Bisfluoroalkyl-1,4-benzodiazepinone compounds

1. A compound of Formula (I):

wherein:

R 1 is —CH 2 CF 3 or —CH 2 CH 2 CF 3 ;

R 2 is —CH 2 CF 3 , —CH 2 CH 2 CF 3 , or —CH 2 CH 2 CH 2 CF 3 ;

R 3 is H or —CH 3 ;

each R a is independently F, Cl, —CN, —OCH 3 , and/or —NHCH 2 CH 2 OCH 3 ; and

z is zero, 1, or 2.

2. The compound according to claim 1 wherein:

R 1 is —CH 2 CF 3 or —CH 2 CH 2 CF 3 ; and

R 2 is —CH 2 CF 3 or —CH 2 CH 2 CF 3 .

3. The compound according to claim 1 wherein:

z is zero or 1.

4. The compound according to claim 1 wherein:

R 1 is —CH 2 CH 2 CF 3 ; and

R 2 is —CH 2 CH 2 CF 3 .

5. The compound according to claim 4 wherein:

z is zero or 1.

6. The compound according to claim 1 wherein:

z is 1 or 2.

7. A compound according to claim 1 selected from: (2R,3S)—N-((3S)-1-Methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (1); (2R,3S)—N-((3S)-2-Oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (2); (2R,3S)—N-((3S)-1-Methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2-(2,2,2-trifluoroethyl)-3-(3,3,3-trifluoropropyl)succinamide (3); (2R,3S)—N-((3S)-1-Methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-3-(2,2,2-trifluoroethyl)-2-(3,3,3-trifluoropropyl)succinamide (4); (2R,3S)—N-((3S)-1-( 2 H 3 )Methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (5); (2R,3S)—N-((3S)-7-chloro-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (6); (2R,3S)—N-((3S)-8-methoxy-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (7); (2R,3S)—N-((3S)-8-fluoro-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (8); (2R,3S)—N-((3S)-7-methoxy-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (9); (2R,3S)—N-((3S)-7-fluoro-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (10); (2R,3S)—N-((3S)-8-chloro-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (11); (2R,3S)—N-((3S)-9-methoxy-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (12); (2R,3S)—N-((3S)-8-methoxy-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (13); (2R,3S)—N-((3S)-7-methoxy-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (14); (2R,3S)—N-((3S)-8-cyano-9-methoxy-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (15); (2R,3S)—N-((3S)-8,9-dichloro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (16); (2R,3S)—N-((3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (17); (2R,3S)—N-((3S)-9-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (18); (2R,3S)—N-((3S)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-3-(4,4,4-trifluorobutyl)-2-(3,3,3-trifluoropropyl)succinamide (19); (2R,3S)—N-((3S)-8-Methoxy-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-3-(4,4,4-trifluorobutyl)-2-(3,3,3-trifluoropropyl)succinamide (20); and (2R,3S)—N-((3S)-9-((2-Methoxyethyl)amino)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (21).

8. The compound according to claim 1 selected from:

9. The compound according to claim 1 wherein said compound is:

10. A compound having the structure:

11. The compound according to claim 10 wherein said compound is crystalline.

12. The compound according to claim 11 wherein said compound is in crystalline Form N-1 which is characterized by one of the following:

a) a simulated powder x-ray diffraction pattern substantially as shown in FIG. 1 and/or by an observed powder x-ray diffraction pattern substantially as shown in FIG. 1 ;

b) a powder x-ray diffraction pattern comprising four or more, preferably five or more, 2θ values (CuKα λ=1.5418 Å) selected from: 5.7±0.2, 7.5±0.2, 10.3±0.2, 10.7±0.2, 15.2±0.2, 16.8±0.2, 20.2±0.2, and 20.7±0.2, wherein the powder x-ray diffraction pattern of Form N-1 is measured at a temperature of about 20° C.;

c) unit cell parameters substantially equal to the following:

Cell dimensions:

a=9.41 Å

b=17.74 Å

c=31.94 Å

α=90.0°

β=98.4°

γ=90.0°

Space group: P2 1

Molecules of said compound/asymmetric unit: 4

wherein the unit cell parameters of Form N-1 are measured at a temperature of about −10° C.; and/or

d) fractional atomic coordinates at a temperature of about 25° C. substantially having values of:

Atom

x

y

z

N(7)

10824(5) 

7415(3)

1732(1)

N(3)

4985(5)

 565(2)

1293(1)

O(3)

7152(4)

 45(2)

1509(1)

N(8)

9981(6)

10557(3) 

1329(2)

O(7)

12033(5) 

10000(2) 

1229(1)

O(6)

8697(5)

7992(2)

1768(1)

F(4)

11039(5) 

8541(3)

 79(1)

C(17)

5836(7)

  8(3)

1469(1)

N(11)

3979(5)

1500(3)

3735(1)

N(2)

5338(6)

2530(3)

 994(1)

C(8)

7012(6)

1237(3)

 77(2)

N(15)

9277(5)

4606(3)

3230(1)

C(39)

9990(7)

8020(3)

1739(2)

O(2)

3365(5)

1827(2)

1076(1)

N(6)

10513(6) 

5383(3)

1910(2)

C(41)

10028(6) 

9204(3)

1300(2)

C(18)

5094(6)

−692(3)

1616(2)

C(22)

5502(6)

−1369(3) 

1360(2)

C(23)

4828(7)

−2081(3) 

1501(2)

C(2)

6832(7)

2584(3)

 978(2)

C(14)

5639(7)

1198(3)

1113(2)

C(36)

10130(7) 

6682(3)

1698(2)

C(15)

4647(7)

1875(3)

1071(2)

O(14)

3524(5)

−2130(3) 

1484(2)

O(9)

5867(5)

1970(2)

3461(1)

C(64)

4608(7)

2008(3)

3517(2)

C(49)

7025(7)

 893(4)

5004(2)

O(12)

7212(5)

3943(2)

3143(1)

F(5)

8960(5)

8082(2)

 93(1)

C(33)

8030(8)

6274(4)

 −21(2)

N(5)

9704(5)

6528(3)

1249(1)

C(42)

10783(8) 

9965(4)

1287(2)

O(5)

12472(5) 

6155(3)

1945(1)

C(37)

11163(8) 

6062(4)

1872(2)

F(7)

9290(6)

2987(3)

5202(1)

C(65)

3707(6)

2688(3)

3341(2)

N(4)

5716(6)

−2636(3) 

1628(2)

C(7)

6778(6)

1429(3)

 518(2)

O(8)

2612(5)

 231(2)

3943(1)

O(11)

10584(6) 

5864(3)

3001(1)

C(89)

8963(6)

2807(3)

3658(2)

C(70)

4269(7)

3355(4)

4041(2)

N(13)

8438(5)

5493(3)

3689(1)

C(20)

5588(7)

−808(3)

2089(2)

C(85)

9369(8)

5946(4)

3070(2)

N(14)

8611(7)

6593(3)

3016(2)

N(16)

8948(7)

1437(3)

3656(2)

N(9)

5416(5)

1109(3)

4375(1)

C(71)

4930(8)

4055(3)

4280(2)

N(12)

4314(6)

4592(3)

3189(2)

C(1)

7546(7)

2068(3)

 746(2)

O(13)

11084(5) 

2050(3)

3796(2)

C(73)

7471(7)

6206(4)

4209(2)

C(6)

9033(7)

2147(4)

 744(2)

C(88)

9391(7)

3239(3)

3270(2)

C(40)

10716(7) 

8794(3)

1708(2)

C(54)

7871(7)

 381(4)

5261(2)

C(67)

3574(8)

4095(4)

3382(2)

F(6)

8838(6)

3995(2)

4842(1)

C(79)

7137(9)

6649(4)

3054(2)

C(24)

8991(7)

5283(3)

1841(2)

C(31)

8282(6)

5837(3)

 703(2)

C(47)

9570(7)

9167(4)

 501(2)

C(63)

4839(6)

 898(3)

3940(2)

C(90)

9762(7)

2060(3)

3707(2)

C(55)

6443(6)

 715(3)

4559(2)

C(68)

3723(8)

2732(4)

2864(2)

C(59)

8345(10) 

−1056(5) 

3924(2)

C(75)

7821(8)

5880(5)

4945(2)

C(32)

8425(7)

6417(3)

 405(2)

O(10)

2312(5)

4203(3)

3420(2)

C(48)

9694(8)

8740(4)

 112(2)

N(10)

4682(6)

−430(3)

4071(1)

C(60)

9196(10) 

−525(5)

4132(3)

C(72)

7560(6)

5996(3)

3766(2)

C(11)

7228(8)

 906(5)

−774(2)

C(95)

9510(8)

3334(4)

4845(2)

C(86)

8534(6)

5301(3)

3249(2)

C(16)

4463(10) 

3237(4)

 980(2)

C(62)

3917(7)

 205(4)

3981(2)

C(46)

10181(7) 

8747(4)

 901(2)

C(57)

6210(8)

−445(3)

4106(2)

C(30)

8759(6)

5995(3)

1157(2)

C(66)

4345(6)

3404(3)

3568(2)

C(87)

8540(6)

3940(3)

3212(2)

C(93)

9371(7)

3266(3)

4063(2)

C(58)

6870(9)

−1041(4) 

3907(2)

F(2)

11777(9) 

10008(4) 

2879(2)

C(74)

7871(7)

5699(4)

4528(2)

C(25)

8132(7)

5566(3)

1483(2)

C(4)

9061(10) 

3259(5)

1173(2)

C(26)

6645(7)

5450(3)

1443(2)

C(12)

7727(9)

1590(5)

−595(2)

C(56)

7085(7)

 83(4)

4344(2)

C(34)

7488(7)

5600(4)

−167(2)

C(9)

6519(7)

 574(4)

−101(2)

C(3)

7607(10) 

3182(4)

1190(2)

C(81)

5158(10) 

6468(4)

3438(2)

C(45)

11099(16) 

9317(7)

2895(3)

C(43)

10543(9) 

9268(4)

2103(2)

F(3)

9787(11) 

9550(9)

2938(2)

C(53)

8327(8)

 558(5)

5683(2)

C(29)

8344(10) 

4873(4)

2138(2)

C(5)

9774(10) 

2734(5)

 964(2)

C(80)

6621(7)

6399(3)

3417(2)

C(94)

9050(7)

2877(4)

4460(2)

C(38)

11435(9) 

4768(4)

2102(2)

C(13)

7606(7)

1760(3)

−179(2)

C(61)

3913(9)

−1147(4) 

4095(2)

C(52)

8010(10) 

1214(6)

5841(2)

C(10)

6633(9)

 406(4)

−526(2)

C(35)

7696(8)

5160(4)

 553(2)

C(84)

9357(12) 

7262(4)

2869(3)

C(91)

9330(8)

2785(4)

2864(2)

C(27)

6019(9)

5060(4)

1739(2)

C(44)

11196(10) 

8906(4)

2495(2)

C(69)

3191(8)

2018(4)

2628(2)

C(78)

7034(8)

6922(4)

4311(2)

C(83)

6199(12) 

7012(5)

2740(3)

C(82)

4221(10) 

6784(6)

3121(4)

C(51)

7187(10) 

1748(5)

5591(2)

C(76)

7428(9)

6592(6)

5047(2)

F(1)

11661(10) 

8983(5)

3228(2)

C(50)

6711(8)

1571(4)

5174(2)

C(77)

7057(9)

7114(5)

4734(3)

N(1)

5875(5)

 999(2)

 684(1)

C(102)

5582(7)

−1953(3) 

 630(2)

C(101)

5084(7)

−1277(3) 

 879(2)

C(100)

5214(10) 

−152(4)

2344(2)

C(104)

7326(8)

5036(4)

 115(2)

C(28)

6897(11) 

4774(4)

2086(3)

F(40)

9173(5)

9112(2)

−241(1)

C(105)

8587(8)

 41(4)

4352(2)

C(124)

2922(10) 

2104(6)

2165(3)

F(42)

4029(8)

2397(5)

2012(2)

F(43)

1850(8)

2595(5)

2046(2)

F(41)

2570(8)

1475(4)

1965(2)

C(122)

5045(7)

3962(4)

4744(2)

F(44)

5920(5)

3370(2)

4887(1)

F(45)

5616(5)

4563(2)

4959(1)

F(46)

3833(5)

3823(2)

4879(1)

C(108)

4748(13) 

7054(5)

2773(3)

F(47)

8547(9)

2143(4)

2026(2)

F(48)

6731(8)

1653(4)

2180(2)

F(49)

10919(5) 

3510(3)

4901(1)

C(123)

7913(9)

2494(5)

2683(2)

C(121)

7997(12) 

1902(6)

2341(3)

C(120)

5377(8)

−1834(4) 

 184(2)

C(109)

5564(11) 

−282(5)

2811(2)

F(55)

3970(4)

−1704(2) 

 15(1)

F(54)

6048(5)

−1235(2) 

 59(1)

F(56)

5748(5)

−2425(2) 

 −34(1)

F(53)

4868(7)

−845(3)

2948(1)

F(51)

5179(13) 

 300(4)

3035(2)

F(52)

6924(8)

−420(6)

2920(2)

F(60)

8732(11) 

1307(3)

 2477(2).

13. A pharmaceutical composition comprising a compound according to claim 1 ; and a pharmaceutically acceptable carrier.

14. The pharmaceutical composition according to claim 13 wherein said compound is:

15. A method for treating cancer comprising administering to a human in need thereof, a therapeutically effective dose of the compound according to claim 10 , wherein said cancer is T-cell acute lymphoblastic leukemia, breast cancer, pancreatic cancer, ovarian cancer, non small cell lung cancer, colon cancer, osteosarcoma, or neuroblastoma.

16. The method for treating cancer according to claim 15 , further comprising administering sequentially or concurrently one or more addition agents selected from dasatinib, paclitaxel, tamoxifen, dexamethasone, and carboplatin.

17. The method for treating cancer according to claim 15 , further comprising administering sequentially or concurrently a glucocorticoid.

18. The pharmaceutical composition according to claim 14 wherein said pharmaceutically acceptable carrier is polyethoxylated castor oil.

19. The pharmaceutical composition according to claim 18 further comprising dehydrated alcohol.