TRICYCLIC HETEROCYCLES AS ANTICANCER AGENTS

Abstract

Tricyclic chemical modulators of FOXO transcription factor proteins are disclosed. The compounds are useful to treat cancer, age-onset proteotoxicity, stress-induced depression, inflammation, and acne. The compounds are of the following and similar genera:

##STR00001##

in which Het is an aromatic heterocyclic ring and Y is a point of attachment of various side chains and rings. An example of such a compound is 4-chloro-N-(3-(10,11-dihydro-5H-benzo[b]pyrido[2,3-f]azepin-5-yl)propyl)benzenesulfonamide:

##STR00002##

Claims

1. A compound of formula (I): ##STR00067## wherein: T is a benzene ring or a five or six membered heteroaromatic ring; U is a benzene ring or a five or six membered heteroaromatic ring; with the proviso that at least one of T and U is a five or six membered heteroaromatic ring; X is selected from the group consisting of: —S—, —(CH.sub.2—CH.sub.2)—, and —CH═CH—; Y is selected from the group consisting of: ##STR00068## A is a three to six membered aliphatic carbocycle or heterocycle attached at Y as a spiro ring, and A may be additionally substituted with one or two substituents chosen from OH, F, cyano, amino, (C.sub.1-C.sub.3)alkylamino, (C.sub.1-C.sub.3)dialkylamino, (C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy, and (C.sub.1-C.sub.3)alkoxy; R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently selected from the group consisting of: H, halo, —N.sub.3, —NR.sup.6R.sup.7, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl, —OR.sup.6, —C(O)R.sup.6, —OC(O)R.sup.6, —C(O)NR.sup.6R.sup.7, —C(O)OR.sup.6, —SR.sup.6, —SO2R.sup.6, and —SO2NR.sup.6R.sup.7; R.sup.5 is —(CR.sup.15R.sup.16).sub.p-Q.sub.q-(CR.sup.15R.sup.16).sub.n-p-Z or ##STR00069## R.sup.5a is ═CR.sup.14(CR.sup.15R.sup.16).sub.p-Q.sub.q-(CR.sup.15R.sup.16).sub.m-p-Z; Q is chosen from —O—, —NR.sup.14— and ##STR00070## each R.sup.6 and R.sup.7 is independently selected from the group consisting of: H and (C.sub.1-C.sub.6)alkyl; R.sup.14 is H or (C.sub.1-C.sub.3)alkyl; R.sup.15 and R.sup.16, in each occurrence are chosen independently from H, OH, cyano, amino, (C.sub.1-C.sub.3)alkylamino, (C.sub.1-C.sub.3)dialkylamino, (C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy, and (C.sub.1-C.sub.3)alkoxy, or, taken together, two of R.sup.14, R.sup.15 and R.sup.16 may form a three to seven membered heterocycle or non-aromatic carbocycle, wherein said three to seven membered carbocycle or heterocycle may be additionally substituted with one or two substituents chosen from OH, F, cyano, amino, (C.sub.1-C.sub.3)alkylamino, (C.sub.1-C.sub.3)dialkylamino, (C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy, and (C.sub.1-C.sub.3)alkoxy; m is an integer from 1 to 3; n is an integer from 2 to 4; p is zero, 1 or 2; q is zero or 1; t is zero, 1 or 2; u is zero, 1 or 2, with the proviso that when Y is ##STR00071## u is 2; v is 1, 2 or 3; with the proviso that when q is zero and R.sup.15 and R.sup.16, in all of their occurrences are H, n is not 4; Z is selected from the group consisting of: —NHSO.sub.2R.sup.17, —NHC(O)NR.sup.8R.sup.9, —NHC(O)OR.sup.8, —S(O).sub.2NR.sup.8R.sup.9, substituted or unsubstituted cyclic carbamate; substituted or unsubstituted cyclic urea, cyclic imide and cyanoguanidine; R.sup.8 and R.sup.9 are independently selected from H, substituted or unsubstituted (C.sub.1-C.sub.6)alkyl, substituted or unsubstituted (C.sub.3-C.sub.7) cycloalkyl and substituted or unsubstituted (C5-C.sub.14)aryl; and R.sup.17 is chosen from phenyl and monocyclic heteroaryl, said phenyl and monocyclic heteroaryl optionally substituted with one or two substituents chosen from OH, halogen, cyano, nitro, (C.sub.1-C.sub.3)alkylamino, (C.sub.1-C.sub.3)dialkylamino, (C.sub.1-C.sub.3)acylamino, (C.sub.1-C.sub.3)alkylsulfonyl, (C.sub.1-C.sub.3)alkylthio, (C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy, and (C.sub.1-C.sub.3)alkoxy.

2. A compound according to claim 1 of formula ##STR00072## wherein each of W.sup.10, W.sup.11, W.sup.12 and W.sup.13 is independently chosen from N, CH and C—R.sup.3.

3. A compound according to claim 1 of formula ##STR00073## wherein each of W.sup.20, W.sup.21 and W.sup.22 is independently chosen from S, O, NH, CH and C—R.sup.3.

4. A compound according to claim 1, wherein Z is selected from the group consisting of: —NHSO.sub.2R.sup.17, —NHC(O)NR.sup.8R.sup.9, and —NHC(O)OR.sup.8.

5. A compound according to claim 4 wherein Z is —NHSO.sub.2R.sup.17.

6. A compound according to claim 5 of formula: ##STR00074## wherein Ar is a substituted or unsubstituted phenyl, thienyl, furanyl or pyrrolyl.

7. A compound according to claim 6 of formula: ##STR00075## wherein: each of W.sup.10, W.sup.11, W.sup.12 and W.sup.13 is independently chosen from N, CH and C—R.sup.3; each of W.sup.20, W.sup.21 and W.sup.22 is independently chosen from S, O, NH, CH and C—R.sup.3. R.sup.1 and R.sup.3 are independently selected from the group consisting of: H and halo; and R.sup.2 and R.sup.4 are H.

8. A compound according to claim 7 wherein X is —CH═CH— or —CH.sub.2CH.sub.2—.

9. A compound according to claim 7 wherein p and q are both zero, R.sup.15 is H and R.sup.16 is chosen from H and OH.

10. A compound according to claim 9 of formula: ##STR00076## wherein: R.sup.1 and R.sup.3 are independently selected from the group consisting of: H and halo; and R.sup.2 and R.sup.4 are H.

11. A compound according to claim 7 wherein two R.sup.15 or R.sup.16 taken together form a three to seven membered carbocycle or heterocycle B, wherein said three to seven membered carbocycle or heterocycle B may be additionally substituted with one or two substituents chosen from OH, F, cyano, amino, (C.sub.1-C.sub.3)alkylamino, (C.sub.1-C.sub.3)dialkylamino, (C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy, and (C.sub.1-C.sub.3)alkoxy, said compound being of formula: ##STR00077## wherein t is zero, 1 or 2; and Ar is a substituted or unsubstituted phenyl, thienyl, furanyl or pyrrolyl.

12. A compound according to claim 11 wherein (a) B is a five-membered ring of formula: ##STR00078## wherein, in the five-membered ring: W.sup.1 and W.sup.2 are both —CH.sub.2—; or one of W.sup.1and W.sup.2 is —O— and the other is —CH.sub.2—; or one of W.sup.1 and W.sup.2 is —CH(OH)— and the other is —CH.sub.2— and the arylsulfonamide replaces one hydrogen on one CH.sub.2 group; or (b) B is a six-membered ring of formula: ##STR00079## wherein, in the six-membered ring: all of W.sup.1 W.sup.2 and W.sup.3 are —CH.sub.2—; or one of W.sup.1 W.sup.2 and W.sup.3 is —O— and the other two are —CH.sub.2—; or one of W.sup.1 W.sup.2 and W.sup.3 is —CH(OH)— and the other two are —CH.sub.2— and the arylsulfonamide replaces one hydrogen on one CH.sub.2 group.

13. A compound according to claim 7 wherein two R.sup.15 or R.sup.16 taken together form a three to seven membered carbocycle or heterocycle B, wherein said three to seven membered carbocycle or heterocycle B may be additionally substituted with one or two substituents chosen from OH, F, cyano, amino, (C.sub.1-C.sub.3)alkylamino, (C.sub.1-C.sub.3)dialkylamino, (C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy, and (C.sub.1-C.sub.3)alkoxy, said compound being of formula: ##STR00080## wherein t is zero, 1 or 2; and Ar is a substituted or unsubstituted phenyl, thienyl, furanyl or pyrrolyl.

14. A compound according to claim 13 wherein (a) B is a five-membered ring of formula: ##STR00081## wherein, in the five-membered ring: W.sup.1 and W.sup.2 are both —CH.sub.2—; or one of W.sup.1 and W.sup.2 is —O— and the other is —CH.sub.2—; or one of W.sup.1 and W.sup.2 is —CH(OH)— and the other is —CH.sub.2— and the arylsulfonamide replaces one hydrogen on one CH.sub.2 group; or (b) B is a six-membered ring of formula: ##STR00082## wherein, in the six-membered ring: all of W.sup.1 W.sup.2 and W.sup.3 are —CH.sub.2—; or one of W.sup.1 W.sup.2 and W.sup.3 is —O— and the other two are —CH.sub.2—; or one of W.sup.1 W.sup.2 and W.sup.3 is —CH(OH)— and the other two are —CH.sub.2— and the arylsulfonamide replaces one hydrogen on one CH.sub.2 group.

15. A compound according to claim 7 wherein Ar is phenyl or thienyl, optionally substituted with one or two substituents chosen from (C.sub.1-C.sub.3)alkyl, halogen, cyano, nitro, (C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)alkylsulfonyl, (C.sub.1-C.sub.3)haloalkoxy, and acetylamino.

16.-23. (canceled)

24. A compound according to claim 1 wherein t is zero.

25. A compound according to claim 2 wherein one of W.sup.10, W.sup.11, W.sup.12 and W.sup.13 is N, and the remaining three are CH.

26. A compound according to claim 2 wherein two of W.sup.10, W.sup.11, W.sup.12, and W.sup.13 are N, and the remaining two are CH.

27. A compound according to claim 3 wherein one of W.sup.20, W.sup.21 and W.sup.22 is S and the remaining two are CH.

28. (canceled)

29. A compound according to claim 6 wherein Ar is phenyl, optionally substituted at the 3, 4 or 5 positions with one or two substituents chosen from methyl, halogen, cyano, trifluoromethyl and trifluoromethoxy; R.sup.1 and R.sup.3 are independently selected from the group consisting of H and halo; and R.sup.2 and R.sup.4 are H.

30. (canceled)

31. A method of treating a disease chosen from: (a) cancer (b) diabetes (c) autoimmune disease (d) age onset proteotoxic disease (e) mood disorder (f) acne vulgaris (g) solid organ transplant rejection; (h) graft vs host disease; and (i) cardiac hypertrophy; said method comprising administering a therapeutically effective amount of a compound according to claim 1.

32.-39. (canceled)

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

Description

EXAMPLES

Example 100

[0084] ##STR00040##

[0085] 1-(5H-Benzo[b]pyrido[3,2-f]azepin-11(6H)-yl)-2-chloroethanone. A solution of 6,11-dihydro-5H-benzo[b]pyrido[3,2-f]azepine (0.150 g, 0.764 mmol) in 1:1 toluene-CH.sub.2Cl.sub.2, prepared according to a literature method (Villani, F. J.; Mann, T. A. J. Med. Chem. 1968, 11(4), 894-5) was treated with chloroacetyl chloride (85.1 μL, 1.07 mmol) and heated to 100° C. for 1 h. The mixture was cooled to 25° C., concentrated in vacuo to remove most of the solvent. The residue is suspended in a minimal amount of CH.sub.2C.sub.12 and purified by flash chromatography (SiO.sub.2, 0-25% hexanes-ethyl acetate) to afford the title compound as a beige oil (0.053 g, 25%). .sup.1H NMR (600 MHz, CDCl.sub.3) δ (mixture of rotamers) 9.15 (0.5 H, d, J=4.8 Hz), 8.24 (1H, d, J=4.8 Hz), 8.01 (0.5 H, d, J=7.2 Hz), 7.63 (0.5 H, br s). 7.48 (1H, dd, J=7.8, 1.2 Hz), 7.44 (0.5 H, t, J=6.6 Hz), 7.35-7.37 (1H, m), 7.17-7.20 (2H, m), 7.15 (1H, dd, J=7.2, 4.2 Hz), 6.05 (1H, br s), 4.23, (2H, br s), 3.05 (4H, br s); LCMS m/z 273.1306 ([M+H.sup.+], C.sub.15H.sub.13ClN.sub.2O requires 273.0789).

##STR00041##

[0086] 3-(5H-Benzo[b]pyrido[3,2-f]azepin-11(6H)-yl)-3-oxopropanenitrile. A solution of 1-(5H-benzo[b]pyrido[3,2-f]azepin-11(6H)-yl)-2-chloroethanone (1.45 g, 5.32 mmol) in DMF (5.0 mL) was cooled to 0° C. and treated with finely ground sodium cyanide (0.518 g, 10.6 mmol). The mixture was stirred for 14 h at 25° C. The solution was diluted with CH.sub.2Cl.sub.2 (500 mL) and washed with H.sub.2O (3×200 mL), saturated aqueous NaCl (200 mL), dried (Na.sub.2SO.sub.4), and concentrated in vacuo. The residue was suspended in a minimal amount of CH.sub.2Cl.sub.12 and purified by flash chromatography (SiO.sub.2, 0-40% hexanes-ethyl acetate) to afford the title compound as a beige solid (0.560 g, 40%). .sup.1H NMR (600 MHz, CDCl.sub.3) δ (as a mixture of rotamers) 8.34 (1H, d, J=3.6 Hz), 7.57 (1H, d, J=7.8 Hz), 7.42-7.43 (1H, m), 7.26-7.30 (3H, m), 7.25 (1H, dd, J=8.4, 5.4 Hz), 3.78 (2H, br s), 3.41 (2H, br s), 2.95 (2H, br s); .sup.13C NMR (150 MHz, CDCl.sub.3) δ162.1, 151.0, 147.0, 141.1, 139.7, 136.3, 131.1, 129.7, 129.0, 128.3, 127.6, 124.3, 113.9, 31.4, 29.4, 26.7; LCMS m/z 264.2823 ([M+H.sup.+], C.sub.16H.sub.13N.sub.3O requires 264.1131).

##STR00042##

[0087] 3-(5H-Benzo[b]pyrido[3,2-f]azepin-11(6H)-yl)propan-1-amine. A solution of 3-(5H-benzo[b]pyrido[3,2-f]azepin-11(6H)-yl)-3-oxopropanenitrile (0.560 g, 2.13 mmol) in THF (10.0 mL) was cooled to 0° C. and treated with a BH.sub.3-THF (1 M solution in THF, 8.50 mL, 8.50 mmol). The flask was sealed, heated to 70° C. for 5 h, and then cooled to 0° C. The solution was treated slowly, dropwise with a solution of aqueous 1 M HCl (8.5 mL), stirred for an additional 0.5 h at to 0° C., and then heated to 70° C. for 1 h. The mixture was cooled to 25° C., treated with aqueous 4 M NaOH until pH>8, and extracted with THF (3×100 mL). The combined extracts were concentrated to dryness. The residue was dissolved in a minimal amount of CH.sub.2Cl.sub.2 and purified by flash chromatography (SiO.sub.2, 0-50% hexanes-ethyl acetate to remove nonpolar impurities followed by 17:2:1 CH.sub.2Cl.sub.2:MeOH:NH.sub.4OH to elute the product). The combined fractions of pure product were concentrated, dried azeotropically with toluene to afford the title compound as a clear oil (0.267 g, 49%). .sup.1H NMR (600 MHz, CDCl.sub.3) δ8.09 (1H, dd, J=4.8, 1.8 Hz), 7.25 (1H, dd, J=7.2, 1.2 Hz), 7.17-7.18 (2H, m), 7.14 (1H, d, J=7.8 Hz), 7.02-7.04 (1H, m), 6.70 (1H, dd, J=7.8, 4.8 Hz), 4.09 (2H, t, J=6.6 Hz), 3.09-3.11 (2H, m), 3.06-3.07 (2H, m), 2.98 (2H, m), 2.75 (2H, (2H, t, J=6.6 Hz), 1.78 (2H, quintet, J=6.6 Hz). .sup.13C NMR (150 MHz, CDCl.sub.3) δ156.3, 147.4, 144.8, 139.5, 138.3, 128.3, 126.9, 124.4, 124.0, 122.9, 116.2, 47.6, 39.8, 34.7, 31.7, 30.8; LCMS m/z 254.2144 ([M+H.sup.+], C.sub.16H.sub.19N.sub.3 requires 254.1652).

##STR00043##

[0088] N-(3-(5H-Benzo[b]pyrido[3,2-f]azepin-11(6H)-yl)propyl)-4-(trifluoromethoxy)benzenesulfonamide. A solution of 3-(5H-benzo[b]pyrido[3,2-f]azepin-11(6H)-yl)propan-1-amine (0.080 g, 0.316 mmol) in DMF (1.0 mL) was cooled to 0° C., treated with Et.sub.3N (48.0 μL, 0.348 mmol), and 4-trifluoromethoxybenzenesulfonyl chloride (56.0 μL, 0.332 mmol). The mixture was warmed to 25° C., and stirred for 2 h. The mixture was partitioned between saturated aqueous NaCl (50 mL), and CH.sub.2Cl.sub.2 (100 mL). The organic layer was washed with saturated aqueous NaCl (3×50 mL), dried (Na.sub.2SO.sub.4), and concentrated in vacuo. The residue was dissolved in a minimal amount of CH.sub.2Cl.sub.2 and purified by flash chromatography (SiO.sub.2, 0-30% hexanes-ethyl acetate). The purified fractions were combined, dissolved in a minimal amount of ethyl acetate and were precipitated with the addition of hexanes to afford the title compound as a white solid (0.078 g, 52%). .sup.1H NMR (600 MHz, CDCl.sub.3) δ8.02 (1H, dd, J=4.8, 1.8 Hz), 7.74 (2H, d, J=7.2 Hz), 7.16-7.18 (3H, m), 7.07 (1H, td, J=7.2 Hz), 7.03 (1H, d, J=7.2 Hz), 6.94-6.97 (2H, m), 6.64 (1H, dd, J=7.2, 4.8 Hz), 6.22 (1H, br s), 3.86 (2H, t, J=6.6 Hz), 2.93-2.95 (2H, m), 2.91-2.93 (2H, m), 2.89-2.91 (2H, m), 1.74 (2H, quintet, J=6.6 Hz); .sup.13C NMR (150 MHz, CDCl.sub.3) δ155.6, 152.0, 147.3, 144.5, 140.0, 138.6, 138.2, 129.3, 128.3, 127.1, 124.8, 124.0, 122.8, 121.0, 119.6, 116.2, 47.8, 41.5, 35.1, 30.9, 28.3; LCMS m/z 478.7886 ([M+H.sup.+], C.sub.23H.sub.22ClF.sub.3N.sub.3O.sub.3S requires 478.1407).

Example 101

[0089] ##STR00044##

[0090] N-(3-(5H-Benzo[b]pyrido[3,2-f]azepin-11(6H)-yl)propyl)-4-chlorobenzenesulfonamide. A solution of 3-(5H-benzo[b]pyrido[3,2-f]azepin-11(6H)-yl)propan-1-amine (0.0800 g, 0.316 mmol) in DMF (1.0 mL) was cooled to 0° C., treated with Et.sub.3N (48.0 μL, 0.348 mmol), and 4-chlorobenzenesulfonyl chloride (0.0700 g, 0.348 mmol). The mixture was warmed to 25° C. and stirred for 2 h. The mixture was partitioned between saturated aqueous NaCl (50 mL), and CH.sub.2Cl.sub.2 (100 mL). The organic layer was washed with saturated aqueous NaCl (3×50 mL), dried (Na.sub.2SO.sub.4), and concentrated in vacuo. The residue was dissolved in a minimal amount of CH.sub.2Cl.sub.2 and purified by flash chromatography (SiO.sub.2, 0-30% hexanes-ethyl acetate). The purified fractions were combined, dissolved in a minimal amount of ethyl acetate and were precipitated with the addition of hexanes to afford the title compound as a white solid (0.067 g, 49%). .sup.1H NMR (600 MHz, CDCl.sub.3) δ7.61 (2H, dd, J=9.0, 1.8 Hz), 7.28 (2H, dd, J=8.5, 1.6 Hz), 7.17 (1H, d, J=7.2 Hz), 7.07 (1H, tt, J=8.4, 1.8 Hz), 7.03 (1H, td, J=7.2, 1.8 Hz), 6.96 (1H, t, J=1.2 Hz), 6.94 (1H, d, J=1.8 Hz), 6.63-6.65 (1H, m), 6.11 (1H, br s), 3.84 (2H, t, J=6.0 Hz), 2.93-2.94 (2H, m), 2.90-2.93 (2H, m), 2.87-2.90 (2H, m), 1.71 (2H, quintet, J=6.6 Hz); .sup.13C NMR (150 MHz, CDCl.sub.3) δ155.6, 147.2, 144.5, 139.9, 138.9, 138.7, 138.2, 129.4, 128.7, 128.3, 127.1, 124.7, 124.0, 122.8, 116.2, 47.7, 41.4, 35.1, 30.9, 28.3; LCMS m/z 428.4579 ([M+H.sup.+], C.sub.22H.sub.22ClN.sub.3O.sub.2S requires 428.1194).

Example 102

[0091] ##STR00045##

[0092] 2-Chloro-N-(2-vinylphenyl)pyridin-3-amine. A solution of 2-chloropyridin-3-amine (5.43 g, 42.2 mmol) in dioxane (80.0 mL) was treated with 2-bromostyrene (5.20 mL, 40.2 mmol), Pd.sub.2(dba).sub.3 (0.277 g, 0.302 mmol), and Davephos (0.356 g, 0.905 mmol). The solution was degassed for several minutes with Ar(g) and heated to 110° C. for 14 h. The solution was cooled to 25° C., concentrated in vacuo, then partitioned between saturated aqueous NaCl (500 mL), and CH.sub.2Cl.sub.2 (1000 mL). The organic phase was washed with saturated aqueous NaCl (2×300 mL), dried (Na.sub.2SO.sub.4), and concentrated in vacuo. The residue was dissolved in a minimal amount of CH.sub.2Cl.sub.2 and purified by flash chromatography (SiO.sub.2, 0-10% hexanes-ethyl acetate) to afford the title compound which crystallized slowly upon standing to provide a beige solid (3.59 g, 39%). .sup.1H NMR (600 MHz, CDCl.sub.3) δ7.84 (1H, q, J=1.8 Hz), 7.61 (1H, d, J=7.8 Hz), 7.31 (1H, t, J=7.8 Hz), 7.21-7.25 (2H, m), 7.02-7.06 (2H, m), 6.83 (1H, dd, J=17.4, 11.4 Hz), 6.02 (1H, s), 5.76 (1H, d, J=18.0 Hz), 5.34 (1H, d, J=11.4 Hz); .sup.13C NMR (150 MHz, CDCl.sub.3) δ139.95, 138.89, 138.1, 137.1, 133.4, 132.4, 129.1, 127.3, 125.9, 124.5, 123.3, 121.1, 117.1; LCMS m/z 231.1964 ([M+H.sup.+], C.sub.13H.sub.11ClN.sub.2 requires 231.0684).

##STR00046##

[0093] 5H-Benzo[b]pyrido[2,3-f]azepine. A solution of 2-chloro-N-(2-vinylphenyl)pyridin-3-amine (1.46 g, 6.33 mmol) in 1:1 DMF-Et.sub.3N (6.0 mL) was treated with Pd(OAc).sub.2 (0.142 g, 0.633 mmol) and tri-o-tolylphosphine (0.578 g, 1.90 mmol). The solution was heated in a microwave to 150° C. for 2 h and then cooled to 25° C. The mixture was partitioned between saturated aqueous NaCl (100 mL), and CH.sub.2Cl.sub.2 (300 mL). The organic layer was washed with saturated aqueous NaCl (3×200 mL), dried (Na.sub.2SO.sub.4), and concentrated in vacuo. The residue was dissolved in a minimal amount of CH.sub.2Cl.sub.2 and purified by flash chromatography (SiO.sub.2, 0-30% hexanes-ethyl acetate). The purified fractions were combined, dissolved in a minimal amount of ethyl acetate and precipitated with the addition of hexanes to afford the title compound as a yellow solid (0.579 g, 47%). .sup.1H NMR (600 MHz, CDCl.sub.3) δ8.06 (1H, d, J=4.8 Hz), 7.05 (2H, td, J=9.0, 1.2 Hz), 6.49 (1H, d, J=7.8 Hz), 6.47 (1H, d, J=3.6 Hz), 4.84(1H, br s); .sup.13C NMR (150 MHz, CDCl.sub.3) δ149.7, 148.1, 144.8, 143.9, 135.2, 133.5, 131.4, 130.2, 129.4, 126.0, 123.8, 123.7, 119.5; LCMS m/z 195.1824 ([M +H.sup.+], C.sub.13H.sub.10N.sub.2 requires 195.0917).

##STR00047##

[0094] 10,11-Dihydro-5H-benzo[b]pyrido[2,3-f]azepine. A solution of 5H-benzo[b]pyrido[2,3-f]azepine (1.60 g, 8.23 mmol) in 1:1 THF-MeOH (10.0 mL) was treated with 10% Pd/C (0.712 g, 0.823 mmol), placed under an atmosphere of H.sub.2 (g), and stirred for 6 h at 25° C. The mixture was filtered thru Celite and concentrated in vacuo. The residue was dissolved in a minimal amount of Et.sub.2O and precipitated with the addition of hexanes to afford the title compound as a beige solid (1.55 g, 96%). .sup.1H NMR (600 MHz, CDCl.sub.3) δ8.03 (1H, d, J=1.8 Hz), 7.10-7.12 (2H, m), 7.03-7.05 (2H, m), 6.85 (1H, d, J=7.2 Hz), 6.79 (1H, d, J=7.8 Hz), 6.00 (1H, s), 3.32 (2H, t, J=5.4 Hz), 3.13 (2H, t, J=5.4 Hz); .sup.13C NMR (150 MHz, CDCl.sub.3) δ147.7, 142.1, 139.9, 139.0, 130.7, 129.8, 127.2, 124.8, 122.0, 120.8, 118.4, 38.5, 33.2; LCMS m/z 197.1975 ([M+H.sup.+], C.sub.13H.sub.12N.sub.2 requires 197.1073).

##STR00048##

[0095] 3-(10,11-Dihydro-5H-benzo[b]pyrido[2,3-f]azepin-5-yl)propanenitrile. A solution of 10,11-dihydro-5H-benzo[b]pyrido[2,3-f]azepine (1.00 g, 5.09 mmol) in toluene (5.0 mL) was treated with acrylonitrile (5.0 mL), Triton B (0.5 mL), and warmed to 80° C. for 2 h. The mixture was cooled to 25° C., concentrated under a stream of N.sub.2 (g), resuspended in a minimal amount of toluene and purified by flash chromatography (SiO.sub.2, 0-25% hexanes-ethyl acetate). The purified fractions were combined, dissolved in a minimal amount of ethyl acetate, and precipitated with the addition of hexanes to afford the title compound as a white solid (0.400 g, 32%). .sup.1H NMR (600 MHz, CDCl.sub.3) δ7.35-7.36 (1H, m), 7.29 (1H, dd, J=8.4, 1.2 Hz), 7.25 (1H, d, J=7.2 Hz), 7.20 (1H, td, J=7.2, 1.2 Hz), 7.08-7.10 (2H, m), 7.05 (1H, d, J=8.4 Hz), 4.06 (2H, t, J=6.6 Hz), 3.33-3.36 (2H, m), 3.29-3.31 (2H, m), 2.62 (2H, t, J=6.6 Hz); .sup.13C NMR (150 MHz, CDCl.sub.3) δ153.4, 146.5, 143.2, 137.9, 129.9, 128.7, 127.2, 125.9, 125.2, 121.6, 120.6, 118.2, 46.6, 36.5, 30.0, 17.3; LCMS m/z 250.1808 ([M+H.sup.+], C.sub.16H.sub.15N.sub.3 requires 250.1339).

##STR00049##

[0096] 3-(10,11-Dihydro-5H-benzo[b]pyrido[2,3-f]azepin-5-yl)propan-1-amine. A solution of 3-(10,11-dihydro-5H-benzo[b]pyrido[2,3-f]azepin-5-yl)propanenitrile (0.400 g, 1.60 mmol) in THF (10.0 mL) was cooled to 0° C. and treated with BH.sub.3-THF (1 M solution in THF, 6.40 mL, 6.40 mmol). The flask was sealed, heated to 70° C. for 5 h, and then cooled to 0° C. The solution was treated slowly, dropwise with a solution of aqueous 1 M HCl (6.40 mL), stirred for an additional 0.5 h at 0° C., and then heated to 70° C. for 1 h. The mixture was cooled to 25° C., treated with aqueous 4 M NaOH until pH>8, and then extracted with THF (3×100 mL). The combined extracts were concentrated to dryness. The residue was dissolved in a minimal amount of CH.sub.2Cl.sub.2 and purified by flash chromatography (SiO.sub.2, 0-50% hexanes-ethyl acetate to remove nonpolar impurities followed by 17:2:1 CH.sub.2Cl.sub.2:MeOH:NH.sub.4OH to elute the product). The combined fractions of pure product were concentrated, dried azeotropically with toluene to afford the title compound as a clear oil (0.181 g, 45%). .sup.1H NMR (600 MHz, CDCl.sub.3) δ8.07 (1H, dd, J=4.2, 1.2 Hz), 7.32 (1H, dd, J=8.4, 1.2 Hz), 7.14-7.18 (2H, m), 7.06 (1H, d, J=7.8 Hz), 7.02 (1H, dd, J=8.4, 4.2 Hz), 7.00 (1H, td, J=7.8, 0.6 Hz), 3.77 (2H, t, J=6.6 Hz), 3.29 (2H, t, J=6.6 Hz), 3.19 (2H, t, J=6.6 Hz), 2.71 (2H, t, J=6.6 Hz), 2.17 (2H, br s), 1.70 (2H, t, J=6.6 Hz); .sup.13C NMR (150 MHz, CDCl.sub.3) δ152.6, 148.2, 144.2, 141.9, 136.8, 129.2, 126.8, 126.1, 124.0, 121.4, 120.9, 47.8, 39.8, 36.6, 31.3, 30.2; LCMS m/z 254.2198 ([M+H.sup.+], C.sub.16H.sub.19N.sub.3 requires 254.1652).

##STR00050##

[0097] N-(3-(10,11-Dihydro-5H-benzo[b]pyrido[2,3-f]azepin-5-yl)propyl)-4-(trifluoromethoxy)benzenesulfonamide. A solution of 3-(10,11-dihydro-5H-benzo[b]pyrido[2,3-f]azepin-5-yl)propan-1-amine (0.060 g, 0.237 mmol) in DMF (1.0 mL) was cooled to 0° C., treated with Et.sub.3N (36.0 μL, 0.261 mmol), and 4-trifluoromethoxybenzenesulfonyl chloride (42.0 μL, 0.249 mmol). The mixture was warmed to 25° C. and stirred for 2 h. The mixture was partitioned between saturated aqueous NaCl (50 mL), and CH.sub.2Cl.sub.2 (100 mL). The organic layer was washed with saturated aqueous NaCl (3×50 mL), dried (Na.sub.2SO.sub.4), and concentrated in vacuo. The residue was dissolved in a minimal amount of CH.sub.2Cl.sub.2 and purified by flash chromatography (SiO.sub.2, 0-30% hexanes-ethyl acetate). The purified fractions were combined, dissolved in a minimal amount of ethyl acetate and were precipitated with the addition of hexanes to afford the title compound as a white solid (0.065 g, 57%). .sup.1H NMR (600 MHz, CDCl.sub.3) δ8.04 (1H, dd, J=4.6, 1.0 Hz), 7.80 (2H, d, J=7.2 Hz), 7.28 (1H, d, J=7.8 Hz), 7.26 (2H, d, J=9.0 Hz), 7.15-7.18 (2H, m), 7.02-7.04 (3H, m), 5.40 (1H, s), 3.75 (2H, t, J=6.6 Hz), 3.19 (2H, t, J=6.0 Hz), 3.04 (2H, t, J=6.0 Hz), 3.00 (2H, t, J=6.6 Hz), 1.78 (2H, t, J=6.6 Hz); .sup.13C NMR (150 MHz, CDCl.sub.3) δ152.5, 152.2, 147.5, 144.2, 142.2, 138.5, 136.8, 129.5, 129.3, 127.1, 126.1, 124.5, 121.6, 121.4, 121.1, 120.8, 46.9, 41.0, 36.4, 30.1, 27.7; LCMS m/z 478.3604 ([M+H.sup.+], C.sub.23H.sub.22ClF.sub.3N.sub.3O.sub.3S requires 478.1407).

Example 103

[0098] ##STR00051##

[0099] 4-Chloro-N-(3-(10,11-dihydro-5H-benzo[b]pyrido[2,3-f]azepin-5-yl)propyl)benzenesulfonamide. A solution of 3-(10,11-dihydro-5H-benzo[b]pyrido[2,3-f]azepin-5-yl)propan-1-amine (0.0600 g, 0.237 mmol) in DMF (1.0 mL) was cooled to 0° C., treated with Et.sub.3N (36.0 μL, 0.261 mmol), and 4-chlorobenzenesulfonyl chloride (0.0530 g, 0.249 mmol). The mixture was warmed to 25° C. and stirred for 2 h. The mixture was partitioned between saturated aqueous NaCl (50 mL), and CH.sub.2Cl.sub.2 (100 mL). The organic layer was washed with saturated aqueous NaCl (3×50 mL), dried (Na.sub.2SO.sub.4), and concentrated in vacuo. The residue was dissolved in a minimal amount of CH.sub.2Cl.sub.2 and purified by flash chromatography (SiO.sub.2, 0-30% hexanes-ethyl acetate). The purified fractions were combined, dissolved in a minimal amount of ethyl acetate and were precipitated with the addition of hexanes to afford the title compound as a white solid (0.059 g, 58%). .sup.1H NMR (600 MHz, CDCl.sub.3) δ8.06 (1H, dd, J=4.8, 1.2 Hz), 7.68 (2H, d, J=8.4 Hz), 7.40 (2H, d, J=8.4 Hz), 7.26 (1H, d, J=7.8 Hz), 7.15-7.17 (2H, m), 7.02-7.05 (2H, m), 7.02 (1H, s), 5.22 (1H, t, J=5.4 Hz), 3.73 (2H, t, J=6.6 Hz), 3.19 (2H, t, J=6.0 Hz), 3.04 (2H, t, J=6.6 Hz), 2.98 (2H, q, J=6.0 Hz), 1.75 (2H, quintet, J=6.0 Hz); .sup.13C NMR (150 MHz, CDCl.sub.3) δ152.6, 147.5, 144.2, 142.2, 139.3, 138.6, 136.8, 129.6, 129.5, 128.6, 127.0, 126.0, 124.5, 121.6, 120.8, 46.9, 41.0, 36.5, 30.2, 27.7; LCMS m/z 428.2336 ([M +H.sup.+], C.sub.22H.sub.22ClN.sub.3O.sub.2S requires 428.1194).

Example 104

[0100] ##STR00052##

[0101] (R)-N-(3-(10,11-dihydro-5H-benzo[b]pyrido[2,3-f]azepin-5-yl)-2-hydroxypropyl)-4-(trifluoromethoxy)benzenesulfonamide. A solution of (S)-1-amino-3-(10,11-dihydro-5H-benzo[b]pyrido[2,3-f]azepin-5-yl)propan-2-ol (0.056 g, 0.208 mmol) in DMF (1.0 mL) was cooled to 0° C., treated with Et.sub.3N (30.0 μL, 0.218 mmol), and 4-trifluoromethoxybenzenesulfonyl chloride (37.0 μL, 0.218 mmol). The mixture was warmed to 25° C. and stirred for 2 h. The mixture was partitioned between saturated aqueous NaCl (50 mL), and CH.sub.2Cl.sub.2 (100 mL). The organic layer was washed with saturated aqueous NaCl (3×50 mL), dried (Na.sub.2SO.sub.4), and concentrated in vacuo. The residue was dissolved in a minimal amount of CH.sub.2Cl.sub.2 and purified by flash chromatography (SiO.sub.2, 0-30% hexanes-ethyl acetate). The purified fractions were combined, dissolved in a minimal amount of ethyl acetate and were precipitated with the addition of hexanes to afford the title compound as a clear film (0.061 g, 59%). .sup.1H NMR (600 MHz, CDCl.sub.3) δ7.97 (1H, d, J=4.8 Hz), 7.78 (2H, d, J=6.6 Hz), 7.30 (1H, d, J=7.8 Hz), 7.21 (2H, d, J=8.4 Hz), 7.10-7.14 (2H, m), 7.01-7.04 (2H, m), 6.97 (1H, dd, J=7.8, 4.8 Hz), 6.28 (1H, br s), 3.81 (1H, dd, J=6.0, 3.0 Hz), 3.77 (1H, d, J=6.6 Hz), 3.69 (1H, dd, J=12.6, 6.0 Hz), 3.17-3.20 (1H, m), 3.12-3.14 (2H, m), 3.05-3.07 (2H, m), 2.92-2.95 (1H, m); .sup.13C NMR (150 MHz, CDCl.sub.3) δ152.4, 152.1, 147.7, 144.0, 142.1, 138.4, 136.6, 129.4, 129.2, 127.2, 126.5, 124.8, 121.7, 121.2, 121.1, 120.8, 67.1, 54.0, 47.1, 36.7, 36.2; LCMS m/z 494.6078 ([M+H.sup.+], C.sub.23H.sub.22F.sub.3N.sub.3O.sub.4S requires 494.5061).

Example 105

[0102] ##STR00053##

[0103] 9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ol. To a solution of 9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-one (5.70 g, 26.6 mmol) in ethanol (106 mL), and THF (42 mL), was added sodium borohydride (4.02 g, 106 mmol) slowly. The reaction mixture was brought to boiling, and then stirred at 80° C. for 10 min, and at RT for 18 h, in a sealed vessel. The mixture was poured in to ice water, treated with sat. aq. NH.sub.4Cl solution, concentrated to remove EtOH, and THF, extracted with DCM, concentrated to give 9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ol (5.69 g, 99%). .sup.1H NMR (600 MHz, DMSO-d.sup.6) δ7.39-7.38 (1H, m), 7.24-7.23 (1H, m), 7.20-7.17 (2H, m), 7.06 (1H, d, J=5.4 Hz), 5.89-5.87 (2H, m), 3.34-3.30 (1H, m), 3.12-3.02 (2H, m), 2.97-2.92 (1H, m); .sup.13C NMR (150 MHz, DMSO-d.sup.6) δ145.1, 140.3, 139.2, 136.7, 129.5, 129.1, 127.6, 126.5, 125.3, 121.9, 69.4, 31.1, 29.1.

##STR00054##

[0104] 4-allyl-9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophene. To a solution of 9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ol (0.101 g, 0.481 mmol) in dry DCM (1 mL) at 0° C., allyltrimethylsilane (0.109 g, 0.962 mmol) and iron(III) chloride hexahydrate (0.007 g, 0.0.024 mmol) were added. The mixture stirred at RT, under argon for 30 min. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (SiO.sub.2, 0% ethylacetate in hexanes) to afford 4-allyl-9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophene (0.050 g, 43%) as a yellow oil.

[0105] .sup.1H NMR (600 MHz, CDCl.sub.3) δ7.23-7.13 (4H, m), 7.06-7.04 (1H, m), 6.85-6.84 (1H, m), 5.79-5.73 (1H, m), 5.03-4.98 (2H, m), 4.11 (1H, t, J=7.8 Hz), 3.52-3.48 (1H, m), 3.29-3.25 (1H, m), 3.03-2.98 (2H, m), 2.81-2.77 (2H, m); .sup.13C NMR (150 MHz, CDCl.sub.3) δ142.3, 140.2, 137.7, 130.6, 130.1, 129.7, 127.0, 126.4, 121.2, 116.3, 48.8, 42.5, 33.4, 29.1.

##STR00055##

[0106] 3-(9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-yl)propane-1,2-diol. A solution of 4-allyl-9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophene (0.025 g, 0.104 mmol), osmium tetroxide (0.012 mL, 0.001 mmol, 2.5% in tent-butanol), and N-methylmorpholine N-oxide (0.013 g, 0.114 mmol) in tent-butanol:water (0.5 mL:1 mL) was stirred at RT for 14 h. The reaction mixture was treated with solid sodium bisulfite for 1 h, concentrated, and purified by flash chromatography (SiO.sub.2, 2%-10% methanol-dichloromethane) to afford 3-(9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-yl)propane-1,2-diol (0.027 g, 96%). The diastereomeric ratio was determined to be 1:1.2 by .sup.1H NMR analysis. .sup.1H NMR (600 MHz, CDCl.sub.3) δ7.24-7.15 (4H, m), 7.05-7.03 (1H, m), 1H [6.90 (d, J=5.4 Hz), 6.86 (d, J=4.8 Hz)], 1H [4.38 (dd, J=10.2, 4.2 Hz), 4.32-4.31 (m)], 1H [3.78-3.76 (m), 3.63 (dd, J=10.3, 3.0 Hz)], 3.52-3.37 (3H, m), 3.26-3.24 (1H, m), 2.96-2.92 (2H, m), 2.18-1.98 (4H, m); .sup.13C NMR (150 MHz, CDCl.sub.3) δ143.0, 141.3, 140.4, 140.3, 138.1, 137.5, 137.4, 137.0, 131.0, 130.4, 129.2, 127.3, 127.0, 126.6, 121.8, 121.4, 70.7, 70.1, 67.3, 67.1, 44.8, 44.4, 41.4, 33.6, 33.3, 29.0; LCMS m/z 275.1161 ([M+H.sup.+], C.sub.16H.sub.19O.sub.2S requires 275.3853).

##STR00056##

[0107] 1-azido-3-(9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-yl)propan-2-ol.

[0108] To a solution 3-(9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-yl)propane-1,2-diol (2.50 g, 9.11 mmol), and triethylamine (2.50 mL, 18.2 mmol) in DCM (9.0 mL) under argon, at 0° C., was added methane sulfonyl chloride (1.48 mL, 0.843 mmol). The mixture was stirred for 21 h at RT. The reaction mixture was treated with 1 N HCl, extracted with DCM, organic layer was washed with brine, concentrated, to obtain a residue which was purified by flash chromatography (SiO.sub.2, 25%-50% ethylacetate-hexanes) to afford crude 3-(9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-yl)-2-hydroxypropyl methanesulfonate (0.429 g) which was taken to the next step without further purification.

[0109] A solution of 3-(9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-yl)-2-hydroxypropyl methanesulfonate (0.429 g, ˜1.22 mmol)), and sodium azide (0.095 g, 1.46 mmol) in DMF (0.3 mL) was heated to 70° C. in a sealed vessel for 1 h. The mixture was cooled to 25° C., brine was added, extracted with DCM, concentrated in vacuo, purified by flash chromatography (SiO.sub.2, 10%-20% ethylacetate-hexanes) to afford 1-azido-3-(9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-yl)propan-2-ol (0.204 g, 8% over two steps). The diastereomeric ratio was determined to be 1:1.2 by .sup.1H NMR analysis. .sup.1H NMR (600 MHz, CDCl.sub.3) δ7.25-7.18 (4H, m), 7.08-7.06 (1H, m), 1H [6.91 (d, J=5.4 Hz), 6.89 (d, J=4.8 Hz)], 1H [4.41 (dd, J=11.4, 4.8 Hz), 4.33 (d, J=9.6, 6.6 Hz)], 1H [3.85-3.81 (m), 3.56-3.53 (m)], 3.51-3.35 (2H, m), 3.32-3.18 (2H, m), 2.98-2.93 (2H, m), 2.38-2.13 (2H, m), 2.10-2.04 (1H, m); .sup.13C NMR (150 MHz, CDCl.sub.3) δ142.9, 141.0, 140.4, 140.3, 137.8, 137.7, 137.5, 136.7, 130.9, 130.5, 130.4, 130.3, 129.2, 127.5, 127.4, 127.1, 126.6, 121.9, 121.6, 69.3, 68.7, 57.7, 57.5, 44.7, 44.4, 42.6, 33.6, 33.3, 29.0; LCMS m/z 272.1137 ([M−N.sub.2+H.sup.+], C.sub.16H.sub.18NOS requires 272.3847).

##STR00057##

[0110] 1-amino-3-(9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-yl)propan-2-ol. A solution of 1-azido-3-(9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-yl)propan-2-01 (0.153 g, 0.511 mmol) in THF (1 mL) was cooled to 0° C., treated with PPh.sub.3 (0.147 g, 0.562 mmol), H.sub.2O (0.055 mL, 3.06 mmol), and stirred for 12 h at RT. The solution was concentrated to dryness, dissolved in a minimal amount of CH.sub.2Cl.sub.2 and purified by flash chromatography (SiO.sub.2, 100% hexanes, 50% ethyl acetate-hexanes, 5%, methanol-dichloromethane, 17:2:1 dichloromethane: methanol: 35% ammonium hydroxide) to afford 1-amino-3-(9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-yl)propan-2-ol (0.109 g, 78%). The diastereomeric ratio was determined to be 1:1.2 by .sup.1H NMR analysis. .sup.1H NMR (600 MHz, CDCl.sub.3) δ7.27-7.25 (1H, m), 7.22-7.14 (3H, m), 7.04-7.02 (1H, m), 1H [6.94 (d, J=5.4 Hz), 6.88 (d, J=4.8 Hz)], 1H [4.43 (dd, J=11.4, 4.2 Hz), 4.36 (dd, J=9.6, 6.0 Hz)], 3.56-3.42 (2H, m), 3.28-3.24 (1H, m), 2.99-2.91 (2H, m), 1H [2.82 (d, J=10.8 Hz), 2.69 (d, J=10.8 Hz)], 2.53-2.46 (1H, m), 2.14-.05 (1H, m), 1.97-1.91 (4 H, m); .sup.13C NMR (150 MHz, CDCl.sub.3) δ143.6, 141.5, 140.4, 140.2, 138.5, 137.4, 137.2, 131.3, 130.6, 130.2, 129.2, 127.1, 126.9, 126.4, 121.6, 121.1, 70.0, 69.5, 47.8, 47.7, 44.7, 44.6, 43.3, 43.2, 33.6, 33.3, 29.0; LCMS m/z 274.2863 ([M+H.sup.+], C.sub.16H.sub.20NOS requires 274.4006).

##STR00058##

[0111] N-(3 -(9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-yl)-2-hydroxypropyl)-4-(trifluoromethoxy)benzenesulfonamide. A solution 1-amino-3-(9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-yl)propan-2-ol (0.041 g, 0.150 mmol) in DMF (1.0 mL) was cooled to 0° C., treated with Et.sub.3N (0.021 mL, 0.150 mmol), and 4-(trifluoromethoxy)benzene-1-sulfonyl chloride (0.025 mL, 0.150 mmol). The mixture was warmed to RT, and stirred for 18 h. The mixture was partitioned between water (10 mL) and CH.sub.2Cl.sub.2 (10 mL). The organic layer was washed with saturated aqueous NaCl (30 mL×3) to remove DMF, and concentrated in vacuo. The residue was dissolved in a minimal amount of CH.sub.2Cl.sub.2 and purified by flash chromatography (SiO.sub.2, 20%-50% ethylacetate-hexanes) to afford N-(3 -(9,10-dihydro-4H-benzo[4,5] cyclohepta[1,2-b]thiophen-4-yl)-2-hydroxypropyl)-4-(trifluoromethoxy)benzenesulfonamide (105) (0.065 g, 88%). The diastereomeric ratio was determined to be 1:1.2 by .sup.1H NMR analysis. .sup.1H NMR (600 MHz, CD.sub.3OD) δ7.93-7.86 (2H, m), 7.42-7.37 (2H, m), 7.17-7.04 (5H, m), 1H [6.87 (d, J=4.8 Hz), 6.81 (d, J=5.4 Hz)], 1H [4.31 (dd, J=11.4, 3.6 Hz), 4.27 (d, J=9.0, 6.0 Hz)], 3.54-3.17 (4H, m), 2.93-2.78 (5H, m), 1H [2.49-2.20 (m), 2.17-2.13 (m)], 1.82-1.78 (1H, m); .sup.13C NMR (150 MHz, CD.sub.3OD) δ151.7, 143.4, 141.2, 140.5, 140.3, 139.8, 139.7, 138.3, 137.0, 136.7, 130.6, 130.0, 129.9, 129.8, 129.0, 128.7, 126.8, 126.7, 126.4, 126.0, 121.1, 121.0, 120.8, 67.9, 67.6, 49.1, 48.7, 44.0, 43.7, 42.6, 42.4, 33.1, 32.8, 28.6; LCMS m/z 498.1076 ([M+H.sup.+], C.sub.23H.sub.23F.sub.3NO.sub.4S.sub.2 requires 498.5577).

Examples 106 and 107

[0112] ##STR00059##

[0113] (E)-5-(2-nitrostyryl)pyrimidin-4-amine. A solution of 4-aminopyrimidine-5-carbaldehyde (1.00 g, 8.12 mmol) in DMF (10.0 mL) was treated with sodium methoxide (0.527 g, 9.75 mmol), diethyl 2-nitrobenzylphosphonate (2.22 g, 8.12 mmol) and stirred overnight at 25° C. The mixture was poured over methanol (100 mL) and the white solid that had formed was collected by filtration to afford the title compound (1.61 g, 82%). .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ8.40 (1H, d, J=3.6 Hz), 8.34 (1H, d, J=4.2 Hz), 8.03-8.04 (1H, m), 7.99-8.00 (1H, m), 7.75-7.77 (1H, m), 7.53-7.55 (1H, m), 7.37 (1H, dd, J=15.6, 3.6 Hz), 7.28 (1H, dd, J=16.2, 4.2 Hz), 7.16 (2H, br s); .sup.13C NMR (150 MHz, DMSO-d.sub.6) δ160.7, 157.7, 151.9, 147.8, 133.4, 131.9, 128.7, 128.6, 125.6, 124.5, 124.3, 113.5; LCMS m/z 243.2593 ([M+H.sup.+], C.sub.12H.sub.10N.sub.4O.sub.2 requires 243.2408).

##STR00060##

[0114] 5-(2-aminophenethyl)pyrimidin-4-amine. A solution of (E)-5-(2-nitrostyryl)pyrimidin-4-amine (1.61 g, 6.65 mmol) in DMF:MeOH (1:1, 10.0 mL) was treated with 10% Pd/C (0.353 g), placed under an atmosphere of H.sub.2 (g), and stirred for 14 h at 25° C. The mixture was filtered thru Celite and concentrated in vacuo. The residue was treated with H.sub.2O (50 mL) and the white solid that had formed was collected by filtration to afford the title compound (1.06 g, 74%). .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ8.22 (1H, s), 7.90 (1H, s), 6.93 (1H, d, J=7.2 Hz), 6.89 (1H, d, J=7.2, 1.2 Hz), 6.69 (4H, br s), 6.61 (1H, d, J=7.8 Hz), 6.48 (1H, d, J=7.2 Hz), 2.65-2.68 (2H, m), 2.60-2.62 (2H, m); .sup.13C NMR (150 MHz, DMSO-d.sub.6) δ161.8, 156.1, 153.4, 146.1, 129.0, 126.6, 124.4, 116.6, 116.1, 114.6, 28.6, 26.4; LCMS m/z 215.2180 ([M+H.sup.+], C.sub.12H.sub.14N.sub.4O requires 215.1291).

##STR00061##

[0115] 5-(2-aminophenethyl)pyrimidin-4-amine phosphoric acid salt. A solution of 5-(2-aminophenethyl)pyrimidin-4-amine (1.06 g, 4.93 mmol) in EtOH (10.0 mL) was cooled to 0° C. and treated with phosphoric acid (85%, 0.67 mL, 9.86 mmol). The solution was warmed to 25° C. and stirred for 1 h. The white solid that had formed was collected by filtration to afford the title compound as a white solid (1.91 g, 99%). .sup.1H NMR (600 MHz, CD.sub.3OD) δ8.40 (1H, s), 7.76 (1H, s), 6.98 (1H, td, J=7.8, 1.8 Hz), 6.88 (1H, dd, J=7.2, 1.2 Hz), 6.74 (1H, dd, J=7.8, 0.6 Hz), 6.62 (1H, td, J=7.8, 1.2 Hz), 2.85-2.88 (2H, m), 2.80-2.83 (2H, m).

##STR00062##

[0116] 6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepine. A suspension of 5-(2-aminophenethyl)pyrimidin-4-amine phosphoric acid salt (7.72 g, 19.5 mmol) in xylenes (20 mL) was heated to 200° C. for 2 h. The mixture was cooled to 25° C. and partitioned between saturated aqueous sodium bicarbonate (200 mL) and ethyl acetate (200 mL). The organic phase was dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was dissolved in a minimal amount of CH.sub.2Cl.sub.2 and purified by flash chromatography (SiO.sub.2, 0-50% ethyl acetate-hexanes). The purified fractions were combined, concentrated in vacuo, suspended in a minimal amount of diethyl ether and precipitated with the addition of hexanes to afford the title compound (3.26 g, 85%) as a beige solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ8.48 (1H, s), 8.17 (1H, s), 7.28 (1H, d, J=7.8 Hz), 7.16 (1H, t, J=7.2 Hz), 7.14 (1H, d, J=7.2 Hz), 6.91 (1H, t, J=7.2 Hz), 2.99-3.00 (2H, m), 2.88-2.90 (2H, m); .sup.13C NMR (150 MHz, DMSO-d.sub.6) δ158.4, 156.1, 155.9, 139.3, 130.6, 130.1, 126.9, 121.7, 120.0, 118.0, 33.9, 31.0; LCMS m/z 198.1862 ([M+H.sup.+], C.sub.12H.sub.11N.sub.3 requires 198.2432).

##STR00063##

[0117] 2-(3-(5H-benzo[b]pyrimido[5,4-f]azepin-11(6H)-yl)propyl)isoindoline-1,3-dione. A solution of 6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepine (1.00 g, 5.07 mmol) in DMF (10 mL) was cooled to 0° C., treated with NaH (60%, 0.304 g, 7.60 mmol), and N-(3-bromopropyl)phthalimide 2.04 g, 7.60 mmol). The solution was warmed to 25° C. and stirred for 14 h. The mixture was poured over saturated aqueous NaCl (100 mL) and extracted with CH.sub.2Cl.sub.2 (3×100 mL). The combined extracts were washed with saturated aqueous NaCl (3×100 mL), dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was dissolved in a minimal amount of CH.sub.2Cl.sub.2 and purified by flash chromatography (SiO.sub.2, 0-75% ethyl acetate-hexanes) to afford the title compound as a brown oil (1.60 g, 82%). .sup.1H NMR (600 MHz, CDCl.sub.3) δ8.45 (1H, s), 8.09 (1H, s), 7.81 (2H, dd, J=5.4, 3.0 Hz), 7.70 (2H, dd, J=5.4, 2.4 Hz), 7.21 (2H, d, J=3.6 Hz), 7.14 (1H, d, J=7.2 Hz), 7.08-7.11 (1H, m), 4.27 (2H, t, J=7.2 Hz), 3.71 (2H, t, J=7.2 Hz), 3.13-3.15 (2H, m), 2.96-2.98 (2H, m), 2.06 (2H, quintet, J=6.6 Hz); .sup.13C NMR (150 MHz, CDCl.sub.3) δ168.5, 159.9, 157.4, 155.5, 144.6, 138.6, 134.1, 132.3, 128.7, 127.3, 125.6, 123.9, 123.4, 119.6, 48.3, 36.1, 33.7, 31.6, 27.6; LCMS m/z 385.2550 ([M+H.sup.+], C.sub.23H.sub.20N.sub.4O.sub.2 requires 385.1659).

##STR00064##

[0118] 3-(5H-benzo[b]pyrimido[5,4-f]azepin-11(6H)-yl)propan-1-amine. A solution of 2-(3-(5H-benzo[b]pyrimido[5,4-f]azepin-11(6H)-yl)propyl)isoindoline-1,3 -dione (1.60 g, 4.16 mmol) in EtOH (10.0 mL) was treated with NH.sub.2NH.sub.2—H.sub.2O (0.41 mL, 8.32 mmol) and heated to 90° C. for 1 h. The mixture was cooled to 25° C., filtered and concentrated in vacuo. The residue was dissolved in a minimal amount of CH.sub.2Cl.sub.2 and purified by flash chromatography (SiO.sub.2, 17:2:1 CH.sub.2Cl.sub.2:MeOH:NH4OH). The purified fractions were concentrated, dried azeotropically with toluene to provide the title compound as a beige oil (0.335 g, 32%); .sup.1H NMR (600 MHz, CDCl.sub.3) δ8.60 (1H, s) 8.09 (1H, s), 7.23-7.24 (2H, m), 7.14 (1H, d, J=7.2 Hz), 7.09-7.11 (1H, m), 4.27 (2H, t, J=7.2 Hz), 3.04-3.06 (2H, m), 2.95-2.97 (2H, m), 2.71 (2H, t, J=6.6 Hz), 1.79 (2H, quintet, J=6.6 Hz); .sup.13C NMR (150 MHz, CDCl.sub.3) δ160.1, 157.3, 155.6, 144.8, 138.5, 128.5, 127.3, 125.5, 124.1, 119.5, 48.5, 40.0, 33.7, 32.4, 31.6; LCMS m/z 255.1636 ([M+H.sup.+], C.sub.15H.sub.18N4 requires 255.1604).

##STR00065##

[0119] N-(3-(5H-benzo[b]pyrimido[5,4-f]azepin-11(6H)-yl)propyl)-4-(trifluoromethoxy)-benzenesulfonamide. A solution of 3-(5H-benzo[b]pyrimido[5,4-f]azepin-11(6H)-yl)propan-1-amine (0.068 g, 0.267 mmol) in DMF (1.0 mL) was cooled to 0° C., treated with Et.sub.3N (37.0 μL, 0.267 mmol), and 4-trifluoromethoxybenzenesulfonyl chloride (45.0 μL, 0.267 mmol). The mixture was warmed to 25° C., and stirred for 2 h. The mixture was partitioned between saturated aqueous NaCl (50 mL) and CH.sub.2Cl.sub.2 (100 mL). The organic layer was washed with saturated aqueous NaCl (3×50 mL), dried (Na.sub.2SO.sub.4), and concentrated in vacuo. The residue was dissolved in a minimal amount of CH.sub.2Cl.sub.2 and purified by flash chromatography (SiO.sub.2, 0-50% ethyl acetate-hexanes). The pure fractions were combined, concentrated, and the residue was dissolved in a minimal amount of ethyl acetate and precipitated with the addition of hexanes to afford the title compound (106) as a white solid (0.0608 g, 48%). .sup.1H NMR (600 MHz, CDCl.sub.3) δ8.61 (1H, s), 8.10 (1H, s), 7.84 (2H, d, J=8.4 Hz), 7.30 (2H, d, J=8.4 Hz), 7.21-7.24 (1H, m), 7.16 (1H, d, J=7.8 Hz), 7.10-7.14 (2H, m), 5.79 (1H, t, J=5.4 Hz), 4.16 (2H, t, J=6.6 Hz), 3.01 (2H, q, J=6.6 Hz), 2.92-2.96 (4H, m), 1.92 (2H, quintet, J=6.6 Hz); .sup.13C NMR (150 MHz, CDCl.sub.3) δ159.6, 157.5, 155.3, 152.2, 144.4, 138.5, 138.2, 129.3, 128.8, 127.5, 125.9, 123.8, 121.2, 119.7, 119.6, 48.3, 41.2, 33.8, 31.8, 28.5; LCMS m/z 479.2451 ([M+H.sup.+], C.sub.22H.sub.21F.sub.3N.sub.4O.sub.3S requires 479.1359).

##STR00066##

[0120] N-(3-(5H-benzo[b]pyrimido[5,4-f]azepin-11(6H)-yl)propyl)-4-chlorobenzene-sulfonamide. A solution of 3-(5H-benzo[b]pyrimido[5,4-f]azepin-11(6H)-yl)propan-1-amine (0.068 g, 0.267 mmol) in DMF (1.0 mL) was cooled to 0° C., treated with Et.sub.3N (37.0 μL, 0.267 mmol), and 4-chlorobenzenesulfonyl chloride (0.056 g, 0.267 mmol). The mixture was warmed to 25° C., and stirred for 2 h. The mixture was partitioned between saturated aqueous NaCl (50 mL) and CH.sub.2Cl.sub.2 (100 mL). The organic layer was washed with saturated aqueous NaCl (3×50 mL), dried (Na.sub.2SO.sub.4), and concentrated in vacuo. The residue was dissolved in a minimal amount of CH.sub.2Cl.sub.2 and purified by flash chromatography (SiO.sub.2, 0-50% ethyl acetate-hexanes). The pure fractions were combined, concentrated, and the residue was dissolved in a minimal amount of ethyl acetate and precipitated with the addition of hexanes to afford the title compound (107) as a white solid (0.0647 g, 56%). .sup.1H NMR (600 MHz, CDCl.sub.3) δ8.59 (1H, s), 8.10 (1H, s), 7.73 (2H, d, J=8.4 Hz), 7.44 (2H, d, J=8.4 Hz), 7.22 (1H, td, J=7.8, 1.8 Hz), 7.14 (1H, d, J=8.4 Hz), 7.11-7.13 (2H, m), 5.75 (1H, br s), 4.14 (2H, t, J=6.6 Hz), 3.00 (2H, q, J=6.0 Hz), 2.93 (4H, br s), 1.92 (2H, quintet, J=6.6 Hz); .sup.13C NMR (150 MHz, CDCl.sub.3) δ159.6, 157.5, 155.3, 144.3, 139.2, 138.6, 138.2, 129.6, 128.8, 128.7, 127.5, 125.8, 123.7, 119.7, 48.1, 41.1, 33.8, 31.7, 28.4; LCMS m/z 429.1644 ([M+H.sup.+], C.sub.21H.sub.21ClN.sub.4O.sub.2S requires 429.1147).

Cell Viability Assays (IC50 Determination)

[0121] Cell viability assays were performed according to Denizot, F. and R. Lang, Journal of Immunological Methods, 1986. 89(22): p. 271-277. H1650 lung cancer cells were plated at 150,000 cells per well in a 12 well plate. Twenty-four hours after plating, cells were treated as described with increasing concentrations of drug and control. Forty-eight hours after drug treatment, cells were treated with 100 μL of 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and incubated for 2 hours at 37 C. The MTT solution was subsequently replaced with 300 μL of n-propyl alcohol and re-aliquoted to a 96 well plates. Spectrophotometric analysis of each solution was performed using a 96 well plate reader at 600 nm in triplicate. Results are shown in Table 1. The examples up to number 80 in Table 1 below are taken from PCT WO2013/025882, published 21 Feb. 2013. They illustrate biological activities of compounds that share a tricyclic scaffold.

TABLE-US-00001 TABLE 1 Cell Viability Data Example # IC.sub.50 (μM) 3. N-(3-(2-chloro-10H-phenothiazin- 20 10-yl)propyl)-4- methylbenzenesulfonamide 4. Methyl (3-(2-chloro-10H- 10 phenothiazin-10-yl)propyl)carbamate 8. N-(3-(3-chloro-10,11-dihydro-5H- 20 dibenzo[b,f]azepin-5-yl)propyl)-4- methylbenzenesulfonamide 9. Methyl (3-(3-chloro-10,11-dihydro- 30 5H-dibenzo[b,f]azepin-5- yl)propyl)carbamate 10. 3-(3-(3-chloro-10,11-dihydro-5H- 20 dibenzo[b,f]azepin-5-yl)propyl)-1,1- dimethylurea 13. N-(3-(3-chloro-10,11-dihydro-5H- 18 μM dibenzo[b,f]azepin-5-yl)propyl)-3,5- difluorobenzenesulfonamide 14. N-(3-(2-chloro-10H-phenothiazin- 40 μM 10-yl)propyl)-4- cyanobenzenesulfonamide 15. 4-Chloro-N-(3-(2-chloro-10H- 20 μM phenothiazin-10- yl)propyl)benzenesulfonamide 17. 3-(3-(2-Chloro-10H-phenothiazin- >50 10-yl)propyl)-1,1-dimethylurea 18. N-(2-(2-chloro-10H-phenothiazin- 24.4 μM 10-yl)ethyl)4- methylbenzenesulfonamide 20. N-(3-(3-chloro-10,11-dihydro-5H- >40 μM dibenzo[b,f]azepin-5-yl)propyl)-4- fluorobenzenesulfonamide 21. N-(3-(3-chloro-10,11-dihydro-5H- 15.3 μM dibenzo[b,f]azepin-5-yl)propyl)-4- (trifluoromethyl)benzenesulfonamide 22. N-(3-(3-chloro-10,11-dihydro-5H- 11.1 μM dibenzo[b,f]azepin-5-yl)propyl)-4- cyanobenzenesulfonamide 23. 4-Chloro-N-(3-(3-chloro-10,11- ~25 μM dihydro-5H-dibenzo[b,f]azepin-5- yl)propyl)benzenesulfonamide 24. N-(3-(3-chloro-10,11-dihydro- 15.1 μM 5H-dibenzo[b,f]azepin-5-yl)propyl)-4- (methylsulfonyl)benzenesulfonamide 25. N-(3-(3-chloro-10,11-dihydro- <40 μM 5H-dibenzo[b,f]azepin-5-yl)propyl)-4- methoxybenzenesulfonamide 26. 2,4-dichloro-N-(3-(3-chloro- >40 μM 10,11-dihydro-5H-dibenzo[b,f]azepin- 5-yl)propyl)benzenesulfonamide 27. 4-chloro-N-(2-(2-chloro-10H- 20 μM phenothiazin-10- yl)ethyl)benzenesulfonamide 28. N-(3-(3-chloro-10,11-dihydro- INACTIVE 5H-dibenzo[b,f]azepin-5-yl)propyl)-4- chloro-2-fluorobenzenesulfonamide 29. 3,4-dichloro-N-(3-(3-chloro- ~25 μM 10,11-dihydro-5H-dibenzo[b,f]azepin- 5-yl)propyl)benzenesulfonamide 30. N-(3-(3-chloro-10,11-dihydro- 12.6 μM 5H-dibenzo[b,f]azepin-5-yl)propyl)-4- (trifluoromethoxy)benzenesulfonamide 33. 4-chloro-N-(2-(3-chloro-10,11- ~20 μM dihydro-5H-dibenzo[b,f]azepin-5- yl)ethyl)benzenesulfonamide 34. N-(2-(3-chloro-10,11-dihydro-5H- ~20 μM dibenzo[b,f]azepin-5-yl)ethyl)-4- (trifluoromethyl)benzenesulfonamide 35. 4-chloro-N-(3-(10,11-dihydro-5H- ~20 μM dibenzo[b,f]azepin-5- yl)propyl)benzenesulfonamide 36. N-(3-(10,11-dihydro-5H- ~15 μM dibenzo[b,f]azepin-5-yl)propyl)-4- (trifluoromethyl)benzenesulfonamide 37. N-(2-(3-chloro-10,11-dihydro- ~25 μM 5H-dibenzo[b,f]azepin-5-yl)ethyl)-4- (trifluoromethoxy)benzenesulfonamide 38. N-(3-(2-chloro-10,11-dihydro-5H- ~10 μM dibenzo[b,f]azepin-5-yl)propyl)-4- (trifluoromethyl)benzenesulfonamide 39. N-(3-(3-chloro-10,11-dihydro-5H- ~10 μM dibenzo[b,f]azepin-5-yl)propyl)-3- trifluoromethylbenzenesulfonamide 40. N-(3-(3-chloro-10,11-dihydro- ~15 μM 5H-dibenzo[b,f]azepin-5-yl)propyl)-4- nitrobenzenesulfonamide 41. 4-trifluoromethyl-N-(2-(2-chloro- ~25 μM 10H-phenothiazin-10- yl)ethyl)benzenesulfonamide 42. 4-trifluoromethoxy-N-(2-(2- ~25 μM chloro-10H-phenothiazin-10- yl)ethyl)benzenesulfonamide 43. N-(3-(3-amino-10,11-dihydro- ~35 5H-dibenzo[b,f]azepin-5-yl)propyl)-4- (trifluoromethyl)benzenesulfonamide 44. N-(3-(3-azido-10,11-dihydo-5H- ~30 dibenzo[b,f]azepin-5-yl)propyl)-4- (trifluoromethyl)benzenesfulfonamide 45. N-(3-(3-chloro-10,11-dihydro- ~25 μM 5H-dibenzo[b,f]azepin-5- yl)propyl)benzenesulfonamide 46. N-(2-(10H-phenothiazin-10- ~30 μM yl)ethyl)-4- trifluoromethoxybenzenesulfonamide 47. N-(2-(10H-phenothiazin-10- ~30 μM yl)ethyl)-4-chlorobenzenesulfonamide 50. N-(3-(9H-thioxanthen-9- ~15 μM ylidene)propyl)-4- (trifluoromethoxy)benzenesulfonamide 51. N-(3-(10,11-dihydro-5H- ~20 μM dibenzo[a,d][7]annulen-5- ylidene)propyl)-4- (trifluoromethoxy)benzenesulfonamide 52. 4-Chloro-N-(3-(2,8-dichloro- ~10 μM 10,11-dihydro-5H-dibenzo[b,f]azepin- 5-yl)propyl)benzenesulfonamide 53. 4-Trifluoromethoxy-N-(3-(2,8- ~10 μM dichloro-10,11-dihydro-5H- dibenzo[b,f]azepin-5- yl)propyl)benzenesulfonamide 54. N-(3-(3-chloro-10,11-dihydro- ~15 μM 5H-dibenzo[b,f]azepin-5-yl)propyl)-3- (trifluoromethoxy)benzenesulfonamide 55. 4-Chloro-N-(2-((10,11-dihydro- ~25 μM 5H-dibenzo[a,d][7]annulen-5- yl)amino)ethyl)benzenesulfonamide 56. 4-Trifluoromethoxy-N-(2- ~25 μM ((10,11-dihydro-5H- dibenzo[a,d][7]annulen-5- yl)amino)ethyl)benzenesulfonamide 57. 4-Chloro-N-(3-(3-chloro-10,11- ~10 μM dihydro-5H-dibenzo[b,f]azepin-5-yl)- 2-hydroxypropyl)benzenesulfonamide 58. 4-Trifluoromethoxy-N-(3-(3- ~5 μM chloro-10,11-dihydro-5H- dibenzo[b,f]azepin-5-yl)-2- hydroxypropyl)benzenesulfonamide 59. 4-Chloro-N-(3-(10,11-dihydro- ~25 μM 5H-dibenzo[b,f]azepin-5-yl)-2- hydroxypropyl)benzenesulfonamide 60. 4-Trifluoromethoxy-N-(3-(10,11- ~15 μM dihydro-5H-dibenzo[b,f]azepin-5-yl)- 2-hydroxypropyl)benzenesulfonamide 61. 4,5-dichloro-N-(3-(3-chloro- ~20 μM 10,11-dihydro-5H-dibenzo[b,f]azepin- 5-yl)propyl)thiophene-2-sulfonamide 62. 2,5-dichloro-N-(3-(3-chloro- ~25 μM 10,11-dihydro-5H-dibenzo[b,f]azepin- 5-yl)propyl)thiophene-3-sulfonamide 63. 5-Bromo-6-chloro-N-(3-(3- 65% @ 20 μM chloro-10,11-dihydro-5H- dibenzo[b,f]azepin-5- yl)propyl)pyridine-3-sulfonamide 64. N-(3-(10,11-dihydro-5H- ~35 μM dibenzo[b,f]azepin-5-yl)-2- oxopropyl)-4- (trifluoromethoxy)benzenesulfonamide 65. N-(2-cyano-3-(10,11-dihydro- ~15 μM 5H-dibenzo[b,f]azepin-5-yl)propyl)-4- (trifluoromethoxy)benzenesulfonamide 66. N-(3-(10,11-dihydro-5H- N/A dibenzo[b,f]azepin-5- yl)propyl)pyridine-3-sulfonamide 67. N-(3-(10,11-dihydro-5H- ~20 μM dibenzo[b,f]azepin-5-yl)-2- methylpropyl)-4- (trifluoromethoxy)benzenesulfonamide 68. 4-Chloro-N-(3-(10,11-dihydro- ~20 μM 5H-dibenzo[b,f]azepin-5-yl)-2- methylpropyl)benzenesulfonamide 69. N-(3-(4-chloro-10,11-dihydro- ~20 μM 5H-dibenzo[b,f]azepin-5-yl)propyl)-4- (trifluoromethoxy)benzenesulfonamide 70. 4-Chloro-N-(3-(4-chloro-10,11- ~20 μM dihydro-5H-dibenzo[b,f]azepin-5- yl)propyl)benzenesulfonamide 71. N-(3-(10,11-dihydro-5H- 25 dibenzo[a,d][7]annulen-5- ylidene)propyl)-4- cyanobenzenesulfonamide 72. N-(3-(10,11-dihydro-5H- 20 dibenzo[a,d][7]annulen-5- ylidene)propyl)-4- fluorobenzenesulfonamide 73. trans-N-(3-(10,11-dihydro-5H- 15 dibenzo[b,f]azepin-5-yl)cyclohexyl)-4- (trifluoromethoxy)benzenesulfonamide 73. cis-N-(3-(10,11-dihydro-5H- 5 dibenzo[b,f]azepin-5-yl)cyclohexyl)-4- (trifluoromethoxy)benzenesulfonamide 74. (S)-N-(3-(10,11-dihydro-5H- ~15 μM dibenzo[b,f]azepin-5-yl)-2- hydroxypropyl)-4- (trifluoromethoxy)benzenesulfonamide 75. (R)-N-(3-(10,11-dihydro-5H- ~15 μM dibenzo[b,f]azepin-5-yl)-2- hydroxypropyl)-4- (trifluoromethoxy)benzenesulfonamide 76. N-(3-(10,11-dihydro-5H- 20 dibenzo[b,f]azepin-5-yl)cyclopentyl)- 4-(trifluoromethoxy)benzenesulfonamide 77. N-(3-(10,11-dihydro-5H- 15 dibenzo[a,d][7]annulen-5- ylidene)cyclohexyl)-4- (trifluoromethoxy)benzenesulfonamide 78. N-(3-(10,11-dihydro-5H- 15 dibenzo[a,d][7]annulen-5- ylidene)cyclohexyl)-4- chlorobenzenesulfonamide 79. N-(4-(10,11-dihydro-5H- ~20 dibenzo[a,d][7]annulen-5- ylidene)cyclohexyl)-4- (trifluoromethoxy)benzenesulfonamide 80. N-(4-(10,11-dihydro-5H- ~20 dibenzo[a,d][7]annulen-5- ylidene)cyclohexyl)-4- chlorobenzenesulfonamide 100. 20 μM 101. 25 μM 102. 30 μM 103. 30 μM

[0122] Colony Formation Assay. The protocol follows Sangodkar et al. J Clin Invest 2012;122:2637-51.

[0123] Cell culture and staining: For both A549Iuc and H292 cells, 500 cells were seeded into each well of a 6-well plate and allowed to attach for 24 hours before drug treatment. The following day, cells were treated with either the appropriate dose of drug or an equivalent volume of DMSO (two replicates were treated for each condition). For each condition, depleted media was replaced with fresh media containing the equivalent drug dose four days after initial treatment. Cells were harvested either 7 (A549luc) or 8 (H292) days after initial treatment. Briefly, media was aspirated from each well and the cells were washed twice with ice-cold PBS, then plates were allowed to dry at room temperature for 4 hours. Cells were fixed for one hour in a fixing solution consisting of 10% methanol and 10% glacial acetic acid in distilled water, then stained overnight in 1% (w/v) crystal violet dissolved in methanol. The next day, staining solution was aspirated from the wells and plates were washed gently with distilled water to remove excess stain before colony counting. Colonies were imaged on a ChemiDoc XRS+ (Bio-Rad) and images were exported as 8-bit TIFF files. Colonies were counted using the Colony Counter plugin in ImageJ, with colony size defined as between 4 and 400 square pixels, and minimum circularity set at 0.6. Duplicate wells were averaged to obtain a single value for each condition. Results (number of colonies) for A549luc cells are shown in Table 2 and results (number of colonies) for H292 cells are shown in Table 3:

TABLE-US-00002 TABLE 2 Example # 5 μM 7.5 μM 10 μM DMSO blank 146 159 161.5 30 116 111.5 67.5 60 126.5 118.5 56 74 135.5 118.5 96 75 133.5 105 63.5 73 2 0 0

TABLE-US-00003 TABLE 3 Example # 5 μM 7.5 μM 10 μM DMSO blank 111 108 120 30 95 74.5 61 60 107 105 42 74 85.5 65.5 46.5 75 109.5 80 47 73 40.5 16.5 7

[0124] In Vivo Cancer Model

The in vivo lung cancer model is described in Politi et al., Genes Dev. Jun. 1, 2006 20: 1496-1510. EGFR-L858R/CCSP mice were fed doxycycline-impregnanted food pellets to induce tumor formation. After 8-12 weeks, mice were imaged in a Bruker 4.7T Biospec scanner to confirm lung nodule development. After tumor confirmation, the compound of Example 30 was prepared in DMSO (Sigma) and administered i.p. at 100 mg/kg every other day for two weeks. After treatment, the mice were re-imaged by MRI, and pre-treatment and post-treatment lung volumes were calculated by visible lung opacity present in each axial image using Osirix 4.1.1. DMSO control animals show a 20% increase in tumor volume over two week treatment period. Animals treated with the compound of Example 30 show a 60% decrease in tumor volume over two week treatment period.

[0125] As mentioned above, CD4+Foxp3+ regulatory T cells (Tregs) are required for self-tolerance and are essential for induction of allograft tolerance in animals. Immunosuppressive medications required for treating autoimmunity and preventing transplant rejection, including calcineurin inhibitors, nonspecifically inhibit all T cells including Treg. Such pharmacological inhibition of Treg prevents, rather than promotes, allograft tolerance, subjecting the individual to the toxicities of long term immunosuppression, including an increased risk of developing malignancy because anti-tumor immune surveillance is blocked. Thus, immunosuppressants capable of facilitating Treg induction and function, and simultaneously preventing malignancy could be transformative in the care of patients with immune mediated diseases, including transplant rejection.

[0126] Example 30 has been tested for its ability to induce Treg from naive CD4 T cells. These experiments revealed that Example 30 facilitated upregulation of Foxp3 in naive polyclonal treated with TGFβ and TCR transgenic T cells stimulated in vivo during costimulatory blockade, and the induced Tregs functionally suppressed alloreactive T cells in a suppression assay. Fifty thousand CD4 naïve cells (CD62Lhi,CD25 low, CD4 positive) were incubated with 2 ng/mL TGFβ, lug/mL anti-CD3, 100 ng/mL IL-2, 50000 APCs per well and the compounds 10 μM, 5 μM and 2.5 μM concentrations. The cells were incubated for 3 days and then stained for CD4 and Foxp3 expression. Results were expressed as fold increase over the % induced in control (DMSO) wells (typically 20-25% Foxp3+). AKTi, a small molecule AKT inhibitor, was used as a positive control; it induced about a 4-fold increase. Haloperidol was used as a specificity control; it did not induce a statistically significant increase. Example 30 exhibited a greater than 2 fold increase in iTreg at 2.5 μM. Example 27 exhibited a 2 fold increase in iTreg at 5 μM. The effects of Example 30 on iTreg induction are amplified as the TGFβ concentration decreases. Results of suppression assays using iTreg induced with or without Example 30 demonstrate equivalent suppressive capacity, presented as % inhibition of maximal proliferation induced in the absence of Treg.

[0127] To test for a clinically relevant in vivo effect, BALB/c hearts were transplanted into fully allogeneic B6 recipients. While untreated animals rejected their grafts by day 8 n=4, the grafts in the mice treated with 100 mg/kg i.p. of Example 30 lasted 18 days n=4, p<0.05 vs control, a statistically and clinically significant effect.