyl, alkenyi, alkynyl, or R ^{1 A} ; wherein the alkyl, alkenyi, or alkynyl are unsubstituted or substituted with one or more F, CI, Br, or I;

R ^{1 A} is cycioalkyi;

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , and R ^,0A are independently selected from the group consisting of hydrogen, R ¹³ , OR ¹³ , SR ¹³ , S(0)R ¹³ , S0 ₂ R ¹³ , C(0)R ¹³ , CO(0)R ¹³ , OC(0)R ¹³ , OC(0)OR ¹³ , NH ₂ , NHR ¹³ , N(R ^{, 3} ) ₂ , NHC(0)R ¹³ , NR ¹³ C(0)R ¹³ , NHS(0) ₂ R ¹³ , NR ^{, 3} S(0) ₂ R ¹³ , NHC(0)OR ¹³ , NR ^,3 C(0)OR ¹³ , NHC(0)NH ₂ , NHC(0)NHR ¹³ ,

NHC(0)N(R ^{l 3} ) ₂ , NR ¹³ C(0)NHR ¹³ , NR ^{, 3} C(0)N(R ^,3 ) ₂ , C(0)NH ₂ , C(0)NHR ¹³ ,

C(0)N(R ^{, 3} ) ₂ , C(0)NHOH, C(0)NHOR ¹³ , C(0)NHS0 ₂ R ¹³ , C(0)NR ¹³ S0 ₂ R ¹³ , S0 ₂ NH ₂ , S0 ₂ NHR' ³ , S0 ₂ N(R ^{, 3} ) ₂ , C(0)H, C(0)OH, C(N)NH ₂ , C(N)NHR ¹³ , C(N)N(R ^{I 3} ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , N0 ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, CI, Br and I;

each R ¹³ is independently R ¹⁴ , R ¹⁵ , R ¹⁶ , or R ¹⁷ ;

R ¹⁴ is aryl;

R ¹⁵ is heteroaryi;

R ¹⁶ is cycioalkyi, cycioalkenyl, heterocycioaikyi, or heterocycioalkenyl;

R ¹⁷ is alkyl, alkenyi, or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R , OR , SR , S(0)R , S0 ₂ R , C(0)R ¹⁸ , CO(0)R ¹⁸ , OC(0)R ¹⁸ , OC(0)OR ¹⁸ , NH ₂ , NHR ¹⁸ , N(R ¹⁸ ) ₂ , NHC(0)R ¹⁸ , NR ¹⁸ C(0)R ¹⁸ , NHS(0) ₂ R ¹⁸ , NR ¹⁸ S(0) ₂ R ¹⁸ , NHC(0)OR ¹⁸ , NR ¹⁸ C(0)OR ¹⁸ ,

NHC(0)NH ₂ , NHC(0)NHR ¹⁸ , NHC(0)N(R ^{l 8} ) ₂ , NR ¹⁸ C(0)NHR ¹⁸ , NR ^{l 8} C(0)N(R ¹⁸ ) ₂ , C(0)NH ₂ , C(0)NHR ¹⁸ , C(0)N(R ¹⁸ ) ₂ , C(0)NHOH, C(0)NHOR ¹⁸ , C(0)NHS0 ₂ R ¹⁸ , C(0)NR ¹⁸ S0 ₂ R ¹⁸ , S0 ₂ NH ₂ , S0 ₂ NHR ¹⁸ , S0 ₂ N(R ¹⁸ ) ₂ , C(0)H, C(0)OH, C(N)NH ₂ , C(N)NHR ¹⁸ , C(N)N(R ¹⁸ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , N0 ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , 0CF ₂ CF ₃ , F, CI, Br, or I;

each R ¹⁸ is independently R ¹⁹ , R ²⁰ , R ²¹ or R ²² ;

R ¹⁹ is aryl; R ²⁰ is heteroaryl;

21

R is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;

22

R is alkyl, alkenyl or alkenyl, each of which is unsubstituted or substituted with one or two or three of independently selected R ²³ , OR ²³ , SR ²³ , S(0)R ²³ , S0 ₂ R ²³ , C(0)R ²³ , CO(0)R ²³ , OC(0)R ²³ , OC(0)OR ²³ , NH ₂ , NHR ²³ , N(R ²³ ) ₂ , NHC(0)R ²³ , NR ²³ C(0)R ²³ , NHS(0) ₂ R ²³ , NR ²³ S(0) ₂ R ²³ , NHC(0)OR ²³ , NR ²³ C(0)OR ²³ ,

NHC(0)NH ₂ , NHC(0)NHR ²³ , NHC(0)N(R ²³ ) ₂ , NR ²³ C(0)NHR ²³ , NR ²³ C(0)N(R ²³ ) ₂ , C(0)NH ₂ , C(0)NHR ²³ , C(0)N(R ²³ ) ₂ , C(0)NHOH, C(0)NHOR ²³ , C(0)NHS0 ₂ R ²³ , C(0)NR ²³ S0 ₂ R ²³ , S0 ₂ NH ₂ , S0 ₂ NHR ²³ , S0 ₂ N(R ²³ ) ₂ , C(0)H, C(0)OH, C(N)NH ₂ , C(N)NHR ²³ , C(N)N(R ²³ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , N0 ₂ , CF ₃ , CF ₂ CF ₃ ,

OCF ₃ , OCF2CF3, F, CI, Br or I substituents;

23

each R is independently alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;

wherein the moieties represented by R ¹⁴ , R ¹⁵ , R ¹⁶ , R ^18A , R ¹⁹ , R ²⁰ , and R ²¹ are independently unsubstituted or substituted with one or two or three or four of independently selected R ²⁴ , OR ²⁴ , SR ²⁴ , S(0)R ²⁴ , S0 ₂ R ²⁴ , C(0)R ²⁴ , CO(0)R ²⁴ , OC(0)R ²⁴ , OC(0)OR ²⁴ , NH ₂ , NHR ²⁴ , N(R ²⁴ ) ₂ , NHC(0)R ²⁴ , NR ²⁴ C(0)R ²⁴ ,

NHS(0) ₂ R ²⁴ , NR ²⁴ S(0) ₂ R ²⁴ , NHC(0)OR ²⁴ , NR ²⁴ C(0)OR ²⁴ , NHC(0)NH ₂ ,

NHC(0)NHR ²⁴ , NHC(0)N(R ²⁴ ) ₂ , NR ²⁴ C(0)NHR ²⁴ , NR ⁴ C(0)N(R ²⁴ ) ₂ , C(0)NH ₂ , C(0)NHR ²⁴ , C(0)N(R ²⁴ ) ₂ , C(0)NHOH, C(0)NHOR ²⁴ , C(0)NHS0 ₂ R ²⁴ ,

C(0)NR ²⁴ S0 ₂ R ²⁴ , S0 ₂ NH ₂ , S0 ₂ NHR ²⁴ , S0 ₂ N(R ²⁴ ) ₂ , C(0)H, C(0)OH, C(N)NH ₂ , C(N)NHR ²⁴ , C(N)N(R ²⁴ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , N0 ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF2CF3, F, CI, Br or I;

each R ²⁴ is independently R ²⁵ , R ²⁶ , R ²⁷ or R ²⁸ ;

R ²⁵ is aryl;

R ²⁶ is heteroaryl;

27

R is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; R is alkyl, alkenyl or alkenyl, each of which is unsubstituted or substituted with one or two or three of independently selected R ²⁹ , OR ²⁹ , SR ²⁹ , S(0)R ²⁹ , S0 ₂ R ²⁹ , C(0)R ²⁹ , CO(0)R ²⁹ , OC(0)R ²⁹ , OC(0)OR ²⁹ , NH ₂ , NHR ²⁹ , N(R ²⁹ ) ₂ , NHC(0)R ²⁹ , NR ²⁹ C(0)R ²⁹ , NHS(0) ₂ R ²⁹ , NR ²⁹ S(0) ₂ R ²⁹ , NHC(0)OR ²⁹ , NR ²⁹ C(0)OR ²⁹ ,

NHC(0)NH ₂ , NHC(0)NHR ²⁹ , NHC(0)N(R ²⁹ ) ₂ , NR ²⁹ C(0)NHR ²⁹ , NR ²⁹ C(0)N(R ²⁹ ) ₂ , C(0)NH ₂ , C(0)NHR ²⁹ , C(0)N(R ²⁹ ) ₂ , C(0)NHOH, C(0)NHOR ²⁹ , C(0)NHS0 ₂ R ²⁹ , C(0)NR ²⁹ S0 ₂ R ²⁹ , S0 ₂ NH ₂ , S0 ₂ NHR ²⁹ , S0 ₂ N(R ²⁹ ) ₂ , C(0)H, C(0)OH, C(N)NH ₂ , C(N)NHR ²⁹ , C(N)N(R ²⁹ ) ₂ , CNOH, CNOCH3, OH, (O), CN, N ₃ , N0 ₂ , CF ₃ , CF ₂ CF ₃ ,

OCF ₃ , OCF ₂ CF ₃ , F, CI, Br or I;

29

each R is independently alkyl, alkenyl, alkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; and

25 26 27

the moieties represented by R , R , and R independently are unsubstituted or substituted with one or two or three or four of independently selected alkyl, alkenyl, alkynyl, NH ₂ , C(0)NH ₂ , C(0)NHOH, S0 ₂ NH ₂ , CF ₃ , CF ₂ CF ₃ , C(0)H, C(0)OH, C(N)NH ₂ , OH, (O), CN, N ₃ , N0 ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, CI, Br or I.

In another embodiment of formula (I),

X is CR ^{, 0A} or ;

A is NR ¹ 'S0 ₂ R ¹² or S0 ₂ NR ¹ 'R ¹² ;

R ^{1 1} is hydrogen or alkyl;

R ¹² is alkyl, or R ^,2A ; wherein the alkyl is unsubstituted or substituted with one or more F, CI, Br, or I;

R ^12A is cycloalkyl;

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , and R ^IOA are independently selected from the group consisting of hydrogen, R ¹³ , C(0)R ¹³ , CO(0)R ¹³ , NH ₂ , NHC(0)R ¹³ ,

NHC(0)OR' ³ , C(0)NH ₂ , C(0)NHR ¹³ , C(0)OH, and N0 ₂ ;

each R ¹³ is independently R ¹⁴ , R ¹⁵ , R ¹⁶ , or R ¹⁷ ;

R ¹⁴ is aryl;

R ¹⁵ is heteroaryl; R ¹⁶ is cycloalkyl, or heterocycloalkyl;

17

R is alkyl, which is unsubstituted or substituted with one or two or three of independently selected R ¹⁸ , OR ¹⁸ , NH ₂ , N(R ¹⁸ ) ₂ , C(0)NH ₂ , or OH;

each R ¹⁸ is independently R ¹⁹ , R ²⁰ , R ²¹ or R ²² ;

R is aryl;

R ²⁰ is heteroaryl;

21

R is cycloalkyl, or heterocycloalkyl;

R ²² is alkyl;

wherein the moieties represented by R ¹⁴ , R ¹⁵ , R ¹⁶ , R ^18A , R ¹⁹ , R ²⁰ , and R ²¹ are independently unsubstituted or substituted with one or two or three or four of independently selected R ²⁴ , OR ²⁴ , C(0)R ²⁴ , N(R ²⁴ ) ₂ , C(0)NH ₂ , C(0)NHR ²⁴ ,

C(0)N(R ²⁴ ) ₂ , S0 ₂ NHR ²⁴ , (O), or OCF ₃ ;

each R ²⁴ is independently R ²⁶ , R ²⁷ or R ²⁸ ;

26

R is heteroaryl;

27

R is heterocycloalkyl;

28

R is alkyl, each of which is unsubstituted or substituted with one or two or three

29 29

of independently selected R , or N(R ) ₂ ;

29

each R is independently alkyl, or heterocycloalkyl; and

26 27

the moieties represented by R , and R independently are unsubstituted or substituted with one or two or three or four of independently selected alkyl.

In one embodiment of formula (I), X is CR ^10A . In another embodiment of formula (I), X is N.

In one embodiment of formula (I), A is NR ⁿ S0 ₂ R ¹² . In another embodiment of formula (I), A is S0 ₂ NR ⁿ R ¹² . In another embodiment of formula (I), X is CR ^I0A , and A is NR ⁿ S0 ₂ R ¹² . In another embodiment of formula (I), X is CR ^10A , and A is S0 ₂ NR ⁿ R ¹² . In another embodiment of formula (I), X is N, and A is NR ^U S0 ₂ R ¹² . In another embodiment of formula (I), X is N, and A is S0 ₂ NR ⁿ R ¹² . In one embodiment of formula (I), R is hydrogen. In another embodiment of formula (I), R ^{1 1} is alkyl. In another embodiment of formula (I), X is CR ^{I 0A} , A is

NR ^N S0 ₂ R ¹² , and R ^{1 1} is hydrogen. In another embodiment of formula (I), X is CR ^I0A , A is S02NR" R' ² , and R ^{1 1} is hydrogen. In another embodiment of formula (I), X is N, A is R" S02R ¹² , and R ^{1 1} is hydrogen. In another embodiment of formula (I), X is N, A is S0 ₂ NR" R ¹² , and R ^{1 1} is hydrogen. In another embodiment of formula (I), X is CR ^I0A , A is NR ^{L ,} S0 ₂ R' ² , and R ^U is alkyl. In another embodiment of formula (I), X is CR ^{, 0A} , A is S0 ₂ NR ^U R ¹² , and R ^N is alkyl. In another embodiment of formula (I), X is N, A is NR ^N S02R ¹² , and R ^{1 1} is alkyl. In another embodiment of formula (I), X is N, A is S0 ₂ NR ^N R ¹² , and R ^N is alkyl.

In one embodiment of formula (1), R ¹² is alkyl. In another embodiment of formula (I), R ¹² is alkyl, which is unsubstituted. In another embodiment of formula (I), R ¹² is alkyl, which is substituted with three F. In another embodiment of formula (I), R ¹² is R ^{I 2A} , and R ^12A is cycloalkyl.

In another embodiment of formula (I), X is CR ^{, 0A} , A is R ^N S02R ¹² , R ¹ ' is hydrogen, and R ¹² is alkyl, which is unsubstituted. In another embodiment of formula (I), X is CR ^{I 0A} , A is S02 R ^H R ¹ , R" is hydrogen, and R ¹² is alkyl, which is unsubstituted.

In another embodiment of formula (I), X is N, A is NR ^N S0 ₂ R ¹² , R ^{1 1} is hydrogen, and R ¹² is alkyl, which is unsubstituted. In another embodiment of formula (I), X is N, A is S02 R ^U R ¹² , R" is hydrogen, and R ¹² is alkyl, which is unsubstituted. In another embodiment of formula (I), X is CR ^,0A , A is NR ^N S0 ₂ R ¹² , R ^{1 1} is alkyl, and R ¹² is alkyl, which is unsubstituted. In another embodiment of formula (I), X is CR ^{I 0A} , A is

S02 R ^N R ¹² , R" is alkyl, and R ¹² is alkyl, which is unsubstituted. In another embodiment of formula (I), X is N, A is NR ^N S0 ₂ R ¹² , R ^{1 1} is alkyl, and R ¹² is alkyl, which is unsubstituted. In another embodiment of formula (I), X is N, A is SC^NR ¹ "R ¹² , R ^{1 1} is alkyl, and R ¹² is alkyl, which is unsubstituted.

In another embodiment of formula (I), X is CR ^10A , A is R ^M S02R ¹² , R" is hydrogen, and R ¹² is R ^{I 2A} , and R ^12A is cycloalkyl. In another embodiment of formula (I), X is CR ^{, 0A} , A is S0 ₂ NR ^N R ¹² , R ^{1 1} is hydrogen, and R ¹² is R ^{I 2A} , and R ^12A is cycloalkyl. In another embodiment of formula (I), X is N, A is NR" SC>2R ¹² , R" is hydrogen, and R ¹² is R ^12A , and R ^12A is cycloalkyl. In another embodiment of formula (I), X is N, A is S0 ₂ NR ^u R ¹² , R ^{1 1} is hydrogen, and is R ^I2A , and R ^,2A is cycloalkyl. In another embodiment of formula (I), X is CR ^10A , A is NR ⁿ S0 ₂ R ¹² , R ⁿ is alkyl, and R ¹² is R ^{, A} , and R ^{I A} is cycloalkyl. In another embodiment of formula (I), X is CR ^10A , A is

S0 ₂ NR ^{, ,} R ¹² , R" is alkyl, and R ¹² is R ^{I 2A} , and R ^12A is cycloalkyl. In another embodiment of formula (I), X is N, A is NR ⁿ S0 ₂ R ¹² , R ^{1 1} is alkyl, and R ¹² is R ^{I 2A} , and R ^{I A} is cycloalkyl. In another embodiment of formula (I), X is N, A is S0 ₂ NR ⁿ R ¹² , R ^{1 1} is alkyl, and R ¹² is R ^{I A} , and R ^I2A is cycloalkyl.

In one embodiment of formula (I), R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , and R ^I0A are hydrogen, and X, and A are as described in embodiments herein. In another embodiment of formula (I), R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^,0A are hydrogen, and R ⁵ is selected from the group consisting of R ¹³ , NH ₂ , NHC(0)R ¹³ , NHC(0)OR ¹³ , C(0)NH ₂ , and C(0)NHR ¹³ and X, and A are as described in embodiments herein. In another embodiment of formula (I), R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^I0A are hydrogen, and R ⁵ is selected from the group consisting of NHC(0)R ¹³ and C(0)NHR ¹³ and X, and A are as described in embodiments herein. In another embodiment of formula (I), R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^I0A are hydrogen, and R ⁶ is selected from the group consisting of

R ¹³ , C(0)R ¹³ , CO(0)R ¹³ , NH ₂ , NHC(0)R ¹³ , C(0)NH ₂ , C(0)NHR ¹³ , and C(0)OH and X, and A are as described in embodiments herein. In another embodiment of formula (I), R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^10A are hydrogen, and R ⁶ is selected from the group consisting of NHC(0)R ¹³ , and C(0)NHR ¹³ and X, and A are as described in

embodiments herein.

One embodiment of this invention, therefore, pertains to compounds or therapeutically acceptable salts, prodrugs or salts of prodrugs thereof, which are useful as inhibitors of focal adhesion kinase (FA ), the compounds having Formula (II)

wherein

X is CR ^,0A or N; A is NR"S0 ₂ R ¹² or S0 ₂ NR ^M R ¹² ;

R ^{1 1} is hydrogen or alkyl;

R ¹² is alkyl, alkenyl, alkynyl, or R ^I2A ; wherein the alkyl, alkenyl, or alkynyl are unsubstituted or substituted with one or more F, CI, Br, or I;

R ^{I A} is cycloalkyl;

R ⁵ , R ⁶ , R ⁸ , R ⁹ , R ¹⁰ , and R ^10A are independently selected from the group consisting of hydrogen, R ¹³ , OR ⁿ , SR ¹³ , S(0)R ¹³ , S0 ₂ R ¹³ , C(0)R ¹³ , CO(0)R ¹³ , OC(0)R ¹³ , OC(0)OR ¹³ , NH ₂ , NHR ¹³ , N(R ¹³ ) ₂ , NHC(0)R ¹³ , NR ^l3 C(0)R ¹³ , NHS(0) ₂ R ¹³ ,

NR ^{l 3} S(0) ₂ R ¹³ , NHC(0)OR ¹³ , NR ^l3 C(0)OR ¹³ , NHC(0)NH ₂ , NHC(0)NHR ¹³ ,

NHC(0)N(R ^{l 3} ) ₂ , NR ¹³ C(0)NHR ¹³ , NR ¹³ C(0)N(R ^{, 3} ) ₂ , C(0)NH ₂ , C(0)NHR ¹³ ,

C(0)N(R ^{l 3} ) ₂ , C(0)NHOH, C(0)NHOR ¹³ , C(0)NHS0 ₂ R ¹³ , C(0)NR ^l3 S0 ₂ R ¹³ , S0 ₂ NH ₂ , S0 ₂ NHR ¹³ , S0 ₂ N(R ¹³ ) ₂ , C(0)H, C(0)OH, C(N)NH ₂ , C(N)NHR ¹³ , C(N)N(R ¹³ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , N0 ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, CI, Br or I;

each R ¹³ is independently R ¹⁴ , R ¹⁵ , R ¹⁶ , or R ¹⁷ ;

R ¹⁴ is aryl;

R ¹⁵ is heteroaryl;

R ¹⁶ is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;

17

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 , S(0)R , S0 ₂ R °, C(0)R ¹⁸ , CO(0)R ¹⁸ , OC(0)R ¹⁸ , OC(0)OR ¹⁸ , NH ₂ , NHR ¹⁸ , N(R ¹⁸ ) ₂ , NHC(0)R ¹⁸ , NR ¹⁸ C(0)R ¹⁸ , NHS(0) ₂ R ¹⁸ , NR ¹⁸ S(0) ₂ R ¹⁸ , NHC(0)OR ¹⁸ , NR ¹⁸ C(0)OR ¹⁸ ,

NHC(0)NH ₂ , NHC(0)NHR ¹⁸ , NHC(0)N(R ^{l 8} ) ₂ , NR ¹⁸ C(0) HR ¹⁸ , NR ¹⁸ C(0)N(R ¹⁸ ) ₂ , C(0)NH ₂ , C(0)NH ¹⁸ , C(0)N(R ¹⁸ ) ₂ , C(0)NHOH, C(0)NHOR ¹⁸ , C(0)NHS0 ₂ R ¹⁸ , C(0)NR ¹⁸ S0 ₂ R ¹⁸ , S0 ₂ NH ₂₎ S0 ₂ NHR ¹⁸ , S0 ₂ N(R ^{l 8} ) ₂ , C(0)H, C(0)OH, C(N)NH ₂ , C(N)NHR ¹⁸ , C(N)N(R ^{, 8} ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , N0 ₂ , CF ₃ , CF ₂ CF ₃ , OCF3, OCF2CF3, F, CI, Br, or I;

each R ¹⁸ is independently R ¹⁹ , R ²⁰ , R ²¹ or R ²² ;

R ¹⁹ is aryl; R ²⁰ is heteroaryl;

21

R is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;

22

R is alkyl, alkenyl or alkenyl, each of which is unsubstituted or substituted with one or two or three of independently selected R ²³ , OR ²³ , SR ²³ , S(0)R ²³ , S0 ₂ R ²³ , C(0)R ²³ , CO(0)R ²³ , OC(0)R ²³ , OC(0)OR ²³ , NH ₂ , NHR ²³ , N(R ²³ ) ₂ , NHC(0)R ²³ , NR ²³ C(0)R ²³ , NHS(0) ₂ R ²³ , NR ²³ S(0) ₂ R ²³ , NHC(0)OR ²³ , NR ²³ C(0)OR ²³ ,

NHC(0)NH ₂ , NHC(0)NHR ²³ , NHC(0)N(R ²³ ) ₂ , NR ²³ C(0)NHR ²³ , NR ²³ C(0)N(R ²³ ) ₂ , C(0)NH ₂ , C(0)NH ²³ , C(0)N(R ²³ ) ₂ , C(0)NHOH, C(0)NHOR ²³ , C(0)NHS0 ₂ R ²³ , C(0)NR ²³ S0 ₂ R ²³ , S0 ₂ NH ₂ , S0 ₂ NHR ²³ , S0 ₂ N(R ²³ ) ₂ , C(0)H, C(0)OH, C(N)NH ₂ , C(N)NHR ²³ , C(N)N(R ²³ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , N0 ₂ , CF ₃ , CF ₂ CF ₃ ,

OCF ₃ , OCF ₂ CF ₃ , F, CI, Br or I substituents;

23

each R is independently alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;

wherein the moieties represented by R ¹⁴ , R ¹⁵ , R ¹⁶ , R ^18A , R ¹⁹ , R ²⁰ , and R ²¹ are independently unsubstituted or substituted with one or two or three or four of independently selected R ²⁴ , OR ²⁴ , SR ²⁴ , S(0)R ²⁴ , S0 ₂ R ²⁴ , C(0)R ²⁴ , CO(0)R ²⁴ , OC(0)R ²⁴ , OC(0)OR ²⁴ , NH ₂ , NHR ²⁴ , N(R ²⁴ ) ₂ , NHC(0)R ²⁴ , NR ²⁴ C(0)R ²⁴ ,

NHS(0) ₂ R ²⁴ , NR ² S(0) ₂ R ²⁴ , NHC(0)OR ²⁴ , NR ⁴ C(0)OR ²⁴ , NHC(0)NH ₂ ,

NHC(0)NHR ²⁴ , NHC(0)N(R ²⁴ ) ₂ , NR ²⁴ C(0)NHR ²⁴ , NR ²⁴ C(0)N(R ²⁴ ) ₂ , C(0)NH ₂ , C(0)NHR ²⁴ , C(0)N(R ²⁴ ) ₂ , C(0)NHOH, C(0)NHOR ²⁴ , C(0)NHS0 ₂ R ²⁴ ,

C(0)NR ²⁴ S0 ₂ R ²⁴ , S0 ₂ NH ₂ , S0 ₂ NHR ²⁴ , S0 ₂ N(R ²⁴ ) ₂ , C(0)H, C(0)OH, C(N)NH ₂ , C(N)NHR ²⁴ , C(N)N(R ²⁴ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , N0 ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, CI, Br or I;

each R ²⁴ is independently R ²⁵ , R ²⁶ , R ²⁷ or R ²⁸ ;

R ²⁵ is aryl;

R ²⁶ is heteroaryl;

27

R is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; 28

R is alkyl, aikenyl or aikenyl, each of which is unsubstituted or substituted with

29 29 29 29 29 one or two or three of independently selected R , OR , SR , S(0)R , S0 ₂ R , C(0)R ²⁹ , CO(0)R ²⁹ , OC(0)R ²⁹ , OC(0)OR ²⁹ , NH ₂ , NHR ²⁹ , N(R ²⁹ ) ₂ , NHC(0)R ²⁹ , NR ² C(0)R ²⁹ , NHS(0) ₂ R ²⁹ , NR ²⁹ S(0) ₂ R ²⁹ , NHC(0)OR ²⁹ , NR ⁹ C(0)OR ²⁹ ,

NHC(0)NH ₂ , NHC(0)NHR ²⁹ , NHC(0)N(R ²⁹ ) ₂ , NR ²⁹ C(0)NHR ²⁹ , NR ²⁹ C(0)N(R ²⁹ ) ₂ , C(0)NH ₂ , C(0)NHR ²⁹ , C(0)N(R ²⁹ ) ₂ , C(0)NHOH, C(0)NHOR ²⁹ , C(0)NHS0 ₂ R ²⁹ , C(0)NR ²⁹ S0 ₂ R ²⁹ , S0 ₂ NH ₂ , S0 ₂ NHR ²⁹ , S0 ₂ N(R ²⁹ ) ₂ , C(0)H, C(0)OH, C(N)NH ₂ , C(N)NHR ²⁹ C(N)N(R ²⁹ ) ₂ , CNOH, CNOCH ₃ , OH, (O), CN, N ₃ , N0 ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, CI, Br or I;

29

each R is independently alkyl, aikenyl, aikenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; and

25 26 27

the moieties represented by R , R , and R independently are unsubstituted or substituted with one or two or three or four of independently selected alkyl, aikenyl, alkynyl, NH ₂ , C(0)NH ₂ , C(0)NHOH, S0 ₂ NH ₂ , CF ₃ , CF ₂ CF ₃ , C(0)H, C(0)OH, C(N)NH ₂ , OH, (O), CN, N ₃ , N0 ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, CI, Br or I.

In another embodiment of formula (II),

X is CR ^10A or N;

A is NR" S02R ¹² or SO2 NR ⁿ R ¹² ;

R ¹ ' is hydrogen or alkyl;

R ¹² is alkyl, or R ^I2A ; wherein the alkyl is unsubstituted or substituted with one or more F, CI, Br, or I;

R ^{, 2A} is cycloalkyl;

R ⁵ , R ⁶ , R ⁸ , R ⁹ , R ¹⁰ , and R ^10A are independently selected from the group consisting of hydrogen, R ¹³ , C(0)R ¹³ , CO(0)R ¹³ , NH ₂ , NHC(0)R ¹³ , NHC(0)OR ¹³ , C(0)NH ₂ , C(0)NHR ¹³ , C(0)OH, and N0 ₂ ;

each R ¹³ is independently R ¹⁴ , R ¹⁵ , R ¹⁶ , or R ¹⁷ ;

R ¹ is aryl;

R ¹⁵ is heteroaryl; R ¹⁶ is cycloalkyl, or heterocycloalkyl;

R ^{1 7} is alkyl, which is unsubstituted or substituted with one or two or three of independently selected R ¹⁸ , OR ¹⁸ , NH ₂ , N(R ¹⁸ ) ₂ , C(0)NH ₂ , or OH;

each R ¹⁸ is independently R ¹⁹ , R ²⁰ , R ²¹ or R ²² ;

R ¹⁹ is aryl;

R ²⁰ is heteroaryl;

21

R is cycloalkyl, or heterocycloalkyl;

R ²² is alkyl;

wherein the moieties represented by R ¹⁴ , R ¹⁵ , R ¹⁶ , R ^18A , R ¹⁹ , R ²⁰ , and R ²¹ are independently unsubstituted or substituted with one or two or three or four of independently selected R ²⁴ , OR ²⁴ , C(0)R ²⁴ , N(R ²⁴ ) ₂ , C(0)NH ₂ , C(0)NHR ²⁴ ,

C(0)N(R ²⁴ ) ₂ , S0 ₂ NHR ²⁴ , (O), or OCF ₃ ;

each R ²⁴ is independently R ²⁶ , R ²⁷ or R ²⁸ ;

26

R is heteroaryl;

27

R is heterocycloalkyl;

28

R is alkyl, each of which is unsubstituted or substituted with one or two or three

29 29

of independently selected R , or N(R ) ₂ ;

29

each R is independently alkyl, or heterocycloalkyl; and

26 27

the moieties represented by R , and R independently are unsubstituted or substituted with one or two or three or four of independently selected alkyl.

In one embodiment of formula (II), X is CR ^{I 0A} . In another embodiment of formula (II), X is N.

In one embodiment of formula (II), A is NR ^M S0 ₂ R ¹² . In another embodiment of formula (II), A is S0 ₂ NR ^N R ¹² . In another embodiment of formula (II), X is CR ^10A , and A is NR ⁿ S0 ₂ R ¹² . In another embodiment of formula (II), X is CR ^{, 0A} , and A is

S0 ₂ R" R ⁱ² . In another embodiment of formula (II), X is N, and A is NR ⁿ S0 ₂ R ¹² . In another embodiment of formula (II), X is N, and A is S0 ₂ NR ^N R ¹² . In one embodiment of formula (II), R is hydrogen. In another embodiment of formula (II), R ^{1 1} is alkyl. In another embodiment of formula (II), X is CR ^10A , A is

1000 NR"S0 ₂ R' ² , and R" is hydrogen. In another embodiment of formula (II), X is CR ^10A , A is SO2NR ¹ 'R ¹² , and R ^{1 1} is hydrogen. In another embodiment of formula (II), X is N, A is NR"S02R ¹² , and R ⁿ is hydrogen. In another embodiment of formula (II), X is N, A is S0 ₂ NR ⁿ R ¹² , and R ^{1 1} is hydrogen. In another embodiment of formula (ll), X is CR ^10A , A is NR ⁿ S0 ₂ R ¹ , and R ^{1 1} is alkyl. In another embodiment of formula (II), X is CR ^10A , A is

1005 S0 ₂ NR ^u R ¹² , and R ^{1 1} is alkyl. In another embodiment of formula (II), X is N, A is

NR"S0 ₂ R ¹² , and R ^{1 1} is alkyl. In another embodiment of formula (II), X is N, A is S0 ₂ NR ⁿ R ¹² , and R ^{1 1} is alkyl.

In one embodiment of formula (II), R ¹² is alkyl. In another embodiment of formula (II), R ¹² is alkyl, which is unsubstituted. In another embodiment of formula (II),

1010 R ¹² is alkyl, which is substituted with three F. In another embodiment of formula (II), R ¹² is R ^12A , and R ^12A is cycloalkyl.

In another embodiment of formula (II), X is CR ^I0A , A is NR" S0 ₂ R ^I2 , a ¹¹ is hydrogen, and R ¹² is alkyl, which is unsubstituted. In another embodiment of formula (II), X is CR ^10A , A is S0 ₂ NR ⁿ R ¹² , R ^{1 1} is hydrogen, and R ¹² is alkyl, which is

1015 unsubstituted. In another embodiment of formula (II), X is N, A is NR" S02R ^{1 2} , R" is hydrogen, and R ¹² is alkyl, which is unsubstituted. In another embodiment of formula (II), X is N, A is S0 ₂ NR ⁿ R ¹² , R" is hydrogen, and R ¹² is alkyl, which is unsubstituted. In another embodiment of formula (II), X is CR ^10A , A is NR ⁿ S0 ₂ R ¹² , R ^{1 1} is alkyl, and R ¹² is alkyl, which is unsubstituted. In another embodiment of formula (II), X is CR ^{I 0A} ,

1020 A is S0 ₂ NR ⁿ R ¹² , R" is alkyl, and R ¹² is alkyl, which is unsubstituted. In another

embodiment of formula (II), X is N, A is NR"S0 ₂ R ¹² , R ^{1 1} is alkyl, and R ¹² is alkyl, which is unsubstituted. In another embodiment of formula (II), X is N, A is S02NR ⁿ R ¹² , R ^{1 1} is alkyl, and R ¹² is alkyl, which is unsubstituted.

In another embodiment of formula (I1), X is CR ^{I 0A} , A is NR ^N S02R ¹² , R ⁿ is

1025 hydrogen, and R ¹² is R ^{, A} , and R ^{1 A} is cycloalkyl. In another embodiment of formula (II), X is CR ^10A , A is S0 ₂ NR ⁿ R ¹² , R ^{1 1} is hydrogen, and R ¹² is R ^12A , and R ^{1 A} is cycloalkyl. In another embodiment of formula (II), X is N, A is NR"S0 ₂ R ¹² , R ^{1 1} is hydrogen, and R ¹² is R ^{I 2A} , and R ^{I A} is cycloalkyl. In another embodiment of formula (II), X is N, A is S0 ₂ NR ⁿ R ¹² , R ^{1 1} is hydrogen, and is R ^12A , and R ^12A is cycloalkyl. In

1030 another embodiment of formula (II), X is CR ^10A , A is NR ^M S0 ₂ R ¹² , R ^{1 1} is alkyl, and R' ² is R ^{, 2A} , and R ^12A is cycloalkyl. In another embodiment of formula (II), X is CR ^,0A , A is S0 ₂ NR ⁿ R ¹² , R" is alkyl, and R ¹² is R ^I2A , and R ^I2A is cycloalkyl. In another embodiment of formula (II), X is N, A is NR"S0 ₂ R ¹² , R ⁿ is alkyl, and R ¹² is R ^12A , and R ^12A is cycloalkyl. In another embodiment of formula (II), X is N, A is S0 ₂ NR" R ¹² , R ¹ ' is

1035 alkyl, and R ¹² is R ^12A , and R ^12A is cycloalkyl.

In one embodiment of formula (II), R ⁵ , R ⁶ , R ⁸ , R ⁹ , R ¹⁰ , and R ^,0A are hydrogen; and X and A are as described in embodiments herein. In another embodiment of formula (II), R ⁶ , R ⁸ , R ⁹ , R ¹⁰ , R ^,0A are hydrogen; and R ⁵ is selected from the group consisting of R ¹³ , NH ₂ , NHC(0)R ¹³ , NHC(0)OR ¹³ , C(0)NH ₂ , and C(0)NHR ¹³ ; and X and A are as

1040 described in embodiments herein. In another embodiment of formula (II), R ⁶ , R ⁸ , R ⁹ , R ¹⁰ , R ^10A are hydrogen, and R ⁵ is selected from the group consisting of NHC(0)R ¹³ and C(0)NHR ¹³ ; and X and A are as described in embodiments herein. In another embodiment of formula (II), R ⁵ , R ⁸ , R ⁹ , R ¹⁰ , R ^10A are hydrogen; and R ⁶ is selected from the group consisting of R ¹³ , C(0)R ¹³ , CO(0)R ¹³ , NH ₂ , NHC(0)R ¹³ , C(0)NH¾

1045 C(0)NHR ¹³ , and C(0)OH; and X and A are as described in embodiments herein. In another embodiment of formula (II), R ⁵ , R ⁸ , R ⁹ , R ¹⁰ , R ^I0A are hydrogen; R ⁶ is selected from the group consisting of NHC(0)R ¹³ and C(0)NHR ¹³ ; and X and A are as described in embodiments herein.

Pharmaceutical Compositions, Combination Therapies, Methods of Treatment, and

1050 Administration

Another embodiment comprises pharmaceutical compositions comprising a compound having Formula (I) and an excipient.

Still another embodiment comprises methods of treating cancer in a mammal comprising administering thereto a therapeutically acceptable amount of a compound 1055 having Formula (I).

Still another embodiment pertains to compositions for treating diseases during which focal adhesion kinase is expressed, said compositions comprising an excipient and a therapeutically effective amount of the compound having Formula (I). Still another embodiment pertains to methods of treating disease in a patient 1060 during which focal adhesion kinase is expressed, said methods comprising administering to the patient a therapeutically effective amount of a compound having Formula (I).

Still another embodiment pertains to compositions for treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic 1065 leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin,

melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer or spleen cancer, said compositions comprising an excipient and a therapeutically effective amount of the compound having Formula (I).

1070 Still another embodiment pertains to methods of treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell 1075 lung cancer, prostate cancer, small cell lung cancer or spleen cancer in a patient, said methods comprising administering to the patient a therapeutically effective amount of a compound having Formula (I).

Still another embodiment pertains to compositions for treating diseases during which focal adhesion kinase is expressed, said compositions comprising an excipient and 1080 a therapeutically effective amount of the compound having Formula (I) and a

therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.

Still another embodiment pertains to methods of treating disease in a patient during which focal adhesion kinase is expressed, said methods comprising administering 1085 to the patient a therapeutically effective amount of a compound having Formula (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.

Still another embodiment pertains to compositions for treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic 1090 leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer or spleen cancer, said compositions comprising an excipient and a therapeutically

1095 effective amount of the compound having Formula (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.

Still another embodiment pertains to methods of treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic

1 100 leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin,

melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer or spleen cancer in a patient, said methods comprising administering to the patient a therapeutically effective amount of the compound having Formula (I) and a

1 105 therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.

Metabolites of compounds having Formula (I), produced by in vitro or in vivo metabolic processes, may also have utility for treating diseases associated with focal adhesion kinase.

1 1 10 Certain precursor compounds which may be metabolized in vitro or in vivo to form compounds having Formula (I) may also have utility for treating diseases associated with expression of focal adhesion kinase.

Compounds having Formula (I) may exist as acid addition salts, basic addition salts or zwitterions. Salts of the compounds are prepared during isolation or following

1 1 15 purification of the compounds. Acid addition salts of the compounds are those derived from the reaction of the compounds with an acid. For example, the acetate, adipate, alginate, bicarbonate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate, digluconate, formate, fumarate, glycerophosphate, glutamate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,

1 120 hydroiodide, lactobionate, lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate, picrate, propionate, succinate, tartrate, thiocyanate, trichloroacetic, trifluoroacetic, para-toluenesulfonate, and undecanoate salts of the compounds and prodrugs thereof are contemplated as being embraced by this invention. Basic addition salts of the

1 125 compounds are those derived from the reaction of the compounds with the hydroxide, carbonate or bicarbonate of cations such as lithium, sodium, potassium, calcium, and magnesium.

The compounds having Formula (I) may be administered, for example, bucally, ophthalmically, orally, osmotically, parenterally (intramuscularly, intraperitoneally 1 130 intrasternally, intravenously, subcutaneously), rectally, topically, transdermally or

vaginally.

Therapeutically effective amounts of compounds having Formula (I) depend on the recipient of the treatment, the disorder being treated and the severity thereof, the composition containing the compound, the time of administration, the route of

1 135 administration, the duration of treatment, the compound potency, its rate of clearance and whether or not another drug is co-administered. The amount of a compound of this invention having Formula (I) used to make a composition to be administered daily to a patient 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

1 140 submultiples thereof.

Compounds having Formula (I) may be administered with or without an excipient. Excipients include, for example, encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents,

1 145 humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof.

Excipients for preparation of compositions comprising a compound having Formula (I) to be administered orally in solid dosage form include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1 ,3-butylene glycol,

1 150 carbomers, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil,

hydroxypropylmethyl cellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil,

1 155 potassium phosphate salts, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethyl cellulose, sodium phosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acids, stearyl fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof. Excipients for preparation of compositions comprising a compound of

1 160 this invention having Formula (I) to be administered ophthalmically or orally in liquid dosage forms include, for example, 1 ,3-butylene glycol, castor oil, corn oil, cottonseed oil, ethanol, fatty acid esters of sorbitan, germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethylene glycols, propylene glycol, sesame oil, water and mixtures thereof. Excipients for preparation of compositions comprising a compound of this invention

1 165 having Formula (1) to be administered osmotically include, for example,

chlorofluorohydrocarbons, ethanol, water and mixtures thereof. Excipients for preparation of compositions comprising a compound of this invention having Formula (I) to be administered parenterally include, for example, 1 ,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut

1 1 70 oil, Ringer's solution, safflower oil, sesame oil, soybean oil, U.S. P. or isotonic sodium chloride solution, water and mixtures thereof. Excipients for preparation of compositions comprising a compound of this invention having Formula (I) to be administered rectally or vaginally include, for example, cocoa butter, polyethylene glycol, wax and mixtures thereof.

1 1 75 Compounds having Formula (I) are expected to be useful when used with

alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors, apoptosis promoters (for example, Bcl-xL, Bcl-w and Bfl- 1 ) inhibitors, activators of death receptor pathway, Bcr-Abl kinase inhibitors, BiTE (Bi-Specific T cell Engager) antibodies, antibody drug conjugates, 1 180 biologic response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVDs, leukemia viral oncogene homolog (ErbB2) receptor inhibitors, growth factor inhibitors, heat shock protein (HSP)-90 inhibitors, histone deacetyiase (HDAC) inhibitors, hormonal therapies, immunologicals, inhibitors of inhibitors of apoptosis proteins (IAPs), intercalating antibiotics, kinase inhibitors, kinesin

1 185 inhibitors, Jak2 inhibitors, mammalian target of rapamycin inhibitors, microR A's, mitogen-activated extracellular signal-regulated kinase inhibitors, multivalent binding proteins, non-steroidal anti-inflammatory drugs (NSAIDs), poly ADP (adenosine diphosphate)-ribose polymerase (PARP) inhibitors, platinum chemotherapeutics, pololike kinase (Plk) inhibitors, phosphoinositide-3 kinase (PI3 ) inhibitors, proteosome

1 190 inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors,

etinoids/deltoids plant alkaloids, small inhibitory ribonucleic acids (siRNAs), topoisomerase inhibitors, ubiqutin ligase inhibitors, and the like, and in combination with one or more of these agents .

BiTE antibodies are bi-specific antibodies that direct T-cells to attack cancer cells

1 195 by simultaneously binding the two cells. The T-cell then attacks the target cancer cell.

Examples of BiTE antibodies include adecatumumab (Micromet MT201 ), blinatumomab (Micromet MT103) and the like. Without being limited by theory, one of the mechanisms by which T-cells elicit apoptosis of the target cancer cell is by exocytosis of cytolytic granule components, which include perforin and granzyme B.

1200 SiRNAs are molecules having endogenous RNA bases or chemically modified nucleotides. The modifications do not abolish cellular activity, but rather impart increased stability and/or increased cellular potency. Examples of chemical

modifications include phosphorothioate groups, 2'-deoxynucleotide, 2'-OCH3-containing ribonucleotides, 2'-F-ribonucleotides, 2'-methoxyethyl ribonucleotides, combinations

1205 thereof and the like. The siRNA can have varying lengths (e.g., 10-200 bps) and

structures (e.g., hairpins, single/double strands, bulges, nicks/gaps, mismatches) and are processed in cells to provide active gene silencing. A double-stranded siRNA (dsRNA) can have the same number of nucleotides on each strand (blunt ends) or asymmetric ends (overhangs). The overhang of 1-2 nucleotides can be present on the sense and/or the

1210 antisense strand, as well as present on the 5'- and/ or the 3 -ends of a given strand. Multivalent binding proteins are binding proteins comprising two or more antigen binding sites. Multivalent binding proteins are engineered to have the three or more antigen binding sites and are generally not naturally occurring antibodies. The term "multispecific binding protein" means a binding protein capable of binding two or more

1215 related or unrelated targets. Dual variable domain (DVD) binding proteins are tetravalent or multivalent binding proteins binding proteins comprising two or more antigen binding sites. Such DVDs may be monospecific (i.e., capable of binding one antigen) or multispecific (i.e., capable of binding two or more antigens). DVD binding proteins comprising two heavy chain DVD polypeptides and two light chain DVD polypeptides

1220 are referred to as DVD Ig's. Each half of a DVD Ig comprises a heavy chain DVD

polypeptide, a light chain DVD polypeptide, and two antigen binding sites. Each binding site comprises a heavy chain variable domain and a light chain variable domain with a total of 6 CDRs involved in antigen binding per antigen binding site.

Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone,

1225 bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU), chlorambucil, CLORETAZINE ^® (laromustine, VNP 40101M), cyclophosphamide, decarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, W-2170, lomustine (CCNU), mafosfamide, melphalan, mitobronitol, mitolactol, nimustine, nitrogen mustard N-oxide, ranimustine, temozolomide, thiotepa, TREANDA ^® (bendamustine), treosulfan,

1230 rofosfamide and the like.

Angiogenesis inhibitors include endothelial-specific receptor tyrosine kinase

(Tie-2) inhibitors, epidermal growth factor receptor (EGFR) inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrix metal loproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9 (MMP-9) inhibitors, platelet-derived growth factor receptor

1235 (PDGFR) inhibitors, thrombospondin analogs, vascular endothelial growth factor

receptor tyrosine kinase (VEGFR) inhibitors and the like.

Antimetabolites include ALIMTA ^® (pemetrexed disodium, LY231514, MTA), 5-azacitidine, XELODA ^® (capecitabine), carmofur, LEUSTAT ^® (cladribine), clofarabine, cytarabine, cytarabine ocfosfate, cytosine arabinoside, decitabine, deferoxamine, 1240 doxifluridine, eflornithine, EICAR (5-ethynyl-l-P -D-ribofuranosylimidazole-4- carboxamide), enocitabine, ethnylcytidine, fludarabine, 5-fluorouracil alone or in combination with leucovorin, GEMZAR ^® (gemcitabine), hydroxyurea,

ALKERAN ^® (melphalan), mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolic acid, nelarabine, nolatrexed, ocfosfate, pelitrexoi, pentostatin, raltitrexed,

1245 Ribavirin, triapine, trimetrexate, S- 1 , tiazofurin, tegafur, TS- 1 , vidarabine, UFT and the like.

Antivirals include ritonavir, hydroxychloroquine and the like.

Aurora kinase inhibitors include ABT-348, AZD- 1 152, MLN-8054, VX-680, Aurora A-specific kinase inhibitors, Aurora B-specific kinase inhibitors and pan-Aurora 1250 kinase inhibitors and the like.

Bcl-2 protein inhibitors include AT-101 ((-)gossypol), GENASENSE ^® (G3139 or oblimersen (Bcl-2-targeting antisense oligonucleotide)), IPI-194, IPI-565, N-(4-(4-((4'- ch loro( 1 , 1 '-bipheny l)-2-y l)methy piperazin- 1 -y l)benzoy l)-4-((( 1 R)-3-(dimethy lam ino)- l -((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfona mide) (ABT-737), 1255 N-(4-(4-((2-(4-chloropheny l)-5,5-dimethy 1- 1 -cyclohex- 1 -en- 1 -yl)methy Opiperazin- 1 - yl)benzoyl)-4-(((lR)-3-(mo holin-4-yI)- l-((phenylsulfanyl)methyI)propyl)amino)-3- ((trifluoromethyl)sulfonyl)benzenesulfonamide (ABT-263), GX-070 (obatoclax) and the like.

Bcr-Abl kinase inhibitors include DASATIN1B ^® (B S-354825), GLEEVEC ^® 1260 (imatinib) and the like.

CDK inhibitors include AZD-5438, BMI- 1040, BMS-032, BMS-387, CVT-2584, flavopyridol, GPC-286199, MCS-5A, PD0332991 , PHA-690509, seliciclib (CYC-202, R-roscovitine), ZK-304709 and the like.

COX-2 inhibitors include ABT-963, ARCOXIA ^® (etoricoxib), BEXTRA ^® 1265 (valdecoxib), BMS347070, CELEBREX ^® (celecoxib), COX- 189 (lumiracoxib), CT-3, DERAMAXX ^® (deracoxib), JTE-522, 4-methyl-2-(3,4-dimethylphenyl)-l-(4- sulfamoylphenyl- l H-pyrrole), MK-663 (etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381 , SVT-2016, S-2474, T-614, VIOXX ^® (rofecoxib) and the like.

EGFR inhibitors include ABX-EGF, anti-EGFR immunoliposomes, EGF-vaccine, 1270 EMD-7200, ERBITUX ^® (cetuximab), HR3, IgA antibodies, IRESSA ^® (gefitinib), TARCEVA* (eriotinib or OSl-774), TP-38, EGFR fusion protein, TYKERB (lapatinib) and the like.

ErbB2 receptor inhibitors include CP-724-714, CI- 1033 (canertinib),

HERCEPTIN ^® (trastuzumab), TYKERB ^® (lapatinib), OMNITARG ^® (2C4, petuzumab), 1275 TAK- 165, GW-572016 (ionafarnib), GW-282974, EKB-569, PI-166, dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), anti-HER/2neu bispecific antibody, B7.her2IgG3, AS HER2 trifunctional bispecfic antibodies, mAB AR-209, mAB 2B-1 and the like.

Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid and the like.

1280 HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101 , CNF-1010,

CNF-2024, 1 7-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB ^® (human recombinant antibody to HSP-90), NCS-683664, PU24FC1, PU-3, radicicol, SNX-21 12, STA-9090 VER49009 and the like.

Inhibitors of inhibitors of apoptosis proteins include HGS 1029, GDC-0145, GDC- 1285 0152, LCL- 161 , LBW-242 and the like.

Antibody drug conjugates include anti-CD22-MC-MMAF, anti-CD22-MC- MMAE, anti-CD22-MCC-DM l , CR-01 1 -vcMMAE, PSMA-ADC, MEDI-547, SGN- 19Am SGN-35, SGN-75 and the like

Activators of death receptor pathway include TRAIL, antibodies or other agents 1290 that target TRAIL or death receptors (e.g., DR4 and DR5) such as Apomab,

conatumumab, ETR2-ST01 , GDC0145, (lexatumumab), HGS- 1029, LBY-135, PRO- 1762 and trastuzumab.

Kinesin inhibitors include Eg5 inhibitors such as AZD4877, ARRY-520; CENPE inhibitors such as GSK923295A and the like.

1295 JAK-2 inhibitors include CEP-701 (lesaurtinib), XL019 and I CB018424 and the like.

MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901 , PD-98059 and the like.

mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001 , rapamycin, 1300 temsirolimus, ATP-competitive TORC 1/TORC2 inhibitors, including PI- 103, PP242, PP30, Torin 1 and the like. Non-steroidal anti-inflammatory drugs include AMIGESIC (salsalate),

DOLOBID ^® (diflunisal), MOTRIN ^® (ibuprofen), ORUDIS ^® (ketoprofen), RELAFEN ^® (nabumetone), FELDENE ^® (piroxicam), ibuprofen cream, ALEVE ^® (naproxen) and 1305 NAPROSYN ^® (naproxen), VOLTAREN ^® (diclofenac), INDOCIN ^® (indomethacin), CLINORIL ^® (sulindac), TOLECTIN ^® (tolmetin), LODINE ^® (etodolac), TORADOL ^® (ketorolac), DAYPRO ^® (oxaprozin) and the like.

PDGFR inhibitors include C-451 , CP-673, CP-868596 and the like.

Platinum chemotherapeutics include cisplatin, ELOXATIN ^® (oxaliplatin)

13 10 eptapiatin, lobaplatin, nedaplatin, PARAPLATIN ^® (carbop latin), satraplatin, picoplatin and the like.

Polo-like kinase inhibitors include BI-2536 and the like.

Phosphoinositide-3 kinase (PI3 ) inhibitors include wortmannin, LY294002, XL- 147, CAL-120, ONC-21, AEZS- 127, ETP-45658, PX-866, GDC-0941 , BGT226,

13 15 BEZ235, XL765 and the like.

Thrombospondin analogs include ABT-510, ABT-567, ABT-898, TSP- 1 and the like.

VEGFR inhibitors include AVASTIN ^® (bevacizumab), ABT-869, AEE-788, ANGIOZYME™ (a ribozyme that inhibits angiogenesis (Ribozyme Pharmaceuticals 1320 (Boulder, CO.) and Chiron, (Emeryville, CA)) , axitinib (AG- 13736), AZD-2171 ,

CP-547,632, IM-862, MACUGEN (pegaptamib), NEXAVAR ^® (sorafenib, BAY43- 9006), pazopanib (GW-786034), vatalanib (PTK-787, ZK-222584), SUTENT ^® (sunitinib, SU-1 1248), VEGF trap, ZACTIMA™ (vandetanib, ZD-6474) and the like.

Antibiotics include intercalating antibiotics aclarubicin, actinomycin D,

1325 amrubicin, annamycin, adriamycin, BLENOXANE ^® (bleomycin), daunorubicin,

CAELYX ^® or MYOCET ^® (liposomal doxorubicin), elsamitrucin, epirbucin, glarbuicin, ZAVEDOS ^® (idarubicin), mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin, VALSTAR ^® (valrubicin), zinostatin and the like. 1330 Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin, amonafide, amsacrine, becatecarin, belotecan, BN-80915, CAMPTOSAR ^® (irinotecan

hydrochloride), camptothecin, CARDIOXANE ^® (dexrazoxine), diflomotecan, edotecarin, ELLENCE ^® or PHARMORUBICIN ^® (epirubicin), etoposide, exatecan,

10-hydroxycamptothecin, gimatecan, lurtotecan, mitoxantrone, orathecin, pirarbucin,

1335 pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide, topotecan and the like.

Antibodies include AVASTIN ^® (bevacizumab), CD40-specific antibodies, chTNT- l/B, denosumab, ERBITUX ^® (cetuximab), HUMAX-CD4 ^® (zanolimumab), IGF l R-specific antibodies, lintuzumab, PANOREX ^® (edrecolomab), RENCAREX ^® (WX G250), RITUXAN ^® (rituximab), ticilimumab, trastuzimab, CD20 antibodies types I

1340 and II and the like.

Hormonal therapies include ARI IDEX ^® (anastrozole), AROMASIN ^®

(exemestane), arzoxifene, CASODEX ^® (bicalutamide), CETROTIDE ^® (cetrorelix), degarelix, deslorelin, DESOPAN ^® (trilostane), dexamethasone, DROGENIL ^®

(flutamide), EVISTA ^® (raloxifene), AFEMA™ (fadrozole), FARESTON ^® (toremifene),

1345 FASLODEX ^® (fulvestrant), FEMARA ^® (letrozole), formestane, glucocorticoids,

HECTOROL ^® (doxercalciferol), RENAGEL ^® (sevelamer carbonate), lasofoxifene, leuprolide acetate, MEGACE ^® (megesterol), MIFEPREX ^® (mifepristone),

NILANDRON™ (nilutamide), NOLVADEX ^® (tamoxifen citrate), PLENAXIS™

(abarelix), prednisone, PROPECIA ^® (finasteride), rilostane, SUPREFACT ^® (buserelin),

1350 TRELSTAR ^® (luteinizing hormone releasing hormone (LHRH)), VANTAS ^® (Histrelin implant), VETORYL ^® (trilostane or modrastane), ZOLADEX ^® (fosrelin, goserelin) and the like.

Deltoids and retinoids include seocalcitol (EB 1089, CB 1093), lexacalcitrol (KH 1060), fenretinide, PANRETIN ^® (aliretinoin), ATRAGEN ^® (liposomal tretinoin), 1355 TARGRETI ^® (bexarotene), LGD-1550 and the like.

PARP inhibitors include ABT-888, olaparib, U-59436, AZD-2281, AG-014699, BSI-201 , BGP-15, ΓΝΟ- 1001 , ONO-2231 and the like.

Plant alkaloids include, but are not limited to, vincristine, vinblastine, vindesine, vinorelbine and the like. 1360 Proteasome inhibitors include VELCADE (bortezomib), MG 132, NPI-0052,

PR-171 and the like.

Examples of immunologicals include interferons and other immune-enhancing agents. Interferons include interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma- l a, ACTIMMU E ^® (interferon gamma- lb) or

1365 interferon gamma-nl , combinations thereof and the like. Other agents include

ALFAFERONE ^® ,(IFN-a), BAM-002 (oxidized glutathione), BEROMUN ^®

(tasonermin), BEXXAR ^® (tositumomab), CAMPATH ^® (alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4), decarbazine, denileukin, epratuzumab,

GRANOCYTE ^® (lenograstim), lentinan, leukocyte alpha interferon, imiquimod,

1370 MDX-010 (anti-CTLA-4), melanoma vaccine, mitumomab, molgramostim,

MYLOTARG™ (gemtuzumab ozogamicin), NEUPOGEN ^® (filgrastim), OncoVAC-CL, OVAREX ^® (oregovomab), pemtumomab (Y-muHMFG l ), PROVENGE ^® (sipuleucel-T), sargaramostim, sizofilan, teceleukin, THERACYS ^® (Bacillus Calmette-Guerin), ubenimex, VIRULIZIN ^® (immunotherapeutic, Lorus Pharmaceuticals), Z-100 (Specific

1375 Substance of Maruyama (SSM)), WF- 10 (Tetrachlorodecaoxide (TCDO)),

PROLEU JN ^® (aldesleukin), ZADAXIN ^® (thymalfasin), ZENAPAX ^® (daclizumab), ZEVALIN ^® (90Y-Ibritumomab tiuxetan) and the like.

Biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth or differentiation of

1380 tissue cells to direct them to have anti-tumor activity and include krestin, lentinan,

sizofiran, picibanil PF-3512676 (CpG-8954), ubenimex and the like.

Pyrimidine analogs include cytarabine (ara C or Arabinoside C), cytosine arabinoside, doxifluridine, FLUDARA ^® (fludarabine), 5-FU (5-fluorouracil), floxuridine, GEMZAR ^® (gemcitabine), TOMUDEX ^® (ratitrexed), TROXATYL™ (triacet luridine

1385 troxacitabine) and the like.

Purine analogs include LANVIS ^® (thioguanine) and PURI- ETHOL ^®

(mercaptopurine).

Antimitotic agents include batabulin, epothilone D ( OS-862), N-(2-((4- hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamid e, ixabepilone (BMS 1390 247550), paclitaxel, TAXOTERE (docetaxel), PNU100940 (109881 ), patupilone, XRP-9881 (larotaxel), vinflunine, ZK-EPO (synthetic epothilone) and the like.

Ubiqutin ligase inhibitors include MDM2 inhibitors, such as nutlins, NEDD8 inhibitors such as MLN4924 and the like.

Compounds of this invention can also be used as radiosensitizers that enhance the

1395 efficacy of radiotherapy. Examples of radiotherapy include external beam radiotherapy, teletherapy, brachytherapy and sealed, unsealed source radiotherapy and the like.

Additionally, compounds having Formula (I) may be combined with other chemotherapeutic agents such as ABRAXANE™ (ABI-007), ABT- 100 (farnesyl transferase inhibitor), ADVEXIN ^® (Ad5CMV-p53 vaccine), ALTOCOR ^® or

1400 MEVACOR ^® (lovastatin), AMPLIGEN ^® (poly I:poly C 12U, a synthetic RNA),

APTOSYN ^® (exisulind), AREDIA ^® (pamidronic acid), arglabin, L-asparaginase, atamestane (l-methyl-3, 17-dione-androsta-l ,4-diene), AVAGE ^® (tazarotene), AVE-8062 (combreastatin derivative) BEC2 (mitumomab), cachectin or cachexin (tumor necrosis factor), canvaxin (vaccine), CEAVAC ^® (cancer vaccine), CELEUK ^® (celmoleukin),

1405 CEPLENE ^® (histamine dihydrochloride), CERVARIX ^® (human papillomavirus vaccine), CHOP ^® (C: CYTOXAN ^® (cyclophosphamide); H: ADRIAMYCIN ^®

(hydroxydoxorubicin); O: Vincristine (ONCOVIN ^® ); P: prednisone), CYPAT™

(cyproterone acetate), combrestatin A4P, DAB(389)EGF (catalytic and translocation domains of diphtheria toxin fused via a His-Ala linker to human epidermal growth factor)

1410 or TransMID- 107R™ (diphtheria toxins), dacarbazine, dactinomycin, 5,6- dimethylxanthenone-4-acetic acid (DMXAA), eniluracil, EVIZON™ (squalamine lactate), DIMERICINE ^® (T4N5 liposome lotion), discodermolide, DX-8951 f (exatecan mesylate), enzastaurin, EPO906 (epithilone B), GARDASIL ^® (quadrivalent human papillomavirus (Types 6, 1 1 , 16, 18) recombinant vaccine), GASTRIMMUNE ^® ,

1415 GENASENSE ^® , GM (ganglioside conjugate vaccine), GVAX ^® (prostate cancer

vaccine), halofuginone, histerelin, hydroxycarbamide, ibandronic acid, IGN-101 , IL- 13- PE38, IL- 13-PE38QQR (cintredekin besudotox), IL- 13-pseudomonas exotoxin, interferon-a, interferon-γ, JUNOVAN™ or MEPACT™ (mifamurtide), lonafarnib, 5, 10- methylenetetrahydrofolate, miltefosine (hexadecylphosphocholine), NEOVASTAT ^® (AE-

1420 941 ), NEUTREXIN ^® (trimetrexate glucuronate), NIPENT ^® (pentostatin), ONCONASE ^® (a ribonuclease enzyme), ONCOPHAGE (melanoma vaccine treatment), ONCOVAX (IL-2 Vaccine), ORATHECI ™ (rubitecan), OSIDEM ^® (antibody-based cell drug), OVAREX ^® MAb (murine monoclonal antibody), paclitaxel, PANDIMEX™ (aglycone saponins from ginseng comprising 20(S)protopanaxadiol (aPPD) and

1425 20(S)protopanaxatriol (aPPT)), panitumumab, PANVAC ^® -VF (investigational cancer vaccine), pegaspargase, PEG Interferon A, phenoxodiol, procarbazine, rebimastat, REMOVAB ^® (catumaxomab), REVLIMID ^® (lenalidomide), RSR13 (efaproxiral), SOMATULI E ^® LA (lanreotide), SORIATANE ^® (acitretin), staurosporine

(Streptomyces staurospores), talabostat (PT100), TARGRETTN ^® (bexarotene),

1430 TAXOPREXI ^® (DHA-paclitaxel), TELCYTA ^® (canfosfamide, TLK286), temilifene, TEMODAR ^® (temozolomide), tesmilifene, thalidomide, THERATOPE ^® (STn- LH), thymitaq (2-amino-3,4-dihydro-6-methy)-4-oxo-5-(4-pyridylthio)quinazo line dihydrochloride), TNFERADE™ (adenovector: DNA carrier containing the gene for tumor necrosis factor-a), TRACLEER ^® or ZAVESCA ^® (bosentan), tretinoin (Retin-A),

1435 tetrandrine, TRISENOX ^® (arsenic trioxide), VIRULIZI ^® , ukrain (derivative of

alkaloids from the greater celandine plant), vitaxin (anti-alphavbeta3 antibody), XCYTRIN ^® (motexafin gadolinium), XiNLAY™ (atrasentan), XYOTAX™ (paclitaxel poliglumex), YONDELIS ^® (trabectedin), ZD-6126, ZI ECARD ^® (dexrazoxane), ZOMETA ^® (zolendronic acid), zorubicin and the like.

1440 Data

Procedure used to determine FA Activity

Focal adhesion kinase (recombinant human FAK fragment, amino acids 41 1-686; Millipore cat. no. 14-720) activity was measured using the HTRF assay format (Cisbio HTRF KinEASE-TK kit, cat. no. 62K0PEB). The assay was run in a 20 ul volume, in

1445 384 well plates (Corning 384-well, white, low-volume NSB plate, cat. no. 3673).

Reaction conditions consisted of 4 nM FAK, 50 μΜ ATP, and 0.2 μΜ TK substrate- biotin in a buffer containing 50 mM Tris pH 7.5, 10 mM magnesium chloride, 2 mM manganese chloride, 2.5 mM dithiothreitol, 100 uM sodium orthovanadate, and 0.01 percent bovine serum albumin (BSA). Compound IC50s were measured in 8 point

1450 dilution curves using 3-fold dilutions beginning at a maximum compound concentration of 10 or 1 uM, and resulting in a final DMSO concentration in the assay of no more than 5 percent. The reaction was carried out for 1 hour at room temperature, and terminated with 10 μΐ/well Stop Buffer, consisting of 20 mM HEPES, 240 mM potassium fluoride, 0.05 percent BSA, 0.005 percent Tween 20, 0.025 uM T -StreptXL665, and lxT -Ab- 1455 Cryptate. After a 1.25 hour incubation, the fluorescence was measured on a Perkin Elmer Envision plate reader at 320 nm excitation/620 nm and 665 nm emissions. The ratio of 665/620 was used to calculate specific signal for each well. IC50s were calculated using the standard 4-parameter curve fit model. Results are shown in Table 1 .

Table 1

1460 FA Activity

1577

51

30 0.469 1 12 0.0395

3 1 0.493 1 13 0.03 19

32 0.703 1 14 0.0298

33 0.264 1 15 0.0288

34 0.722 1 16 0.0303

35 0.671 1 17 0.0209

36 0.59 1 18 0.0349

37 0.593 1 19 0.03

38 0.0582 120 0.0235

39 0.0152 121 0.0271

40 0.0667 122 0.0326

41 0.326 123 0.0231

42 0.335 124 0.022

43 0.136 125 0.026

44 1.2 126 0.0154

45 0.0388 127 0.00661

46 0.0333 128 0.00534

47 0.0493 129 0.00675

48 0.0174 130 0.00544

49 0.00678 131 0.00481

50 0.00565 132 0.0305

51 0.00976 133 0.0102

52 0.00836 134 0.0209

53 0.0063 135 0.0285

54 0.00804 136 0.0285

55 0.0067 137 0.028

56 0.00882 138 0.0243

57 0.00363 139 0.0142

58 0.00959 140 0.0271

59 0.00617 141 0.00413

60 0.00601 142 0.0169

61 0.00529 143 0.0173

62 0.00907 144 0.0162

63 0.00866 145 0.0235

64 0.00753 146 0.0303

65 0.00749 147 1 .05

66 0.0054 148 0.821

67 0.0061 1 149 6.44

68 0.00732 150 2.44

69 0.00517 151 6.21

70 0.00855 152 0.0103

71 0.00645 153 0.0106

72 0.00853 154 0.0106

73 0.00564 155 0.0107

74 0.00878 156 0.01 12 75 0.014 157 0.01 19

76 0.00806 158 0.0151

77 0.00868 159 0.0233

78 0.0144 160 0.0399

79 0.0269 161 0.0498

80 0.021 1 162 0.0506

81 0.0416 163 0.121

82 0.0251 164 1.92

Therefore, compounds of the present invention assessed by the above-described assay were found to have FA inhibiting activity.

Involvement of FAK in cancer is described in Sieg et al, J. Cell Science, 1999,

1 12, 2677-2691 ; Richardson A. and Parsons T., Cell, 1997, 97, 221 -231 ; and Xu et al,

1465 Cell Growth Differ. 1996, 4, 413-418.

Schemes and Experimental

The following abbreviations have the meanings indicated. ADDP means l , r-(azodicarbonyl)dipiperidine; AD-mix-β means a mixture of (DHQD) ₂ PHAL, K ₃ Fe(CN) ₆ , K ₂ C0 ₃ , and K ₂ S0 ₄ ; 9-BBN means 9-borabicyclo(3.3.1 )nonane; Boc means

1470 tert-butoxycarbonyl; (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 diisopropylethylamine; DMAP means Ν,Ν-dimethylaminopyridine; DMF means Ν,Ν-dimethylformamide; dmpe means l ,2-bis(dimethyIphosphino)ethane; DMSO means dimethylsulfoxide; dppb means

1475 l ,4-bis(diphenylphosphino)-butane; dppe means l ,2-bis(diphenylphosphino)ethane; dppf means l , l'-bis(diphenylphosphino)ferrocene; dppm means

l , l-bis(diphenylphosphino)methane; EDAGHCl means l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride; Fmoc means fluorenylmethoxycarbonyl; HATU means 0-(7-azabenzotriazol- l-yl)-N,N ^r 'N'-tetramethyluronium hexafluorophosphate; HMPA

1480 means hexamethylphosphoramide; IPA means isopropyl alcohol; MP-BH3 means

macroporous triethylammonium methylpolystyrene cyanoborohydride; TEA means triethylamine; TFA means trifluoroacetic acid; THF means tetrahydrofuran; NCS means N-chlorosuccinimide; NMM means N-methylmorpholine; NMP means

N-methylpyrrolidine; PPli3 means triphenylphosphine.

1485 The following schemes are presented to provide what is believed to be the most useful and readily understood description of procedures and conceptual aspects of this invention. Compounds of this invention may be made by synthetic chemical processes, examples of which are shown herein. 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 1490 be substituted for those specifically mentioned, and that vulnerable moieties may be protected and deprotected, as necessary.

Schemes

1495 As shown in Scheme 1 , a compound of formula (1 ), wherein X ¹ is a halogen or triflate and R ¹ , R ² , and R ³ are as described herein, can be reacted with a compound of formula (2), wherein R ⁴ , R ⁵ , R ⁶ , and R ⁷ are as described herein, and copper powder to provide a compound of formula (3). The reaction is typically performed at an elevated temperature in a solvent such as but not limited to chlorobenzene. Compounds of

1500 formula (6), which are representative of compounds of this invention, can be prepared from compounds of formula (3) and a compound of formula (4) or formula (5), wherein R ⁸ , R ⁹ , R ¹⁰ , X, and A are as described herein, using Suzuki coupling conditions described herein, known to those skilled in the art, and readily available in the literature.

Scheme 2

1505 ^{(14) (15} >

As shown in Scheme 2, compounds of formula (8) wherein X ¹ is a halogen or triflate and R ¹ , R ² , and R ³ are as described herein, can be prepared from compounds of formula (7) by reacting the latter with trimethylsilyldiazomethane in methanol. The reaction is typically performed at room temperature. Compounds of formula (8) can be

1510 reacted with compounds of formula (9), wherein R ⁴ , R ⁶ , and R ⁷ are as described herein, and copper powder to provide compounds of formula (10). The reaction is typically performed at an elevated temperature with a base such as but not limited to potassium carbonate in a solvent such as but not limited to chlorobenzene. Compounds of formula (10) can be heated in the presence of an acid such as but not limited to hydrochloric acid

1515 to provide compounds of formula (1 1 ). A solvent such as but not limited to methanol is typically used, and the reaction is typically performed at an elevated temperature.

Compounds of formula (13) can be prepared by reacting compounds of formula (1 1 ) with compounds of formula (12), wherein R ⁸ , R ⁹ , R ¹⁰ , X, and A are as described herein, using Suzuki coupling conditions described herein, known to those skilled in the art, and

1520 readily available in the literature. Compounds of formula (13) can be reacted with an aqueous base such as but not limited to sodium hydroxide, to provide compounds of formula (14). The reaction is typically performed at room temperature in a solvent such as but not limited to tetrahydrofuran, methanol, or mixtures thereof. Compounds of formula (14) can be coupled with amines of formula NH ₂ R ¹³ or NH(R ^{I 3} ) ₂ , wherein each 1525 R ¹³ is as described herein, using conditions described herein, known to those skilled in the art, and readily available in the literature, to provide compounds of formula ( 15), which are representative of the compounds of this invention.

Scheme 3

1530 As shown in Scheme 3, compounds of formula (16A), wherein R ⁴ , R ⁶ , and R ⁷ are as described herein, can be prepared from compounds of formula (16) by reacting the latter with potassium bis(trimethylsilyl)amide, followed by di-tert-butyl carbonate. The reaction is typically conducted at a reduced temperature in a solvent such as but not limited to tetrahydrofuran. Compounds of formula (16A) can be reacted with compounds 1535 of formula (8), wherein X ¹ is a halogen or triflate, and R ¹ , R ² , and R ³ are as described herein, to provide compounds of formula (17) using Buchwald-Hartwig coupling conditions described herein, known to those skilled in the art, and readily available in the literature. Compounds of formula (18) can be prepared form compounds of formula (17) by reacting the latter with hydrogen in the presence of a catalyst such as but not limited to

1540 Raney-Nickel. The reaction is typically performed under pressure at room temperature in a solvent such as but not limited to tetrahydrofuran, methanol, or mixtures thereof.

Compounds of formula (18) can be reacted with an aqueous base such as but not limited to lithium hydroxide, to provide compounds of formula (19). The reaction is typically performed at room temperature in a solvent such as but not limited to water,

1545 tetrahydrofuran, methanol, or mixtures thereof. Compounds of formula ( 19) can be reacted with a activating group such as but not limited to O-(benzotriazol- l -yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate (TBTU) in the presence of a base such as but not limited to triethylamine to provide compounds of formula (20). The reaction is typically performed at room temperature in a solvent such as but not limited to N,N-

1550 di methyl formamide. Compounds of formula (22) can be prepared by reacting

compounds of formula (20) with compounds of formula (21 ), wherein R ⁸ , R ⁹ , R ¹⁰ , X, and A are as described herein, using Suzuki coupling conditions described herein, known to those skilled in the art, and readily available in the literature. Compounds of formula (22) can be reacted with an acid such as trifluoroacetic acid, in a solvent such as but not

1555 limited to dichloromethane, to provide compounds of formula (23). The reaction is

typically performed in a solvent such as but not limited to dichloromethane. Compounds of formula (14) can be coupled with acids of formula R ¹³ C(0)OH, wherein R ¹³ is as described herein, using conditions described herein, known to those skilled in the art, and readily available in the literature to provide compounds of formula (23), which are

1560 representative of the compounds of this invention.

Scheme 4

As shown in Scheme 4, compounds of formula (24) wherein X ¹ is I, Br or triflate, and R ¹ , R ² , and R ³ are as described herein, can be reacted with compounds of formula

1565 (25), wherein X ² is CI and R ⁴ , R ⁵ , and R ⁷ are as described herein, in the presence of a base such as but not limited to cesium carbonate, to provide compounds of formula (26). The reaction is typically performed at an elevated temperature in a solvent such as but not limited to Ν,Ν-dimethylformamide. Compounds of formula (26) can be converted to compounds of formula (27) by reacting the former with iron under acidic conditions. The

1570 reaction is typically performed at an elevated temperature in a solvent such as but not limited to ethanol, water, or mixtures thereof. Compounds of formula (27) can be reacted with a activating group such as but not limited to 0-(benzotriazol- l-yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate (TBTU) in the presence of a base such as but not limited to N,N-diisopropylethylamine to provide compounds of formula (28). The 1575 reaction is typically performed at room temperature in a solvent such as but not limited to Ν,Ν-dimethylformamide. Compounds of formula (28) can be reacted with a compound of formula (4) or formula (5), wherein R ⁸ , R ⁹ , R ¹⁰ , X, and A are as described herein, using Suzuki coupling conditions described herein, known to those skilled in the art, and readily available in the literature to provide a compound of formula (29). Compounds of

1580 formula (29) can be reacted with a compound of formula (30) or formula (31 ) wherein R ⁶ is an aryl, heteroaryl or a vinyl group using Suzuki coupling conditions described herein, known to those skilled in the art, and readily available in the literature to provide a compound of formula (32), which are representative of the compounds of this invention.

1585 < ³² >

As shown in Scheme 5, compounds of formula (28), wherein X is CI and X is I,

Br or triflate and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and R ⁷ are as described herein; and which can be prepared as described in US 20040254159, can be reacted with a compound of formula

(30) or formula (3 1 ) wherein R ⁶ is an aryl, heteroaryl or a vinyl group using Suzuki

1590 coupling conditions described herein, known to those skilled in the art, and readily

available in the literature, to provide a compound of formula (33). Compounds of formula (33) can be reacted with a compound of formula (4) or formula (5), wherein R ,

R ⁹ , R ¹⁰ , X, and A are as described herein, using Suzuki coupling conditions described herein, known to those skilled in the art, and readily available in the literature to provide 1595 a compound of formula (32), which are representative of the compounds of this invention.

Scheme 6

As shown in Scheme 6, compounds of formula (8), wherein X is a halogen or 1600 triflate and R ¹ , R ² , and R ³ are as described herein, can be reacted with compounds of formula (33), wherein R ⁴ , R ⁵ , R ⁶ , and R ⁷ are as described herein, to provide compounds of formula (34) using Buchwald-Hartwig coupling conditions described herein, known to those skilled in the art, and readily available in the literature. Compounds of formula (35) can be prepared form compounds of formula (34) by reacting the latter with 1605 hydrogen in the presence of a catalyst such as but not limited to Raney-Nickel. The reaction is typically performed under pressure at room temperature in a solvent such as but not limited to tetrahydrofuran, methanol, or mixtures thereof. Compounds of formula (35) can be heated in the presence of an acid such as but not limited to hydrochloric acid to provide compounds of formula (36). A solvent such as but not limited to methanol is

1610 typically used, and the reaction is typically performed at an elevated temperature.

Compounds of formula (36) can be reacted with a compound of formula ( 12), wherein R ⁸ , R ⁹ , R ¹⁰ , X, and A are as described herein, using Suzuki coupling conditions described herein, known to those skilled in the art, and readily available in the literature to provide a compound of formula (37). Compounds of formula (37) can be reacted with an

1615 aqueous base such as but not limited to sodium hydroxide, to provide compounds of formula (38). The reaction is typically performed at room temperature in a solvent such as but not limited to tetrahydrofuran, methanol, or mixtures thereof. Compounds of formula (38) can be coupled with amines of formula NH ₂ R ¹³ or NH(R ^{I 3} )2, wherein each R ¹³ is as described herein, using conditions described herein, known to those skilled in

1620 the art, and readily available in the literature, to provide compounds of formula (39), which are representative of the compounds of this invention.

Scheme 7

Compounds of formula (40), wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and R ⁷ are as described herein, and which can be prepared as described in US20040254159, can be reacted with a compound of formula (41 ), wherein X ¹ is a halogen or triflate and wherein R ⁸ , R ⁹ , R ¹⁰ , X, and A are as described herein, using Suzuki coupling conditions described herein, known to those skilled in the art, and readily available in the literature to provide a compound of formula (42). Compounds of formula (42) can be coupled with acids of formula

1630 R ^l3 C(0)OH, wherein R ¹³ is as described herein, using conditions described herein,

known to those skilled in the art, and readily available in the literature to provide compounds of formula (43), which are representative of the compounds of this invention.

Scheme 8

1635 As shown in Scheme 8, compounds of formula (24) wherein X ¹ is I, Br or triflate and R ¹ , R ² , and R ³ are as described herein, can be reacted with compounds of formula (44), wherein X ² is CI and R ⁴ , R ⁶ , and R ⁷ are as described herein; in the presence of a base such as but not limited to cesium carbonate, to provide compounds of formula (45). The reaction is typically performed at an elevated temperature in a solvent such as but not

1640 limited to Ν,Ν-dimethylformamide. Compounds of formula (45) can be converted to compounds of formula (46) by reacting the former with iron under acidic conditions. The reaction is typically performed at an elevated temperature in a solvent such as but not limited to ethanol, water, or mixtures thereof. Compounds of formula (46) can be reacted with a activating group such as but not limited to 0-(benzotriazol- l-yl)-N,N,N',N'-

1645 tetramethyluronium tetrafluoroborate (TBTU) in the presence of a base such as but not limited to N,N-diisopropylethylamine to provide compounds of formula (47). The reaction is typically performed at room temperature in a solvent such as but not limited to Ν,Ν-dimethyIformamide. Compounds of formula (47) can be reacted with a compound of formula (4) or formula (5), wherein R ⁸ , R ⁹ , R ¹⁰ , X, and A are as described herein,

1650 using Suzuki coupling conditions described herein, known to those skilled in the art, and readily available in the literature to provide a compound of formula (48). Compounds of formula (48) can be reacted with a compound of formula (49) or formula (50) wherein R ⁵ is an aryl, heteroaryl or a vinyl group using Suzuki coupling conditions described herein, known to those skilled in the art, and readily available in the literature to provide a

1655 compound of formula (51 ), which are representative of the compounds of this invention.

Scheme 9

As shown in Scheme 9, compounds of formula (52), wherein X ¹ is I, Br or triflate and X ² is CI and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , and R ⁷ are as described herein,; and which can be 1660 prepared as described in US 20040254159, can be reacted with a compound of formula (4) or formula (5), wherein R ⁸ , R ⁹ , R ¹⁰ , X, and A are as described herein, using Suzuki coupling conditions described herein, known to those skilled in the art, and readily available in the literature, to provide a compound of formula (53). Compounds of formula (53) can be reacted with a compound of formula (49) or formula (50) wherein R ⁵ 1665 is an aryl, heteroaryl or a vinyl group using Suzuki coupling conditions described herein, known to those skilled in the art, and readily available in the literature to provide a compound of formula (54), which are representative of the compounds of this invention. Examples

The following examples are presented to provide what is believed to be the most 1670 useful and readily understood description of procedures and conceptual aspects of this invention. The exemplified compounds were named using ACD/ChemSketch Version 5.06 (05 June 2001 , Advanced Chemistry Development Inc., Toronto, Ontario), or ChemDraw® Ver. 9.0.5 (CambridgeSoft, Cambridge, MA). Intermediates were named using ChemDraw® Ver. 9.0.5 (CambridgeSoft, Cambridge, MA).

1675

Example 1

N-[2-( l l-oxo- 10, 1 l-dihydro-5H-dibenzo[b,e][ l ,4]diazepin-3- yl)phenyl]methanesulfonamide

1680 Example 1 A

3-bromo-5H-dibenzo[b,e][l ,4]diazepin-l l ( 10H)-one

A mixture of 4-bromo-2-chlorobenzoic acid (0.235 g, 1.0 mmol), benzene- 1 ,2- diamine (0.108 g, 1.0 mmol) and copper powder (0.064 g, 1.0 mmol) in chlorobenzene (15 ml) was refluxed at 132°C for 48 hours. The mixture was cooled to room

1685 temperature and concentrated. The crude product was purified by reverse phase HPLC on a customized Waters Purification system, eluting with 10-95% CH ₃ CN / 0.1 % TFA in water to yield the title compound. MS ESI(+) m/z 289.0 [M+H] ⁺

Example I B

1690 N-[2-( l 1-oxo- 10,1 l-dihydro-5H-dibenzo[b,e][l ,4]diazepin-3- yl)phenyl]methanesulfonamide To Example 1A (0.029|g, 0.1 mmol) and N-(2-(4,4,5,5-tetramethyl- 1 ,3,2- dioxaborolan-2-yl)phenyl)methanesulfonamide (0.030 g, 0.10 mmol) in a microwave vial was added ethanol ( 1.0 ml) followed by FibreCat 1032 (0.01 1 g, 5.00 μιηοΙ) and 1M

1695 aqueous 2CO3 (0.1 10 ml, 0.1 10 mmol). The vial was heated in the Biotage Initiator

Microwave Synthesizer at 120°C for 15 minutes. After cooling at room temperature, the reaction mixture was filtered and concentrated. The crude product was purified by reverse phase HPLC on a customized Waters Purification system, eluting with 10-95% CH ₃ CN / 0.1% TFA in water to yield the title compound. Ή NMR (300 MHz, DMSO-d ₆ )

1700 8 ppm 9.85 (s, 1 H), 8.94-8.97 (bs, 1 H), 7.90 (s, 1 H), 7.71 (d, J = 8.0 Hz, 1 H), 7.37-7.48 (m, 2H), 7.28-7.31 (m, 2H), 6.90-7.03 (m, 6H), 2.89 (s, 3H); MS ESI(+) m/z 380 [M+H] ⁺

Example 2

N-methy l-N-[2-( 1 1 -oxo- 10, 1 1 -dihydro-5 H-dibenzo[b,e] [ 1 ,4]diazepin-3-

1705 yl)phenyl]methanesulfonamide

To a cold dispersion of 60% NaH (0.0036 g, 0.150 mmol) in tetrahydrofuran (0.5 ml) was added a cold solution of Example I B (0.038 g, 0.1 mmol) in tetrahydrofuran (0.5 ml) dropwise at 0°C and reaction mixture was stirred at 0°C for 1 hour. Then

iodomethane (0.014 g, 0.1 mmol) in tetrahydrofuran (0.5 ml) was added and mixture was

1710 stirred at 0°C for 4 hours then continued at room temperature for 72 hours. The reaction mixture was filtered and concentrated. The crude product was purified by reverse phase HPLC on a customized Waters Purification system, eluting with 10-95% CH3CN / 0.1 % TFA in water to yield the title compound. Ή NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.84 (s, 1 H), 7.91 (s, 1 H), 7.69 (d, J= 8.1 Hz, 1 H), 7.55-7.58 (m, 1 H), 7.37-7.48 (m, 3H), 6.91 -

1715 7.01 (m, 6H), 3.08 (s, 3H), 2.89 (s, 3H); MS ESI(-) m/z 392 [M-H] ^"

Example 3

N-[3-(4-methylpiperazin- l -yl)propyl]-3-{2-[(methylsulfonyl)amino]phenyl}- l 1 -oxo- 10, 1 1 -dihydro-5H-dibenzo[b,e][ 1 ,4]diazepine-8-carboxamide

1720

Example 3A

methyl 4-chloro-2-iodobenzoate To a solution of 4-chIoro-2-iodobenzoic acid (10.61 g, 37.62 mmol) in methanol (75 ml), trimethylsilyldiazomethane (30 ml, 2.0 M in ether) was added drop by drop. 1725 After 1 hour, another batch of trimethylsilyldiazomethane (26 ml, 2.0 M in ether) was added drop by drop. The reaction mixture was stirred at room temperature overnight and concentrated. The crude product was purified by column chromatography (0-20% ethyl acetate in hexanes) to yield the title compound.

1730

Example 3B

methyl 2-(2-amino-5-(methoxycarbonyl)phenylamino)-4-chlorobenzoate Example 3 A (3.0 g, 10.12 mmol), methyl-3,4-diaminobenzoate (3.39 g, 10.12 mmol), ₂ C0 ₃ (1.47 g, 10.63 mmol), Cu (0.648 g, 10.12 mmol) and chlorobenzene ( 100 1 735 ml) were mixed. The reaction mixture was heated to reflux ( 135°C) overnight then filtered hot through a thin layer of diatomaceous earth. The flask was rinsed and the cake was washed with CH2CI2 (100 ml). The filtrate was washed with water, dried (Na^SC^), filtered and concentrated. The crude product was purified by column chromatography with an Analogix SF-150 g Si column using 90: 10 CH2CI2: hexanes (25 minutes) then 1740 100% CH2CI2 to yield the title compound. MS ESI(+) m/z 334.9 [M+H] ⁺

Example 3C

methyl 3-chloro- l l -oxo- 10, 1 l -dihydro-5H-dibenzo[b,e][ l ,4]diazepine-7-carboxylate To Example 3B (1 .02 g, 3.048 mmol) in methanol (50 ml) was added

1745 concentrated HCI (10 ml) and the mixture was heated to reflux overnight. After cooling at room temperature, the reaction mixture was filtered and the cake was washed with water to yield the title compound. MS ESl(-) m/z 300.9 [M-H] ^"

Example 3D

1750 methyl 3-(2-(N-methylmethylsulfonamido)phenyl)- l l-oxo- 10,1 l -dihydro-5 H- dibenzo[b,e][ l ,4]diazepine-8-carboxylate

To the mixture of Example 3C ( 1.05 g, 3.47 mmol), N-(2-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (2.07 g, 6.94 mmol), CsF ( 1 .58 g, 10.41 mmol) and Cy-Map (2-dicyclohexylphosphine-2'-(N,N-dimethylamino)biphenyl) 1755 (0.406 g, 1.04 mmol) in N,N-dimethylacetamide (80 ml) and methanol (40 ml) nitrogen was bubbled, and palladium(II) acetate (0.135 g, 0.6 mmol) was added. The reaction mixture was refluxed for 2 days. After cooling at room temperature, the reaction mixture was filtered through a layer of diatomaceous earth. The filtrate was washed with water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were 1760 washed with brine, dried (Na ₂ S0 ₄ ), filtered and concentrated onto silica gel and loaded onto an Analogix SF40- 150 g column for separation (10-80%) using ethyl acetate in hexanes to yield the title compound. MS ESI(-) m/z 436.0 [M-H] ^"

Example 3E

1765 3-(2-( -methylmethylsulfonamido)phenyI)- l l -oxo- 10, 1 l -dihydro-5H- dibenzo[b,e][l ,4]diazepine-8-carboxylic acid

To Example 3D (1.8 g, 4.1 1 mmol) was added tetrahydrofuran ( 14 ml) and methanol (14 ml) followed by 2.5 N aqueous NaOH solution (9.4 ml). The reaction mixture was stirred at room temperature overnight. Water ( 100 ml) was added to the

1770 reaction and the mixture was extracted with ethyl acetate (2x 50 ml). The aqueous layer was acidified with 2N aqueous HC1 solution to pH 2-3. The slurry was extracted with ethyl acetate (4x 100 ml). The combined organic layers were dried (Na ₂ S0 ₄ ), filtered, and concentrated to yield the title compound. MS ESI(+) m/z 424.0 [M+H] ⁺ , 441.0

[M+NH ₄ ] ⁺ .

1775

Example 3F

N-[3-(4-methylpiperazin- l-yl)propyl]-3-{2-[(methylsulfonyl)amino]phenyl}- l l -oxo- 10, 1 1 -dihydro-5H-dibenzo[b,e][ 1 ,4]diazepine-8-carboxamide

To Example 3E (0.021 g, 0.05 mmol) in N,N-dimethylformamide (0.8 ml) was 1780 added 0-(benzotriazol- l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (0.029 g, 0.09 mmol), N,N-diisopropylethylamine (0.0097 g, 0.075 mmol) and 3-(4- methylpiperazin- l -yl)propan-l -amine (0.010 g, 0.065 mmol). The crude product was purified by reverse phase HPLC on a customized Waters Purification system, eluting with 10-95% CH ₃ CN / 0.1 % TFA in water to yield the title compound. Ή NMR (300 1785 MHz, DMSO-d ₆ ) δ ppm 9.95 (s, 1 H), 8.98 (s, 1 H), 8.33-8.39 (bs, 1H), 8.22 (s, 1 H), 7.74 (d, J= 8.0 Hz, 1H), 7.42-7.48 (m, 4H), 7.30-7.33 (m, 2H), 6.98-7.04 (m, 3H), 3.23-3.31 (m, 4H), 2.89 (s, 4H), 2.70-2.77 (m, 5H), 1.72-1.81 (m, 2H); MS ESI(+) m/z 563

[M+H] ⁺ .

1 790 Example 4

N-methyl-N-[3-(l l-oxo-10, 1 l-dihydro-5H-dibenzo[b,e][l ,4]diazepin-3-yl)pyridin-2- yljmethanesulfonamide

Example 4A

1795 3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-5H-dibenzo[b,e][ 1 ,4]diazepin- 1 1 (10H)- one

A-mixture of tricyclohexylphosphine (0.034 g, 0.12 mmol) and

tris(dibenzylideneacetone)dipalladium(0) (0.023 g, 0.025 mmol) in dioxane (6 ml) purged with nitrogen was stirred at room temperature for 30 minutes. To this reaction mixture,

1800 Example 1A (0.38 g, 1.0 mmol), bis(pinacolato)diboron (0.279 g, 1.1 mmol) and

potassium acetate (0.147 g, 1.5 mmol) were added. It was purged with nitrogen and stirred at 85°C overnight. After cooling, the reaction mixture was diluted with ethyl acetate and washed with water twice. The organic layers were dried (Na ₂ S0 ₄ ), filtered and concentrated. The crude product was purified by flash chromatography on silica gel,

1805 eluting with 20% ethyl acetate in hexane to yield the title compound.

Example 4B

3-(2-fluoropyridin-3-y l)-5H-dibenzo[b,e][ 1 ,4]diazepin- 1 1 (10H)-one

To Example 4A (0.037 g, 0.1 10 mmol) and 3-bromo-2-fluoropyridine (0.018 g, 1810 0.1 mmol) in a microwave vial was added 1 ,2-dimethoxyethane (0.6 ml) and methanol (0.3 ml) followed by CsF (0.03 g, 0.2 mmol) and

tetrakis(triphenylphosphine)palladium(0) (0.0058 g, 5.0 μιηοΐ). The vial was heated in the Biotage Initiator Microwave Synthesizer at 120°C for 20 minutes. After cooling, the reaction mixture was filtered and concentrated. The crude product was purified by 1815 reverse phase HPLC on a customized Waters Purification system, eluting with 10-95% CH ₃ CN / 0.1 % TFA in water to yield the title compound. MS ESI(-) m/z 304.0 [M-H]\

Example 4C

N-methyI-N-[3-(l l -oxo- 10,1 l-dihydro-5H-dibenzo[b,e][l ,4]diazepin-3-yl)pyridin-2-

1820 yl]methanesulfonamide

To Example 4B (0.02 g, 0.066 mmol) and Cs ₂ C0 ₃ (0.043 g, 0.132 mmol) in N,N- dimethylformamide (0.5 ml) was added N-methylmethanesulfonamide (0.0079 g, 0.073 mmol) in N,N-dimethylformamide (0.5 ml). The reaction mixture was heated at 60°C for 20 hours. After cooling, the reaction mixture was filtered and concentrated. The crude

1825 product was purified by reverse phase HPLC on a customized Waters Purification

system, eluting with 10-95% CH ₃ CN / 0.1 % TFA in water to yield the title compound. Ή NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.90 (s, 1 H), 8.55 (dd, J = 4.7, 1.9 Hz, 1 H), 7.99 (s, 1 H), 7.90 (dd, J = 7.6, 1 .9 Hz, 1 H), 7.73 (d, J= 8.1 Hz, 1 H), 7.54 (dd, J= 7.7, 4.7 Hz, 1 H), 7.06 (d, J = 1.7 Hz, 1 H), 6.92-7.04 (m, 5H), 3.13 (s, 3H), 3.02 (s, 3H); MS ESI(+)

1830 m/z 395 [M+H] ⁺ .

Example 5

N-{2-[l l -oxo-8-(3,4,5-trimethoxyphenyl)-10, l l-dihydro-5H-dibenzo[b,e][ l ,4]diazepin-

3-yl]phenyl}methanesulfonamide

1835

Example 5A

8-bromo-3-chloro-5H-dibenzo[b,e][ l ,4]diazepin-l l(10H)-one

The title compound was prepared as described in US 20040254159 (Example 2B).

1840 Example 5B

3-chloro-8-(3,4,5-trimethoxyphenyl)-5H-dibenzo[b,e][ 1 ,4]diazepin- 1 1 (10H)-one To Example 5A (0.065 g, 0.2 mmol) and 3,4,5-trimethoxyphenylboronic acid (0.047 g, 0.22 mmol) in a microwave vial was added 1 ,2-dimethoxyethane (0.6 ml) and methanol (0.3 ml) followed by CsF (0.061 g, 0.4 mmol) and

1845 tetrakis(triphenylphosphine)palladium(0) (0.012 g, 10.0 μπιοΙ). The vial was heated in the Biotage Initiator Microwave Synthesizer at 120°C for 10 minutes. After cooling the reaction mixture was filtered and concentrated. The crude product was purified by reverse phase HPLC on a customized Waters Purification system, eluting with 10-95% CH ₃ CN / 0.1% TFA in water to yield the title compound. MS ESI(-) m/z 409 [M-H]\

1850

Example 5C

N-{2-[l l -oxo-8-(3,4,5-trimethoxyphenyl)-10, l l-dihydro-5H-dibenzo[b,e][ l ,4]diazepin-

3-yl]phenyl}methanesulfonamide

To Example 5B (0.021 g, 0.05 mmol) and N-(2-(4,4,5,5-tetramethyl- 1 ,3,2-

1855 dioxaborolan-2-yl)phenyl)methanesulfonamide (0.016 g, 0.055 mmol) in a vial was added 1 ,2-dimethoxyethane (2.0 ml) and methanol (1.0 ml) followed by CsF (0.023 g, 0.1 5 mmol) and palladium(II) acetate (0.002 g, 8.50 μηιοΐ). The vial was heated at 80°C for 48 hours. After cooling, the reaction mixture was filtered and concentrated. The crude product was purified by reverse phase HPLC on a customized Waters Purification

1860 system, eluting with 10-95% CH ₃ CN / 0.1% TFA in water to yield the title compound. Ή NMR (300 MHz, DMSO-d ₆ ) 6 ppm 9.82 (s, 1 H), 8.98 (s, 1 H), 8.04 (s, 1 H), 7.74 (d, J = 8.1 Hz, 1 H), 7.37-7.50 (m, 2H), 7.26-7.36 (m, 4H), 7.06 (d, J = 8.5 Hz, 1 H), 7.03 (d, J = 1.4 Hz, 1 H), 6.98 (dd, J= 8.1 , 1.6 Hz, 1 H), 6.82 (s, 2H), 3.84 (s, 6H), 3.68 (s, 3H), 2.90 (s, 3H); MS ESI(-) m/z 544 [M-H]\

1865

Example 6

N-[3-(8-amino- 1 1 -oxo- 10, 1 1 -dihydro-5H-dibenzo[b,e][ 1 ,4]diazepin-3-y l)pyridin-2-yl]-

N-methylmethanesulfonamide

1870 Example 6A

8-amino-3-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl)-5H-dibenzo[b,e][l ,4]diazepin- l l(10H)-one

The title compound was prepared as described in US 20040254159 (Example

155A).

1875

Example 6B N-[3-(8-amino- l l-oxo- 10,1 l-dihydro-5H-dibenzo[b,e][l ,4]diazepin-3-yl)pyridin-2-yl]-

N-methylmethanesulfonamide

To Example 6A (0.077 g, 0.22 mmol) and N-(3-bromopyridin-2-yl)-N- 1880 methylmethanesulfonamide in a microwave vial was added 1,2-dimethoxyethane ( 1.2 ml) and methanol (0.6 ml) followed by CsF (0.061 g, 0.4 mmol) and

tetrakis(triphenylphosphine)palladium(0) (0.012 g, 10.0 μιτιοΐ). The vial was heated in the Biotage Initiator Microwave Synthesizer at 120°C for 20 minutes. After cooling, the reaction mixture was filtered and concentrated. The crude product was purified by 1885 reverse phase HPLC on a customized Waters Purification system, eluting with 10-95%

CH ₃ CN / 0.1 % TFA in water to yield the title compound. Ή NMR (300 MHz, DMSO-d ₆ ) 5 ppm 10.06 (s, IH), 8.60-9.33 (bs, IH), 8.56 (dd, J = 4.7, 1.8 Hz, I H), 8.02-8.04 (bs, I H), 7.89 (dd, J = 7.7, 1.9 Hz, I H), 7.74 (d, J= 8.1 Hz, I H), 7.54 (dd, J= 7.7, 4.7 Hz, I H), 6.98-7.05 (m, 3H), 6.76-6.82 (m, 2H), 5.92-7.31 (bs, I H), 3.12 (s, 3H), 3.02 (s, 3H); 1890 MS ESI(+) m/z 410 [M+H] ⁺ , 427 [M+NH ₄ ] ⁺ .

Example 7

3-{2-[(methylsulfonyl)amino]phenyl}- l l-oxo-10, 1 l-dihydro-5H- dibenzo[b,e][l ,4]diazepine-8-carboxamide

1895 Example 3E (0.021 g, 0.05 mmol), l-ethyl-3-[3-(dimethylamino)propyl]- carbodiimide hydrochloride (0.012 g, 0.06 mmol), ammonium chloride (0.0055 g, 0.100 mmol), triethylamine (0.021 ml, 0.15 mmol) and 1 - hydroxybenzotriazole hydrate (0.008 g, 0.055 mmol) in N,N-dimethylformamide (0.5 ml) were stirred at 25°C for 18 hours. The reaction mixture was concentrated. The crude product was purified by reverse phase

1900 HPLC on a customized Waters Purification system, eluting with 10-95% CH ₃ CN / 0.1 % TFA in water to yield the title compound. Ή NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.93 (s, I H), 8.98 (s, IH), 8.20 (s, I H), 7.73-7.78 (bs, I H), 7.74 (d, J= 8.1 Hz, I H), 7.38-7.52 (m, 4H), 7.30-7.33 (m, 2H), 7.17-7.23 (bs, I H), 6.98-7.03 (m, 3H), 2.90 (s, 3H); MS ESI(-) m/z 421 [M-H]\

1905

Example 8 N-methyl-2-( 1 1 -oxo- 10, 1 1 -dihydro-5H-dibenzo[b,e] [ 1 ,4]d iazepin-3- yl)benzenesulfonamide

The title compound was prepared as described in Example 4B, except substituting 1910 2-bromo-N-methylbenzenesulfonamide for 3-bromo-2-fiuoropyridine. Ή NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.84-9.89 (m, 1H), 7.88-7.93 (m, 2H), 7.52-7.70 (m, 4H), 7.35 (dd, J= 7.1 , 1.8 Hz, 1H), 7.26 (q, J= 4.8 Hz, 1H), 6.89-7.02 (m, 5H), 6.87 (dd, J= 8.1 , 1.5 Hz, 1 H), 2.40 (d, J = 4.8 Hz, 2H); MS ESI(-) m/z 378 [M-H]\

1915 Example 9

N-ethyl-N-[2-(l l -oxo- 10, l l-dihydro-5H-dibenzo[b,e][l ,4]diazepin-3- yl)phenyl]methanesulfonamide

Example 9A

1920 N-(2-bromophenyl)-N-ethylmethanesulfonamide

To a solution of N-(2-bromophenyl)methanesulfonamide (0.075 g, 0.3 mmol) and K2CO3 (0.083 g, 0.6 mmol) in Ν,Ν-dimethylformamide (1 .5 ml) was added iodoethane (0.027 ml, 0.33 mmol) and it was stirred at 25°C for 20 hours. The reaction mixture was diluted with ethyl acetate; washed with water twice and brine, dried (MgS0 ₄ ) and

1925 filtered. The filtrate was concentrated to yield the title compound. MS ESI(-) m/z 278.3 [M-H] ^" .

Example 9B

N-ethyl-N-[2-( 1 1 -oxo- 10,1 1 -dihydro-5H-dibenzo[b,e][ 1 ,4]diazepin-3- 1930 yl)phenyI]methanesulfonamide

The title compound was prepared as described in Example 4B, except substituting Example 9A for 3-bromo-2-fluoropyridine. Ή NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.86 (s, 1 H), 7.90 (s, 1 H), 7.69 (d, J = 8.1 Hz, 1 H), 7.43-7.51 (m, 3H), 7.35-7.38 (m, 1 H), 6.90-7.02 (m, 6H), 3.32 (m, 2H), 3.00 (s, 3H), 0.90 (t, J= 7.1 Hz, 3H); MS ESI(-) m/z 1935 406.0 [M-H] ^' .

Example 10 N-methyl-N-[4-methyl-2-(l l -oxo-10,1 l-dihydro-5H-dibenzo[b,e][ l ,4]diazepin-3- yl)phenyl]methanesulfonamide

1940 The title compound was prepared as described in Example 9A, except substituting iodomethane for iodoethane and Example 4B, except substituting N-(2-bromo-4- methylphenyl)methanesulfonamide for 3-bromo-2-fluoropyridine, to afford the title compound. Ή NMR (300 MHz, DMSO-d ₆ ) δ ppm 7.90 (s, 1H), 7.69 (d, J= 8.2 Hz, 1 H), 7.51 -7.66 (m, 1 H), 7.45 (d, J= 8.1 Hz, 1 H), 7.28 (dd, J= 7.8, 2.3 Hz, 1 H), 7.18-7.23 (m, 1945 1H), 6.87-7.02 (m, 6H), 3.07 (s, 3H), 2.88 (s, 3H), 2.36 (s, 3H); MS ESI(+) m/z 408.3 [M+H] ⁺ .

Example 1 1

N-methyl-N-[3-methyl-2-(l l -oxo-10,1 l -dihydro-5H-dibenzo[b,e][ l ,4]diazepin-3- 1950 yl)phenyl]methanesulfonamide

The title compound was prepared as described in Example 9A, except substituting iodomethane for iodoethane and Example 4B, except substituting N-(2-bromo-3- methylphenyl)methanesulfonamide for 3-bromo-2-fluoropyridine to afford the title compound. Ή NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.85 (s, 1 H), 7.88 (s, 1 H), 7.72 (d, J = 1955 8.0 Hz, 1 H), 7.29-7.39 (m, 3H), 6.88-7.01 (m, 4H), 6.83-6.86 (m, 1 H), 6.72-6.77 (m, 1 H), 2.93 (s, 3H), 2.82 (s, 3H), 2.04 (s, 3H); MS ESI(-) m/z 406.0 [M-H]\

Example 12

N-(3-{2-[methyl(methylsulfonyl)amino]pyridin-3-yl}-l l -oxo- 10, 1 l -dihydro-5H- 1960 dibenzo[b,e][l ,4]diazepin-8-yl)acetamide

Acetyl chloride (5.54 mg, 0.071 mmol) was added to a solution of Example 6 (0.03 g, 0.047 mmol) and triethylamine (0.023 ml, 0.165 mmol) in CH ₂ C1 ₂ (1.0 ml). The reaction mixture was stirred at 25°C for 20 hours and concentrated. The residue was dissolved in ethyl acetate and washed with water and brine. Insoluble precipitates were 1965 filtered off. The filtrate was dried (MgSC^), filtered and concentrated. The crude product was purified by reverse phase HPLC on a customized Waters Purification system, eluting with 10-95% CH ₃ CN / 0.1% TFA in water to yield the title compound. Ή NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.94 (s, 1 H), 9.83 (s, 1 H), 8.55 (dd, 7= 4.7, 1 .8 Hz, 1 H), 7.87- 7.91 (m, 2H), 7.72 (d, J= 8.0 Hz, IH), 7.53 (dd, J= 7.7, 4.7 Hz, I H), 7.25 (d, J= 2. 1 Hz,

1970 I H), 7.17 (dd, J= 8.5, 2.3 Hz, I H), 6.99-7.08 (m, 2H), 6.91 (d, J= 8.5 Hz, I H), 3.12 (s, 3H), 3.01 (s, 3H), 2.00 (s, 3H); MS ESI(-) m/z 450.0 [M-H]\

Example 13

N-methyl-N-[5-methyl-2-( 1 1-oxo- 10, 1 1 -dihydro-5H-dibenzo[b,e][ 1 ,4]diazepin-3- 1975 yl)phenyl]methanesulfonamide

The title compound was prepared as described in Example 9A, except substituting iodomethane for iodoethane and Example 4B, except substituting N-(2-bromo-5- methylphenyl)methanesulfonamide for 3-bromo-2-fluoropyridine to afford the title compound. Ή NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.83 (s, 1 H), 7.90 (s, I H), 7.68 (d, J = 1980 8.1 Hz, I H), 7.38 (s, I H), 7.26 (s, 2H), 6.89-7.02 (m, 6H), 3.08 (s, 3H), 2.90 (s, 3H), 2.38 (s, 3H); MS ESI(+) m/z 408 [M+H] ⁺ , 425 [M+ NH ₄ ] ⁺ .

Example 14

tert-butyl 3- {2-[methyl(methylsulfonyl)amino]phenyl}- l l-oxo-10, 1 l-dihydro-5H- 1985 dibenzo[b,e][l ,4]diazepin-7-ylcarbamate

Example 14A

tert-butyl 3-amino-4-nitrophenylcarbamate

A solution of 2,4-diamino-nitrobenzene (2.0 g, 13.0 mmol, Alfa Aesar Chemical 1990 Company) in tetrahydrofuran (131 ml) was cooled to -10°C and treated with a solution of potassium bis(trimethylsilyl)amide (27.4 ml, 0.5M in toluene, 13.7 mmol). After 15 minutes at - 10°C, the solution was treated with di-tert-buryl carbonate (3.0 g, 13.7 mmol). The resulting solution was allowed to warm to room temperature over 18 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer 1995 was washed with H ₂ 0 and brine, dried (MgS0 ₄ ), filtered and concentrated. The crude product was purified by flash chromatography on silica gel, eluting with a 0 - 60% ethyl acetate / hexanes gradient to yield the title compound. MS ESI(+) m/z 254.4 [M+H] ⁺ .

Example 14B 2000 methyl 2-(5-(tert-butoxycarbonylamino)-2-nitrophenylamino)-4-chloro benzoate

A mixture of Example 14A (700 mg, 2.76 mmol), Example 3A (820 mg, 2.76 mmol), CS2CO3 (901 mg, 2.76 mmol), palladium(II) acetate (31 mg, 0.14 mmol), and 1 , l '-bis(diphenylphosphino)ferrocene (153 mg, 0.28 mmol) in toluene (27.6 ml) was heated at 95°C over 16 hours. After cooling to room temperature, the mixture was

2005 diluted with ethyl acetate. The organic layer was washed with aqueous ammonium

chloride and brine, dried (MgS0 ₄ ), filtered, and concentrated. The crude product was purified by flash chromatography on silica gel, eluting with a 0 - 40% ethyl acetate / hexanes gradient to yield the title compound. MS ESI(+) m/z 422.1 [M+H] ⁺ .

2010 Example 14C

methyl 2-(2-amino-5-(tert-butoxycarbonylamino)phenylamino)-4-chloro benzoate Example 14B (740 mg, 1.75 mmol) was dissolved in a mixture of methanol (10 ml) and tetrahydrofuran (5 ml) in a 250 mL stainless steel pressure bottle. Ra-Ni (740 mg, 12.6 mmol, water-wet) was added and the resulting mixture stirred at room

2015 temperature over 3 hours under a hydrogen atmosphere at 30 psi. The mixture was filtered through a nylon membrane and concentrated to yield the title compound. MS ESI(+) m/z 392.4 [M+H] ⁺ .

Example 14D

2020 2-(2-amino-5-(tert-butoxycarbonylamino)phenylamino)-4-chloro benzoic acid

To a solution of Example 14C (150 mg, 0.38 mmol) in methanol/water (5 mL, 1 : 1 ) was added LiOH (92 mg, 3.83 mmol). The resulting solution was heated at 60 °C for 16 hours. After cooling the reaction mixture to room temperature, IN aqueous HC1 was added until a pH = 6 was reached. The solution was extracted several times with

2025 ethyl acetate. The combined organic layers were dried (MgS04), filtered, and

concentrated to yield the title compound. MS ESI(+) m/z 378.4 [M+H] ⁺ .

Example 14E

tert-butyl 3-chloro-l l-oxo-10,1 l-dihydro-5H-dibenzo[b,e][l ,4]diazepin-7-ylcarbamate 2030 To a solution of Example 14D (145 mg, 0.38 mmol) in N,N-dimethylformamide

(3.84 ml) was added 0-(benzotriazol- l-yl)-N,N,N',N'-tetramethyluronium

tetrafluoroborate (123 mg, 0.38 mmol) and triethylamine (0.054 ml, 0.38 mmol). After stirring 96 hours at room temperature, the crude reaction mixture was diluted with ethyl acetate and washed several times with aqueous ammonium chloride. The organic layer

2035 was dried (MgS0 ₄ ), filtered, and concentrated. The crude product was purified by flash chromatography on silica gel, eluting with a 20 - 80% ethyl acetate / hexanes gradient to yield the title compound. MS ESI(+) m/z 360.4 [M+H] ⁺ .

Example 14F

2040 tert-butyl 3-{2-[methyl(methylsulfonyl)amino]phenyl}- l l -oxo- 10, 1 l-dihydro-5H- dibenzo[b,e][l ,4]diazepin-7-ylcarbamate

Example 14E ( 1 12 mg, 0.3 1 mmol), Example 39C ( 1 16 mg, 0.37 mmol), [(t-Bu) ₂ - P(OH)PdCl ₂ ]2 ( 10.6 mg, 0.02 mmol), and cesium carbonate (406 mg, 1 .25 mmol), were combined in a 5 mL microwave tube containing a conical stir bar. N,N-

2045 Dimethyl formamide ( 1.3 mL) and water (0.26 mL) were added and the resulting mixture was heated in the microwave (Biotage Initiator Microwave Synthesizer) at 150° for 30 minutes. The solvent was evaporated and the crude product was purified by flash chromatography on silica gel, eluting with a 20 - 80% ethyl acetate / hexanes gradient to yield the title compound. Ή NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.70 (s, 1 H), 9.26 (s, 1

2050 H), 7.94 (s, 1 H), 7.69 (d, 1 H), 7.60 - 7.35 (m, 5 H), 7.04 (d, 1 H), 6.94 (dd, 1 H), 6.81 (s, 2 H), 3.10 (s, 3 H), 2.89 (s, 3 H), 1.48 (s, 9 H). MS ESI(+) m/z 509.3 [M+H] ⁺ .

Example 15

N-[3-(4-methylpiperidin- l -yl)propyl]-3-{2-[(methylsulfonyl)amino]phenyl}- l 1 -oxo- 2055 10, 1 l-dihydro-5H-dibenzo[b,e][l ,4]diazepine-8-carboxamide

A scintillation vial (20 ml) was charged with a solution of Example 3E (23.44 mg, 0.055 mmol) in Ν,Ν-dimethylacetamide, 3-(4-methylpiperidin-l-yl)propan- l -amine ( 10.3 mg, 0.066 mmol) in Ν,Ν-dimethylacetamide, a solution of 0-(7-azabenzotriazol-l-yl)- Ν,Ν,Ν',Ν'-tetramethyluronium hexafluorophosphate (25.26 mg, 0.066 mmol) in N,N- 2060 dimethylacetamide, and triethylamine (23.31 μΙ, 0.166 mmol). The reaction mixture was stirred at room temperature overnight and concentrated. The crude product was purified by reverse phase HPLC on an Agilent 1100 Series Purification system, eluting with 10- 100% CH ₃ CN / 0.1% TFA in water to yield the title compound. Ή NMR (500 MHz, Pyridine-ds / D ₂ 0) δ ppm 8.24-8.25 (m, IH), 8.23 (d, J= 5.3 Hz, IH), 7.96 (dd,J= 8.4, 2065 1.8 Hz, IH), 7.92 (d,J= 8.1 Hz, IH), 7.55 (d, J= 1.7 Hz, IH), 7.45-7.49 (m, 2H), 7.39 (d, J= 8.0 Hz, IH), 7.32-7.34 (m, IH), 7.25-7.29 (m, 2H), 3.75-3.78 (m, 2H), 3.52-3.60 (m, 3H), 3.29-3.33 (m, 2H), 3.24 (s, 3H), 2.29-2.35 (m, 2H), 1.69-1.73 (m, 2H), 1.52- 1.57 (m, 3H), 0.76-0.78 (m, 3H); MS ESI(+) m/z 562 [M+H] ⁺ .

2070 Example 16

N-(l -methylpiperidin-4-yl)-3- {2-[(methylsulfonyl)amino]phenyl}- 11 -oxo- 10, 11 -dihydro- 5H-dibenzo[b,e][l,4]diazepine-8-carboxamide

The title compound was prepared as described in Example 15, except substituting l-methylpiperidin-4-amine for 3-(4-methylpiperidin-l-yl)propan-l -amine. Ή NMR (500

2075 MHz, Pyridine-ds / D ₂ 0) δ ppm 8.24-8.24 (m, IH), 8.23 (d, J= 5.7 Hz, IH), 7.95 (dd, J = 8.2,2.0 Hz, IH), 7.93 (d,J=8.1 Hz, IH), 7.53 (d,J= 1.6 Hz, IH), 7.45-7.49 (m, 2H), 7.38 (dd,J= 7.6, 1.4 Hz, IH), 7.30-7.34 (m, IH), 7.25 (dd,J=8.2, 1.6 Hz, 1H),4.44- 4.51 (m, IH), 3.47-3.52 (m, 2H), 3.25 (s, 3H), 2.98-3.12 (m, 2H), 2.84 (s, 3H), 2.26-2.32 (m, 4H); MS ESI(+) m/z 520 [M+H] ⁺ .

2080

Example 17

N-[3-(2-methylpiperidin-l-yl)propyl]-3-{2-[(methylsulfonyl)a mino]phenyl}-l 1-oxo- 10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepine-8-carboxamide

The title compound was prepared as described in Example 15, except substituting 2085 3-(2-methylpiperidin-l-yl)propan-l -amine for 3-(4-methylpiperidin-l-yl)propan-l- amine. Ή NMR (500 MHz, Pyridine-d ₅ / D ₂ 0) δ ppm 8.25 (d, J= 2.0 Hz, IH), 8.24 (d, J = 8.2 Hz, IH), 7.97 (dd,J= 8.2, 2.0 Hz, IH), 7.93 (d,J=8.1 Hz, IH), 7.54 (d, J = 1.6 Hz, IH), 7.45-7.50 (m, 2H), 7.37-7.41 (m, IH), 7.31-7.35 (m, IH), 7.24-7.28 (m, IH), 3.77 (t, J= 6.6 Hz, 2H), 3.40-3.54 (m, 2H), 3.21-3.34 (m, 2H), 3.25 (s, 3H), 2.95-3.05 2090 (m, 1 H), 2.26-2.33 (m,2H), 1.71-1.81 (m, 3H), 1.54-1.68 (m, 2H), 1.37-1.47 (m, IH), 1.32 (d, J= 6.4 Hz, 3H); MS APCI(+) m/z 562 [M+H] ⁺ . Example 18

N-[2-(4-methylpiperazin-I-yl)ethyl]-3-{2-[(methylsulfonyI)am ino]phenyl}-l I-oxo- 2095 10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepine-8-carboxamide

The title compound was prepared as described in Example 15, except substituting 2-(4-methylpiperazin-l-yl)ethanamine for 3-(4-methylpiperidin-l-yl)propan-l-amine. Ή NMR (500 MHz, Pyridine-d ₅ / D ₂ 0) δ ppm 8.26 (d,J= 2.1 Hz, 1H), 8.23 (d,J= 8.1 Hz, 1H),7.98 (dd,J=8.2,2.1 Hz, 1H), 7.93 (d,J=8.0 Hz, 1H), 7.53 (d, J= 1.7 Hz, 1H), 2100 7.45-7.49 (m, 2H), 7.37-7.40 (m, 1H), 7.30-7.35 (m, 1 H), 7.25 (dd, J= 8.2, 1.4 Hz, 1H), 3.80-3.84 (m, 2H), 3.22-3.31 (m, 4H), 3.24 (s, 3H), 2.86-3.02 (m, 4H), 2.83 (s, 3H), 2.81- 2.86 (m, 2H); MS ESI(+) m/z 549 [M+H] ⁺ .

Example 19

2105 3-{2-[(methylsulfonyl)amino]phenyl}-l l-oxo-N-(2-pyridin-4-ylethyl)-10,l 1-dihydro-

5H-dibenzo[b,e][l,4]diazepine-8-carboxamide

The title compound was prepared as described in Example 15, except substituting 2-(pyridin-4-yl)ethanamine for 3-(4-methylpiperidin-l -yl)propan-l -amine. Ή NMR (500 MHz, Pyridine-ds / D ₂ 0 δ ppm 8.57-8.58 (m, 2H), 8.28 (d, J= 2.0 Hz, 1H), 8.23 (d, J = 2110 8.1 Hz, 1H), 7.94 (dd,J= 8.2, 2.0 Hz, 1H), 7.93 (d, J= 7.6 Hz, 1H), 7.53 (d, J= 1.6 Hz, 1H), 7.44-7.48 (m, 2H), 7.38 (dd,J= 7.6, 1.6 Hz, 1H), 7.30-7.34 (m, 1H), 7.26-7.30 (m, 2H), 7.25 (dd,J= 8.1, 1.5 Hz, 1H), 3.90 (t,J= 7.3 Hz, 2H), 3.25 (s, 3H), 3.09 (t,J= 7.2 Hz, 2H); MS APCI(+) m/z 528 [M+H] ⁺ .

2115 Example 20

N-(2-methoxyethyl)-3- {2-[(methylsulfonyl)amino]phenyl}- 11 -oxo- 10, 11 -dihydro-5H- dibenzo[b,e][l,4]diazepine-8-carboxamide

The title compound was prepared as described in Example 15, except substituting 2-methoxyethanamine for 3-(4-methylpiperidin-l-yl)propan-l -amine. Ή NMR (500 2120 MHz, Pyridine-ds /D ₂ 0)8 ppm 8.27 (d, J =2.0 Hz, 1H), 8.22 (d,J= 8.1 Hz, 1H),7.95

(dd,J=8.2,2.0 Hz, 1H), 7.93 (d,J=8.1 Hz, 1H), 7.52 (d,J= 1.6 Hz, 1H), 7.44-7.48 (m, 2H), 7.37 (dd,J= 7.7, 1.7 Hz, 1H), 7.29-7.33 (m, 1H), 7.24 (dd,J=8.1, 1.6 Hz, 1H), 3.87 (t, J= 5.7 Hz, 2H), 3.70 (t, J= 5.7 Hz, 2H), 3.30 (s, 3H), 3.25 (s, 3H); MS ESI(-) m/z 479 [M-H]\

2125

Example 21

N-(4-hydroxybutyl)-3-{2-[(methylsulfonyl)amino]phenyI}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepine-8-carboxamide

The title compound was prepared as described in Example 15, except substituting 2130 4-aminobutan-l-ol for 3-(4-methyIpiperidin-l-yl)propan-l -amine. Ή NMR (500 MHz, Pyridine-d ₅ / D ₂ 0) δ ppm 8.28 (d, J= 2.0 Hz, 1H), 8.23 (d, J= 8.1 Hz, 1H), 7.97 (dd, J = 8.2,2.1 Hz, 1H), 7.93 (d,J=8.1 Hz, 1H), 7.52 (d,J=1.7 Hz, 1H), 7.44-7.48 (m, 2H), 7.38 (dd,J= 7.6, 1.7 Hz, 1H), 7.31 (d,J=8.7 Hz, 1H), 7.24 (dd, J= 8.0, 1.7 Hz, 1H), 3.87 (t, J= 6.3 Hz, 2H), 3.72 (t, J= 6.9 Hz, 2H), 3.25 (s, 3H), 1.94-2.01 (m, 2H), 1.83- 2135 1.89 (m, 2H); MS ESI(-) m/z 493 [M-H] ^' .

Example 22

N-[3-(lH-imidazol-l-yl)propyl]-3-{2-[(methylsulfonyl)amino]p henyl}-l l-oxo-10,11- dihydro-5H-dibenzo[b,e][l,4]diazepine-8-carboxamide

2140 The title compound was prepared as described in Example 15, except substituting

3-(lH-imidazol-l-yl)propan-l -amine for 3-(4-methylpiperidin-l-yl)propan-l -amine. Ή NMR (500 MHz, Pyridine-d ₅ / D ₂ 0) δ ppm 8.27 (d, J= 2.0 Hz, 1H), 8.23 (d, J= 8.1 Hz, 1H), 8.15-8.17 (bs, 1H), 7.97 (dd,J= 8.2, 2.0 Hz, 1H), 7.93 (d,J= 8.6 Hz, 1H), 7.53 (d, J= 1.5 Hz, 1H), 7.49 (d,J=8.2 Hz, 1H), 7.44-7.47 (m, 1H), 7.38 (dd, J= 7.7, 1.7 Hz, 2145 1H), 7.30-7.35 (m, 3H), 7.25 (dd,J = 8.0, 1.6 Hz, 1H), 4.15 (t, J= 7.0 Hz, 2H), 3.64 (t,J = 6.7 Hz, 2H), 3.25 (s, 3H), 2.21 (p, J= 6.9 Hz, 2H); MS APCI(+) m/z 531 [M+H] ⁺ .

Example 23

3- {2-[(meth lsulfonyl)amino]phenyl}-N-(2-moφholin-4-ylethyl)-l l-oxo-10,11-dihydro- 2150 5H-dibenzo[b,e][l,4]diazepine-8-carboxamide

The title compound was prepared as described in Example 15, except substituting 2-morpholinoethanamine for 3-(4-methylpiperidin-l-yl)propan-l -amine. Ή NMR (500 MHz, Pyridine-ds / D ₂ 0) δ ppm 8.29 (d,J= 2.0 Hz, 1H), 8.23 (d,J= 8.1 Hz, 1H), 7.99 (dd,J=8.2, 2.0 Hz, IH), 7.92-7.94 (m, IH), 7.52 (d, J= 1.6 Hz, IH), 7.44-7.48 (m, 2H), 2155 7.37-7.42 (m, IH), 7.30-7.34 (m, IH), 7.25 (dd, 7 = 8.1, 1.7 Hz, IH), 3.87 (t, J= 6.7 Hz, 2H), 3.76 (t, 7 = 4.4 Hz, 4H), 3.25 (s, 3H), 2.76 (t, 7 = 6.6 Hz, 2H), 2.52-2.58 (m, 4H); MS ESI(+) m/z 536 [M+H] ⁺ .

Example 24

2160 3-{2-[(methylsulfonyl)amino]phenyl}-l l-oxo-N-(pyridin-3-ylmethyl)-10,l l-dihydro-5H- dibenzo[b,e] [ 1 ,4]diazepine-8-carboxamide

The title compound was prepared as described in Example 15, except substituting pyridin-3-ylmethanamine for 3-(4-methylpiperidin-l-yl)propan-l-amine. Ή NMR (500 MHz, ) δ ppm 8.94 (d,7=2.1 Hz, IH), 8.58 (dd, 7 = 4.8, 1.6 Hz, IH), 8.28 (d,J=2.0 2165 Hz, IH), 8.23 (d, 7=8.1 Hz, IH), 7.98 (dd, 7= 8.2, 2.0 Hz, IH), 7.90-7.94 (m, 2H), 7.53 (d,7= 1.6 Hz, IH), 7.48 (d,7=8.2 Hz, IH), 7.44-7.48 (m, IH), 7.38 (dd, 7= 7.7, 1.7 Hz, IH), 7.29-7.33 (m, IH), 7.21-7.27 (m, 2H), 4.85 (s, 2H), 3.24 (s, 3H); MS ESI(+) m/z 514 [M+H] ⁺ .

2170 Example 25

3-{2-[(methylsulfonyl)amino]phenyl}-l l-oxo-N-(pyridin-4-ylmethyl)-10,l l-dihydro-5H- dibenzo[b,e][l,4]diazepine-8-carboxamide

The title compound was prepared as described in Example 15, except substituting pyridin-4-ylmethanamine for 3-(4-methylpiperidin-l-yl)propan-l -amine. Ή NMR (500

2175 MHz, Pyridine-ds / D ₂ 0) δ ppm 8.60-8.64 (m, 2H), 8.32 (d, 7= 2.0 Hz, IH), 8.24 (d, 7 = 8.1 Hz, 1 H), 8.04 (dd, 7= 8.2, 2.0 Hz, IH), 7.93 (d, 7= 8.1 Hz, IH), 7.55 (d, 7= 1.6 Hz, IH), 7.52 (d,7= 8.2 Hz, IH), 7.43-7.48 (m, 3H), 7.38 (dd,7= 7.6, 1.7 Hz, IH), 7.30- 7.34 (m, IH), 7.25 (dd, 7= 8.1, 1.5 Hz, IH), 4.86 (s, 2H), 3.25 (s, 3H); MS APCI(+) m/z 514 [M+H] ⁺ .

2180

Example 26

3-{2-[(methylsulfonyl)amino]phenyl}-N-(3-moφholin-4-ylpropy l)-l l-oxo-10,11- dihydro-5H-dibenzo[b,e][l,4]diazepine-8-carboxamide The title compound was prepared as described in Example 15, except substituting 2185 3-morpholinopropan-l-amine for 3-(4-methylpiperidin-l-yl)propan-l-amine. 'HNMR (500 MHz, Pyridine-ds / D ₂ 0) δ ppm 8.28 (d,J=2.0 Hz, 1H), 8.23 (d,J=8.1 Hz, 1H), 7.98 (dd,J=8.2, 2.0 Hz, 1H), 7.93 (d,J=8.2 Hz, 1H), 7.54 (d, J= 1.6 Hz, 1H), 7.49 (d, J=8.2 Hz, 1H), 7.44-7.47 (m, 1H), 7.38 (dd,J= 7.6, 1.6 Hz, 1H), 7.32 (t,J= 7.3 Hz, 1H), 7.25 (dd, J= 8.0, 1.6 Hz, 1H), 3.84 (t, J= 4.5 Hz, 4H), 3.75 (t, J= 6.9 Hz, 2H), 3.25 2190 (s, 3H), 2.59-2.79 (m, 6H), 2.12 (p,J= 7.1 Hz, 2H); MS ESI(-) m/z 548 [M-H]\

Example 27

3-{2-[(methylsulfonyl)amino]phenyl}-l l-oxo-N-(pyridin-2-ylmethyl)-10,l l-dihydro-5H- dibenzo[b,e][l,4]diazepine-8-carboxamide

2195 The title compound was prepared as described in Example 15, except substituting pyridin-2-ylmethanamine for 3-(4-methylpiperidin-l-yl)propan-l-amine. Ή NMR (500 MHz, Pyridine-ds / D ₂ 0) δ ppm 8.62 (d, J= 3.9 Hz, 1H), 8.32 (d, J= 2.0 Hz, 1H), 8.24 (d,J=8.1 Hz, 1H), 8.02 (dd,J= 8.2, 2.0 Hz, 1H), 7.93 (d,J=8.l Hz, 1H), 7.64 (td,J= 7.7, 1.7 Hz, 1H), 7.57 (d,J= 7.8 Hz, 1H), 7.54 (d, J= 1.5 Hz, 1H), 7.50 (d,J= 8.2 Hz,

2200 IH), 7.46(ddd,J=8.0, 7.3, 1.8 Hz, 1H), 7.38 (dd, J= 7.6, 1.7 Hz, 1H), 7.30-7.34 (m, 1H), 7.25 (dd,J= 8.1, 1.7 Hz, 1H), 7.15-7.18 (m, 1H), 5.07 (s, 2H), 3.25 (s, 3H); MS ESI(+) m/z5\ [M+H] ⁺ .

Example 28

2205 3- {2-[(methylsulfonyl)amino]phenyl} - 11 -oxo-N-(3-pyrrolidin- 1 -ylpropyl)- 10, 11 - dihydro-5H-dibenzo[b,e][l,4]diazepine-8-carboxamide

The title compound was prepared as described in Example 15, except substituting 3-(pyrrolidin- 1 -yl)propan- 1 -amine for 3-(4-methylpiperidin- 1 -yl)propan- 1 -amine. Ή NMR (500 MHz, Pyridine-d ₅ / D ₂ 0) δ ppm 8.24 (d, J= 8.1 Hz, 1H), 8.22 (d, J= 2.0 Hz, 2210 1H), 7.91-7.95 (m,2H), 7.55 (d,J= 1.6 Hz, 1H), 7.45-7.49 (m, 2H), 7.38-7.40 (m, 1H), 7.31-7.35 (m, 1H), 7.26 (dd,J= 8.2, 1.6 Hz, 1H), 3.77 (t,J= 6.7 Hz, 2H), 3.41-3.45 (m, 2H), 3.35-3.42 (m, 4H), 3.24 (s, 3H), 2.28-2.34 (m, 2H), 1.93-1.99 (m, 4H); MS ESI(+) m/z 534 [M+H] ⁺ . 2215 Example 29

3-{2-[(methylsulfonyl)amino]phenyl}-l l-oxo-N-(2-pyridin-3-ylethyl)-10,l 1-dihydro- 5H-dibenzo[b,e][l,4]diazepine-8-carboxamide

The title compound was prepared as described in Example 15, except substituting 2-(pyridin-3-yl)ethanamine for 3-(4-methylpiperidin-l-yl)propan-l -amine. Ή NMR (500 2220 MHz, Pyridine-ds / D ₂ 0) δ ppm 8.54 (dd, J= 4.8, 1.6 Hz, 1H), 8.26 (d, J= 2.0 Hz, 1H), 8.22 (d,J= 8.1 Hz, 1H), 7.92-7.94 (m, 2H), 7.83 (m, 1H), 7.67-7.69 (m, 1H), 7.52 (d,J = 1.6 Hz, 1H), 7.44-7.49 (m, 1H), 7.44 (d, J= 8.2 Hz, 1H), 7.38 (dd, J= 7.6, 1.6 Hz, 1H), 7.32 (t,J= 7.4 Hz, 1H), 7.25 (dd,J=8.1, 1.6 Hz, 1H), 7.20 (dd, J= 7.7, 4.8 Hz, 1H), 3.88 (t, J= 7.3 Hz, 2H), 3.25 (s, 3H), 3.08 (t, J= 7.3 Hz, 2H); MS ESl(-) m/z 526.0 [M- 2225 H]\

Example 30

3-{2-[(methylsulfonyl)amino]phenyl}-l l-oxo-N-(2-pyridin-2-ylethyl)-10,l 1-dihydro- 5H-dibenzo[b,e][l,4]diazepine-8-carboxamide

2230 The title compound was prepared as described in Example 15, except substituting

2- (pyridin-2-yl)ethanamine for 3-(4-methylpiperidin-l-yl)propan-l -amine. Ή NMR (500 MHz, Pyridine-ds / D ₂ 0) δ ppm 8.60 (d, J= 5.6 Hz, 1H), 8.26 (d, J= 2.0 Hz, 1H), 8.22 (d,J=8.1 Hz, 1H), 7.93 (dd,J= 8.2, 2.0 Hz, 2H), 7.58 (td, J= 7.6, 1.8 Hz, 1H), 7.52 (d, J= 1.6 Hz, 1H), 7.43-7.49 (m, 2H), 7.38 (dd, J= 7.7, 1.4 Hz, 1H), 7.29-7.34 (m, 2H),

2235 7.24 (dd, J =8.0, 1.6 Hz, 1H), 7.10-7.13 (m, 1H), 4.11 (t,J=7.3 Hz, 2H), 3.36 (t, J= 7.3 Hz, 2H), 3.25 (s, 3H); MS ESI(-) m/z 526 [M-H] ^" .

Example 31

3- {2-[(methylsulfonyl)amino]phenyl}-l l-oxo-N-(2-pyrrolidin-l-ylethyl)-10,l 1-dihydro- 2240 5H-dibenzo[b,e][l,4]diazepine-8-carboxamide

The title compound was prepared as described in Example 15, except substituting 2-(pyrrolidin-l-yl)ethanamine for 3-(4-methylpiperidin-l-yl)propan-I-amine. Ή NMR (500 MHz, Pyridine-ds /D ₂ 0)8 ppm 8.24 (d, J =8.1 Hz, 1H), 8.17 (d,J= 2.0 Hz, 1H), 7.90-7.93 (m, 2H), 7.53 (d,J= 1.6 Hz, 1H), 7.45-7.49 (m, 1H), 7.41 (d,J=8.2 Hz, 1H), 2245 7.39 (dd, J =7.6, 1.4 Hz, 1H), 7.31-7.35 (m,.lH), 7.26 (dd,J= 8.2, 1.5 Hz, lH),4.08(t,J = 6.1 Hz, 2H), 3.66(t,J=6.1 Hz, 2H), 3.45-3.52 (m,4H),3.24 (s, 3H), 1.92-1.95 (m, 4H); MS ESI(+) m/z 520 [M+H] ⁺ .

Example 32

2250 N-[2-(dimethylamino)ethyl]-3-{2-[(methylsulfonyl)amino]pheny l}-l l-oxo-10,11- dihydro-5H-dibenzo[b,e][ 1 ,4]diazepine-8-carboxamide

The title compound was prepared as described in Example 15, except substituting N',N'-dimethylethane-l,2-diamine for 3-(4-methylpiperidin-l-yl)propan-l-amine. Ή NMR (500 MHz, Pyridine-d ₅ / D ₂ 0) δ ppm 8.23 (d, J= 8.0 Hz, 1H), 8.17 (d, J= 1.9 Hz, 2255 1H), 7.90-7.93 (m, 2H), 7.53 (s, 1H), 7.44-7.49 (m, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.37- 7.40 (m, 1H), 7.30-7.35 (m, 1H), 7.24-7.28 (m, 1H),4.02 (t,J=6.3 Hz, 2H), 3.40 (t, J= 6.3 Hz, 2H), 3.24 (s, 3H), 2.85-2.93 (m, 6H); MS APCI(+) m/z 494 [M+H] ⁺ .

Example 33

2260 3-{2-[(methylsulfonyl)amino]phenyl}-l l-oxo-N-[3-(2-oxopyrrolidin-l-yl)propyl]-10,l 1- d ihydro- 5H-d i benzo [b,e] [ 1 ,4]d iazepine-8-carboxam ide

The title compound was prepared as described in Example 15, except substituting l-(3-aminopropyl)pyrrolidin-2-one for 3-(4-methylpiperidin-l-yl)propan-l -amine. Ή NMR (500 MHz, Pyridine-d ₅ / D ₂ 0) δ ppm 8.27 (d, J= 1.9 Hz, 1H), 8.23 (d,J=8.1 Hz,

2265 1H), 8.00 (dd, 7= 8.2, 2.0 Hz, 1H), 7.93 (d, J= 8.0 Hz, 1H), 7.52 (d, J= 1.4 Hz, 1H), 7.49(d,J=8.2 Hz, 1H), 7.46 (ddd,J= 8.1, 7.4, 1.8 Hz, 1H), 7.38 (dd,J= 7.6, 1.6 Hz, 1H), 7.30-7.33 (m, 1H), 7.24 (dd,J= 8.1, 1.5 Hz, 1H), 3.62 (t,J=6.6 Hz, 2H), 3.42 (t,J = 6.7 Hz, 2H), 3.25 (s, 3H),3.21 (t,J=7.0 Hz, 2H), 2.33 (t, J= 8.1 Hz, 2H), 1.91 (p, J = 6.7 Hz, 2H), 1.75 (p, J= 7.5 Hz, 2H); MS APCI(+) m/z 548 [M+H] ⁺ .

2270

Example 34

3- {2-[(methy lsulfony l)amino]pheny 1 } - 11 -oxo-N-(2-piperidin- 1 -y lethy I)- 10,11 -dihydro- 5H-dibenzo[b,e][l,4]diazepine-8-carboxamide

The title compound was prepared as described in Example 15, except substituting 2275 2-(piperidin-l-yl)ethanamine for 3-(4-methylpiperidin-l-yl)propan-l -amine. 'HNMR (500 MHz, Pyridine-d ₅ / D ₂ 0) δ ppm 8.24 (d, J = 8.0 Hz, 1 H), 8.18 (d,J= 2.1 Hz, 1 H), 7.90-7.93 (m, 2H), 7.54 (d,J= 1.7 Hz, 1H), 7.45-7.49 (m, 1H), 7.43 (d,J = 8.2 Hz, 1H), 7.39 (dd,J=7.6, 1.3 Hz, 1H), 7.31-7.35 (m, 1H), 7.26 (dd,J= 8.2, 1.4 Hz, 1H),4.05- 4.09 (m, 2H), 3.41-3.45 (m, 2H), 3.25 (s, 3H), 3.16-3.28 (m, 4H), 1.72-1.76 (m, 4H), 2280 1.40-1.46 (m, 2H); MS ESI(+) m/z 534 [M+H] ⁺ .

Example 35

N-[2-( 1 H-imidazol-4-yl)ethyl]-3- {2-[(methy Isulfony l)amino]pheny 1} - 11 -oxo- 10,11- dihydro-5H-dibenzo[b,e][l,4]diazepine-8-carboxamide

2285 The title compound was prepared as described in Example 15, except substituting

2- (lH-imidazoI-4-yl)ethanamine for 3-(4-methylpiperidin-l-yl)propan-l -amine. Ή NMR (500 MHz, Pyridine-ds / D ₂ 0) δ ppm 8.32 (s, 1H), 8.25 (d, J= 2.0 Hz, 1H), 8.23 (d, J = 8.0 Hz, 1H), 7.92-7.95 (m, 2H), 7.52 (d, J= 1.6 Hz, 1H), 7.41-7.48 (m, 2H), 7.38 (dd,J = 7.5, 1.1 Hz, 1H), 7.31-7.34 (m, 1H), 7.26-7.29 (m, 1H), 7.25 (dd, J= 8.2, 0.9 Hz, 1H),

2290 4.03 (t,J= 7.2 Hz, 2H), 3.23-3.27 (m, 2H), 3.25 (s, 3H); MS APCI(+) m/z 517 [M+H] ⁺ .

Example 36

3- {2-[(methylsuIfony l)amino]pheny 1 }- 11 -oxo-N-(4-pyrrolidin- 1 -ylbutyl)- 10, 11 -dihydro-

5H-dibenzo[b,e][l,4]diazepine-8-carboxamide

2295 The title compound was prepared as described in Example 15, except substituting

4- (pyrrolidin-l-yl)butan-l -amine for 3-(4-methylpiperidin-l-yl)propan-l -amine. Ή NMR (500 MHz, Pyridine-d ₅ / D ₂ 0) δ ppm 8.22-8.25 (m, 2H), 7.96 (dd, J= 8.2, 2.1 Hz, 1H), 7.92 (d,J=8.1 Hz, 1H), 7.54 (s, 1H), 7.45-7.48 (m, 2H), 7.38 (d, J= 7.5 Hz, 1H), 7.30-7.35 (m, 1H), 7.26 (dd, J= 8.1, 1.4 Hz, 1H), 3.64-3.67 (m, 2H), 3.36-3.44 (m, 4H),

2300 3.30-3.33 (m, 2H), 3.24 (s, 3H), 1.94-1.98 (m, 6H), 1.81-1.87 (m, 2H); MS ESI(+) m/z 548 [M+H] ⁺ .

Example 37

3- {2-[(methylsulfonyl)amino]phenyl}- 11 -oxo-N-(tetrahydrofuran-3-ylmethyl)- 10, 11 - 2305 dihydro-5H-dibenzo[b,e][l,4]diazepine-8-carboxamide

The title compound was prepared as described in Example 15, except substituting (tetrahydrofuran-3-yl)methanamine for 3-(4-methylpiperidin-l-yl)propan-l -amine. Ή NMR (500 MHz, Pyridine-d ₅ / D ₂ 0) δ ppm 8.28 (d, J= 2.0 Hz, 1 H), 8.23 (d, J= 8.1 Hz, 1H), 7.98 (dd,J= 8.2, 2.1 Hz, 1H), 7.93 (d,J=8.0Hz, 1H), 7.53 (d, =1.4 Hz, 1H), 2310 7.48(d,J=8.2Hz, 1H), 7.44-7.47 (m, 1H), 7.38 (dd, J= 7.6, 1.4 Hz, 1H), 7.30-7.34 (m, 1H), 7.25 (dd,J=8.1, 1.2 Hz, 1H), 3.86-3.93 (m, 2H), 3.81 (dd, J= 8.5, 5.5 Hz, 1H), 3.60-3.73 (m, 3H), 3.25 (s, 3H), 2.76-2.85 (m, 1H), 1.93-2.01 (m, lH), 1.67-1.77 (m, 1H); MS ESI(-) m/z 505 [M-H] ^" .

2315 Example 38

N-methyl-N-[2-(l l-oxo-10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepin-3- yl)phenyl]ethanesulfonamide

Example 38A

2320 To a solution of N-(2-bromophenyl)ethanesulfonamide (0.079 g, 0.3 mmol) and

2CO ₃ (0.083 g, 0.6 mmol) in N,N-dimethylformamide (1.5 ml) was added iodomethane (0.021 ml, 0.330 mmol) and the mixture was stirred at 25°C for 20 hours. The reaction mixture was diluted with ethyl acetate; washed with water and brine; dried (MgS04) and filtered. The filtrate was concentrated to yield the title compound. MS APCI(+) m/z 278

2325 [M+H] ⁺ .

Example 38B

The title compound was prepared as described in Example 4B, except substituting Example 38A for 3-bromo-2-fluoropyridine. The crude product was purified by reverse

2330 phase HPLC on a customized Waters Purification system, eiuting with 10-95% CH3CN / 0.1% TFA in water then triturated with hexanes; filtered off and purified again by reverse phase HPLC using same conditions to afford the title compound. Ή NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.86 (s, 1H), 7.91 (s, 1H), 7.70 (d, J= 8.1 Hz, 1H), 7.53-7.59 (m, 1H), 7.41-7.51 (m, 2H), 7.34-7.38(m, 1H), 6.90-7.01 (m, 6H), 3.10 (s, 3H), 2.99(q,J=7.3

2335 Hz, 2H), 1.05 (t, J= 7.3 Hz, 3H); MS ESI(-) m/z 406 [M-H] ^" .

Example 39 methyl 3-{2-[methyl(methylsulfonyl)amino]phenyl}- l l-oxo-10,1 l -dihydro-5H- dibenzo[b,e][l ,4]diazepine-8-carboxylate

2340

Example 39A

methyl 2-(2-amino-4-(methoxycarbonyl)phenylamino)-4-chlorobenzoate To a solution of methyl-3,4-diaminobenzoate (2.8 g, 16.86 mmol, Alfa Aesar Chemical Company) in chlorobenzene (125 ml) was added Example 3A (5.0 g, 16.86 2345 mmol), K2CO3 (2.5 g, 17.71 mmol), and Cu (1.1 g, 16.86 mmol). The resulting mixture was heated at reflux over 18 hours. While hot, the mixture was filtered through a thin layer of diatomaceous earth and the cake washed with dichloromethane. The filtrate was concentrated and the crude product purified by flash chromatography on silica gel, eluting with a 10% - 100% CH2CI2 / hexanes gradient to yield the title compound. MS 2350 ESI(+) /M/Z 334.9 [M+H] ⁺ .

Example 39B

methyl 3-chloro- l l -oxo- 10, 1 l -dihydro-5H-dibenzo[b,e][l,4]diazepine-8-carboxylate Example 39A (1 .4 g, 4.15 mmol) was dissolved in methanol (50 ml) and

2355 concentrated HCI (10 ml) added. The resulting mixture was heated at reflux over 18 hours. After cooling to room temperature, the mixture was filtered through a medium fritted glass funnel and the cake washed with water. The resulting solids were dried to yield the title compound. MS ESI(+) m/z 302.8 [M+H] ⁺ .

2360 Example 39C

N-methyl-N-(2-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide

To a solution of [(2-methylsulfonyl)aminophenyl]boronic acid, pinacol ester (5.4 g, 18.04 mmol, Aldrich) in N,N-dimethylformamide (50 ml) was added K2CO3 (5.0 g, 36.1 mmol) and iodomethane ( 1.24 ml, 19.84 mmol). After stirring at room temperature

2365 for 18 hours, the solution was diluted with water and ethyl acetate. The layers were separated and the aqueous layer further extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na ₂ S0 ₄ ), and concentrated. The crude product was purified by column chromatography on silica gel, eluting with a 5% - 40% ethyl acetate / hexanes gradient to yield the title compound. MS ESI(+) m/z 302.8 2370 [M+H] ⁺ .

Example 39D

methyl 3-{2-[methyl(methylsulfonyl)amino]phenyl}- l l-oxo- 10,1 l-dihydro-5H- dibenzo[b,e][l ,4]diazepine-8-carboxylate

2375 To a solution of Example 39B (1.05 g, 3.47 mmol) in a mixture of

dimethoxyethane (80 ml) and methanol (40 ml) was added Example 39C (2.2 g, 6.94 mmol), cesium fluoride (1.6 g, 10.41 mmol), and 2'-(dicyclohexylphosphino)-N,N- dimethylbiphenyl-2-amine (0.41 g, 1.04 mmol). The resulting mixture was bubbled with nitrogen gas and palladium(II) acetate (0.13 g, 0.59 mmol) was added. After heating at

2380 reflux over 18 hours, the reaction mixture was filtered through a layer of diatomaceous earth. The filtrate was washed with water and brine, dried (Na ₂ S0 ) and concentrated. The crude product was purified by column chromatography on silica gel, eluting with a 10% - 80% ethyl acetate / hexanes gradient to yield the title compound. Ή NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.98 (s, 1 H), 8.41 (s, 1 H), 7.73 (d, 1 H), 7.61 - 7.56 (m, 2 H),

2385 7.54 - 7.35 (m, 4 H), 7.07 (d, 1 H), 7.01 (d, 1 H), 6.97 (dd, 1 H), 3.80 (s, 3 H), 3.10 (s, 3 H), 2.90 (s, 3H). MS ESI(+) m/z 452.0 [M+H] ⁺ .

Example 40

3-{2-[methyl(methylsulfonyl)amino]phenyl}- l l-oxo- 10, 1 l -dihydro-5H- 2390 dibenzo[b,e][l ,4]diazepine-8-carboxylic acid

To a solution of Example 39 (1.77 g, 3.92 mmol) in a mixture of tetrahydrofuran ( 14ml) and methanol (14ml) was added 2.5N aqueous NaOH (9.4 ml, 23.52 mmol). After stirring at room temperature over 18 hours, the reaction mixture was diluted with water and washed with ethyl acetate. The aqueous layer was acidified with 2N aqueous 2395 HCI until the solution reached a pH of 2. The crude product was extracted several times with ethyl acetate. The combined organic layers were dried (Na ₂ S0 ₄ ), filtered, and concentrated to yield the title compound. Ή NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.96 (s, 1 H), 8.35 (s, 1 H), 7.74 (d, 1 H), 7.59 - 7.53 (m, 2 H), 7.48 - 7.45 (m, 4 H), 7.38 (dd, 1 H), 7.05 (dd, 1 H), 7.01 (d, 1 H), 6.97 (dd, 1 H), 3.10 (s, 3 H), 2.89 (s, 3 H). MS 2400 ESI(+) m/z 438.0 [M+H] ⁺ .

Example 41

N-isopropyl-N-[2-(l l -oxo-10, 1 l-dihydro-5H-dibenzo[b,e][l ,4]diazepin-3- yl)phenyl]methanesulfonamide

2405 The title compound was prepared as described in Example 9A and 4B, except substituting 2-iodopropane for iodoethane and N-(2-bromophenyl)-N- isopropylmethanesulfonamide for 3-bromo-2-fiuoropyridine respectively. The reaction mixture was heated in the Biotage Initiator Microwave Synthesizer for 2x 20 minutes at 120°C. After cooling at room temperature, it was filtered and concentrated. The crude

2410 product was purified by reverse phase HPLC on a customized Waters Purification

system, eluting with 10-95% CH ₃ CN / 0.1% TFA in water to yield the title compound. Ή NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.86 (s, 1H), 7.87-7.89 (bs, 1 H), 7.68 (d, J= 8.2 Hz, 1 H), 7.38-7.55 (m, 4H), 7.13 (dd, J = 8.1 , 1.6 Hz, 1 H), 6.89-7.03 (m, 5H), 3.96-4.01 (m, 1 H), 3.14 (s, 3H), 0.99 (d, J= 6.5 Hz, 3H), 0.55 (d, J= 6.6 Hz, 3H); MS ESI(-) m/z 420

2415 [M-H]\

Example 42

N-butyl-N-[2-(l l -oxo-10,1 l -dihydro-5H-dibenzo[b,e][l ,4]diazepin-3- yl)phenyl]methanesulfonamide

2420 The title compound was prepared as described in Example 9A and 4B, except substituting 1 -iodobutane for iodoethane and N-(2-bromophenyl)-N- butylmethanesulfonamide for 3-bromo-2-fluoropyridine respectively. After cooling at room temperature, the reaction mixture was filtered and concentrated. The crude product was purified by reverse phase HPLC on a customized Waters Purification system, eluting

2425 with 10-95% CH ₃ CN / 0.1 % TFA in water and was purified again by SFC on modified Berger Instruments Prep SFC system (gradient of 10-50% methanol and C0 ₂ ) to afford the title compound. Ή NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.86 (s, 1 H), 7.88-7.90 (bs, 1 H), 7.69 (d, J= 8.1 Hz, 1 H), 7.41 -7.56 (m, 3H), 7.34-7.38 (m, 1 H), 7.04 (dd, .7 = 8.1 , 1.6 Hz, 1 H), 6.87-7.02 (m, 5H), 3.08-3.43 (m, 2H), 3.05 (s, 3H), 1.06-1.24 (m, 2H), 0.91- 2430 1.07 (m, 2H), 0.66 (t, J= 7.2 Hz, 3H); MS ESI(-) m/z 434 [M-H]\

Example 43

N-[2-(l 1-oxo- 10, 1 1 -dihydro-5H-dibenzo[b,e][l ,4]diazepin-3-yl)phenyl]-N- propylmethanesulfonamide

2435 The title compound was prepared as described in Example 9 A and 4B, except substituting 1 -iodopropane for iodoethane and N-(2-bromophenyl)-N- propylmethanesulfonamide for 3-bromo-2-fluoropyridine respectively. Ή NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.86 (s, 1 H), 7.89 (s, 1 H), 7.69 (d, J= 8.0 Hz, 1 H), 7.44-7.56 (m, 3H), 7.32-7.38 (m, 1 H), 6.90-7.03 (m, 6H), 3.08-3.45 (m, 2H), 3.03 (s, 3H), 1.20- 2440 1.27 (m, 2H), 0.64 (t, J = 7.3 Hz, 3H); MS ESI(+) m/z 422 [M+H] ⁺ , 439 [M+NH^*.

Example 44

N-isobutyl-N-[2-(l 1 -oxo- 10, 1 l-dihydro-5H-dibenzo[b,e][ 1 ,4]diazepin-3- yl)phenyl]methanesulfonamide

2445 The title compound was prepared as described in Example 9A and 4B, except substituting l -iodo-2-methylpropane for iodoethane and N-(2-bromophenyl)-N- isobutylmethanesulfonamide for 3-bromo-2-fluoropyridine respectively. Ή NMR (300 MHz, DMSO-d ₆ ) 6 ppm 9.87 (s, 1 H), 7.87 (s, 1 H), 7.69 (d, J = 8.1 Hz, 1 H), 7.57 (dd, J = 7.5, 1 .8 Hz, 1H), 7.41-7.52 (m, 2H), 7.33 (dd, J= 7.2, 2.0 Hz, 1 H), 7.04 (dd, J = 8.1 , 1 .5

2450 Hz, 1 H), 6.90-6.98 (m, 5H), 3.1 1 (s, 3H), 3.04-3.15 (m, 1 H), 2.84-2.93 (m, 1 H), 1 .24 (t, J = 6.7 Hz, 1 H), 0.68-0.72 (m, 3H), 0.39-0.43 (m, 3H) ; MS ESI(+) m/z 436 [M+H] ⁺ , 453 [M+NH4] ⁺ , 458 [M+Na] ⁺ .

Example 45

2455 3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo- 10, 1 l -dihydro-5H- d i benzo[b,e] [ 1 ,4]diazepine-7-carboxam ide

Example 45A

N-methyl-N-(2-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide 2460 To a solution of N-(2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)methanesulfonamide (0.297 g, 1 mmol) and 2CO ₃ (0.276 g, 2.0 mmol) in N,N-dimethylformamide (5 ml) was added iodomethane (0.069 ml, 1.1 mmol) and the reaction mixture was stirred at 25°C for 20 hours. The reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water and brine; dried (MgSC^)

2465 and filtered. The filtrate was concentrated and the crude product was triturated with hexane to yield the title compound. MS ESI(+) m/z 312 [M+H] ⁺ .

Example 45B

methyl 4-chloro-2-(5-(methoxycarbonyl)-2-nitrophenylamino)benzoate 2470 A solution of Example 3 A (5.35 g, 18.04 mmol), methyl 3-amino-4-nitrobenzoate

(3.54 g, 18.04 mmol), CsC0 ₃ (5.88 g, 18.04 mmol), palladium(II) acetate (0.202 g, 0.902 mmol) and 1 , 1 '-bis(diphenylphosphino)ferrocene ( 1.0 g, 1.804 mmol) in toluene was heated at 95°C for 16 hours. The reaction mixture was brought to 80°C; filtered through a plug of silica gel and washed with ethyl acetate. The solvent was removed and residue 2475 was purified over silica gel. The material was collected and washed with minimum

amount of hot ethanol to yield the title compound. MS ESI(+) m/z 365 [M+H] ⁺ .

Example 45C

methyl 2-(2-amino-5-(methoxycarbonyl)phenylamino)-4-chlorobenzoate 2480 A solution of Example 45B (3.25g, 8.91 mmol) in methanol (60 ml) was added to solvent washed Ra-Ni (3.25 g, 55.4 mmol) in a SS pressure bottle (250 mL). The mixture was stirred for 2 hours at 30 psi and room temperature. Some substrate was observed upon filtration. The filter cake was washed with tetrahydrofuran and equivalent weight of RaNi was added. The reaction was continued under same conditions. The reaction 2485 mixture was filtered through a nylon membrane and concentrated to yield the title

compound. MS ESI(-) m/z 333 [M-H] ^" .

Example 45D

methyl 3-chloro-l l -oxo- 10, 1 l -dihydro-5H-dibenzo[b,e][l ,4]diazepine-7-

2490 carboxylate To Example 45C ( 1.3 g, 3.88 mmol) in methanol was added concentrated HC1 (15 ml) drop by drop in small batches at various intervals then reaction mixture was refluxed for 20 hours. Upon cooling the reaction mixture at room temperature, the solid precipitated out. It was filtered and dried to yield the title compound. MS ES1(+) m/z 303 2495 [M+H] ⁺ .

Example 45E

methyl 3-(2-(N-methylmethylsulfonamido)phenyl)- l l-oxo- 10, 1 l -dihydro-5H- dibenzo[b,e][l ,4]diazepine-7-carboxylate

2500 A mixture of Example 45 A ( 1.95 g, 6.25 mmol), Example 45D (0.946 mg, 3.13 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethyIamino)biphenyl (369 mg, 0.938 mmol), palladium(II) acetate ( 1 19 mg, 0.53 mmol) and CsF ( 1.424 g, 9.38 mmol) in dimethoxyethane (2 ml) and methanol (1 ml) was heated under reflux for 12 hours. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The

2505 aqueous layer was extracted with additional ethyl acetate. The combined organic layers were dried (MgS0 ₄ ); filtered and purified over a silica gel column, eiuting with 20-50 % ethyl acetate /hexanes to afford the title compound.

Example 45F

2510 3-(2-(N-methylmethy lsulfonamido)phenyl)- 1 1 -oxo- 10, 1 1 -dihydro-5H- dibenzo[b,e][l ,4]diazepine-7-carboxylic acid

Example 45E (0.770 g, 1.705 mmol), and aqueous NaOH (7.5 ml, 15.0 mmol) in tetrahydrofuran (3.75 ml) and ethanol (3.75 ml) were stirred at 25°C for 18 hours. The reaction mixture was concentrated to yield the title compound. MS ESI(+) m/z 438 2515 [M+H] ⁺ , 455 [M+N¾] ⁺ .

Example 45G

3-{2-[methyI(methylsulfonyl)amino]phenyl}- l l-oxo- 10, 1 l -dihydro-5H- d ibenzo[b,e] [ 1 ,4]d iazepine-7-carboxam ide

2520 Example 45F (0.022 g, 0.05 mmol), l-ethyl-3-[3-(dimethylamino)propyl]- carbodiimide hydrochloride (0.012 g, 0.06 mmol), NFL,CI (5.35 mg, 0.1 mmol), N,N- diisopropylethylamine (0.026 ml, 0.15 mmol) and 1 -hydroxybenzotriazole hydrate (8.42 mg, 0.055 mmol) in N,N-dimethylformamide (0.5 ml) were stirred at 25°C for 18 hours. The reaction mixture was concentrated. The crude product was purified by reverse phase 2525 HPLC on a customized Waters Purification system, eluting with 10-95% CH ₃ CN / 0.1 % TFA in water to yield the title compound. Ή NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.02 (s, I H), 8.07 (s, I H), 7.69-7.82 (m, 2H), 7.54-7.61 (m, 2H), 7.35-7.53 (m, 4H), 7.22-7.25 (m, IH), 6.93-7.02 (m, 3H), 3.1 1 (s, 3H), 2.90 (s, 3H) ; MS ESI(+) m/z 437 [M+H]\ 454 [M+N¾] ⁺ ,459 [M+Na] ⁺ .

2530

Example 46

3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l ,4]diazepine-8-carboxamide

Example 40 (0.022 g, 0.05 mmol), l-ethyl-3-[3-(dimethylamino)propyl]- 2535 carbodiimide hydrochloride (0.012 g, 0.06 mmol), ammonium chloride (5.35 mg, 0.1 mmol), triethylamine (0.021 ml, 0.15 mmol) and 1 -hydroxybenzotriazole hydrate (8.42 mg, 0.055 mmol) in N,N-dimethylformamide (0.5 ml) were stirred at 25°C for 18 hours. The reaction mixture was concentrated. The crude product was purified by reverse phase HPLC on a customized Waters Purification system, eluting with 10-95% CH ₃ CN / 0.1% 2540 TFA in water to yield the title compound. Ή NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.93 (s, IH), 8.21 (s, I H), 7.74-7.78 (bs, I H), 7.72 (d, J= 8.1 Hz, I H), 7.56-7.61 (m, I H), 7.42- 7.53 (m, 4H), 7.36-7.41 (m, 1 H), 7.18-7.22 (bs, 1 H), 7.01 (d, J = 1.8 Hz, 1 H), 6.96-7.04 (bs, I H), 6.96 (dd, J = 8.2, 1.5 Hz, 1 H), 3.09 (s, 3H), 2.90 (s, 3H); MS ESI(-) m/z 435 [M-H]\

2545

Example 47

3- {2-[methy l(methy lsulfony l)amino]pheny 1 } -N-( 1 -methy lpiperidin-4-y 1)- 1 1 -oxo- 10, 1 1- dihydro-5H-dibenzo[b,e][l ,4]diazepine-8-carboxamide

To Example 40 (0.022 g, 0.05 mmol) and 0-(benzotriazol- l -yl)-N,N,N',N'- 2550 tetramethyluronium tetrafluoroborate (0.029 g, 0.09 mmol) in N,N-dimethylformamide (0.5 ml) was added N,N-diisopropylethylamine (0.026 ml, 0.15 mmol) followed by 1- methylpiperidin-4-amine (8.56 mg, 0.075 mmol) in N,N-dimethylformamide (0.3 ml). The reaction mixture was stirred at 25 °C for 18 hours. The crude product was purified by reverse phase HPLC on a customized Waters Purification system, eluting with 10-95% 2555 CH ₃ CN / 0.1 % TFA in water to yield the title compound. Ή NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.91 (s, 1 H), 9.17-9.22 (m, 1 H), 8.27 (d, J = 7.7 Hz, 1 H), 8.24-8.24 (m, 1 H), 7.72 (d, J = 8.1 Hz, 1 H), 7.59 (d, J = 8.5 Hz, 1 H), 7.42-7.53 (m, 4H), 7.36-7.40 (m, 1 H), 6.94- 7.04 (m, 3H), 3.94-4.00 (m, 1 H), 3.10 (s, 3H), 2.98-3.15 (m, 2H), 2.90 (s, 3H), 2.76-2.80 (m, 3H), 1.93-2.05 (m, 2H), 1.68- 1.74 (m, 2H); MS ESI(-) m/z 532 [M-H]\

2560

Example 48

3-{2-[methyl(methylsulfonyl)amino]phenyl}- l l-oxo-N-(pyrimidin-4-ylmethyl)-10,l 1- dihydro-5H-dibenzo[b,e][ l ,4]diazepine-7-carboxamide

To a 20 mL vial was added Example 45F( 15 mg, 0.03 mmol), dissolved in N,N- 2565 dimethylacetamide (0.5 mL) followed by the addition of pyrimidin-4-ylmethanamine (4.4 mg, 0.04 mmol) dissolved in N,N-dimethylacetamide (0.137 mL). Then a solution of 0-(7-azabenzotriazol- l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ( 15 mg, 0.04 mmol) dissolved in N,N-dimethylacetamide (0.6 mL) was added followed by triethylamine (10 mg, 0.1 mmol). The mixture was shaken overnight at room temperature 2570 then concentrated to dryness. The crude product was purified by reverse phase HPLC on an Agilent 1 100 Series Purification system, eluting with 10- 100% CH ₃ CN / 0.1 % TFA in water to yield the title compound. Ή NMR (500 MHz, Pyridine-d ₅ / D ₂ 0) δ ppm 9.28 (s, 1 H), 8.73 (m, 1 H), 8.40 (d, J = 8.1 Hz, 1 H), 8.37-8.38 (m, 1 H), 8.02-8.04 (m, 1 H), 7.64 (m, 1 H), 7.61 (s, 1 H), 7.56 (d, J = 5.2 Hz, 1 H), 7.39-7.50 (m, 4H), 7.32-7.34 (m, 1 H), 2575 4.98-4.99 (bs, 2H), 3.18 (s, 3H), 3.06 (s, 3H); MS ESI(-) m/z 527 [M-H]\

Example 49

3- {2-[methyl(methylsulfonyl)amino]phenyl}- 1 1 -oxo-N-(4-pyrrolidin- 1 -ylbutyl)- 10, I I - dihydro-5H-dibenzo[b,e][ l ,4]diazepine-7-carboxamide

2580 The title compound was prepared as described in Example 48, except substituting

4-(pyrrolidin- l-yl)butan- l-amine for pyrimidin-4-ylmethanamine. Ή NMR (500 MHz, Pyridine-d ₅ / D ₂ 0) δ ppm 8.38 (d, J= 8.1 Hz, 1 H), 8.36 (d, J= 1.9 Hz, 1 H), 7.96 (dd, J = 8.2, 1.9 Hz, 1 H), 7.62-7.66 (m, 2H), 7.38-7.49 (m, 4H), 7.32 (dd, J= 8.1 , 1 .6 Hz, 1 H), 3.61 (d,J= 5.2 Hz, 2H), 3.35-3.41 (m, 4H), 3.28-3.32 (m, 2H), 3.21 (s, 3H), 3.05 (s, 3H), 2585 1.93-1.99 (m, 2H), 1.89-1.93 (m, 4H), 1.78 (p,J= 7.0 Hz, 2H); MS ESI(+) m/z 562

[M+H] ⁺ .

Example 50

3-{2-[methyl(methylsulfonyl)amino]phenyl}-N-[3-(4-methylpipe ridin-l-yl)propyl]-l 1- 2590 oxo- 10,11 -dihydro-5H-dibenzo[b,e][ 1 ,4]diazepine-7-carboxamide

The title compound was prepared as described in Example 48, except substituting 3-(4-methylpiperidin-l-yl)propan-l -amine for pyrimidin-4-yImethanamine. Ή NMR (500 MHz, Pyridine-ds / D ₂ 0) δ ppm 8.39 (d,J= 8.1 Hz, 1H), 8.37 (d, J= 1.9 Hz, 1H), 7.96 (dd, J= 8.2, 1.9 Hz, 1H), 7.62-7.67 (m, 2H), 7.39-7.49 (m, 4H), 7.32 (d, J= 8.2 Hz, 2595 1 H), 3.72 (t, J= 6.4 Hz, 2H), 3.56-3.61 (m, 2H), 3.38 (t, J= 7.7 Hz, 2H), 3.22 (s, 3H), 3.05 (s, 3H), 2.89-2.96 (m, 2H), 2.31 (t,J= 7.2 Hz, 2H), 1.65-1.69 (m, 2H), 1.48-1.61 (m, 3H), 0.75 (d, J= 5.9 Hz, 3H); MS ESI(+) m/z 576 [M+H] ⁺ .

Example 51

2600 3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-N-(tetrahydrofuran-3-ylmethyl)- 10, 11 -dihydro-5H-dibenzo[b,e][ 1 ,4]diazepine-7-carboxamide

Example 52

2605 3-{2-[methyl(methylsulfonyl)amino]phenyl}-N-(3-moφholin-4-y lpropyl)-l l-oxo-10,11- dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide

The title compound was prepared as described in Example 48, except substituting 3-morpholinopropan-l -amine for pyrimidin-4-ylmethanamine. Ή NMR (500 MHz, Pyridine-ds / D ₂ 0) δ ppm 8.38 (d,J= 8.1 Hz, 1H), 8.34 (s, 1H), 7.92-7.95 (m, 1H), 7.63- 2610 7.66 (m, 1H), 7.61 (s, 1H), 7.39-7.48 (m, 4H), 7.32 (d, J = 8.2 Hz, 1H), 3.83 (t,J=4.5

Hz, 4H), 3.71 (t, J= 6.7 Hz, 2H), 3.19 (s, 3H), 3.05 (s, 3H), 2.79-2.83 (m, 2H), 2.74-2.80 (m, 4H), 2.10 (p, J = 7.0 Hz, 2H); MS ESI(+) m/z 564 [M+H] ⁺ .

Example 53 2615 3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-N-(2-pyridin-2-ylethyl)-10,l 1- dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide

The title compound was prepared as described in Example 48, except substituting 2-(pyridin-2-yl)ethanamine for pyrimidin-4-ylmethanamine. Ή NMR (500 MHz, Pyridine-ds / D ₂ 0) δ ppm 8.59-8.61 (m, 1H), 8.38 (d, J= 8.1 Hz, 1H), 8.30 (s, 1H), 7.88 2620 (d,J=7.5Hz, 1H), 7.63-7.66 (m, 1H), 7.58-7.59 (m, 1H), 7.51-7.55 (m, 1H), 7.37-7.48 (m, 4H), 7.29-7.33 (m, 1H), 7.22-7.25 (m, 1H), 7.06-7.09 (m, 1H), 4.09 (t,J= 7.2 Hz, 2H), 3.32 (t,J= 7.2 Hz, 2H), 3.18 (s, 3H), 3.05 (s, 3H); MS APCI(+) m/z 542 [M+H] ⁺ .

Example 54

2625 3-{2-[methyl(methylsuIfonyl)amino]phenyl}-l l-oxo-N-(2-piperidin-l-ylethyl)-10,l 1- dihydro-5H-dibenzo[b,e][ 1 ,4]diazepine-7-carboxamide

The title compound was prepared as described in Example 48, except substituting 2-(piperidin-l-yl)ethanamine for pyrimidin-4-ylmethanamine. Ή NMR (500 MHz, Pyridine-ds / D ₂ 0) δ ppm 8.39 (d, J = 8.1 Hz, 1 H), 8.28 (d, J = 1.9 Hz, 1 H), 7.91 (dd, J = 2630 8.2, 1.9 Hz, 1 H), 7.64-7.67 (m, 1 H), 7.63-7.65 (m, 1 H), 7.49 (d, J = 7.5 Hz, 1 H), 7.39- 7.47 (m, 2H), 7.37 (d, J = 8.2 Hz, 1 H), 7.31 -7.34 (m, 1 H), 4.07 (t, J = 6.1 Hz, 2H), 3.54- 3.61 (m, 2H), 3.25-3.43 (m, 4H), 3.24 (s, 3H), 3.06 (s, 3H), 1.72-1.76 (m, 4H), 1.37-1.43 (m, 2H); MS ESI(+) m/z 548 [M+H] ⁺ .

2635 Example 55

3- {2-[methy l(methylsulfonyl)amino]phenyl}- 11 -oxo-N-(2-pyrrolidin- 1 -ylethyl)- 10, 11- dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide

The title compound was prepared as described in Example 48, except substituting 2-(pyrrolidin-l-yl)ethanamine for pyrimidin-4-ylmethanamine. Ή NMR (500 MHz, 2640 Pyridine-ds / D ₂ 0) δ ppm 8.39 (d, J =8.1 Hz, 1H), 8.27 (d, J= 1.9 Hz, 1H), 7.90-7.92 (m, 1H), 7.64-7.68 (m, 1H), 7.63-7.65 (m, 1H), 7.48-7.51 (m, 1H), 7.38-7.47 (m, 2H), 7.36 (d, J= 8.2 Hz, 1H), 7.31-7.34 (m, 1H), 4.05 (t, J= 5.8 Hz, 2H), 3.70 (t, J= 5.8 Hz, 2H), 3.54-3.61 (m, 4H), 3.24 (s, 3H), 3.06 (s, 3H), 1.88-1.95 (m, 4H); MS APC1(+) m/z 534 [M+H] ⁺ .

2645 Example 56

N-[2-(dimethylamino)ethyl]-3-{2-[methyl(methylsulfonyl)amino ]phenyl }- 11 -oxo- 10, 11- dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide

The title compound was prepared as described in Example 48, except substituting 2650 N^N'-dimethylethane-l^-diamine for pyrimidin-4-ylmethanamine. Ή NMR (500 MHz, Pyridine-ds / D ₂ 0) δ ppm 8.38 (d,J= 8.1 Hz, 1H), 8.27 (d, J= 1.9 Hz, 1H), 7.90 (d,J = 7.5 Hz, 1H), 7.64-7.68 (m, 1H), 7.63-7.65 (m, 1H), 7.48-7.51 (m, 1H), 7.39-7.47 (m, 2H), 7.34 (d,J= 8.2 Hz, 1H), 7.30-7.33 (m, 1H), 4.03 (t, J= 5.9 Hz, 2H), 3.55 (t, J = 6.0 Hz, 2H), 3.24 (s, 3H), 3.06 (s, 3H), 3.00 (s, 6H); MS ESI(+) m/z 508 [M+H] ⁺ .

2655

Example 57

3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-N-(2-pyridin-4-ylethyl)-10,l 1- dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide

The title compound was prepared as described in Example 48, except substituting 2660 2-(pyridin-4-yl)ethanamine for pyrimidin-4-ylmethanamine. Ή NMR (500 MHz,

Pyridine-ds / D ₂ 0) δ ppm 8.57-8.59 (m, 2H), 8.38 (d, J= 8.1 Hz, 1 H), 8.33 (d, J= 1.9 Hz, 1H), 7.89 (dd,J=8.2, 1.9 Hz, 1H), 7.63-7.66 (m, 1H), 7.57-7.59 (m, 1H), 7.39-7.49 (m, 3H), 7.38 (d,J = 8.1 Hz, 1H), 7.30-7.33 (m, 1H), 7.21-7.24 (m, 2H), 3.86 (t,J= 7.2 Hz, 2H), 3.18 (s, 3H), 3.06 (s, 3H), 3.02-3.07 (m, 2H); MS APCI(+) m/z 542 [M+H] ⁺ .

2665

Example 58

3-{2-[methyl(methylsulfonyl)amino]phenyl}-N-[3-(2-methylpipe ridin-l-yl)propyl]-l 1- oxo- 10, 11 -dihydro-5H-dibenzo[b,e][ 1 ,4]diazepine-7-carboxamide

The title compound was prepared as described in Example 48, except substituting 2670 3-(2-methyIpiperidin-l-yl)propan-l-amine for pyrimidin-4-ylmethanamine. Ή NMR (500 MHz, Pyridine-ds / D ₂ 0) δ ppm 8.37-8.40 (m, 2H), 7.98 (dd, J= 8.2, 1.9 Hz, 1H), 7.63-7.66 (m, 1H), 7.62-7.65 (m, 1H), 7.38-7.49 (m, 4H), 7.32 (d, J= 8.2 Hz, 1H), 3.69- 3.79 (m, 2H), 3.50-3.59 (m, 1H), 3.39-3.50 (m, 1H), 3.30-3.37 (m, 1H), 3.17-3.32 (m, 1H),3.22 (s,3H),3.05 (s, 3H), 2.97-3.08 (m, 1H), 2.25-2.31 (m, 2H), 1.60-1.81 (m, 4H), 2675 1.49-1.55 (m, IH), 1.30-1.41 (m, 1H), 1.30 (d, J= 6.4 Hz, 3H); MS ESI(+) m/z 576

[M+H] ⁺ . Example 59

3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-N-(2-pyridin-3-ylethyl)-10, l 1- 2680 dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide

The title compound was prepared as described in Example 48, except substituting 2-(pyridin-3-yl)ethanamine for pyrimidin-4-ylmethanamine. Ή NMR (500 MHz, Pyridine-ds / D ₂ 0) δ ppm 8.68-8.70 (m, IH), 8.53-8.55 (m, I H), 8.38 (d, J = 8.1 Hz, I H), 8.31 (s, I H), 7.87-7.90 (m, I H), 7.62-7.66 (m, I H), 7.60-7.63 (m, I H), 7.58-7.60 (m, 2685 I H), 7.39-7.48 (m, 3H), 7.37 (d, J = 8.2 Hz, I H), 7.30-7.33 (m, I H), 7.14-7.17 (m, I H), 3.84 (t, J= 7.2 Hz, 2H), 3.19 (s, 3H), 3.06 (s, 3H), 3.02-3.07 (m, 2H); MS APCI(+) m/z 542 [M+H] ⁺ .

Example 60

2690 3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-N-(pyridin-3-ylmethyl)-10, l 1- dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide

The title compound was prepared as described in Example 48, except substituting pyridin-3-ylmethanamine for pyrimidin-4-ylmethanamine. Ή NMR (500 MHz, Pyridine- ds / D ₂ 0) δ ppm 8.92-8.93 (bs, I H), 8.58 (d, J= 4.9 Hz, IH), 8.38 (d, J= 8.1 Hz, I H), 2695 8.33 (d, J= 1.9 Hz, IH), 7.94 (dd, J= 8.2, 1.9 Hz, I H), 7.85-7.87 (m, I H), 7.63-7.66 (m, IH), 7.58-7.60 (m, I H), 7.39-7.48 (m, 4H), 7.30-7.34 (m, IH), 7.20 (dd, J= 7.8, 4.8 Hz, IH), 4.82-4.82 (bs, 2H), 3.17 (s, 3H), 3.05 (s, 3H); MS APCI(+) m/z 528 [M+H] ⁺ .

Example 61

2700 N-[2-(l H-imidazol-4-yl)ethyl]-3-{2-[methyl(methylsulfonyl)amino]phe nyl}- l 1-oxo- 10, 1 1 -dihydro-5H-dibenzo[b,e][ 1 ,4]diazepine-7-carboxamide

The title compound was prepared as described in Example 48, except substituting 2-( l H-imidazol-4-yl)ethanamine for pyrimidin-4-ylmethanamine. Ή NMR (500 MHz, Pyridine-ds / D ₂ 0) δ ppm 8.47 (s, I H), 8.38 (d, J= 8.1 Hz, I H), 8.3 1 (s, I H), 7.89-7.92 2705 (m, I H), 7.63-7.66 (m, I H), 7.59-7.61 (m, I H), 7.39-7.49 (m, 3H), 7.37 (d, J= 8.2 Hz, I H), 7.29-7.33 (m, 2H), 4.01 (t, J= 7.1 Hz, 2H), 3.23 (t, J= 7.1 Hz, 2H), 3.19 (s, 3H), 3.05 (s, 3H); MS ESI(+) m/z 531 [M+H] ⁺ . Example 62

2710 3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-N-(3-pyrrolidin-l-ylpropyl)-10,l 1- dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide

The title compound was prepared as described in Example 48, except substituting 3-(pyrrolidin-l-yl)propan-l -amine for pyrimidin-4-ylmethanamine. Ή NMR (500 MHz, Pyridine-dj / D ₂ 0) δ ppm 8.39 (d, J= 8.1 Hz, 1H), 8.33 (s, 1H), 7.92-7.95 (m, 1H), 7.62- 2715 7.67 (m, 2H), 7.37-7.49 (m, 4H), 7.31-7.33 (m, 1H), 3.72 (t,J= 6.5 Hz, 2H), 3.38-3.45 (m, 6H), 3.21 (s, 3H), 3.06 (s, 3H), 2.28 (t, J= 7.2 Hz, 2H), 1.89-1.92 (m, 4H); MS ESI(+) m/z 548 [M+H] ⁺ .

Example 63

2720 N-[3-(diethylamino)propyl]-3-{2-[methyl(methylsulfonyl)amino ]phenyl}-l l-oxo-10,11- dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide

The title compound was prepared as described in Example 48, except substituting N' _j N'-diethylpropane-l^-diamine for pyrimidin-4-ylmethanamine. Ή NMR (500 MHz, Pyridine-d ₅ /D ₂ 0)5 ppm 8.39-8.39 (m, 1H), 8.38 (d, J= 5.0 Hz, 1H), 7.96-7.98 (m, 1H), 2725 7.63-7.66 (m, 2H), 7.39-7.49 (m, 4H), 7.31-7.33 (m, 1H), 3.75 (t, J= 6.4 Hz, 2H), 3.41- 3.44 (m, 2H), 3.22-3.28 (m, 4H), 3.22 (s, 3H), 3.05 (s, 3H), 2.26-2.31 (m, 2H), 1.25 (t, J = 7.3 Hz, 6H); MS ESI(+) m/z 550 [M+H] ⁺ .

Example 64

2730 N-[3-(dimethylamino)propyl]-3-{2-[methyl(methylsulfonyl)amin o]phenyl}-l l-oxo- 10,11 -dihydro-5H-dibenzo[b,e][ 1 ,4]diazepine-7-carboxamide

The title compound was prepared as described in Example 48, except substituting N^N'-dimethylpropane-l^-diamine for pyrimidin-4-ylmethanamine. Ή NMR (500 MHz, Pyridine-d ₅ /D ₂ 0)5ppm8.39(d,J=8.1 Hz, 1H), 8.35 (d,J= 1.9 Hz, 1H), 7.94 2735 (dd,J=8.2, 1.9 Hz, 1H), 7.63-7.67 (m, 1H), 7.61-7.65 (m, 1H), 7.38-7.49 (m, 4H), 7.30- 7.34 (m, 1H), 3.72 (t, J= 6.4 Hz, 2H), 3.42 (t, J= 7.7 Hz, 2H), 3.22 (s, 3H), 3.05 (s, 3H), 2.98 (s, 6H), 2.24-2.29 (m, 2H); MS ESI(+) m/z 522 [M+H] ⁺ . Example 65

2740 N-[3-(lH-imidazol-l-yl)propyl]-3-{2-[methyl(methylsulfonyl)a mino]phenyl}-l l-oxo- 10,11 -dihydro-5H-dibenzo[b,e][ 1 ,4]diazepine-7-carboxamide

The title compound was prepared as described in Example 48, except substituting 3-( 1 H-imidazol- 1 -yl)propan- 1 -amine for pyrimidin-4-y Imethanamine. ¹ H NMR (500 MHz, Pyridine-d ₅ / D ₂ 0) δ ppm 8.40-8.41 (m, 1H), 8.38 (d, J= 8.1 Hz, 1H), 8.35 (d,J = 2745 1.9 Hz, 1H), 7.94 (dd,J= 8.2, 1.9 Hz, 1H), 7.62-7.67 (m, 2H), 7.39-7.49 (m, 6H), 7.32 (dd,J=8.2, 1.1 Hz, 1H), 4.18 (t,J= 7.0 Hz, 2H),3.61 (t,J=6.5 Hz, 2H), 3.20 (s, 3H), 3.06 (s, 3H), 2.19 (p, J= 6.8 Hz, 2H); MS APCI(+) m/z 545 [M+H] ⁺ .

Example 66

2750 N-(3-methoxypropyl)-3-{2-[methyl(methylsulfonyl)amino]phenyl }-l l-oxo-10,11- dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide

Example 67

3- {2-[methyl(methylsulfonyl)amino]phenyl} -N-(2-moφholin-4-ylethyl)- 11 -oxo- 10, 11- 2755 dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide

The title compound was prepared as described in Example 48, except substituting

2- morpholinoethanamine for pyrimidin-4-ylmethanamine. Ή NMR (500 MHz, Pyridine- d ₅ /D ₂ O)5ppm8.38(d,J=8.0 Hz, 1H), 8.32 (d,J= 1.9 Hz, 1H), 7.93 (dd,J=8.2, 1.9 Hz, 1H), 7.64-7.66 (m, 1H), 7.60-7.61 (m, 1H), 7.38-7.49 (m, 4H), 7.31 (dd,J= 8.1, 0.9

2760 Hz, 1H), 3.87 (t,J= 6.5 Hz, 2H), 3.75-3.77 (m, 4H), 3.19 (s, 3H), 3.06 (s, 3H), 2.88 (t,J = 6.5 Hz, 2H), 2.66-2.72 (m, 4H); MS ESI(-) m/z 548 [M-H]\

Example 68

N-(3-hydroxypropyl)-3-{2-[methyl(methylsuIfonyl)amino]phenyl }- 11 -oxo- 10, 11- 2765 dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide

The title compound was prepared as described in Example 48, except substituting

3- aminopropan-l-ol for pyrimidin-4-ylmethanamine. Ή NMR (500 MHz, Pyridine-ds / D ₂ 0)5ppm 8.38(d,J=8.1 Hz, 1H), 8.30 (d, J= 1.9 Hz, 1H),7.89 (dd,J=8.1, 1.9 Hz, 1H), 7.64-7.66 (m, 1H), 7.58-7.60 (m, 1H), 7.37-7.48 (m,4H),7.31 (dd,J=8.1, 1.5 Hz, 2770 1H), 3.96 (t, J= 6.0 Hz, 2H), 3.88 (t,J= 6.7 Hz, 2H), 3.18 (s, 3H), 3.05 (s, 3H), 2.11 (p, J= 6.4 Hz, 2H); MS ESI(-) m/z 493 [M-H]\

Example 69

3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-N-(pyridin-2-ylmethyl)-10,l 1- 2775 dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide

The title compound was prepared as described in Example 48, except substituting pyridin-2-ylmethanamine for pyrimidin-4-ylmethanamine. Ή NMR (500 MHz, Pyridine- d ₅ /D ₂ 0)5ppm 8.61 (d,J=4.0 Hz, 1H), 8.39 (d, J= 8.0 Hz, 1H), 8.36 (d,J= 1.9 Hz, 1H), 7.99 (dd,J=8.1,2.0 Hz, 1H), 7.63-7.67 (m, 1H), 7.56-7.61 (m, 2H), 7.51-7.55 (m, 2780 1H), 7.39-7.49 (m,4H), 7.32 (dd,J= 8.1, 1.6 Hz, 1H), 7.10-7.13 (m, 1H), 5.05 (s, 2H), 3.18 (s, 3H), 3.05 (s, 3H); MS APCI(+) m/z 528 [M+H] ⁺ .

Example 70

N-(2-methoxyethyl)-3-{2-[methyl(methylsulfonyl)amino]phenyl} -l l-oxo-10,11-dihydro- 2785 5H-dibenzo[b,e][l ,4]diazepine-7-carboxamide

The title compound was prepared as described in Example 48, except substituting

2- methoxyethanamine for pyrimidin-4-ylmethanamine. Ή NMR (500 MHz, Pyridine-ds / D ₂ 0)5ppm 8.38 (d,J= 8.1 Hz, 1H), 8.29 (d,J= 1.9 Hz, 1H), 7.90 (dd, J= 8.1, 2.0 Hz, 1H), 7.64-7.67 (m, 1H), 7.57 (d, J= 1.6 Hz, 1H), 7.39-7.51 (m, 3H), 7.38 (d, J= 8.2 Hz,

2790 1H), 7.31 (dd,J=8.0, 1.7Hz, 1H), 3.83 (t, J= 5.7 Hz, 2H), 3.64 (t, J= 5.7 Hz, 2H), 3.25 (s, 3H), 3.17 (s, 3H), 3.05 (s, 3H); MS ESI(+) m/z 495 [M+H] ⁺ .

Example 71

3- {2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-N-[3-(2-oxopyrrolidin-l-yl)propyl]- 2795 10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide

The title compound was prepared as described in Example 48, except substituting l-(3-aminopropyl)pyrrolidin-2-one for pyrimidin-4-ylmethanamine. Ή NMR (500 MHz, Pyridine-d ₅ / D ₂ 0) δ ppm 8.38 (d, J= 7.9 Hz, 1 H), 8.28 (d, J= 1.9 Hz, 1H), 7.98 (dd, J = 8.2, 1.7 Hz, 1H), 7.63-7.67 (m, 1H), 7.61-7.63 (m, 1H), 7.37-7.51 (m, 4H), 7.29-7.33 (m, 2800 1H), 3.56 (t,J= 6.5 Hz, 2H), 3.38 (t,J= 6.6 Hz, 2H), 3.19 (s, 3H), 3.14-3.18 (m, 2H), 3.05 (s, 3H), 2.30 (t,J= 8.1 Hz, 2H), 1.84 (p,J= 6.6 Hz, 2H), 1.72 (p,J= 7.5 Hz, 2H); MS ESI(+) m/z 562 [M+H] ⁺ .

Example 72

2805 N-[2-(diethylamino)ethyl]-3-{2-[methyl(methylsulfonyl)amino] phenyl}-l l-oxo-10,11- dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide

The title compound was prepared as described in Example 48, except substituting N' _j N'-diethylethane-l^-diamine for pyrimidin-4-ylmethanamine. 'HNMR (500 MHz, Pyridine-ds / D ₂ 0) δ ppm 8.39 (d,J = 8.1 Hz, 1H), 8.32 (d, J= 1.9 Hz, 1H), 7.94 (dd,J = 2810 8.2, 2.0 Hz, 1H), 7.63-7.67 (m, 2H), 7.38-7.50 (m, 4H), 7.32 (dd,J= 8.1, 1.6 Hz, 1H),

4.07 (t, J= 6.2 Hz, 2H), 3.58-3.62 (m, 2H), 3.34-3.38 (m, 4H), 3.23 (s, 3H), 3.05 (s, 3H), 1.28 (t, J= 7.2 Hz, 6H); MS APCI(+) m/z 536 [M+H] ⁺ .

Example 73

2815 N-(4-hydroxybutyl)-3-{2-[methyl(methylsulfonyl)amino]phenyl} -l l-oxo-10,11-dihydro-

5H-dibenzo[b,e][l,4]diazepine-7-carboxamide

The title compound was prepared as described in Example 48, except substituting 4-aminobutan-l-ol for pyrimidin-4-ylmethanamine. Ή NMR (500 MHz, Pyridine-ds / D ₂ 0)8ppm 8.38 (d,J= 8.1 Hz, 1H), 8.30 (d, J= 1.9 Hz, 1H), 7.91 (dd,J=8.1, 1.9 Hz, 2820 1H), 7.63-7.66 (m, 1H), 7.58 (d, J= 1.2 Hz, 1 H), 7.40-7.49 (m, 3H), 7.39 (d, J = 8.2 Hz, 1H), 7.31 (dd,J=8.2, 1.4 Hz, 1H), 3.85 (t,J=6.3 Hz, 2H), 3.70 (t,J=6.9 Hz, 2H), 3.17 (s, 3H), 3.05 (s, 3H), 1.92-1.98 (m, 2H), 1.81-1.87 (m, 2H); MS ESI(-) m/z 507 [M+H] ⁺ .

Example 74

2825 3-{2-[methyl(methylsulfonyl)amino]phenyl}-N-[2-(4-methylpipe razin-l-yl)ethyl]-l 1- oxo- 10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide

The title compound was prepared as described in Example 48, except substituting 2-(4-methylpiperazin-l-yl)ethanamine for pyrimidin-4-ylmethanamine. Ή NMR (500 MHz, Pyridine-ds / D ₂ 0) δ ppm 8.38 (d, J =8.1 Hz, 1H), 8.35 (d,J= 1.9 Hz, 1H), 7.94 2830 (dd,J=8.2, 1.9 Hz, 1H), 7.61-7.67 (m, 2H), 7.40-7.49 (m, 3H), 7.39 (d,J= 8.1 Hz, 1H), 7.31 (dd,J=8.2, 1.3 Hz, 1H), 3.79 (t, J= 6.4 Hz, 2H), 3.16-3.27 (m,4H), 3.21 (s, 3H), 3.06 (s, 3H), 2.85-3.00 (m, 4H), 2.81 (t,J= 6.4 Hz, 2H), 2.77 (s, 3H); MS ESI(+) m/z 563 [M+H] ⁺ .

2835 Example 75

3-{2-[methyl(methylsulfonyl)amino]phenyl}-N-(l-methylpiperid in-4-yl)-l l-oxo-10,11- dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide

The title compound was prepared as described in Example 48, except substituting l-methylpiperidin-4-amine for pyrimidin-4-ylmethanamine. Ή NMR (500 MHz, 2840 Pyridine-ds / D ₂ 0) δ ppm 8.38 (d, J =8.1 Hz, 1H), 8.34-8.35 (bs, 1H), 7.93 (dd, J= 8.2, 1.9 Hz, 1H), 7.63-7.66 (m, 1H), 7.60-7.62 (m, 1H), 7.40-7.50 (m, 3H), 7.39 (d, J= 8.2 Hz, 1H), 7.32 (dd,J= 8.1, 1.4 Hz, 1H), 4.48-4.55 (m, 1H), 3.60-3.64 (m, 2H), 3.20 (s, 3H), 3.12-3.22 (m, 2H), 3.06 (s, 3H), 2.92 (s, 3H), 2.31-2.40 (m, 2H), 2.21-2.26 (m, 2H); MS ESI(+) m/z 534 [M+H] ⁺ .

2845

Example 76

3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-N-(3-piperidin-l-ylpropyl)-10,l 1- dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide

The title compound was prepared as described in Example 48, except substituting 2850 3-(piperidin-l-yl)propan-l-amine for pyrimidin-4-ylmethanamine. Ή NMR (500 MHz, Pyridine-ds / D ₂ 0) δ ppm 8.39 (d,J= 8.0 Hz, 1H), 8.37 (d,J= 2.0 Hz, 1H), 7.96 (dd, J = 8.2, 2.0 Hz, 1H), 7.63-7.67 (m, 2H), 7.38-7.49 (m, 4H), 7.32 (dd,J= 8.0, 1.6 Hz, 1H), 3.71 (t,J= 6.4 Hz, 2H), 3.34-3.40 (m, 2H), 3.02-3.47 (m, 4H), 3.22 (s, 3H), 3.05 (s, 3H), 2.27-2.32 (m, 2H), 1.69-1.83 (m, 4H), 1.37-1.44 (m, 2H); MS APCI(+) m/z 562 [M+H] ⁺ .

2855

Example 77

3-{2-[methyl(methylsulfonyl)amino]phenyl}-N-[3-(4-methylpipe razin-l-yl)propyl]-l 1- oxo-10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepine-7-carboxamide

The title compound was prepared as described in Example 47, except substituting 2860 Example 45Ffor Example 40 and 3-(4-methylpiperazin-l-yl)propan-l -amine for 1- methylpiperidin-4-amine. Ή NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.04 (s, 1H), 8.39-8.47 (m, 1H), 8.09-8.12 (bs, 1H), 7.71 (d,J=8.1 Hz, 1H), 7.59 (dd,J=7.4, 1.7 Hz, 1H), 7.54 (d,J= 1.7 Hz, 1H), 7.42-7.53 (m, 2H), 7.34-7.40 (m, 2H), 7.01-7.02 (m, 1H), 6.98 (d,J = 6.4 Hz, 1H), 6.95 (dd, J =8.1, 1.4 Hz, 1H),3.28 (q,J=6.4 Hz, 2H), 3.11 (s, 3H), 2.90 (s, 2865 3H), 2.72-2.78 (bs,3H), 2.5-3.8 (m, 10H), 1.71-1.85 (m, 2H); MS ESI(+) m/z 5Π

[M+H] ⁺ .

Example 78

N-methyl-N-{2-[l l-oxo-8-(pyrrolidin-l-ylcarbonyl)-10,l l-dihydro-5H- 2870 dibenzo[b,e][l,4]diazepin-3-yl]phenyl}methanesulfonamide

The title compound was prepared as described in Example 47, except substituting pyrrolidine for l-methylpiperidin-4-amine. Ή NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.92 (s, 1H), 8.16 (s, 1H), 7.72 (d,J=8.1 Hz, 1H), 7.56-7.61 (m, 1H), 7.42-7.52 (m, 2H), 7.36-7.40 (m, 1H), 7.15-7.17 (m, 2H), 7.00 (d,J= 1.5 Hz, 1H), 7.01 (d,J=8.6 Hz, 1H), 2875 6.96 (dd,J= 8.1, 1.4 Hz, 1H), 3.3 (m, 4H), 3.10 (s, 3H), 2.91 (s, 3H), 1.75-1.91 (m, 4H);

MS (ESI+) m/z 491 [M+H] ⁺ , 508 [M+NH ₄ ] ⁺ .

Example 79

N-methyl-N-{2-[l l-oxo-8-(piperidin-l-ylcarbonyl)-10,l l-dihydro-5H- 2880 dibenzo[b,e][l,4]diazepin-3-yl]phenyl}methanesulfonamide

The title compound was prepared as described in Example 47, except substituting piperidine for l-methylpiperidin-4-amine. Ή NMR (300 MHz, DMSO-de) δ ppm 9.93 (s, 1H), 8.13-8.15 (bs, 1H), 7.72 (d,J= 8.1 Hz, 1H), 7.57-7.61 (m, 1H), 7.42-7.53 (m, 2H), 7.36-7.40 (m, 1H), 6.93-7.04 (m, 5H), 3.4 (m, 4H), 3.10 (s, 3H), 2.91 (s, 3H), 1.57-1.66 2885 (m, 2H), 1.42-1.55 (m, 4H); MS (ESI+) m/z 505 [M+H] ⁺ , 522 [M+NH ₄ ] ⁺ .

Example 80

N-(3- {2-[methyl(methylsulfonyl)amino]phenyl}- 11 -oxo- 10, 11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-8-yl)acetamide

2890 To Example 106 (0.026 g, 0.05 mmol) and triethylamine (0.024 ml, 0.175 mmol) in dichloromethane (1.0 ml) was added acetyl chloride (6.04 μΐ, 0.085 mmol) and the mixture was stirred at 25°C for 20 hours. The reaction mixture was concentrated. The crude product was purified by reverse phase HPLC on a customized Waters Purification system, eluting with 10-95% CH ₃ CN / 0.1% TFA in water to yield the title compound. Ή 2895 NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.90 (s, 1H), 9.83 (s, 1H), 7.81 (s, 1H), 7.68 (d, J= 8.1 Hz, 1H), 7.55-7.59 (m, 1H), 7.40-7.51 (m, 2H), 7.35-7.40 (m, 1H), 7.24 (d, J= 2.3 Hz, 1H), 7.16 (dd,J= 8.5, 2.3 Hz, 1H),6.98 (d,J= 1.6 Hz, 1H), 6.88-6.95 (m,2H),3.09 (s, 3H), 2.89 (s, 3H), 2.00 (s, 3H); MS ESI(-) m/z 449 [M-H]\

2900 Example 81

3-{2-[methyl(methylsulfonyl)amino]phenyl}-N-[3-(4-methylpipe razin-l-yl)propyl]-l 1- oxo- 10, 11 -dihydro-5H-dibenzo[b,e][ 1 ,4]diazepine-8-carboxamide

A scintillation vial (20 ml) was charged with a solution of Example 40 (20.0 mg, 0.046 mmol) in Ν,Ν-dimethylacetamide, 3-(4-methylpiperazin-l-yl)propan-l -amine (8.6

2905 mg, 0.055 mmol) in Ν,Ν-dimethylacetamide, a solution of 0-(7-azabenzotriazol-l-yl)- Ν,Ν,Ν',Ν'-tetramethyluronium hexafluorophosphate (0.86 mg, 0.055 mmol) in N,N- dimethylacetamide, and triethylamine (19.25 \iL, 0.137 mmol). The reaction mixture was stirred at room 60°C overnight. After cooling, it was concentrated. The crude product was purified by reverse phase HPLC on an Agilent 1100 Series Purification system, eluting

2910 with 10-100% CH ₃ CN / 0.1% TFA in water to yield the title compound. Ή NMR (500 MHz, Pyridine-ds, Temp=90°C) δ ppm 10.45-10.47 (bs, IH), 8.34 (d,J= 8.1 Hz, 1H), 8.31-8.35 (bs, 1H), 8.26-8.30 (m, 1H), 8.10 (d,J= 1.9 Hz, 1H), 7.70 (dd,J=8.1, 1.9 Hz, 1H), 7.50-7.53 (m, 1H), 7.29-7.39 (m, 4H), 7.15-7.18 (m, 1H), 7.14-7.16 (m, 1H), 3.61 (q, J= 6.2 Hz, 2H), 3.05 (s, 3H), 2.88 (s, 3H), 2.65-2.73 (m, 8H), 2.57 (t, J= 6.9 Hz, 2H),

2915 2.37 (s, 3H), 1.87 (p, J= 6.8 Hz, 2H); MS ESI(-) m/z 575 [M-H]\

Example 82

N-methy l-N-(2- { 8-[(4-methy Ipiperidin- 1 -yl)carbony I]- 11 -oxo- 10,11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-3-yl}phenyl)methanesulfonamide

2920 The title compound was prepared as described in Example 81, except substituting

4-methylpiperidine for 3-(4-methylpiperazin-l-yl)propan-l -amine. Ή NMR (500 MHz, Pyridine-ds, Temp=90°C) δ ppm 10.49-10.51 (bs, 1H), 8.35 (d, J= 8.1 Hz, 1H), 8.28- 8.29 (bs, 1H), 7.49-7.52 (m, 2H), 7.39 (dd, J= 6.9, 2.3 Hz, 1H), 7.36 (d, J= 1.7 Hz, 1H), 7.29-7.36 (m, 2H), 7.18 (dd,J= 8.2, 1.6 Hz, 2H), 7.14-7.16 (m, 1H), 4.22-4.28 (m, 2H), 2925 3.04 (s, 3H), 2.89 (s, 3H), 2.78-2.84 (m, 2H), 1 .40- 1 .49 (m, 3H), 0.99- 1.07 (m, 2H), 0.81 (d, J= 6.2 Hz, 3H); MS APCI(+) m/z 519 [M+H] ⁺ .

Example 83

N- {2-[8-({4-[2-(dimethy lamino)ethyl]piperazin- 1 -yl Jcarbonyl)- 1 1 -oxo- 10, 1 1 -dihydro- 2930 5H-dibenzo[b,e][l,4]diazepin-3-yl]phenyl}-N-methylmethanesuI fonamide

The title compound was prepared as described in Example 81 , except substituting N,N-dimethyl-2-(piperidin-4-yl)ethanamine for 3-(4-methylpiperazin-l-yl)propan-l- amine. Ή NMR (500 MHz, Pyridine-d ₅ , Temp=90°C) δ ppm 10.47-10.50 (bs, 1 H), 8.3 1- 8.35 (m, 2H), 7.51 -7.53 (m, 1 H), 7.49 (d, J= 1.6 Hz, 1 H), 7.39-7.41 (m, 1 H), 7.37 (d, J = 2935 1.4 Hz, 1 H), 7.29-7.37 (m, 2H), 7.19 (dd, J= 8.1 , 1.5 Hz, 1 H), 7.16-7.17 (m, 1 H), 7.12- 7.15 (m, 1 H), 3.64-3.67 (m, 4H), 3.05 (t, J= 6.2 Hz, 2H), 3.05 (s, 3H), 2.90 (s, 3H), 2.73 (s, 6H), 2.69 (t, J = 6.3 Hz, 2H), 2.43-2.46 (m, 4H); MS ESI(-) m/z 575 [M-H] ^' .

Example 84

2940 N-[2-(8-{ [4-(dimethylamino)piperidin-l-yl]carbonyl}-l l-oxo- 10, 1 l -dihydro-5H- dibenzo[b,e][l,4]diazepin-3-yl)phenyl]-N-methylmethanesulfon amide The title compound was prepared as described in Example 81 , except substituting N,N-dimethylpiperidin-4-amine for 3-(4-methylpiperazin- l-yl)propan- l -amine. Ή NMR (500 MHz, Pyridine-ds, Temp=90°C) δ ppm 10.46- 10.50 (bs, 1 H), 8.34-8.36 (m, 2H), 2945 7.52 (d, J= 9.1 Hz, 1 H), 7.50 (d, J= 1.6 Hz, 2H), 7.30-7.42 (m, 4H), 7.15-7.20 (m, 2H), 4.36-4.41 (m, 2H), 3.05 (s, 3H), 2.90 (s, 3H), 2.84-2.92 (m, 2H), 2.47 (s, 6H), 1.87-1.92 (m, 2H), 1.57 (qd, J= 12.0, 4.3 Hz, 2H); MS APCI(+) m/z 548 [M+H] ⁺ .

Example 85

2950 3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-N-(2-pyrrolidin-l -ylethyl)- 10, l 1 - dihydro-5H-dibenzo[b,e][l ,4]diazepine-8-carboxamide

The title compound was prepared as described in Example 81 , except substituting 2-(pyrrolidin- l -yl)ethanamine for 3-(4-methylpiperazin- l -yl)propan- l -amine. Ή NMR (500 MHz, Pyridine-ds, Temp=90°C) δ ppm 10.42- 10.43 (bs, 1 H), 8.34 (d, J= 8.1 Hz, 2955 1 H), 8.30-8.34 (m, 2H), 8.06 (d, J= 1.9 Hz, 1 H), 7.68 (dd, J= 8.1 , 2.0 Hz, 1 H), 7.50- 7.52 (m, 1H), 7.37 (dd,J= 7.2, 2.1 Hz, 1H), 7.29-7.36 (m, 3H), 7.16-7.18 (m, 1H), 7.11 (d, J= 8.2 Hz, 1H), 3.79 (q, J= 5.9 Hz, 2H), 3.05 (s, 3H), 3.03 (t, J= 6.4 Hz, 2H), 2.88 (s, 3H), 2.83-2.87 (m, 4H), 1.70-1.73 (m, 4H); MS APCI(+) m/z 534 [M+H] ⁺ .

2960 Example 86

N-methyl-N-(2- { 8-[(3-methy Ipiperidin- 1 -y l)carbony 1]- 11 -oxo- 10,11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-3-yl}phenyl)methanesulfonamide

The title compound was prepared as described in Example 81, except substituting 3-methylpiperidine for 3-(4-methylpiperazin-l-yl)propan-l -amine. Ή NMR (500 MHz, 2965 Pyridine-ds, Temp=90°C) δ ppm 10.48-10.50 (bs, 1H), 8.34 (d, J= 8.1 Hz, 1H), 8.27- 8.28 (bs, 1H), 7.50-7.51 (m, 3H), 7.38-7.40 (m, 1H), 7.35 (d, J= 1.4 Hz, 1H), 7.29-7.35 (m, 2H), 7.17 (dd,J= 8.1, 1.5 Hz, 1H), 7.16 (m, 1H), 4.13-4.18 (m, 1H), 4.02-4.12 (m, 1H),3.04 (s,3H),2.88 (s, 3H), 2.83-2.92 (m, 1H), 2.56(dd,J= 12.9, 10.3 Hz, 1H), 1.60- 1.67 (m, 1H), 1.46-1.57 (m, 2H), 1.32-1.43 (m, 1H), 0.96-1.06 (m, 1H), 0.73 (d,J=6.6 2970 Hz, 3H); MS ESI(-) m/z 517 [M-H]\

Example 87

N-(cyclohexylmethyl)-3-{2-[methyl(methylsulfonyl)amino]pheny l}-l 1 -oxo- 10,11- dihydro-5H-dibenzo[b,e][l,4]diazepine-8-carboxamide

2975 The title compound was prepared as described in Example 81, except substituting cyclohexylmethanamine for 3-(4-methylpiperazin-l-yl)propan-l -amine. Ή NMR (500 MHz, Pyridine-d ₅ , Temp=90°C) δ ppm 10.48-10.50 (bs, 1H), 8.35 (d,J= 8.0 Hz, IH), 8.29-8.30 (bs, IH), 8.07 (d,J= 1.9 Hz, IH), 7.94-7.97 (bs, IH), 7.70 (dd,J= 8.1, 2.0 Hz, IH), 7.50-7.53 (m, IH), 7.38 (dd,J= 7.1, 2.1 Hz, IH), 7.29-7.36 (m, 3H), 7.15-7.18 (m,

2980 IH), 7.13 (d, J = 8.2 Hz, IH), 3.42 (t, J= 6.3 Hz, 2H), 3.04 (s, 3H), 2.88 (s, 3H), 1.77-

1.81 (m, 2H), 1.61-1.72 (m, 3H), 1.53-1.57 (m, IH), 0.95-1.21 (m, 5H); MS APCI(+) m/z 533 [M+H] ⁺ .

Example 88 2985 3-{2-[methyl(methylsulfonyl)amino]phenyl}-N-(4-{[(5-methyl-l ,3,4-thiadiazol-2- yl)amino]sulfonyl} phenyl)- 1 l-oxo-10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepine-8- carboxamide

The title compound was prepared as described in Example 81, except substituting 4-((5-methyl-l,3,4-thiadiazol-2-yl)methylsulfonyl)aniline for 3-(4-methylpiperazin-l- _, 2990 yl)propan-l -amine. Ή NMR (500 MHz, Pyridine-d ₅ , Temp=90°C) δ ppm 10.44-10.47 (bs, 1H), 10.40-10.43 (bs, 1H), 8.38-8.41 (bs, 1H), 8.35 (d, J= 8.1 Hz, 1H), 8.18-8.21 (m, 2H), 8.10-8.12 (m, 2H), 8.04-8.05 (bs, 1H), 7.69 (dd,J= 8.1, 2.0 Hz, 1H), 7.50-7.53 (m, 1H), 7.37 (dd,J= 7.2, 2.0 Hz, 1H), 7.30-7.36 (m, 3H), 7.16-7.18 (m, 2H), 7.08 (d,J = 8.2 Hz, 1H), 3.05 (s, 3H), 2.89 (s, 3H), 2.34 (s, 3H); MS ESI(-) m/z 688 [M-H]\

2995

Example 89

3-{2-[methy l(methylsulfonyl)amino]phenyl}- 11 -oxo-N-pyridin-4-yl- 10, 11 -dihydro-5H- dibenzo[b,e] [ 1 ,4]diazepine-8-carboxam ide

The title compound was prepared as described in Example 81, except substituting 3000 pyridin-4-amine for 3-(4-methylpiperazin-l-yl)propan-l -amine. Ή NMR (500 MHz, Pyridine-d ₅ , Temp=90°C) δ ppm 10.47-10.56 (bs, 1H), 10.41-10.45 (bs, 1H), 8.61-8.63 (m, 2H), 8.42-8.44 (bs, 1H), 8.35 (d,J= 8.0 Hz, 1H), 8.06 (d, J= 1.9 Hz, 1H), 7.92-7.93 (m, 2H), 7.71 (dd,J= 8.2, 2.0 Hz, 1H), 7.50-7.53 (m, 1H), 7.30-7.39 (m, 4H), 7.18 (dd, J = 8.1, 1.7 Hz, 1H), 7.10 (d,J = 8.2 Hz, IH), 3.05 (s, 3H), 2.90 (s, 3H); MS APCI(+)m/z 3005 514 [M+H] ⁺ .

Example 90

N-(2-hydroxyethyl)-3-{2-[methyl(methylsulfonyl)amino]phenyl} -l l-oxo-10,11-dihydro- 5H-dibenzo[b,e][l,4]diazepine-8-carboxamide

3010 The title compound was prepared as described in Example 81 , except substituting

2-aminoethanol for 3-(4-methylpiperazin-l-yl)propan-l -amine. Ή NMR (500 MHz, Pyridine-ds, Temp=90°C) δ ppm 10.43-10.45 (bs, 1H), 8.35 (d,J= 8.1 Hz, 1H), 8.28- 8.29 (bs, 1H), 8.15-8.19 (bs, 1H), 8.05 (d,J= 1.9 Hz, 1H), 7.65 (dd, J= 8.1, 2.0 Hz, 1H), 7.50-7.53 (m, 1H), 7.29-7.39 (m, 4H), 7.15-7.18 (m, 1H), 7.10 (d, J = 8.2 Hz, 1H), 3.99 3015 (t, J= 5.6 Hz, 2H), 3.82 (q, J= 5.6 Hz, 2H), 3.04 (s, 3H), 2.88 (s, 3H); MS ESI(-) m/z 479 [M-H]\

Example 91

N-(3-hydroxypropyl)-3- {2-[methyl(methy lsulfonyl)amino]pheny 1 } - 11 -oxo- 10, 11 - 3020 dihydro-5H-dibenzo[b,e][l,4]diazepine-8-carboxamide

The title compound was prepared as described in Example 81, except substituting 3-aminopropan-l-ol for 3-(4-methylpiperazin-l-yl)propan-l -amine. Ή NMR (500 MHz, Pyridine-ds, Temp=90°C) δ ppm 10.46-10.48 (bs, 1H), 8.34 (d, J= 8.1 Hz, 1H), 8.28- 8.29 (bs, 1H), 8.19-8.23 (bs, 1H), 8.06 (d,J= 1.9 Hz, 1H), 7.65 (dd,J=8.1, 1.9 Hz, 1H), 3025 7.49-7.53 (m, 1H), 7.29-7.39 (m, 4H), 7.14-7.18 (m, 1H), 7.11 (d,J=8.2Hz, 1H), 3.88 (t, J= 6.0 Hz, 2H), 3.78 (q, J= 6.2 Hz, 2H), 3.04 (s, 3H), 2.88 (s, 3H), 1.97 (p, J= 6.3 Hz, 2H); MS ESI(-) m/z 493 [M-H]\

Example 92

3030 3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-N-(pyridin-3-ylmethyl)-10,l 1- dihydro-5H-dibenzo[b,e][l,4]diazepine-8-carboxamide

The title compound was prepared as described in Example 81, except substituting pyridin-3-ylmethanamine for 3-(4-methylpiperazin-l-yl)propan-l -amine. Ή NMR (500 MHz, Pyridine-ds, Temp=90°C) δ ppm 10.46-10.49 (bs, 1H), 8.85-8.89 (m, 1H), 8.81- 3035 8.82 (m, 1H), 8.55 (dd, J= 4.7, 1.4 Hz, 1H), 8.34 (d, J= 8.2 Hz, 1H), 8.31-8.34 (bs, 1H), 8.09 (d,J= 1.9 Hz, 1H), 7.70-7.74 (m, 2H), 7.50-7.52 (m, 1H), 7.29-7.39 (m, 4H), 7.16- 7.18 (m, 1H), 7.11-7.15 (m, 2H),4.74 (d,J= 5.8 Hz, 2H), 3.04 (s, 3H), 2.88 (s, 3H); MS APCI(+) m/z 528 [M+H] ⁺ .

3040 Example 93

3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-N-pyridin-3-yl-10,l l-dihydro-5H- dibenzo[b,e][l,4]diazepine-8-carboxamide

The title compound was prepared as described in Example 81 , except substituting pyridin-3-amine for 3-(4-methylpiperazin-l-yl)propan-l-amine. Ή NMR (500 MHz, 3045 Pyridine-d ₅ , Temp=90°C) δ ppm 10.39-10.45 (m, 2H), 9.22 (d, J= 2.5 Hz, 1H), 8.42-8.45 (m, 1H), 8.37-8.42 (m, 2H), 8.35 (d,J= 8.0 Hz, 1H), 8.10 (d,J= 2.0 Hz, 1H), 7.75 (dd, J = 8.2, 2.0 Hz, 1H), 7.51-7.54 (m, 1H), 7.29-7.39 (m, 4H), 7.22 (dd, J= 8.2, 4.7 Hz, 1H), 7.17 (dd, J =8.2, 1.1 Hz, 1H), 7.12 (d, J= 8.2 Hz, 1H), 3.05 (s, 3H), 2.90 (s, 3H); MS APCI(+)w/z514 [M+H] ⁺ .

3050

Example 94

1 -[(3- {2-[methyl(methylsulfonyI)amino]phenyl}- 11 -oxo- 10, 11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-8-yl)carbonyl]piperidine-3-carboxa mide

The title compound was prepared as described in Example 81, except substituting 3055 piperidine-3-carboxamide for 3-(4-methylpiperazin-l-yl)propan-l -amine. Ή NMR (500 MHz, Pyridine-d ₅ , Temp=90°C) δ ppm 10.45-10.47 (bs, 1H), 8.34 (d,J= 8.1 Hz, 1H), 8.26-8.28 (bs, 1H), 7.50-7.53 (m, 2H), 7.39(dd,J= 7.1, 2.1 Hz, 1H), 7.29-7.36 (m, 3H), 6.89-7.56 (bs, 2H), 7.18 (dd,J= 8.1, 1.5 Hz, 1H), 7.13-7.15 (m, 1H), 7.11 (d, J= 8.1 Hz, 1H), 4.53-4.58 (m, 1H), 4.01-4.07 (m, 1H), 3.46-3.54 (m, 1H),3.04 (s, 3H), 3.00-3.06 3060 (m, 1 H), 2.88 (s, 3H), 2.60-2.66 (m, 1 H), 1.91 -2.04 (m, 2H), 1.58- 1.65 (m, 1 H), 1.36- 1.45 (m, 1 H); MS APCI(+) m/z 548 [M+H] ⁺ .

Example 95

1 -[(3- {2-[methy l(methy Isulfony l)amino]pheny I }- 11 -oxo- 10,11 -dihydro-5 H- 3065 dibenzo[b,e][l,4]diazepin-8-yl)carbonyl]piperidine-4-carboxa mide

The title compound was prepared as described in Example 81, except substituting piperidine-4-carboxamide for 3-(4-methylpiperazin-l-yl)propan-l-amine. Ή NMR (500 MHz, Pyridine-ds, Temp=90°C) δ ppm 10.47-10.49 (bs, 1H), 8.34 (d,J= 8.1 Hz, 1H), 8.28-8.30 (bs, 1H), 7.51-7.53 (m, 1H), 7.47-7.49 (m, 1H), 7.38-7.41 (m, 1H), 7.36 (d, J = 3070 1.6 Hz, 1 H), 7.29-7.34 (m, 2H), 7.18 (dd, J = 8.1 , 1.6 Hz, 1 H), 7.03-7.29 (bs, 2H), 7.11- 7.13 (m, 2H), 4.29-4.34 (m, 2H), 3.04 (s, 3H), 2.94-3.02 (m, 2H), 2.88 (s, 3H), 2.57 (p, J = 7.4 Hz, 1H), 1.88-1.90 (m, 4H); MS APCI(+) m/z 548 [M+H] ⁺ .

Example 96

3075 N-methyl-N- {2-[8-(morpholin-4-ylcarbonyl)- 11 -oxo- 10, 11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-3-yl]phenyl}methanesulfonamide The title compound was prepared as described in Example 81, except substituting morpholine for 3-(4-methylpiperazin-l-yl)propan-l -amine. Ή NMR (500 MHz, Pyridine-ds, Temp=90°C) δ ppm 10.47-10.49 (bs, IH), 8.65-8.66 (bs, 2H), 8.35 (d, J = 3080 8.1 Hz, IH), 8.32-8.33 (bs, IH), 7.51-7.53 (m, IH), 7.50 (s, IH), 7.38-7.40 (m, IH), 7.37 (d,J= 1.6 Hz, IH), 7.30-7.36 (m, 2H), 7.18 (dd, 7= 8.1, 1.7 Hz, IH), 3.59-3.59 (m, 8H), 3.04 (s, 3H), 2.89 (s, 3H); MS APCI(+) m/z 507 [M+H] ⁺ .

Example 97

3085 N-(3-methoxypropyl)-3-{2-[methyl(methylsulfonyl)amino]phenyl }-l l-oxo-10,11- dihydro-5H-dibenzo[b,e][l,4]diazepine-8-carboxamide

The title compound was prepared as described in Example 81, except substituting 3-methoxypropan-l -amine for 3-(4-methylpiperazin-l-yl)propan-l-amine. Ή NMR (500 MHz, Pyridine-ds, Temp=90°C) δ ppm 10.47-10.49 (bs, IH), 8.35 (d,J= 8.1 Hz, IH), 3090 8.28-8.29 (bs, IH), 8.03-8.07 (m, 2H), 7.66 (dd, J= 8.2, 1.9 Hz, IH), 7.66 (dd, J= 8.2, 1.6 Hz, 1 H), 7.49-7.53 (m, 1 H), 7.29-7.36 (m, 3H), 7.15-7.18 (m, 1 H), 7.12 (d, J = 8.2 Hz, IH), 3.66 (q,J= 6.4 Hz, 2H), 3.43 (t, J= 6.1 Hz, 2H), 3.19 (s, 3H), 3.04 (s, 3H), 2.88 (s, 3H), 1.93 (p,J= 6.5 Hz, 2H); MS ESI(-) m/z 507 [M-H]\

3095 Example 98

N-methyl-N-(2-{8-[(4-methylpiperazin- 1 -y l)carbonyl]- 11 -oxo- 10, 11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-3-yl}phenyl)methanesulfonamide

The title compound was prepared as described in Example 81, except substituting 1-methylpiperazine for 3-(4-methylpiperazin-l-yl)propan-l -amine. Ή NMR (500 MHz, 3100 Pyridine-ds, Temp=90°C) δ ppm 10.47-10.50 (bs, IH), 8.35 (d,J= 8.1 Hz, 1H),8.29-

8.34 (bs, IH), 7.51-7.54 (m, 2H), 7.49-7.52 (m, IH), 7.39 (dd,J= 6.9, 2.3 Hz, IH), 7.30- 7.37 (m, 3H), 7.18 (dd, J= 8.1, 1.7 Hz, IH), 7.13-7.16 (m, IH), 3.65-3.68 (m, 4H), 3.05 (s, 3H), 2.89 (s, 3H), 2.34-2.36 (m, 4H), 2.20 (s, 3H); MS ESI(-) m/z 518 [M-H]\

3105 Example 99

3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-N-[3-(2-oxopyrrolidin-l-yl)propyl]- 10, 11 -dihydro-5H-dibenzo[b,e][ 1 ,4]diazepine-8-carboxamide The title compound was prepared as described in Example 81 , except substituting l-(3-aminopropyl)pyrrolidin-2-one for 3-(4-methylpiperazin-l-yl)propan-l -amine. Ή

3110 NMR (500 MHz, Pyridine-ds, Temp=90°C) δ ppm 10.53-10.55 (bs, IH), 8.34 (d, J= 8.0 Hz, IH), 8.29-8.31 (bs, IH), 8.19-8.24 (m, IH), 8.13 (s, IH), 7.76 (dd, J= 8.2, 1.9 Hz, IH), 7.50-7.52 (m, IH), 7.38 (dd,J= 7.2, 2.1 Hz, IH), 7.28-7.36 (m, 3H), 7.15-7.18 (m, IH), 7.13 (d, J = 8.2 Hz, IH), 3.51 (q, J=6.3 Hz, 2H), 3.35 (t, J=6.5 Hz, 2H), 3.16 (t, J = 7.0 Hz, 2H), 3.04 (s, 3H), 2.88 (s, 3H), 2.23 (t,J= 8.1 Hz, 2H), 1.71-1.81 (m, 4H); MS

3115 ESI(-) m/z 560 [M-H] ^" .

Example 100

N-(4-hydroxybutyl)-3-{2-[methyl(methylsulfonyl)amino]phenyl} - 11 -oxo- 10, 11 -dihydro- 5H-dibenzo[b,e][l,4]diazepine-8-carboxamide

3120 The title compound was prepared as described in Example 81 , except substituting

4-aminobutan-l-ol for 3-(4-methylpiperazin-l-yl)propan-l-amine. 'HNMR (500 MHz, Pyridine-ds, Temp=90°C) δ ppm 10.45-10.47 (bs, IH), 8.34 (d,J=8.0 Hz, IH), 8.27- 8.28 (bs, IH), 8.10-8.14 (bs, IH), 8.07 (d,J= 1.9 Hz, IH), 7.68 (dd, J= 8.2, 2.0 Hz, IH), 7.50-7.53 (m, IH), 7.37 (dd,J= 6.8, 2.4 Hz, IH), 7.28-7.36 (m, 3H), 7.15-7.18 (m, IH),

3125 7.11 (d,J=8.1 Hz, IH), 3.79 (t, J= 6.2 Hz, 2H), 3.62-3.66 (m, 2H), 3.04 (s, 3H), 2.88 (s, 3H), 1.83-1.90 (m, 2H), 1.71-1.80 (m, 2H); MS ESI(-) m/z 507 [M-H] ^" .

Example 101

N-methyl-N-(2-{8-[(2-methylpiperidin-l-yl)carbonyl]-l l-oxo-10,1 l-dihydro-5H- 3130 dibenzo[b,e][l,4]diazepin-3-yl}phenyl)methanesulfonamide

The title compound was prepared as described in Example 81, except substituting 2-methylpiperidine for 3-(4-methylpiperazin-l-yl)propan-l-amine. Ή NMR (500 MHz, Pyridine-ds, Temp=90°C) δ ppm 10.47-10.49 (bs, IH), 8.35 (d, J= 8.0 Hz, IH), 8.26- 8.28 (bs, IH), 7.50-7.53 (m, IH), 7.46 (d, J = 1.5 Hz, IH), 7.37-7.41 (m, IH), 7.36 (d,J = 3135 1.5 Hz, IH), 7.29-7.35 (m,2H), 7.11-7.19 (m,3H), 4.64-4.67 (m, IH), 4.05-4.14 (m, IH), 3.03 (s,3H), 2.92 (m, IH), 2.88 (s, 3H), 1.49-1.63 (m, 2H), 1.39-1.50 (m, 2H), 1.28-1.39 (m, 2H), 1.13 (d, J = 6.9 Hz, 3H); MS APCI(+) m/z 519 [M+H] ⁺ . Example 102

3140 N-(4-methylcyclohexyl)-3-{2-[methyl(methylsulfonyl)amino]phe nyl}-l l-oxo-10,1 1- dihydro-5H-dibenzo[b,e][l,4]diazepine-8-carboxamide

The title compound was prepared as described in Example 81 , except substituting 4-methylcyclohexanamine for 3-(4-methylpiperazin-l-yl)propan- l-amine. Ή NMR (500 MHz, Pyridine-ds, Temp=90°C) δ ppm 10.41 (d, J= 1 1.2, 1H), 8.35 (dd, J = 8.1 , 2.9,

3 145 1 H), 8.28 (d, J = 7.7, 1 H), 8.00 (dd, J= 23.6, 1.8, 1 H), 7.64 (ddd, J = 8.2, 3.3, 2.0, 1H), 7.5-7.55 (m, 2H), 7.40 - 7.28 (m, 4H), 7.17 (m, 1 H), 7.09 (d, J= 8.2, 1 H), 4.12 (m, 1 H), 3.05 (s, 3H), 2.88 (s, 3H), 2.12 (m, 1 H), 1.84 (m, 1 H), 1.7- 1.61 (m, 2H), 1.50 (d, J= 6.2, 1H), 1.39 - 1 .2 (m, 3H), 1.01 (s, 1 H), 0.82 (dd, J= 15.4, 6.5, 3H); MS APCI(+) m/z 533 [M+H] ⁺ .

3150

Example 103

N-methyl-N-[2-( 1 1 -oxo- 10, 1 1 -dihydro-5H-d ibenzo[b,e][ 1 ,4]diazepin-3- yl)phenyl]cyclopropanesulfonamide

3155 Example 103 A

To the solution of 2-iodoaniline (220 mg, 1.0 mmol) and pyridine ( 160 mg, 2.0 mmol) in dichloromethane (5 ml) was added cyclopropanesulfonyl chloride (280 mg, 2.0 mmol) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with saturated aqueous NH4CI, dried filtered, and

3 160 concentrated to yield the title compound.

Example 103B

To Example 103 A (80 mg, 0.25 mmol) and K2CO3 (69 mg, 0.5 mmol) in acetone (5 ml) was added CH3I (140 mg, 1.0 mmol). The mixture was heated to reflux for 16 3 165 hours, cooled and concentrated. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried (N2SO4), filtered and concentrated to yield the title compound. Example 103C

3 1 70 N-methyl-N-[2-(l l -oxo- 10, 1 l-dihydro-5H-dibenzo[b,e][l ,4]diazepin-3- yl)phenyl]cyclopropanesulfonamide

A mixture of Example 4A (60 mg, 0.179 mmol), Example 103B (67.4 mg, 0.2 mmol), [ l , -bis(diphenylphosphino)ferrocene]dichloropalladium(II) ( 16 mg) and 2CO3 (60 mg, 0.435 mmol) in dioxane (4 ml) and water (2 ml) was refluxed for 3 hours, cooled 3 1 75 down to room temperature, and concentrated. The residue was diluted with CH2CI2 and filtered. The filtrate was washed with water, dried (Na ₂ S04), filtered and concentrated. The residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate, 1 : 1 ) to yield the title compound. 'HNMR (400 MHz, CDCb) δ ppm

7.81 (d, 1 H), 7.62 (t, 1 H), 7.40-7.60 (m, 3H), 6.97-7.05 (m, 6H), 3.16 (s, 3H), 2.35 (t, 3 1 80 1 H), 0.90 (d, 4H); LC/MS m/z 420 [M+H] ⁺ .

Example 104

N-methyl-N- {2-[ 1 1 -oxo-8-(3,4,5-trimethoxypheny I)- 10, 1 1 -dihydro-5H- dibenzo[b,e][l ,4]diazepin-3-yl]phenyl } methanesulfonamide

3 1 85 To Example 5B (0.041 g, 0.1 mmol), N-methyl-N-(2-(4,4,5,5-tetramethyl- 1 ,3,2- dioxaborolan-2-yl)phenyl)methanesulfonamide (0.062 g, 0.2 mmol), 2'- (dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (0.012 g, 0.03 mmol) and CsF (0.046 g, 0.3 mmol) in an round bottom flask (flushed with N ₂ ) was added 1 ,2- dimethoxyethane (4.0 ml) and methanol (2.0 ml). After bubbling N ₂ into the reaction

3 190 mixture, palladium(II) acetate (3.82 mg, 0.017 mmol) was added and the mixture was refluxed at 80°C for 48 hours. After cooling, the reaction mixture was filtered and concentrated. The crude product was purified by reverse phase HPLC on a customized Waters Purification system, eluting with 10-95% CH ₃ CN / 0.1 % TFA in water to yield the title compound. Ή NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.81 -9.83 (bs, 1 H), 8.04-8.07

3 195 (bs, 1 H), 7.73 (d, J = 8.2 Hz, 1 H), 7.56-7.61 (m, 1 H), 7.43-7.54 (m, 2H), 7.35-7.41 (m, 1 H), 7.23-7.32 (m, 2H), 7.06 (d, J= 8.8 Hz, 1 H), 7.01 (d, J= 1 .4 Hz, 1 H), 6.95 (m, 2H),

6.82 (s, 1 H), 3.84 (s, 6H), 3.68 (s, 3H), 3.10 (s, 3H), 2.91 (s, 3H); MS ESI(-) m/z 558 [M- 3200 Example 105

N-[2-(7-amino- 1 1 -oxo- 10, 1 1 -dihydro-5H-dibenzo[b,e][ 1 ,4]diazepin-3-yl)phenyl]-N- methylmethanesulfonamide

To a solution of Example 14 (158 mg, 0.31 mmol) in dichloromethane (5 ml) was added trifluoroacetic acid (0.5 ml, 6.49 mmol). After stirring 2 hours at room

3205 temperature, the solvent was evaporated and the crude product was purified by flash chromatography on silica gel, eluting with a 0 - 100% ethyl acetate / hexanes gradient to yield the title compound. Ή NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.48 (s, 1 H), 7.68 (s, 1 H), 7.64 (d, 1 H), 7.60 - 7.32 (m, 4 H), 6.98 (d, 1 H), 6.93 (dd, 1 H), 6.64 (d, 1 H), 6.23 (d, 1 H), 6.15 (dd, 1 H), 4.90 (br s, 2 H). MS ESI(+) m/z 409.4 [M+H]+.

3210

Example 106

N-[2-(8-amino- 1 1 -oxo- 10, 1 1 -dihydro-5H-dibenzo[b,e][ 1 ,4]diazepin-3-yl)pheny 1]-N- methylmethanesulfonamide

To Example 6A (0.077 g, 0.220 mmol) and N-(2-bromophenyl)-N- 3215 methylmethanesulfonamide (0.053 g, 0.2 mmol) in a microwave vial was added 1 ,2- dimethoxyethane (1.2 ml) and methanol (0.6 ml) followed by CsF (0.061 g, 0.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.012 g, 10.0 μιηοΐ). The vial was heated in the Biotage Initiator Microwave Synthesizer at 120 °C for 20 minutes. After cooling, the reaction mixture was filtered and concentrated. The crude product was purified by 3220 SFC on modified Berger Instruments Prep SFC system (gradient of 10-50%o methanol / C0 ₂ ) to afford the title compound. Ή NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.96-9.98 (bs, 1 H), 7.73-9.23 (bs, 2H), 7.86-7.89 (bs, 1 H), 7.70 (d, J= 8.1 Hz, 1 H), 7.56-7.60 (m, 1 H), 7.43-7.51 (m, 2H), 7.34-7.39 (m, 1 H), 6.98 (d, J= 1.6 Hz, 1 H), 6.91-6.96 (m, 2H), 6.69- 6.74 (bs, 2H), 3.09 (s, 3H), 2.90 (s, 3H); MS ESI(-) m/z 407 [M-H]\

3225

Example 107

l-methyl-N-(3- {2-[methyl(methylsulfonyl)amino]phenyl}- l 1 -oxo- 10,1 l-dihydro-5H- dibenzo[b,e][l ,4]diazepin-7-yl)piperidine-4-carboxamide

To Example 105 (0.02 g, 0.05 mmol) and 2-(l H-benzo[d][l ,2,3]triazol- l-yl)- 3230 1 , 1 ,3,3-tetramethylisouronium tetrafluoroborate (0.029 g, 0.09 mmol) in N,N- dimethylformamide (0.8 ml) was added N,N-diisopropylethylamine (0.026 ml, 0.15 mmol) followed by l-methylpiperidine-4-carbox lic acid (10.74 mg, 0.075 mmol) and the mixture was stirred at 25°C for 18 hours. The reaction mixture was concentrated. The crude product was purified by reverse phase HPLC on a customized Waters Purification

3235 system, eluting with 10-95% CH ₃ CN / 0.1% TFA in water to yield the title compound. Ή NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.95 (s, IH), 9.78 (s, IH), 9.11-9.23 (bs, IH), 7.95 (s, IH), 7.69 (d,J=8.1 Hz, IH), 7.58 (dd, J= 7.2, 1.9 Hz, IH), 7.42-7.51 (m, 3H), 7.36 (dd, J= 7.1, 2.2 Hz, IH), 6.86-7.02 (m, 4H), 3.44-3.52 (m, 2H), 3.10 (s, 3H), 2.89-3.03 (m, 2H), 2.88 (s, 3H), 2.78 (d,J=4.6 Hz, 3H), 2.52 (m, IH), 1.95-2.05 (m, 2H), 1.70-1.89

3240 (m, 2H); MS ESI(+) m/z 534 [M+H] ⁺ .

Example 108

l-methyl-N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-8-yl)piperidine-4-carboxamide

3245 To Example 106 (0.02 g, 0.05 mmol) and 2-(lH-benzo[d][l,2,3]triazol-l-yl)-

1,1,3,3-tetramethylisouronium tetrafluoroborate (0.029 g, 0.09 mmol) in N,N- dimethylformamide (0.8 ml) was added N,N-diisopropylethylamine (0.026 ml, 0.15 mmol) followed by l-methylpiperidine-4-carboxylic acid (10.74 mg, 0.075 mmol) and the mixture was stirred at 25°C for 18 hours. The reaction mixture was concentrated. The

3250 crude product was purified by reverse phase HPLC on a customized Waters Purification system, eluting with 10-95% CH ₃ CN / 0.1% TFA in water to yield the title compound. Ή NMR (300 MHz, DMSO-d ₅ ) δ ppm 9.94 (s, IH), 9.90 (s, IH), 7.82 (s, IH), 7.69 (d, J = 8.1 Hz, IH), 7.55-7.60 (m, IH), 7.42-7.52 (m, 2H), 7.34-7.39 (m, IH), 7.24 (d,J= 2.1 Hz, IH), 7.19 (dd,J= 8.5, 2.3 Hz, 1H),6.98 (d,J= 1.6 Hz, IH), 6.93 (dd,J=8.0, 1.6

3255 Hz, 1 H), 6.92 (d, J= 8.6 Hz, 1 H), 3.4 (m, 3H), 3.09 (s, 3H), 2.90-3.04 (m, 2H), 2.89 (s, 3H), 2.79 (d,J= 4.4 Hz, 3H), 1.97-2.05 (m, 2H), 1.72-1.91 (m, 2H); MS (ESI-) m/z 532 [M-H]\

Example 109

3260 N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-7-yl)acetamide To a solution of Example 39D (25 mg, 0.06 mmol) in dichloromethane (1.2 ml) was added acetyl chloride (0.005 ml, 0.07 mmol) and triethylamine (0.01 mL, 0.07 mmol). After stirring 2 hours at room temperature, the solution was diluted with ethyl 3265 acetate and washed several times with aqueous sodium bicarbonate. The organic layer was dried (MgSO-i), filtered and concentrated. The crude product was purified by flash chromatography on silica gel, eluting with a 0 - 20% ethyl acetate / hexanes gradient to yield the title compound. Ή NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.84 (s, 1 H), 9.75 (s, 1 H), 7.98 (s, 1 H), 7.68 (d, 1 H), 7.60 - 7.55 (m, 1 H), 7.51 (m, 1 H), 7.50 - 7.44 (m, 2 H), 3270 7.38 - 7.34 (m, 1 H), 7.04 (m, 1 H), 6.96 - 6.90 (m, 2 H), 6.85 (d, 1 H), 3.10 (s, 3 H), 2.88 (s, 3 H), 2.00 (s, 3H). MS ES1(+) m/z 451.2 [M+H] ⁺ .

Example 1 10

N-methyl-N-[2-(l l-oxo- 10, 1 l -dihydro-5H-dibenzo[b,e][1 ,4]diazepin-3-

3275 yl)phenyl]propane-l -sulfonamide

The title compound was prepared as described in Examples 103A-103C, except substituting propane- 1-sulfony I chloride for cyclopropylsulfonyl chloride. Ή NMR (400 MHz , CDC ) δ ppm 8.38 (s, 1 H), 7.99 (d, 1 H), 7.33-7.41 (m, 2H), 6.83-7.03 (m, 6H), 5.75 (s, 1 H), 3.01 (s, 3H), 2.82 (m, 2H), 1.70 (q, 2H), 0.87 (t, 3H); LC/MS m/z All

3280 [M+H] ⁺ .

Example 1 1 1

N-(3- {2-[methy l(methylsulfonyl)amino]phenyl}- 1 1 -oxo- 10, 1 1 -dihydro-5H- dibenzo[b,e][l ,4]diazepin-8-yl)-4-(2-oxopyrrolidin-l-yl)butanamide

3285 A scintillation vial (20 mL) was charged with a solution Example 106 ( 16.0 mg,

0.039 mmol) in Ν,Ν-dimethylacetamide, 4-(2-oxopyrrolidin-l-yl)butanoic acid (8.0 mg. 0.047 mmol dissolved in Ν,Ν-dimethylacetamide), a solution of 0-(7-azabenzotriazol- l - yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (22.34 mg, 0.059 mmol) in N,N- dimethylacetamide, and triethylamine (1 1.0 μΐ _^ , 0.078 mmol). The vial was capped and 3290 stirred at 60°C overnight. After cooling, the reaction mixture was concentrated. The crude product was purified by reverse phase HPLC on an Agilent 1 100 Series

Purification system, eluting with 10-100% CH ₃ CN / 0.1% TFA in water to yield the title compound. Ή NMR (500 MHZ, DMSO-d ₆ / D ₂ 0) δ ppm 7.71 (d,J=8.0 Hz, 1H), 7.58 (dd,J=7.6, 1.6 Hz, 1H), 7.46-7.53 (m, 2H), 7.40 (dd, J = 7.3, 2.0 Hz, 1H), 7.31 (d,J = 3295 2.4 Hz, 1H), 7.16 (dd,J= 8.5, 2.4 Hz, 1H),7.01 (d,J= 1.6 Hz, 1H), 6.95 (dd,J= 8.2, 1.7 Hz, 1H), 6.94 (d,J= 8.7 Hz, 1H), 3.36 (t, J= 7.0 Hz, 2H), 3.22 (t, J= 6.9 Hz, 2H), 3.11 (s, 3H), 2.88 (s, 3H), 2.21-2.27 (m, 4H), 1.93 (p, J= 7.5 Hz, 2H), 1.77 (p, J= 7.2 Hz, 2H); MS ESI(-) m/z 560 [M-H] ^" .

3300 Example 112

N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}- 11 -oxo- 10, 11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-8-yl)-lH-pyrazole-4-carboxamide

The title compound was prepared as described in Example 111, except substituting 1 H-pyrazole-4-carboxylic acid for 4-(2-oxopyrrolidin-l-yl)butanoic acid. Ή 3305 NMR (500 MHz, DMSO-d ₆ / D ₂ 0) δ ppm 8.20 (s, 1H), 7.72 (d, J= 8.0 Hz, 1H), 7.59

(dd, J= 7.5, 1.7 Hz, 1H), 7.47-7.53 (m, 2H), 7.39-7.45 (m, 2H), 7.27 (dd, J= 8.5, 2.4 Hz, 1H), 6.95-7.03 (m, 3H), 3.13 (s, 3H), 2.90 (s, 3H); MS ESI(-) m/z 501 [M-H]\

Example 113

3310 N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-8-yl)-3-pyridin-2-ylpropanamide

The title compound was prepared as described in Example 111, except substituting 3-(pyridin-2-yI)propanoic acid for 4-(2-oxopyrrolidin-l-yl)butanoic acid. Ή NMR (500 MHz, DMSO-d ₆ / D ₂ 0) δ ppm 8.73 (d, J= 4.8 Hz, 1H), 8.39 (td, J= 7.8, 1.7

3315 Hz, 1H), 7.89 (d, J =8.0 Hz, 1H), 7.80 (t, J= 6.6 Hz, 1H), 7.70 (d, J= 8.1 Hz, 1H), 7.58- 7.61 (m, 1H), 7.46-7.53 (m, 2H), 7.38-7.41 (m, 1H), 7.26 (d, J= 2.4 Hz, 1H), 7.12 (dd, J = 8.6,2.4 Hz, 1H), 7.00 (d,J=1.5 Hz, 1H), 6.96 (dd, J= 8.2, 1.6 Hz, 1H), 6.94 (d,J = 8.5 Hz, 1H), 3.26 (t, J= 7.2 Hz, 2H), 3.12-3.14 (m, 3H), 2.89 (s, 3H), 2.87-2.90 (m, 2H); MS ESI(-) m/z 540 [M-H] ^" .

3320

Example 114

N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-8-yl)-lH-pyrazole-3-carboxamide The title compound was prepared as described in Example 111, except

3325 substituting lH-pyrazole-3-carboxylic acid for 4-(2-oxopyrrolidin-l-yl)butanoic acid. Ή NMR(500 MHz, DMSO-d ₆ / D ₂ 0) δ ppm 7.84 (d,J=2.3 Hz, 1H), 7.72 (d,J=8.1 Hz, 1H), 7.59 (dd,J = 7.5, 1.7 Hz, 1H), 7.47-7.53 (m, 3H), 7.38-7.42 (m, 1H), 7.34 (dd,J = 8.5,2.4 Hz, 1H), 7.02(d,J= 1.7 Hz, 1H), 6.99(d,J=8.5 Hz, 1H), 6.98 (dd,J=8.2, 1.6 Hz, 1H), 6.83 (d, J= 2.3 Hz, 1H), 3.13 (s, 3H), 2.90 (s, 3H); MS ESI(+) m/z 503 [M+H] ⁺ .

3330

Example 115

3-methoxy-N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-8-yl)propanamide

The title compound was prepared as described in Example 111, except

3335 substituting 3-methoxypropanoic acid for 4-(2-oxopyrrolidin-l-yl)butanoic acid. Ή

NMR(500 MHz, DMSO-d ₆ / D ₂ 0) δ ppm 7.71 (d,J=8.1 Hz, 1H), 7.58 (dd, J= 7.6, 1.6 Hz, 1H), 7.46-7.53 (m, 2H), 7.40 (dd,J= 7.3, 2.0 Hz, 1H), 7.32 (d, J= 2.4 Hz, 1H), 7.17 (dd,J=8.5,2.4 Hz, 1H), 7.01 (d,J= 1.6 Hz, 1H), 6.94-6.98 (m, 2H),3.62 (t,J=6.1 Hz, 2H), 3.25 (s, 3H), 3.12 (s, 3H), 2.89 (s, 3H), 2.50-2.54 (m, 2H); MS ESI(+) m/z 495 3340 (M+H) ⁺ .

Example 116

3,4,5-trimethoxy-N-(3-{2-[methyl(methylsulfonyl)amino]phenyl }-l l-oxo-10,11-dihydro- 5H-dibenzo[b,e][l,4]diazepin-8-yl)benzamide

3345 The title compound was prepared as described in Example 111, except

substituting 3,4,5-trimethoxybenzoic acid for 4-(2-oxopyrrolidin-l-yl)butanoic acid. Ή NMR(500MHz, DMSO-d ₆ / D ₂ 0) δ ppm 7.72 (d,J=8.1 Hz, 1H), 7.58 (dd,J= 7.6, 1.7 Hz, 1H), 7.46-7.53 (m, 2H), 7.39-7.43 (m, 2H), 7.27-7.30 (m, 1H), 7.25 (s, 2H), 7.00- 7.03 (m, 2H), 6.97 (dd, J= 8.0, 1.7 Hz, 1H), 3.87 (s, 5H), 3.87 (s, 1H), 3.74 (s, 3H), 3.13

3350 (s, 3H), 2.90 (s, 3H); MS APCI(+) m/z 603 [M+H] ⁺ .

Example 117

N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-8-yl)-3-(4-methylpiperazin-l-yl)pr opanamide 3355 The title compound was prepared as described in Example 111, except substituting 3-(4-methylpiperazin-l-yl)propanoic acid for 4-(2-oxopyrrolidin-l- yl)butanoic acid. Ή NMR (500 MHz, DMSO-d / D ₂ 0) δ ppm 7.70 (d, J= 8.0 Hz, 1H), 7.58 (dd,J= 7.6, 1.6 Hz, 1H), 7.46-7.53 (m, 2H), 7.38 (dd,J= 7.3, 1.9 Hz, 1H), 7.27 (d, J= 2.3 Hz, 1H), 7.18 (dd, J= 8.5, 2.4 Hz, 1H), 6.95-7.00 (m, 3H), 3.04-3.58 (m, 8H),

3360 3.18-3.24 (m, 2H), 3.12 (s, 3H), 2.89 (s, 3H), 2.83 (s, 3H), 2.69-2.70 (m, 2H); MS ESI(+) m/z 563 [M+H] ⁺ .

Example 118

N-(3- {2-[methyl(methylsulfonyl)amino]phenyl}- 11 -oxo- 10, 11 -dihydro-5H- 3365 dibenzo[b,e][l,4]diazepin-8-yl)-3-(2,3,4-trimethoxyphenyl)pr opanamide

Example 119

N-(3- {2-[methy l(methylsulfonyl)amino]phenyl}- 11 -oxo- 10, 11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-8-yl)-2-(4-methylpiperazin-l-yl)ac etamide

3370 The title compound was prepared as described in Example 111, except

substituting 2-(4-methylpiperazin-l-yl)acetic acid for 4-(2-oxopyrrolidin-l-yl)butanoic acid. Ή NMR (500 MHz, DMSO-de / D ₂ 0) δ ppm 7.71 (dd, J= 8.1, 4.8, 1H), 7.62 - 7.56 (m, 1H), 7.55-7.44 (m, 2H), 7.42 - 7.36 (m, 1H), 7.3 (d, 1H), 7.17 (dd, 1H), 7.06 - 6.94 (m, 3H), 6.65 (m, IH), 3.43 (m, 4H), 3.12 (m, 4H), 2.90 (m, 8H), 2.82 (s, 3H); MS 3375 ESI(+) m/z 549 [M+H] ⁺ .

Example 120

N'-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l 1 -oxo- 10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-8-yl)cyclopropane-l,l-dicarboxamid e

3380 The title compound was prepared as described in Example 111, except

substituting 1-carbamoylcyclopropanecarboxylic acid for 4-(2-oxopyrrolidin-l- yl)butanoic acid. Ή NMR (500 MHz, DMSO-de / D ₂ 0) δ ppm 7.70 (d, J= 8.1 Hz, IH), 7.57 (dd,J= 7.6, 1.6 Hz, IH), 7.45-7.52 (m, 2H), 7.39 (dd,J=7.3, 1.9 Hz, IH), 7.27 (d, J =2.4 Hz, IH), 7.16 (dd,J= 8.5, 2.4 Hz, IH), 7.00 (d, J= 1.6 Hz, IH), 6.94-6.97 (m, 3385 2H), 3.11 (s, 3H), 2.88 (s, 3H), 1.37-1.43 (m, 4H); MS ESI(+) m/z 520 [M+H] ⁺ . Example 121

N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-8-yl)-5-oxoprolinamide

3390 The title compound was prepared as described in Example 111, except

substituting 5-oxopyrrolidine-2-carboxylic acid for 4-(2-oxopyrrolidin-l-yl)butanoic acid. Ή NMR (500 MHz, DMSO-c^ / D ₂ 0) δ ppm 7.70 (d, J= 8.0 Hz, IH), 7.58 (dd, J = 7.6, 1.6 Hz, IH), 7.45-7.52 (m, 2H), 7.39 (dd,J= 7.3, 2.0 Hz, IH), 7.32 (d, J= 2.4 Hz, IH), 7.19 (dd, J = 8.5, 2.4 Hz, 1 H), 7.00 (d, J = 1.6 Hz, 1 H), 6.94-6.98 (m, 2H), 4.18 (dd, 3395 J= 8.6, 4.3 Hz, IH), 3.12 (s, 3H), 2.88 (s, 3H), 2.31-2.39 (m, IH), 2.13-2.27 (m, 2H), 1.93-2.02 (m, 1 H); MS ESI(-) m/z 518 (M-H)\

Example 122

N-(3- {2-[methyl(methylsulfonyl)amino]phenyl}- 11 -oxo- 10, 11 -dihydro-5H- 3400 dibenzo[b,e][l,4]diazepin-8-yl)nicotinamide

The title compound was prepared as described in Example 111, except substituting nicotinic acid for 4-(2-oxopyrrolidin-l-yl)butanoic acid. Ή NMR (500 MHz, DMSO-d ₆ / D ₂ 0) δ ppm 9.12-9.13 (bs, IH), 8.82 (d,J= 3.9 Hz, IH), 8.43 (dt,J= 8.0, 1.9 Hz, IH), 7.73 (d,J=8.2 Hz, IH), 7.69-7.73 (m, IH), 7.58 (dd, J= 7.6, 1.6 Hz, IH), 3405 7.46-7.53 (m, 3H), 7.40 (dd, J= 7.3, 2.0 Hz, IH), 7.34 (dd, J= 8.5, 2.4 Hz, IH), 7.01- 7.04 (m, 2H), 6.98 (dd,J= 8.1, 1.5 Hz, IH), 3.13 (s, 3H), 2.90 (s, 3H); MS ESI(-) m/z 512 [M-H]\

Example 123

3410 N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-8-yl)pyridine-2-carboxamide

The title compound was prepared as described in Example 111, except substituting picolinic acid for 4-(2-oxopyrrolidin-l-yl)butanoic acid. Ή NMR (500 MHz, DMSO DMSO-d ₆ / D ₂ 0) δ ppm 8.74 (d, J = 5.5 Hz, 1 H), 8.15 (d, J = 7.8 Hz, 1 H), 8.07 3415 (td,J=7.6, 1.7 Hz, IH), 7.72 (d,J= 8.1 Hz, IH), 7.67 (ddd, J= 7.5, 4.8, 1.1 Hz, IH), 7.57-7.59 (m, 2H), 7.46-7.53 (m, 2H), 7.44 (dd, J= 8.5, 2.4 Hz, 1 H), 7.40 (dd, J= 7.3, 2.0 Hz, IH), 7.02-7.03 (m, IH), 7.02 (d,J=6.0 Hz, IH), 6.97 (dd,J=8.0, 1.7 Hz, IH), 3.12 (s, 3H), 2.89 (s, 3H); MS ESI(+) m/z 514 [M+H] ⁺ .

3420 Example 124

1 -acetyl-N-(3- {2-[methyl(methy lsulfonyl)amino]phenyl} - 11 -oxo- 10,11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-8-yl)piperidine-4-carboxamide

The title compound was prepared as described in Example 111, except substituting l-acetylpiperidine-4-carboxylic acid for 4-(2-oxopyrrolidin-l-yl)butanoic 3425 acid. Ή NMR (500 MHz, DMSO-d* / D ₂ 0) δ ppm 7.70 (d,J= 8.1 Hz, IH), 7.57(dd,J = 7.6, 1.6 Hz, IH), 7.45-7.52 (m, 2H), 7.39 (dd, J= 7.3, 2.0 Hz, IH), 7.31 (d,J=2.4 Hz, IH), 7.16 (dd,J = 8.5, 2.4 Hz, IH), 7.00 (d, J= 1.6 Hz, IH), 6.93-6.97 (m, 2H), 4.37- 4.41 (m, IH), 3.85-3.89 (m, IH), 3.11 (s, 3H), 3.03-3.10 (m, IH), 2.88 (s, 3H), 2.54-2.63 (m,2H), 2.02 (s, 3H), 1.75-1.82 (m, 2H), 1.52-1.61 (m, IH), 1.43 (qd,J= 12.3,4.3 Hz, 3430 1H);MS APCI(+) m/z 562 [M+H] ⁺ .

Example 125

N-(3- {2-[methy l(methylsulfonyl)amino]phenyl} - 11 -oxo- 10, 11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-8-yl)-2-(3,4,5-trimethoxyphenyl)ac etamide 3435 The title compound was prepared as described in Example 111, except

substituting 2-(3,4,5-trimethoxyphenyl)acetic acid for4-(2-oxopyrrolidin-l-yl)butanoic acid. Ή NMR (500 MHz, DMSO-d ₆ / D ₂ 0) δ ppm 7.70 (d, J= 8.1 Hz, IH), 7.57(dd,J = 7.6, 1.6 Hz, IH), 7.45-7.52 (m, 2H), 7.38 (dd, J= 7.3, 1.9 Hz, IH), 7.30 (d, J= 2.4 Hz, IH), 7.16 (dd,J= 8.5, 2.4 Hz, IH), 6.99 (d,J= 1.6 Hz, IH), 6.95 (dd,J= 8.1, 1.7 Hz, 3440 IH), 6.94 (d,J= 8.5 Hz, IH), 6.65 (s, 2H), 3.76 (s, 6H), 3.64 (s, 3H), 3.53-3.53 (bs, 2H), 3.11 (s,3H),2.88 (s, 3H); MS ESI(-)m/ 615 [M-H]\

Example 126

N-(3- {2-[methyl(methylsulfonyl)amino]phenyl} - 11 -oxo- 10, 11 -dihydro-5H- 3445 dibenzo[b,e][ 1 ,4]diazepin-7-yl)-4-(2-oxopyrrolidin- 1 -yl)butanamide

A scintillation vial (20 mL) was charged with a solution Example 105 (16.0 mg, 0.039 mmol) in Ν,Ν-dimethylacetamide, 4-(2-oxopyrrolidin-l-yl)butanoic acid (8.0 mg. 0.047 mmol dissolved in Ν,Ν-dimethylacetamide), a solution of 0-(7-azabenzotriazol- 1 - yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (22.34 mg, 0.059 mmol) in N,N-

3450 dimethylacetamide, and triethylamine (11.0 μΙ_-, 0.078 mmol). The vial was capped and stirred at 60°C overnight. After cooling, the reaction mixture was concentrated. The crude product was purified by reverse phase HPLC on an Agilent 1100 Series

Purification system, eluting with 10-100% CH ₃ CN / 0.1% TFA in water to yield the title compound. Ή NMR (500 MHz, DMSO-d ₆ / D ₂ 0) δ ppm 7.69 (d, J= 8.0 Hz, 1H), 7.58

3455 (dd,J=7.6, 1.6 Hz, 1H), 7.45-7.52 (m, 3H), 7.38 (dd,J= 7.3, 1.9 Hz, 1H), 7.04 (d, J = 1.6 Hz, 1H), 6.95-6.99 (m, 2H), 6.90 (d, J= 8.5 Hz, 1 H), 3.34 (t, J= 7.0 Hz, 2H), 3.21 (t, J= 6.9 Hz, 2H), 3.12 (s, 3H), 2.88 (s, 3H), 2.25 (t, J= 7.3 Hz, 2H), 2.21 (t, J= 8.1 Hz, 2H), 1.91 (p,J=7.5 Hz, 2H), 1.76 (p,J=7.1 Hz, 2H); MS ESI(+) m/z 562 [M+H] ⁺ .

3460 Example 127

N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-7-yl)-l H-pyrazole-4-carboxamide

The title compound was prepared as described in Example 126, except substituting lH-pyrazole-4-carboxylic acid for 4-(2-oxopyrrolidin-l-yl)butanoic acid. Ή 3465 NMR (500 MHz, DMSO-d ₆ / D ₂ 0) δ ppm 8.19 (s, 2H), 7.71 (d, J= 8.0 Hz, 1H), 7.57- 7.59 (m, 2H), 7.46-7.53 (m, 2H), 7.37-7.40 (m, 1H), 7.12 (dd,J= 8.5, 2.3 Hz, 1H), 7.05 (d,J= 1.6 Hz, 1H),6.98 (dd,J=8.1, 1.7 Hz, 1H), 6.95 (d,J=8.6 Hz, 1H), 3.12 (s, 3H), 2.89 (s, 3H); MS ESI(-) m/z 501 [M-H]\

3470 Example 128

N-(3- {2-[methyl(methylsulfonyl)amino]phenyl}- 11 -oxo- 10, 11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-7-yl)-lH-pyrazole-3-carboxamide

The title compound was prepared as described in Example 126, except substituting lH-pyrazole-3-carboxylic acid for 4-(2-oxopyrrolidin-l-yl)butanoic acid. Ή 3475 NMR (500 MHz, DMSO-d ₆ / D ₂ 0) δ ppm 7.83-7.85 (bs, 1H), 7.71 (d,J=8.0Hz, 1H), 7.64 (d,J=2.3 Hz, 1H), 7.58 (dd, J= 7.5, 1.7 Hz, 1H), 7.46-7.53 (m, 2H), 7.39 (dd,J = 7.3,2.0 Hz, 1H), 7.21 (dd, J= 8.5, 2.3 Hz, 1H), 7.05 (d, J= 1.6 Hz, 1H), 6.98 (dd,J = 8.0, 1.7 Hz, 1H), 6.94 (d,J= 8.5 Hz, 1H), 6.80-6.84 (bs, 1H), 3.13 (s, 3H), 2.89 (s, 3H); MSESI(-) w/z501 [M-H]\

3480

Example 129

N-(3- {2-[methy l(methylsulfonyl)amino]phenyl}- 11 -oxo- 10, 11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-7-yl)-2-pyridin-2-ylacetamide

The title compound was prepared as described in Example 126, except

3485 substituting 2-(pyridin-2-yl)acetic acid for 4-(2-oxopyrrolidin-l-yl)butanoic acid. Ή

NMR (500 MHz, DMSO-d ₆ / D ₂ 0) δ ppm 8.77-8.79 (m, 1H), 8.37 (td, J= 7.8, 1.6 Hz, 1H), 7.87 (d,J= 7.9 Hz, 1H), 7.80-7.83 (m, 1H), 7.70 (d,J= 8.1 Hz, IH), 7.58(dd,J = 7.7, 1.5 Hz, IH), 7.46-7.52 (m, 2H), 7.45 (d,J=2.4 Hz, IH), 7.37 (dd, J= 7.4, 1.9 Hz, IH), 7.04 (dd,J= 8.5, 2.3 Hz, IH), 7.02 (d, J= 1.5 Hz, IH), 6.97 (dd,J= 8.1, 1.5 Hz, 3490 IH), 6.93 (d,J= 8.5 Hz, IH), 3.75 (m, 2H), 3.11 (s, 3H), 2.88 (s, 3H); MS ESI(+) m/z 528 [M+H] ⁺ .

Example 130

3-methoxy-N-(3- {2-[methyl(methy lsulfonyl)amino]pheny 1}- 11 -oxo- 10, 11 -dihydro-5H- 3495 dibenzo[b,e][l,4]diazepin-7-yl)propanamide

The title compound was prepared as described in Example 126, except substituting 3-methoxypropanoic acid for 4-(2-oxopyrrolidin-l-yl)butanoic acid. Ή

NMR (500 MHz, DMSO-d ₆ / D ₂ 0) δ ppm 7.70 (d,J= 8.1 Hz, IH), 7.58 (dd,J= 7.6, 1.6 Hz, IH), 7.45-7.52 (m, 3H), 7.38 (dd, J= 7.3, 1.9 Hz, IH), 7.04 (d,J= 1.6 Hz, IH), 6.96- 3500 6.99 (m, 2H), 6.90 (d,J= 8.5 Hz, 1H),3.61 (t,J=6.1 Hz, 2H), 3.23 (s, 3H), 3.12 (s, 3H), 2.88 (s, 3H), 2.51 (t, J= 6.2 Hz, 2H); MS ESI(-) m/z 493 [M-H]\

Example 131

3,4,5-trimethoxy-N-(3-{2-[methyl(methylsulfonyl)amino]phenyl }- 11 -oxo- 10, 11 -dihydro- 3505 5H-dibenzo[b,e][l,4]diazepin-7-yl)benzamide

The title compound was prepared as described in Example 126, except substituting 3,4,5-trimethoxybenzoic acid for4-(2-oxopyrrolidin-l-yl)butanoic acid. Ή NMR (500 MHz, DMSO-d ₆ / D ₂ 0) δ ppm 7.72 (d, J= 8.1 Hz, IH), 7.56-7.60 (m, 2H), 7.46-7.53 (m, 2H), 7.39 (dd, J= 7.3, 2.0 Hz, 1H), 7.25 (s, 2H), 7.17 (dd, J= 8.5, 2.3 Hz, 3510 1H), 7.05 (d,J= 1.6 Hz, 1H), 6.96-6.99 (m, 2H), 3.86 (s, 6H), 3.73 (s, 3H), 3.13 (s, 3H), 2.89 (s, 3H); MS ESI(-) m/z 601 [M-H]\

Example 132

N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- 3515 dibenzo[b,e][l,4]diazepin-7-yl)-3-(4-methylpiperazin-l-yl)pr opanamide

The title compound was prepared as described in Example 126, except substituting 3-(4-methylpiperazin-l-yl)propanoic acid for 4-(2-oxopyrrolidin-l- yl)butanoic acid. Ή NMR (500 MHz, DMSO-d ₆ / D ₂ 0) δ ppm 7.70 (d, J= 8.1 Hz, 1H), 7.59 (dd,J=7.6, 1.6 Hz, 1H), 7.46-7.53 (m, 2H), 7.44 (d,J=2.3 Hz, 1H), 7.37(dd,J = 3520 7.3, 1.9 Hz, 1H), 7.02-7.06 (m, 2H), 6.97 (dd, J= 8.1, 1.7Hz, 1H), 6.92 (d, J= 8.5 Hz, 1H), 3.06-3.64 (bs, 8H), 3.19-3.27 (m, 2H), 3.14 (s, 3H), 2.88 (s, 3H), 2.84 (s, 3H), 2.70- 2.73 (m, 2H); MS ESI(+) m/z 563 [M+H] ⁺ .

Example 133

3525 N-(3-{2-[methyl(methy!sulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-7-yl)-2-pyridin-3-ylacetamide

The title compound was prepared as described in Example 126, except substituting 2-(pyridin-3-yl)acetic acid for 4-(2-oxopyrrolidin-l-yl)butanoic acid. Ή

NMR (500 MHz, DMSO-d ₆ / D ₂ 0) δ ppm 8.81-8.84 (bs, 1H), 8.78 (d, J= 5.2 Hz, 1H), 3530 8.45-8.47 (m, IH), 7.99 (dd, J= 8.0, 5.6 Hz, IH), 7.70 (d,J= 8.0 Hz, 1H), 7.58 (dd, J= 7.7, 1.5 Hz, IH), 7.45-7.52 (m,3H), 7.37 (dd,J= 7.4, 1.9 Hz, 1 H), 7.01-7.04 (m, 2H), 6.97 (dd,J= 8.0, 1.7 Hz, IH), 6.93 (d, J= 8.5 Hz, IH), 3.95 (s, 2H), 3.12 (s, 3H), 2.88 (s, 3H); MS ESI(-) m/z 526 [M-H]\

3535 Example 134

N-(3- {2-[methyl(methylsulfonyl)amino]phenyl} - 11 -oxo- 10, 11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-7-yl)-3-(2,3,4-trimethoxyphenyl)pr opanamide The title compound was prepared as described in Example 126, except substituting 3-(2,3,4-trimethoxyphenyl)propanoic acid for 4-(2-oxopyrrolidin-l- 3540 yl)butanoic acid. 'HNMR (500 MHz, DMSO-k / D ₂ 0) δ ppm 7.69 (d, J= 8.1 Hz, 1H), 7.58 (dd,J= 7.6, 1.6 Hz, 1H), 7.46-7.52 (m, 3H), 7.38 (dd, J= 7.3, 1.9 Hz, 1H), 7.04 (d, J=1.6 Hz, 1H), 6.96-6.98 (m, 2H), 6.87-6.90 (m, 2H), 6.71 (d,J=8.5 Hz, 1H), 3.79 (s, 3H), 3.74 (s, 3H), 3.73 (s, 3H), 3.12 (s, 3H), 2.88 (s, 3H), 2.80 (t, J= 7.6 Hz, 2H), 2.51- 2.56 (m, 2H); MS ESI(-) m/z 629 [M-H] ^" .

3545

Example 135

N-(3- {2-[methyl(methylsulfonyl)amino]phenyl}- 11 -oxo- 10, 11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-7-yl)-3-pyrrolidin-l-ylpropanamide

3550 Example 136

N-(3- {2-[methyl(methylsulfonyl)amino]phenyl}- 11 -oxo- 10, 11 -dihydro-5H- dibenzo[b,e][ 1 ,4]diazepin-7-yl)-2-(4-methylpiperazin- 1 -y l)acetamide The title compound was prepared as described in Example 126, except substituting 2-(4-methylpiperazin-l-yl)acetic acid for 4-(2-oxopyrrolidin-l-yl)butanoic 3555 acid. Ή NMR (500 MHz, DMSO-d ₆ / D ₂ 0) δ ppm 7.70 (d, J= 8.1 Hz, 1H), 7.58-7.61

(m, 1H), 7.46-7.53 (m, 3H), 7.38 (dd, J= 73, 2.0 Hz, 1H), 7.03-7.06 (m, 2H), 6.98 (dd, J = 8.1, 1.7 Hz, 1H), 6.94 (d,J= 8.5 Hz, 1H), 3.48-3.49 (bs, 2H), 2.65-3.80 (bs, 8H), 3.13 (s, 3H), 2.89 (s, 3H), 2.82 (s, 3H); MS APCI(+) m/z 549 [M+H] ⁺ .

3560 Example 137

N ¹ -(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l 1 -oxo- 10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-7-yl)cyclopropane-l,l-dicarboxamid e

The title compound was prepared as described in Example 126, except substituting 1-carbamoylcyclopropanecarboxylic acid for4-(2-oxopyrrolidin-l- 3565 yl)butanoic acid. Ή NMR (500 MHz, DMSO-d ₆ / D ₂ 0) δ ppm 7.70 (d, J= 8.1 Hz, 1H), 7.58 (dd,J= 7.6, 1.6 Hz, 1H), 7.45-7.52 (m, 2H), 7.41 (d,J=2.3 Hz, 1H), 7.38(dd,J = 7.3, 1.9 Hz, 1H), 7.05 (dd, J= 8.5, 2.3 Hz, 1H), 7.02 (d,J= 1.5 Hz, 1H), 6.97 (dd,J = 8.1, 1.7 Hz, 1H), 6.92 (d,J=8.5 Hz, 1H), 3.12 (s, 3H), 2.89 (s, 3H), 1.38-1.44 (m, 4H); MS ESI(-) m/z 518 [M-H] ^" .

3570 Example 138

N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l 1 -oxo- 10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-7-yl)-lH-pyrrole-2-carboxamide

The title compound was prepared as described in Example 126, except

3575 substituting lH-pyrrole-2-carboxylic acid for 4-(2-oxopyrrolidin-l -yl)butanoic acid. Ή NMR(500MHz, DMSO-d ₆ / D ₂ 0) δ ppm 11.49-11.50 (m, IH), 7.71 (d,J=8.1 Hz, IH), 7.57-7.59 (m, 2H), 7.46-7.53 (m, 2H), 7.39 (dd, J= 7.3, 2.0 Hz, IH), 7.15 (dd,J=8.5, 2.3 Hz, IH), 7.05 (d,J = 1.5 Hz, IH), 7.02-7.04 (m, IH), 6.97-6.99 (m, 2H), 6.94 (d, J = 8.5 Hz, IH), 6.17-6.19 (m, IH), 3.12 (s, 3H), 2.89 (s, 3H); MS ESI(-) m/z 500 [M-H] ^" .

3580

Example 139

N-(3- {2-[methyl(methy lsulfonyl)amino]phenyl}- 11 -oxo- 10, 11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-7-yl)-5-oxoprolinamide

The title compound was prepared as described in Example 126, except

3585 substituting 5-oxopyrrolidine-2-carboxylic acid for4-(2-oxopyrrolidin-l-yl)butanoic acid. Ή NMR (500 MHz, DMSO-d ₆ / D ₂ 0) δ ppm 7.70 (d, J= 8.1 Hz, 1 H), 7.58 (dd, J = 7.6, 1.6 Hz, IH), 7.46-7.52 (m, 3H), 7.38 (dd, J= 7.3, 2.0 Hz, 1 H), 7.04 (d, J= 1.7 Hz, IH), 7.02 (dd,J= 8.9, 2.7 Hz, IH), 6.97 (dd,J= 8.1, 1.7 Hz, IH), 6.93 (d,J= 8.5 Hz, IH), 4.19 (dd,J= 8.6, 4.3 Hz, IH), 3.12 (s, 3H), 2.89 (s, 3H), 2.31-2.39 (m, IH), 2.13- 3590 2.27 (m, 2H), 1.94-2.03 (m, 1 H); MS ESl(-) m/z 518 [M-H] ^" .

Example 140

N-(3- {2-[methyl(methylsulfonyl)amino]phenyl}- 11 -oxo- 10, 11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-7-yl)-3-piperidin-l-ylpropanamide

3595

Example 141

N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l 1 -oxo- 10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-7-yl)nicotinamide

The title compound was prepared as described in Example 126, except

3600 substituting nicotinic acid for 4-(2-oxopyrrolidin-l-yl)butanoic acid. Ή NMR (500 MHz, DMSO-d ₆ / D ₂ 0) δ ppm 9.10-9.11 (bs, IH), 8.79-8.81 (m, IH), 8.39 (dt, J= 8.0, 1.9 Hz, 1H),7.72 (d,J=8.1 Hz, 1H), 7.68 (dd, J= 8.0, 4.9 Hz, 1H),7.65 (d,J=2.3 Hz, 1H), 7.58 (dd,J= 7.5, 1.7 Hz, 1H), 7.46-7.53 (m, 2H), 7.39 (dd,J= 7.3, 2.0 Hz, 1H), 7.18 (dd, J= 8.5, 2.3 Hz, 1H), 7.06 (d,J= 1.6 Hz, 1H), 6.97-7.00 (m, 2H), 3.13 (s, 3H), 2.89 (s, 3605 3H); MS APCI(+) m/z 514 [M+H] ⁺ .

Example 142

N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-7-yl)pyridine-2-carboxamide

3610 The title compound was prepared as described in Example 126, except

substituting picolinic acid for 4-(2-oxopyrrolidin-l-yl)butanoic acid. Ή NMR (500 MHz, DMSO-d ₆ / D ₂ 0) δ ppm 8.74 (d,J=4.9 Hz, 1H), 8.15 (d, J = 7.8 Hz, 1H), 8.07 (td,J =

7.6, 1.7 Hz, 1H), 7.76 (d,J= 2.3 Hz, 1H), 7.72 (d,J=8.0 Hz, 1H), 7.68 (ddd,J=7.5,

4.7, 1.3 Hz, 1H), 7.58 (dd, J =7.5, 1.7 Hz, 1H), 7.46-7.53 (m, 2H), 7.40 (dd, J= 7.3, 2.0 3615 Hz, 1H), 7.31 (dd, J= 8.5, 2.3 Hz, 1H), 7.06 (d, J= 1.6 Hz, 1H), 6.98 (dd, J= 8.0, 1.7

Hz, 1H), 6.97 (d,J= 8.5 Hz, 1H), 3.13 (s, 3H), 2.89 (s, 3H); MS APCI(+) m/z 514

[M+H] ⁺ .

Example 143

3620 l-acetyl-N-(3-{2-[methyl(methylsulfonyI)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][ 1 ,4]diazepin-7-yl)piperidine-4-carboxamide

The title compound was prepared as described in Example 126, except substituting l-acetylpiperidine-4-carboxylic acid for 4-(2-oxopyrrolidin-l-yl)butanoic acid. Ή NMR (500 MHz, DMSO-d6 / D ₂ 0) δ ppm 7.69 (d, J= 8.0 Hz, 1H), 7.58 (dd, J =

3625 7.6, 1.6 Hz, 1H), 7.52 (d, J= 2.1 Hz, 1H), 7.45-7.52 (m, 2H), 7.38 (dd, J= 7.3, 1.9 Hz, 1H), 7.03 (d,J= 1.5 Hz, 1H), 6.94-6.99 (m, 2H), 6.90 (d,J= 8.5 Hz, 1H), 4.36-4.41 (m, 1H), 3.84-3.89 (m, 1H), 3.12 (s, 3H), 3.02-3.10 (m, 1H), 2.88 (s, 3H), 2.53-2.64 (m, 2H), 2.02 (s,3H), 1.73-1.83 (m, 2H), 1.56(qd,J= 12.4,3.9 Hz, 1H), 1.43 (qd,J= 12.3,4.1 Hz, 1H); MS ESI(-) m/z 560 [M-H]\

3630

Example 144 N-(3-{2-[methyl(methylsulfonyl)amino]phenyl}-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-7-yl)-2-pyrrolidin-l-ylacetamide

3635 Example 145

N-(3- {2-[methy l(methylsulfonyl)amino]phenyl}- 11 -oxo- 10, 11 -dihydro-5H- dibenzo[b,e][l,4]diazepin-7-yl)-2-(3,4,5-trimethoxyphenyl)ac etamide

The title compound was prepared as described in Example 126, except substituting 2-(3,4,5-trimethoxyphenyl)acetic acid for 4-(2-oxopyrrolidin-l-yl)butanoic 3640 acid. Ή NMR (500 MHz, DMSO-d ₆ / D ₂ 0) δ ppm 7.69 (d,J= 8.0 Hz, 1H), 7.57 (dd, J-- 7.7, 1.6 Hz, 1H), 7.45-7.52 (m, 3H), 7.37 (dd, J= 7.3, 1.9 Hz, 1H),7.02 (d,J= 1.7 Hz, 1H), 6.99 (dd,J= 8.5, 2.3 Hz, 1H), 6.97 (dd,J=8.2, 1.6 Hz, 1 H), 6.91 (d,J=8.5 Hz, 1H), 6.65 (s, 2H), 3.76 (s, 6H), 3.63 (s, 3H), 3.53 (s, 2H), 3.11 (s, 3H), 2.88 (s, 3H); MS ESI(-)w/z615 [M-H]\

3645

Example 146

N ² ,N ² -dimethyl-N ¹ -(3-{2-[methyl(me :tthhyyllssuullffoonnyyll))aaimino]phenyl}-l l-oxo-10,11-dihydro- 5H-dibenzo[b,e][l,4]diazepin-7-yl)glycinamide

3650 Example 147

N-[2-(l l-oxo-10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepin-3- yl)phenyl]ethanesulfonamide

The title compound was prepared as described in Examples 103A-103C, except substituting ethanesulfonyl chloride for cyclopropylsulfonyl chloride. 'HNMR (400 3655 MHz, CDCb), δ ppm 9.88 (s, 1H), 7.7 (m, 1H), 7.40 (d, 2H), 7.29-7.30 (m, 4H), 6.91- 7.02 (m, 6H), 2.90 (q, 2H), 1.06 (t, 3H); LC/MS m/z 394 [M+H] ⁺ .

Example 148

1,1,1 -trifluoro-N-methy l-N-[2-( 11 -oxo- 10, 11 -dihydro-5H-dibenzo[b,e][ 1 ,4]diazepin-3- 3660 yl)phenyl]methanesulfonamide

The title compound was prepared as described in Examples 103A-103C, except substituting trifluoromethanesulfonyl chloride for cyclopropylsulfonyl chloride. 'HNMR (400 MHz, CDCI ₃ ), δ ppm 9.92 (s, IH), 7.99 (s, I H), 7.56 (t, I H), 7.46-7.56 (d, 4H), 6.93-7.03 (m, 6H), 3.37 (s, 3H); LC/MS m/z 448 [M+H] ⁺ .

3665

Example 149

N-methy l-N-[2-( 1 1 -oxo- 10,1 1 -dihydro-5H-dibenzo[b,e] [ 1 ,4]diazepin-3- yl)phenyl]butane- l-sulfonamide

The title compound was prepared as described in Examples 103A- 103C, except 3670 substituting butane- 1-sulfonyl chloride for cyclopropylsulfonyl chloride. 'HNMR (400 MHz, CDCb), δ ppm 7.82 (d, I H), 7.39-7.52 (m, 4H), 6.97-7.03 (m, 6H), 3.19 (s, 3H), 2.74 (s, 2H), 1.46 (t, 2H), 1.14 (q, 2H), 0.74 (t, 3H); LC/MS m/z 436 [M+H] ⁺ .

Example 150

3675 N-methyl-N-[2-(l l -oxo- 10,1 l -dihydro-5H-dibenzo[b,e][ l ,4]diazepin-3- yl)phenyl]propane-2-sulfonamide

The title compound was prepared as described in Examples 103A- 103C, except substituting propane-2-sulfonyl chloride for cyclopropylsulfonyl chloride. 'HNMR (400 MHz, CDCI3), δ ppm 9.82 (s, I H), 7.88 (s, I H), 7.69 (d, I H), 7.40-7.52 (m, 4H), 6.89- 3680 7.00 (m, 6H), 3.1 1 (s, 3H), 3.06 (q, I H), 1.02 (d, 6H); LC/MS m/z 422 [M+H] ⁺ .

Example 151

N,2-d imethy l-N-[2-( 1 1 -oxo- 10, 1 1 -d ihydro-5H-dibenzo[b,e] [ 1 ,4]diazepin-3- yl)phenyl]propane- 1 -sulfonamide

3685 The title compound was prepared as described in Examples 103A-103C, except

substituting 2-methylpropane- 1-sulfonyl chloride for cyclopropylsulfonyl chloride. "HNMR (400 MHz, CDCI3), δ ppm 9.81 (s, I H), 7.89 (s, I H), 7.69 (d, I H), 7.35-7.53 (m, 4H), 6.89-7.00 (m, 6H), 3.10 (s, 3H), 2.70 (d, 2H), 1.88 (t, I H), 0.81 (d, 6H); LC/MS m/z 436 [M+H] ⁺ .

3690

Example 152

N,N-dimethyl-3-(3-{2-[methyl(methyisuIfonyl)amino]phenyl}-l l -oxo- 10, 1 1 -dihydro- 5H-dibenzo[b,e][l ,4]diazepin-7-yl)benzamide 3695 Example 152A

4-bromo-2-(5-chloro-2-nitrophenylamino)benzoic acid

To a solution of 2-amino-4-bromobenzoic acid (43.2 g, 0.2 mol) and 4-chloro-2- fluoro-1 -nitrobenzene (42 g, 0.24 mol) in N,N-dimethylformamide (250 ml) was added cesium carbonate (97.5 g, 0.3 mol) and the resulting mixture was stirred at 140°C for 4 3700 hours. After cooling at room temperature, it was diluted with water and ethyl acetate. The mixture was acidified with 2N aqueous HC1 and the resulting precipitates were filtered off. The filtrate was extracted in ethyl acetate, dried (Na ₂ S0 ₄ ), filtered, and concentrated. The residue was slurried in ethyl acetate and filtered to afford the title compound.

3705 Example 152B

2-(2-amino-5-chlorophenylamino)-4-bromobenzoic acid

Example 152A (37.1 g, 0.1 mol), and NH ₄ CI ( 18.55 g, 0.35 mol) were dissolved in ethanol (200 ml) and water (100 ml). The reaction mixture was heated to reflux, and iron powder (61.6 g, 1.1 mol) was added in portions over 1 hour. The resulting mixture was 3710 continued to reflux for 2 hours. After cooling at room temperature, the reaction mixture was diluted with CH2CI2, filtered and washed with water. The organic layer was dried (Na ₂ S0 ₄ ), filtered, and concentrated to afford the title compound.

Example 152C

3715 3-bromo-7-chloro-5H-dibenzo[b,e][l ,4]diazepin- l l ( 10H)-one

Example 152B (5.12 g, 0.015 mol), TBTU (O-benzotriazole- l -yl-Ν,Ν,Ν',Ν'- tetramethyluronium tetrafluoroborate) (9.63 g, 0.03 mol), N,N-diisopropylethylamine (10.46 ml, 0.06 mol) were dissolved in Ν,Ν-dimethylformamide (50 ml). The mixture was stirred for 16 hours at room temperature. The solvent was removed in vacuo. The 3720 residue was re-dissolved in CH2CI2 and washed with water, the aqueous phase was

extracted with CH2CI2 twice. The combined organic layers were dried (Na2S0 ₄ ), filtered, concentrated, and the residue was purified by column chromatography of silica gel, eluting with petroleum ether/ethyl acetate, 1 : 1 ) to afford the title compound. MS ESI(-) m/z 32 \ [M-H]\ 3725

Example 152D

N-(2-(7-chloro- l l -oxo- 10, 1 l -dihydro-5H-dibenzo[b,e][ l ,4]diazepin-3-yl)phenyl)-N- methylmethanesulfonamide

To Example 152C (0.129 g, 0.4 mmol) and N-methyl-N-(2-(4,4,5,5-tetramethyl- 3730 l ,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (0.137 g, 0.44 mmol) in a

microwave vial was added 1 ,2-dimethoxyethane (2.4 ml) and methanol ( 1 .20 ml) followed by cesium fluoride (0.122 g, 0.8 mmol) and

tetrakis(triphenylphosphine)palladium(0) (0.023 g, 0.02 mmol). The vial was heated in the Biotage Initiator Microwave Synthesizer at 120°C for 10 minutes. After cooling at 3735 room temperature, the reaction mixture was filtered and concentrated. The crude product was purified by reverse phase HPLC on a customized Waters Purification system, eluting with 10-95% CH ₃ CN / 0.1 % TFA in water to yield the title compound. MS ESI(-) m/z 426 [M-H]\

3740 Example 152E

N,N-dimethyl-3-(3- {2-[methyl(methylsulfonyl)amino]phenyl }- l l -oxo- 10, 1 1 -dihydro- 5H-dibenzo[b,e][ l ,4]diazepin-7-yl)benzamide

A microwave vessel was charged with a stir bar, cesium fluoride ( 14.95 mg, 0.098 mmol), a solution of Example 152D ( 14.04 mg, 0.032 mmol) in methanol, a solution of

3745 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (3.87 mg, 0.010 mmol) in DME, a solution of N,N-dimethyl-3-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2- yl)benzamide ( 17.6 mg, 0.064 mmol) in 1 ,2-dimethoxyethane, and a solution of palladium acetate ( 13.4 mg, 006 mmol) in 1 ,2-dimethoxyethane. The vial was capped and the reaction mixture was heated in the Personal Chemistry Emry's Optimizer

3750 Microwave Reactor at 120°C for 30 minutes. After cooling at room temperature, the reaction mixture was filtered and concentrated. The crude product was purified by reverse phase HPLC on the Agilent 1 100 Series Purification System, eluting with 10- 100% CH ₃ CN / 0.1 % TFA in water to afford the title compound. Ή NMR (500 MHz, DMSO-d ₆ /D ₂ 0) δ ppm 7.73 (t, J = 6.5, 1 H), 7.68 (d, J= 8.0, 1 H), 7.52 (ddt, J = 14.5, 7.4,

3755 6.8, 6H), 7.41 (dd, J = 7.4, 1 .9, 1 H), 7.38 - 7.34 (m, 2H), 7.29 (dd, J = 8.2, 2.0, 1 H), 7.09 (d,J=8.2, 1H), 7.04 (d,J= 1.5, 1H), 6.99 (dd,J=8.1, 1.5, 1H), 3.12 (s, 3H), 3.01 (s, 3H), 2.94 (s, 3H), 2.91 (s, 3H); MS APCI(+) m/z 541 [M+H] ⁺ .

Example 153

3760 Ν-ηιβί1ιΊ-Ν-(2-{7-[4-(ηιθφ1ιοΠη-4->Ίπΐ 6ΐΗΊ)ρ1ΐ6η>Ί]-1 l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-3-yl}phenyl)methanesulfonamide

The title compound was prepared as described in Example 152E, except 4-(4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)moφholi ne was substituted forN,N- dimethyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benz amide. Ή NMR (500 MHz,

3765 DMSO-d6/D ₂ 0) δ ppm 7.74 (d, J= 8.2, 1H), 7.69 (d,J= 8.2, 2H), 7.58 (t, J= 9.6, 3H), 7.54-7.45 (m, 2H), 7.40 (d, J= 5.7, 1H), 7.36 (d,J= 1.9, 1H),7.30 (d,J=8.2, 1H), 7.10 (d, J= 8.2, 1H), 7.05 (s, 1H), 7.00 (d, J= 8.0, 1 H), 4.41 - 4.23 (m, 2H), 3.97 (m, 2H), 3.74 (s, 2H), 3.68 - 3.57 (m, 2H), 3.13 (m, 5H), 2.91 (s, 3H); MS ESI(-) m/z 567 [M-H] ^" .

3770

Example 154

N-methy 1-N- [2-(7- {4-[(4-methy Ipiperazin- 1 -y l)carbony l]pheny 1 } - 11 -oxo- 10,11 -dihydro- 5H-dibenzo[b,e][l,4]diazepin-3-yl)phenyl]methanesulfonamide

The title compound was prepared as described in Example 152E, except

3775 substituting (4-methylpiperazin-l-yl)(4-(4,4,5,5-tetramethyl-l,3,2-dioxab orolan-2- yl)phenyl)methanone for N,N-dimethyl-3-(4,4,5,5-tetramethy 1-1,3 ,2-dioxaborolan-2- yl)benzamide. 'HNMR (500 MHz, DMSO-d6/D ₂ 0) δ ppm 7.74 (d,J= 8.1, 1H), 7.70 (d, J= 8.3, 2H), 7.59 (d, J= 7.7, 1H), 7.56 - 7.45 (m, 4H), 7.40 (dd, J= 7.4, 1.9, 1H), 7.37 (d,J=2.0, 1H), 7.31 (dd,J=8.2,2.0, 1H), 7.10 (d, J= 8.2, 1H), 7.05 (d,J= 1.5, 1H),

3780 6.99 (dd, J =8.1, 1.6, 1H), 3.44 (bs, 4H), 3.11 (m, 7H),2.91 (s, 3H), 2.84 (s, 3H); MS ESI(+) m/z 596 [M+H] ⁺ .

Example 155

N,N-dimethyl-4-(3-{2-[methyl(methylsulfonyl)amino]phenyI}-l l-oxo-10,11-dihydro-

3785 5H-dibenzo[b,e][ 1 ,4]diazepin-7-yl)benzamide The title compound was prepared as described in Example 152E, except substituting N,N-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) benzamide for N,N-dimethyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) benzamide. Ή NMR (500 MHz, DMSO-d ₆ , D ₂ 0) δ ppm 7.72 (dd,J= 14.4, 8.1, 1H), 7.66 (d, J= 8.2, 1H), 7.59 (d, 3790 J=7.9, 1H), 7.49 (t, J= 7.2, 4H), 7.39(dd,J= 18.0, 5.6, 2H), 7.30 (d, J= 10.2, 1H),

7.09 (d, J= 8.2, 1H), 7.05 (s, 1H), 7.03 - 6.94 (m, 2H), 3.12 (d, J= 3.4, 3H), 2.98 (d, J = 21.8, 6H), 2.90 (d, J = 9.1 , 3H) ); MS APCI(+) m/z 541 [M+H] ⁺ .

Example 156

3795 N-[2-(dimethylamino)ethyI]-4-(3-{2-[methyl(methylsulfonyl)am ino]phenyl}-l 1-oxo- 10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepin-8-yl)benzamide

Example 156A

3-bromo-8-chloro-5H-dibenzo[b,e][l,4]diazepin-l l(10H)-one

3800 The title compound was prepared as described in Example 152A tol 52C, except substituting 4-chloro-l-fluoro-2-nitrobenzene for 4-chloro-2-fluoro-l-nitrobenzene in Example 152A. LC/MS m/z 323 [M+H] ⁺

Example 156B

3805 N-(2-(8-chloro-l l-oxo-10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepin-3-yl)phenyl)-N- methylmethanesulfonamide

The title compound was prepared as described in Example 152D, except substituting Example 156A for Example 152C. MS ESI(-) m/z 426 [M-H]\

3810 Example 156C

N-[2-(dimethylamino)ethyl]-4-(3-{2-[methyl(methylsulfonyl)am ino]phenyl}-l l-oxo- 10,11 -dihydro-5H-dibenzo[b,e][l ,4]diazepin-8-yl)benzamide

The title compound was prepared as described in Example 152E, except substituting Example 156B for Example 152D and N-(2-(dimethylamino)ethyl)-4- 3815 (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzamideforN,N -dimethyl-3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide). Ή NMR (500 MHz, DMSO-d ₆ , D ₂ 0) δ ppm 7.93 (d, J= 8.4, 2H), 7.73 (dd, J= 10.0, 8.3, 3H), 7.59 (d, J= 7.6, 1 H), 7.50 (qd, J = 7.4,3.9, 2H), 7.38(ddd,J= 10.5, 7.8, 1.9, 3H), 7.13 (d,J= 8.2, 1H), 7.04 (d,J= 1.5, 1H), 7.00 - 6.96 (m, 1H), 3.64 (t, J= 5.9, 2H), 3.29 (t, J= 6.0, 2H), 3.13 (s, 3H), 2.90 (s, 3820 3H), 2.86 (s, 6H); MS ESI(+) m/z 584 [M+H] ⁺ .

Example 157

N-methyl-N-[2-(7- {3-[(4-methy lpiperazin- 1 -yl)carbonyl]pheny 1 } - 11 -oxo- 10, 11 -dihydro- 5H-dibenzo[b,e][l,4]diazepin-3-yl)phenyl]methanesulfonamide

3825 The title compound was prepared as described in Example 152E, except

substituting (4-methylpiperazin-l-yl)(3-(4,4,5,5-tetramethyl-l,3,2-dioxab orolan-2- yl)phenyl)methanone for N,N-dimethyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzamide. Ή NMR (500 MHz, DMSO-d ₆ , D ₂ 0) δ ppm 7.73 (t, J= 6.6, 2H), 7.63 (s, 1H), 7.61 - 7.55 (m, 2H), 7.53 - 7.45 (m, 2H), 7.45 - 7.38 (m, 2H), 7.36 (d, J= 2.0, 1 H),

3830 7.29 (dd, 7=8.2,2.0, 1H), 7.10 (d, J= 11.3, 1H), 7.05 (d,J= 1.5, 1H), 7.00 (dd,J= 8.1, 1.5, 1H), 3.42 (bs, 4H), 3.10 (m, 7H), 2.91 (s, 3H), 2.83 (s, 3H); MS APCI(+) m/z 596 [M+H] ⁺ .

Example 158

3835 N-methyl-N-{2-[7-(l-methyl-lH-pyrazol-4-yl)-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-3-yl]phenyl}methanesulfonamide

The title compound was prepared as described in Example 152E, except substituting l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole for N,N-dimethyI-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) benzamide. Ή NMR (500 3840 MHz, DMSO-d ₆ , D ₂ 0) δ ppm 7.99 (s, 1H), 7.75 - 7.69 (m, 2H), 7.58 (d,J= 7.7, 1H), 7.50 (dd,J= 17.1,7.9, 2H), 7.40 (d, J= 7.3, 1H), 7.18 (d, J= 1.8, 1H), 7.14 (d, J= 8.2, 1H), 7.03 (s, 1H), 6.98 (dd, J= 8.1, 5.1, 2H), 3.85 (s, 3H), 3.12 (s, 3H), 2.90 (s, 3H); MS ESI(+) m/z 474 [M+H] ⁺ .

3845 Example 159

N-methyl-N-[2-(8-{3-[(4-methylpiperazin-l-yl)carbonyl]phenyl }-l l-oxo-10,11-dihydro- 5H-dibenzo[b,e][l,4]diazepin-3-yl)phenyl]methanesulfonamide The title compound was prepared as described in Example 152E, except substituting Example 156B for Example 152D and (4-methylpiperazin-l-yl)(3-(4,4,5,5-

3850 tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)methanone for N,N-dimethyl-3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide. Ή NMR (500 MHz, DMSO-d ₆ , D ₂ 0) δ ppm 7.73 (t, J= 9.3, 2H), 7.64 - 7.47 (m, 5H), 7.41 (t, J= 5.8, 2H), 7.36 - 7.28 (m, 2H), 7.12 (d,J= 8.1, 1H), 7.04 (s, 1H), 7.01 - 6.96 (m, 1H),4.54 (s, 1H), 3.83 (s, lH),3.38(s, 3H), 3.17 (m, 3H), 3.13 (s, 3H), 2.90 (s, 3H), 2.82 (d,J = 18.4, 3H); MS ESI(-) m/z 594

3855 [M-H] ^" .

Example 160

N-methyl-N-[2-(l l-oxo-8-quinolin-3-yl-10,l l-dihydro-5H-dibenzo[b,e][l,4]diazepin-3- yl)phenyl]methanesulfonamide

3860 The title compound was prepared as described in Example 152E, except

substituting Example 156B for Example 152D and quinolin-3-ylboronic acid for N,N- dimethyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benz amide. 'HNMR (500 MHz, DMSO-d ₆ , D ₂ 0)5 ppm 9.21 (d, J=2.2, 1H), 8.65 (d,J=2.1, 1H), 8.09 (t, J= 8.0, 2H), 7.87-7.79 (m, 1H), 7.76 (d, J= 8.1, 1H), 7.71 (dd,J= 11.2, 4.2, 1H), 7.59 (dt,J=3.4,

3865 1.7, 1H), 7.56 -7.46 (m,4H), 7.41 (dd,J=7.4, 1.9, 1H), 7.20 (d,J= 8.2, lH),7.06(d,J = 1.5, 1H), 7.00 (dd, J =8.1, 1.6, 1H), 3.14 (s, 3H), 2.91 (s, 3H); MS ESI(-) m/z 519 [M- H]\

Example 161

3870 N-(2-{8-[3-(dimethylamino)phenyl]-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepin-3-yl}phenyl)-N-methylmethanesulfon amide

The title compound was prepared as described in Example 152E, except substituting Example 156B for Example 152D and 3-(dimethylamino)phenylboronic acid for N,N-dimethyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) benzamide. Ή NMR 3875 (500 MHz, DMSO-d ₆ , D ₂ 0) δ ppm 7.73 (d, J =8.1, 1H), 7.61 - 7.57 (m, 1H), 7.50 (qd, J = 7.4, 3.9, 2H), 7.40 (dd, J= 7.4, 1.9, 1H), 7.35 (t, J= 7.9, 1H), 7.29 (dt, J= 4.5, 2.1, 2H), 7.11 -7.02 (m, 4H), 6.98 (dd,J=8.1, 1.6, 1H),6.92 (d,J=6.6, 1H), 3.13 (s, 3H), 3.02 (s, 6H), 2.90 (s, 3H); MS ESI(+) m/z 513 [M+H] ⁺ . 3880 Example 162

N- {2-[8-( 1 ,3-benzodioxol-5-yl)- 11 -oxo- 10, 11 -dihydro-5H-dibenzo[b,e][ 1 ,4]diazepin-3- yl]phenyl}-N-methylmethanesulfonamide

The title compound was prepared as described in Example 152E, except substituting Example 156B for Example 152D and benzo[d][l,3]dioxol-5-ylboronic acid 3885 forN,N-dimethyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzamide. Ή NMR (500 MHz, DMSO-d ₆ , D ₂ 0) δ ppm 7.73 (d,J= 8.1, 1H), 7.58 (dd, J= 7.8, 1.0, 1H), 7.49 (tdd, J = 8.6, 7.2, 1.6, 2H), 7.40 (dd, J = 7.4, 2.0, 1 H), 7.24 -7.19 (m, 2H), 7.12 (d,J = 1.6, 1H), 7.08 - 6.95 (m, 5H), 6.12 - 6.00 (m, 2H), 3.12 (d, J= 2.8, 3H), 2.89 (d, J= 4.5, 3H); MS ESI(+) m/z 514 [M+H] ⁺ .

3890

Example 163

N-methyl-N-(2-{ 1 l-oxo-8-[4-(trifluoromethoxy)phenyl]-10,l l-dihydro-5H- dibenzo[b,e][l,4]diazepin-3-yl}phenyl)methanesulfonamide

The title compound was prepared as described in Example 152E, except 3895 substituting Example 156B for Example 152D and 4-(trifluoromethoxy)phenylboronic acid for N,N-dimethyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) benzamide. Ή NMR (500 MHz, DMSO-d ₆ , D ₂ 0) δ ppm 7.93 (d, J= 8.4, 2H), 7.73 (dd, J= 10.0, 8.3, 3H), 7.59 (d, J= 7.6, 1H), 7.50 (qd, J= 7.4, 3.9, 2H), 7.38 (ddd, J= 10.5, 7.8, 1.9, 3H), 7.13 (d, J=8.2, 1H),7.04 (d,J= 1.5, 1H), 7.00-6.96(m, 1H), 3.64 (t, J= 5.9, 2H), 3.29 3900 (t, J= 6.0, 2H), 3.13 (s, 3H), 2.90 (s, 3H), 2.86 (s, 6H); MS ESI(+) m/z 584 [M+H] ⁺ .

Example 164

N-[5-nitro-2-(l 1 -oxo- 10,1 l-dihydro-5H-dibenzo[b,e][l,4]diazepin-3- yl)phenyl]methanesulfonamide

3905

Example 164A

N-(2-bromo-5-nitrophenyl)methanesulfonamide

To a solution of 2-bromo-5-nitroaniline (1.0 g, 4.61 mmol), pyridine (0.820 ml, 10.14 mmol) in dichloromethane (15 ml) was added methanesulfonyl chloride (0.395 ml, 3910 5.07 mmol) in dichloromethane (2 mL) at room temperature and the mixture was stirred overnight. The clear solution was then washed with IN aqueous HC1, brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified on silica gel (10-80% ethyl acetate in hexane) to give the title compound. MS ESI (-) m/z 294.8 [M- H]\

3915

Example 164B

N- [5-n itro-2-( 1 1 -oxo- 10,1 1 -dihydro-5H-d ibenzo[b,e] [ 1 ,4]d iazepin-3 - yl)phenyl]methanesulfonamide

To a degassed suspension of N-(2-bromo-5-nitrophenyl)methanesulfonamide ( 100 3920 mg, 0.339 mmol), Example 4A (95 mg, 0.282 mmol), CsF (129 mg, 0.847 mmol) and 2- dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (22.23 mg, 0.056 mmol) in N,N-dimethylacetamide (2 ml) and methanol(l mL), palladium(II) acetate (6.34 mg, 0.028 mmol) was added. The mixture was purged with nitrogen under vacuum for three times then it was irradiated with microwave (Biotage Initiator) at 85°C for 20 minutes. 3925 The mixture was filtered and the filtrate was concentrated and was then purified on silica gel (20-80% ethyl acetate in hexane) to give the title compound. Ή NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.90 (s, 1 H) 9.45 (s, 1 H) 8.29 (d, J= 2.29 Hz, 1 H) 8.08 (s, 1 H) 7.99 (s, 1 H) 7.76 (d, J= 8.09 Hz, 1 H) 7.54 (d, J = 8.39 Hz, 1 H) 7.06 (s, 1 H) 6.84 - 7.02 (m, 6 H) 3.04 (s, 3 H). MS ESI (-) m/z 423.0 [M-Hp

3930

3935

3940