Abstract
The present invention provides a compound having a PLD inhibitory activity.
The present invention provides a compound of the following structural formula, and the like, or a pharmaceutically acceptable salt thereof.
##STR00001##
wherein each symbol is as defined in the description.
Claims
1. A compound represented by Formula [Ia] or a pharmaceutically acceptable salt thereof: ##STR00658## wherein A.sup.a is CR.sup.10a or N; A.sup.2a is CR.sup.5a or O; Cy.sup.a is (1) C.sub.6-10 aryl, (2) 5 to 10-membered heteroaryl containing one or two nitrogen atoms as a ring constituting atom, besides carbon atom, or (3) a 9- or 10-membered partially unsaturated fused cyclic group containing one or two oxygen atoms as a ring constituting atom, besides carbon atom; R.sup.1a is (1) C.sub.1-6 alkyl wherein the alkyl is optionally substituted by (a) hydroxy, (b) cyano, (c) SO.sub.2R.sup.11 wherein R.sup.11 is C.sub.1-4 alkyl, or (d) NHCOR.sup.12 wherein R.sup.12 is C.sub.1-4 alkyl, (2) C.sub.2-4 alkenyl wherein the alkenyl is optionally substituted by 1 to 3 of (a) NR.sup.13R.sup.14 wherein R.sup.13 and R.sup.14 are each independently hydrogen or C.sub.1-4 alkyl, (b) halogen, (c) COR.sup.35a wherein R.sup.35a is hydroxy or C.sub.1-4 alkoxy, (d) CONR.sup.36aR.sup.37a wherein R.sup.36a and R.sup.37a are each independently hydrogen or C.sub.1-4 alkyl, or (e) a partial structural formula: ##STR00659## (3) C.sub.1-4 haloalkyl wherein the haloalkyl is optionally substituted by hydroxy, (4) C.sub.1-6 alkoxy wherein the alkoxy is optionally substituted by phenyl, (5) NR.sup.15R.sup.16 wherein R.sup.15 and R.sup.16 are each independently (a) hydrogen, (b) C.sub.1-4 alkyl wherein the alkyl is optionally substituted by (i) phenyl wherein the phenyl is optionally substituted by halogen, or (ii) pyridyl, (c) C.sub.1-4 alkoxy, or (d) C.sub.3-4 cycloalkyl, (6) COR.sup.17a wherein R.sup.17a is C.sub.1-4 alkyl or hydroxy, (7) CONR.sup.18aR.sup.19a wherein R.sup.18a and R.sup.19a are each independently (a) hydrogen, (b) C.sub.1-4 alkyl wherein the alkyl is optionally substituted by hydroxy, (c) C.sub.3-4 cycloalkyl, (d) C.sub.5-8 bridged cycloalkyl, (e) C.sub.1-4 haloalkyl, or (f) C.sub.1-4 alkoxy, (8) C.sub.3-4 cycloalkyl wherein the cycloalkyl is optionally substituted by (a) hydroxy, (b) halogen, or (c) phenyl, (9) 4 to 7-membered heterocycloalkyl containing one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms as a ring constituting atom, besides carbon atom, wherein the heterocycloalkyl is optionally substituted by (a) hydroxy, (b) oxo, (c) NR.sup.20R.sup.21 wherein R.sup.20 and R.sup.21 are each independently hydrogen or C.sub.1-4 alkyl, or (d) phenyl, (10) 6 to 11-membered spiro heterocycloalkyl containing one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms as a ring constituting atom, besides carbon atom, (11) phenyl wherein the phenyl is optionally substituted by one or two of (a) halogen, or (b) C.sub.1-4 haloalkyl, (12) 5 to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen atoms as a ring constituting atom, besides carbon atom, wherein the heteroaryl is optionally substituted by one or two R.sup.22a, (13) a 8 to 10-membered saturated or partially unsaturated fused cyclic group containing 1 to 4 heteroatoms selected from the group consisting of nitrogen and oxygen atoms as a ring constituting atom, besides carbon atom, wherein the fused cyclic group is optionally substituted by C.sub.1-4 haloalkyl, or (14) a 5 to 7-membered partially unsaturated cyclic group containing one or two nitrogen atoms as a ring constituting atom, besides carbon atom, wherein the partially unsaturated cyclic group is optionally substituted by an oxo group and C.sub.1-4 alkyl; R.sup.2a in the number of m are each independently (1) hydroxy, (2) cyano, (3) halogen, (4) C1_s alkyl wherein the alkyl is optionally substituted by (a) hydroxy, or (b) C.sub.3-4 cycloalkyl, (5) C.sub.2-4 alkenyl wherein the alkenyl is optionally substituted by C.sub.1-4 alkoxy, (6) C.sub.1-4 haloalkyl, (7) C.sub.1-4 alkoxy wherein the alkoxy is optionally substituted by 1 to 3 substituents selected from the group consisting of (a) hydroxy, and (b) halogen, (8) SR.sup.23a wherein R.sup.23a is C.sub.1-4 alkyl or C.sub.1-4 haloalkyl, (9) COR.sup.24a wherein R.sup.24a is (a) hydroxy, (b) C.sub.1-4 alkyl, or (c) C.sub.1-4 alkoxy, (10) CONR.sup.25aR.sup.26a wherein R.sup.25a and R.sup.26a are each independently (a) hydrogen, (b) C.sub.1-6 alkyl, or (c) C.sub.3-4 cycloalkyl, or R.sup.25a and R.sup.26a are bonded to each other to form 4 to 7-membered heterocycloalkyl together with the nitrogen atom to which they are bonded, wherein the heterocycloalkyl contains one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms as a ring constituting atom, besides carbon atom, and is optionally substituted by one or two halogens, (11) SO.sub.2R.sup.27 wherein R.sup.27 is C.sub.1-6 alkyl, (12) C.sub.3-4 cycloalkyl, (13) 4 to 7-membered heterocycloalkyl containing one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms as a ring constituting atom, besides carbon atom, wherein the heterocycloalkyl is optionally substituted by one or two substituents selected from the group consisting of (a) halogen, (b) C.sub.1-4 alkyl, and (c) C.sub.1-4 haloalkyl, (14) 5 to 9-membered bridged heterocycloalkyl containing one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms as a ring constituting atom, besides carbon atom, (15) 6 to 11-membered spiro heterocycloalkyl containing one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms as a ring constituting atom, besides carbon atom, or (16) phenyl; R.sup.3a is (1) hydrogen, (2) C.sub.1-4 alkyl, or (3) C.sub.1-4 haloalkyl; R.sup.4a is (1) hydrogen, (2) C.sub.1-4 alkyl, or (3) cyano; R.sup.5a is hydrogen or C.sub.1-4 alkyl; the combination of R.sup.6a, R.sup.7a and R.sup.8a is (1) a combination where R.sup.6a is hydrogen or C.sub.1-4 alkyl, and R.sup.7a and R.sup.8a are both hydrogens, (2) a combination where R.sup.6a is hydrogen or C.sub.1-4 alkyl, and R.sup.7a and R.sup.8a are bonded to each other to form a cyclopentane ring together with the spiro carbon atom and the carbon atoms to which they are bonded, or (3) a combination where R.sup.6a and R.sup.7a are bonded to each other to form a cyclopentane ring together with the spiro carbon atom and the carbon atoms to which they are bonded, and R.sup.8a is hydrogen; R.sup.9a is (1) hydrogen, (2) CONHR.sup.28 wherein R.sup.28 is C.sub.3-4 cycloalkyl, or (3) C.sub.1-4 alkyl; R.sup.10a is (1) hydrogen, (2) hydroxy, (3) halogen, (4) C.sub.1-4 alkyl, (5) cyano, or (6) C.sub.1-4 alkoxy; one or two R.sup.22a are each independently (1) halogen, (2) C.sub.1-4 alkyl, (3) C.sub.1-4 haloalkyl, (4) C.sub.1-4 alkoxy, (5) NHCOR.sup.29 wherein R.sup.29 is C.sub.1-4 alkyl, (6) SO.sub.2R.sup.30 wherein R.sup.30 is C.sub.1-4 alkyl, (7) cyano, or (8) C.sub.3-4 cycloalkyl; and m is 0, 1, 2 or 3.
2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is represented by Formula [IIa]: ##STR00660## wherein A.sup.a, Cy.sup.a, R.sup.1a, R.sup.2a, R.sup.3a, R.sup.4a, R.sup.5a, R.sup.6a, R.sup.7a, R.sup.8a and m are as defined in claim 1.
3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is represented by Formula [IIIa]: ##STR00661## wherein Cy.sup.a, R.sup.1a, R.sup.2a, R.sup.3a, R.sup.4a, R.sup.5a, R.sup.6a, R.sup.7a, R.sup.8a and m are as defined in claim 1.
4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is represented by Formula [IVa]: ##STR00662## wherein R.sup.1b is (1) C.sub.1-6 alkyl wherein the alkyl is optionally substituted by (a) hydroxy, (b) cyano, (c) SO.sub.2R.sup.11 wherein R.sup.11 is C.sub.1-4 alkyl, or (d) NHCOR.sup.12 wherein R.sup.12 is C.sub.1-4 alkyl, (2) C.sub.2-4 alkenyl wherein the alkenyl is optionally substituted by 1 to 3 of (a) NR.sup.13R.sup.14 wherein R.sup.13 and R.sup.14 are each independently hydrogen or C.sub.1-4 alkyl, (b) halogen, (c) COR.sup.35a wherein R.sup.35a is hydroxy or C.sub.1-4 alkoxy, (d) CONR.sup.36aR.sup.37a wherein R.sup.36a and R.sup.37a are each independently hydrogen or C.sub.1-4 alkyl, or (e) a partial structural formula: ##STR00663## (3) C.sub.1-6 alkoxy wherein the alkoxy is optionally substituted by phenyl, (4) NR.sup.15R.sup.16 wherein R.sup.15 and R.sup.16 are each independently (a) hydrogen, (b) C.sub.1-4 alkyl wherein the alkyl is optionally substituted by (i) phenyl wherein the phenyl is optionally substituted by halogen, or (ii) pyridyl, (c) C.sub.1-4 alkoxy, or (d) C.sub.3-4 cycloalkyl, (5) CONR.sup.18aR.sup.19a wherein R.sup.18a and R.sup.19a are each independently (a) hydrogen, (b) C.sub.1-4 alkyl wherein the alkyl is optionally substituted by hydroxy, (c) C.sub.3-4 cycloalkyl, (d) C.sub.5-8 bridged cycloalkyl, (e) C.sub.1-4 haloalkyl, or (f) C.sub.1-4 alkoxy, (6) 6 to 11-membered spiro heterocycloalkyl containing one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms as a ring constituting atom, besides carbon atom, (7) 5 to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen atoms as a ring constituting atom, besides carbon atom, wherein the heteroaryl is optionally substituted by one or two R.sup.22a, (8) a 8 to 10-membered saturated or partially unsaturated fused cyclic group containing 1 to 4 heteroatoms selected from the group consisting of nitrogen and oxygen atoms as a ring constituting atom, besides carbon atom, wherein the fused cyclic group is optionally substituted by C.sub.1-4 haloalkyl, or (9) a 5 to 7-membered partially unsaturated cyclic group containing one or two nitrogen atoms as a ring constituting atom, besides carbon atom, wherein the partially unsaturated cyclic group is optionally substituted by an oxo group and C.sub.1-4 alkyl; and Cy.sup.a, R.sup.2a, R.sup.3a, R.sup.4a, R.sup.5a, R.sup.6a, R.sup.7a, R.sup.8a, R.sup.22a and m are as defined in claim 1.
5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, which is represented by Formula [Va]: ##STR00664## wherein Cy.sup.a, R.sup.2a, R.sup.3a, R.sup.4a and m are as defined in claim 1; and R.sup.1b is as defined in claim 4.
6. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, which is represented by Formula [VIa]: ##STR00665## wherein Cy.sup.b is (1) C.sub.6-10 aryl, or (2) 5- or 6-membered heteroaryl containing one or two nitrogen atoms as a ring constituting atom, besides carbon atom; R.sup.1b is as defined in claim 4; and R.sup.2a, R.sup.3a, R.sup.4a and m are as defined in claim 1.
7. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, which is represented by Formula [VIIa]: ##STR00666## wherein Cy.sup.a, R.sup.2a, R.sup.3a, R.sup.5a, R.sup.6a, R.sup.7a, R.sup.8a and m are as defined in claim 1; and R.sup.1b is as defined in claim 4.
8. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, which is represented by Formula [VIIIa]: ##STR00667## wherein Cy.sup.a, R.sup.2a, R.sup.3a and m are as defined in claim 1; and R.sup.1b is as defined in claim 4.
9. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, which is represented by Formula [IXa]: ##STR00668## wherein Cy.sup.b is as defined in claim 6; R.sup.1b is as defined in claim 4; and R.sup.2a, R.sup.3a and m are as defined in claim 1.
10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is represented by Formula [Xa]: ##STR00669## wherein Cy.sup.a, R.sup.1a, R.sup.2a, R.sup.3a, R.sup.4a, R.sup.5a, R.sup.6a, R.sup.7a, R.sup.8a, R.sup.10a and m are as defined in claim 1.
11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is represented by Formula [XIa]: ##STR00670## wherein Cy.sup.a, R.sup.1a, R.sup.2a, R.sup.3a, R.sup.4a, R.sup.5a, R.sup.6a, R.sup.7a, R.sup.8a, R.sup.10a and m are as defined in claim 1.
12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is represented by Formula [XIIa]: ##STR00671## wherein R.sup.1b is (1) C.sub.1-6 alkyl wherein the alkyl is optionally substituted by (a) hydroxy, (b) cyano, (c) SO.sub.2R.sup.11 wherein R.sup.11 is C.sub.1-4 alkyl, or (d) NHCOR.sup.12 wherein R.sup.12 is C.sub.1-4 alkyl, (2) C.sub.2-4 alkenyl wherein the alkenyl is optionally substituted by 1 to 3 of (a) NR.sup.13R.sup.14 wherein R.sup.13 and R.sup.14 are each independently hydrogen or C.sub.1-4 alkyl, (b) halogen, (c) COR.sup.35a wherein R.sup.35a is hydroxy or C.sub.1-4 alkoxy, (d) CONR.sup.36aR.sup.37a wherein R.sup.36a and R.sup.37a are each independently hydrogen or C.sub.1-4 alkyl, or (e) a partial structural formula: ##STR00672## (3) C.sub.1-6 alkoxy wherein the alkoxy is optionally substituted by phenyl, (4) NR.sup.15R.sup.16 wherein R.sup.15 and R.sup.16 are each independently (a) hydrogen, (b) C.sub.1-4 alkyl wherein the alkyl is optionally substituted by (i) phenyl wherein the phenyl is optionally substituted by halogen, or (ii) pyridyl, (c) C.sub.1-4 alkoxy, or (d) C.sub.3-4 cycloalkyl, (5) CONR.sup.18aR.sup.19a wherein R.sup.18a and R.sup.19a are each independently (a) hydrogen, (b) C.sub.1-4 alkyl wherein the alkyl is optionally substituted by hydroxy, (c) C.sub.3-4 cycloalkyl, (d) C.sub.5-8 bridged cycloalkyl, (e) C.sub.1-4 haloalkyl, or (f) C.sub.1-4 alkoxy, (6) 6 to 11-membered spiro heterocycloalkyl containing one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms as a ring constituting atom, besides carbon atom, (7) 5 to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen atoms as a ring constituting atom, besides carbon atom, wherein the heteroaryl is optionally substituted by one or two R.sup.22a, (8) a 8 to 10-membered saturated or partially unsaturated fused cyclic group containing 1 to 4 heteroatoms selected from the group consisting of nitrogen and oxygen atoms as a ring constituting atom, besides carbon atom, wherein the fused cyclic group is optionally substituted by C.sub.1-4 haloalkyl, or (9) a 5 to 7-membered partially unsaturated cyclic group containing one or two nitrogen atoms as a ring constituting atom, besides carbon atom, wherein the partially unsaturated cyclic group is optionally substituted by an oxo group and C.sub.1-4 alkyl; and Cy.sup.a, R.sup.2a, R.sup.3a, R.sup.4a, R.sup.5a, R.sup.6a, R.sup.7a, R.sup.8a, R.sup.10a, R.sup.22a and m are as defined in claim 1.
13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, which is represented by Formula [XIIIa]: ##STR00673## wherein Cy.sup.a, R.sup.2a, R.sup.3a, R.sup.4a, R.sup.10a and m are as defined in claim 1; and R.sup.1b is as defined in claim 12.
14. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, which is represented by Formula [XIVa]: ##STR00674## wherein Cy.sup.b is (1) C.sub.6-10 aryl, or (2) 5- or 6-membered heteroaryl containing one or two nitrogen atoms as a ring constituting atom, besides carbon atom; R.sup.1b is as defined in claim 12; and R.sup.2a, R.sup.3a, R.sup.4a, R.sup.10a and m are as defined in claim 1.
15. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, which is represented by Formula [XVa]: ##STR00675## wherein Cy.sup.a, R.sup.2a, R.sup.3a, R.sup.5a, R.sup.6a, R.sup.7a, R.sup.8a, R.sup.10a and m are as defined in claim 1; and R.sup.1b is as defined in claim 12.
16. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, which is represented by Formula [XVIa]: ##STR00676## wherein Cy.sup.a, R.sup.2a, R.sup.3a, R.sup.10a and m are as defined in claim 1; and R.sup.1b is as defined in claim 12.
17. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, which is represented by Formula [XVIIa]: ##STR00677## wherein Cy.sup.b is as defined in claim 14; R.sup.1b is as defined in claim 12; and R.sup.2a, R.sup.3a, R.sup.10a and m are as defined in claim 1.
18. (canceled)
19. A pharmaceutical composition comprising a compound as defined in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
20-26. (canceled)
27. A method for inhibiting PLD1 in a mammal, comprising administering a therapeutically effective amount of a compound as defined in claim 1, or a pharmaceutically acceptable salt thereof to the mammal.
28. A method for inhibiting PLD1/2 in a mammal, comprising administering a therapeutically effective amount of a compound as defined in claim 1, or a pharmaceutically acceptable salt thereof to the mammal.
29. A method for treating or preventing a disease selected from the group consisting of thrombosis and cancer in a mammal, comprising administering a therapeutically effective amount of a compound as defined in claim 1, or a pharmaceutically acceptable salt thereof to the mammal.
30-40. (canceled)
41. A compound represented by the following formula, or a pharmaceutically acceptable salt thereof: ##STR00678##
42. A compound represented by the following formula, or a pharmaceutically acceptable salt thereof: ##STR00679##
43. A compound represented by the following formula, or a pharmaceutically acceptable salt thereof: ##STR00680##
44. A compound represented by the following formula, or a pharmaceutically acceptable salt thereof: ##STR00681##
45. A compound represented by the following formula, or a pharmaceutically acceptable salt thereof: ##STR00682##
46. A compound represented by the following formula, or a pharmaceutically acceptable salt thereof: ##STR00683##
47. A compound represented by the following formula, or a pharmaceutically acceptable salt thereof: ##STR00684##
48. A compound represented by the following formula, or a pharmaceutically acceptable salt thereof: ##STR00685##
49. A compound represented by the following formula, or a pharmaceutically acceptable salt thereof: ##STR00686##
50. A compound represented by the following formula: ##STR00687##
51. A compound represented by the following formula: ##STR00688##
52. A compound represented by the following formula: ##STR00689##
53. A compound represented by the following formula: ##STR00690##
54. A compound represented by the following formula: ##STR00691##
55. A compound represented by the following formula: ##STR00692##
56. A compound represented by the following formula: ##STR00693##
57. A compound represented by the following formula: ##STR00694##
58. A compound represented by the following formula: ##STR00695##
59. A pharmaceutical composition comprising a compound as defined in any one of claims 41 to 49, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
60. A method for inhibiting PLD1 in a mammal, comprising administering a therapeutically effective amount of a compound as defined in any one of claims 41 to 49, or a pharmaceutically acceptable salt thereof, to the mammal.
61. A method for inhibiting PLD1/2 in a mammal, comprising administering a therapeutically effective amount of a compound as defined in any one of claims 41 to 49, or a pharmaceutically acceptable salt thereof, to the mammal.
62. A method for treating or preventing a disease selected from the group consisting of thrombosis and cancer in a mammal, comprising administering a therapeutically effective amount of a compound as defined in any one of claims 41 to 49, or a pharmaceutically acceptable salt thereof, to the mammal.
63. A pharmaceutical composition comprising a compound as defined in any one of claims 50 to 58 and a pharmaceutically acceptable carrier.
64. A method for inhibiting PLD1 in a mammal, comprising administering a therapeutically effective amount of a compound as defined in any one of claims 50 to 58 to the mammal.
65. A method for inhibiting PLD1/2 in a mammal, comprising administering a therapeutically effective amount of a compound as defined in any one of claims 50 to 58, or a pharmaceutically acceptable salt thereof, to the mammal.
66. A method for treating or preventing a disease selected from the group consisting of thrombosis and cancer in a mammal, comprising administering a therapeutically effective amount of a compound as defined in any one of claims 50 to 58 to the mammal.
Description
EXAMPLES
[1047] Next, the production method of Compound [I] or Compound [Ia] or a pharmaceutically acceptable salt thereof of the present invention will be concretely explained with reference to the following Production Examples. However, the production method of Compound [I] or Compound [Ia] or a pharmaceutically acceptable salt thereof of the present invention should not be limited to such production examples.
[1048] The compound obtained in each step can be, if necessary, isolated or purified according to a method known per se such as distillation, recrystallization and column chromatography, or directly used in the next step without isolation or purification.
[1049] As used herein, the room temperature refers to a temperature in an uncontrolled state, and one embodiment includes 1? C. to 40? C.
[Production Example 1]: Synthesis of tert-butyl (S)-(1-(4-oxocyclohexyl)propan-2-yl)carbamate
[1050] ##STR00081##
(1) ethyl 4-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)-3-oxobutanoate
[1051] ##STR00082##
[1052] Under argon atmosphere, to a solution of 2-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)acetic acid (1.4 kg) in THF (6.2 kg) was added dropwise a solution of carbonyldiimidazole (1 kg) in DMF (4.7 kg) at room temperature, and the mixture was stirred. The washing with DMF (0.7 kg) is combined therewith, and the mixture was stirred for 3 hr. Monoethyl potassium malonate (1.3 kg) was added thereto, and then magnesium chloride (0.6 kg) was added thereto in divided portions. After stirring all day, water (4.2 kg) and 6M hydrochloric acid (3.1 kg) were added thereto at an internal temperature of 5? C., and the mixture was stirred at room temperature for 1 hr. Toluene (6.1 kg) was added thereto, the mixture was subjected to extraction, and the aqueous layer was subjected to re-extraction with toluene (2.4 kg). The combined organic layers were washed twice with 20% brine (7 kg). The organic layer was concentrated under reduced pressure, followed by azeotropy with methanol (2.2 kg). To the obtained residue was added methanol (3.3 kg) to give a methanol solution. The above methanol solution was combined with a methanol solution obtained by the same procedures from 2-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)acetic acid (8 kg) to give a methanol solution (34 kg) of the title compound. A part of it was concentrated to give an NMR sample.
[1053] 1H-NMR (CDCl3) ?: 4.44-4.31 (1H, m), 4.19 (2H, q, J=7.1 Hz), 3.46-3.27 (1H, m), 3.40 (2H, s), 2.43 (2H, d, J=6.3 Hz), 2.04-1.93 (2H, m), 1.88-1.69 (3H, m), 1.44 (9H, s), 1.28 (3H, t, J=7.1 Hz), 1.19-0.97 (4H, m).
(2) tert-butyl (trans-4-(2-oxopropyl)cyclohexyl)carbamate
[1054] ##STR00083##
[1055] The methanol solution obtained in (1) (34 kg) of ethyl 4-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)-3-oxobutanoate was warmed to 35? C., 4M aqueous sodium hydroxide solution (20 kg) was added thereto, and the mixture was stirred. After stirring at 40? C. for 2 hr, a solution of citric acid (8.4 kg) in water (19 kg) was added dropwise thereto at 45? C. Ethyl acetate (25 kg) was added thereto, the mixture was stirred for 20 min, and a solution of citric acid (8.4 kg) in water (19 kg) was added dropwise thereto. After stirring for 3 hr, the mixture was allowed to cool to room temperature, ethyl acetate (25 kg) was added thereto, and the mixture was subjected to liquid separation. The organic layer was washed with 10% brine (47 kg), and concentrated under reduced pressure. Ethyl acetate (17 kg) was added thereto, and the mixture was concentrated under reduced pressure to give the title compound (8.1 kg) in 87% yield.
[1056] 1H-NMR (CDCl3) ?: 4.36 (1H, br s), 3.35 (1H, br s), 2.31 (2H, d, J=6.4 Hz), 2.12 (3H, s), 2.02-1.95 (2H, m), 1.83-1.71 (3H, m), 1.44 (9H, s), 1.18-0.95 (4H, m).
(3) tert-butyl (trans-4-((S)-2-(((S)-1-phenylethyl)amino)propyl)cyclohexyl)carbamate acetate
[1057] ##STR00084##
[1058] A solution of tert-butyl (trans-4-(2-oxopropyl)cyclohexyl)carbamate obtained in (2) (8.1 kg) in methanol (67 kg) was prepared, and under Ar atmosphere, (S)-1-phenethylamine (4.4 kg), acetic acid (1.2 kg) and a suspension of 2% PtC (0.42 kg) in water (1.7 kg) were added thereto at room temperature, and the mixture was stirred. The mixture was stirred under hydrogen atmosphere (4 atm) at 40? C. for 20 hr. After cooling to room temperature, the 2% PtC was removed by filtration with KC flock (registered trademark) as a filter aid, and washed twice with methanol (15 kg). The obtained solution was concentrated under reduced pressure, isopropyl alcohol (20 kg) was added thereto, and the mixture was concentrated under reduced pressure. The same operation was performed again, and to the obtained solid was added isopropyl alcohol (43 kg) to prepare a suspension. This suspension was heated to 70? C., and acetic acid (1 kg) was added dropwise thereto. After stirring for 2 hr, the mixture was allowed to cool to room temperature, and stirred for 17 hr. The mixture was stirred for additional 2 hr at an internal temperature of 5? C., and the obtained solid was collected by filtration, washed with ice-cooled isopropyl alcohol (20 kg), and dried at 30? C. for 19 hr to give the title compound (9 kg) in 65% yield.
[1059] 1H-NMR (DMSO-D6) ?: 7.35-7.25 (4H, m), 7.21-7.15 (1H, m), 6.62 (1H, d, J=7.5 Hz), 3.80 (1H, q, J=6.5 Hz), 3.17-3.01 (1H, m), 2.48-2.38 (1H, m), 1.90 (3H, s), 1.77-1.59 (3H, m), 1.54-1.28 (11H, m), 1.23-0.66 (12H, m).
(4) tert-butyl (S)-(trans-4-(2-aminopropyl)cyclohexyl) carbamate acetate
[1060] ##STR00085##
[1061] To a solution of tert-butyl (trans-4-((S)-2-(((S)-1-phenylethyl)amino)propyl)cyclohexyl)carbamate acetate obtained in (3) (8.9 kg) in methanol (85 kg) was added a suspension of 5% PdC(PE type) (0.89 kg) in water (1.8 kg) under Ar atmosphere at room temperature, and the mixture was stirred. The mixture was stirred under hydrogen atmosphere (4 atm) at 35? C. for 2 hr. After gradually cooling to room temperature, the 5% PdC was removed by filtration with KC flock (registered trademark) as a filter aid, and washed with methanol (21 kg). The filtrate was concentrated under reduced pressure, followed by azeotropy with acetonitrile (21 kg). To the obtained solid was added methanol (42 kg) to give a methanol solution of the title compound. A part of it was concentrated to give an NMR sample.
[1062] 1H-NMR (DMSO-D6) ?: 6.71-6.64 (1H, m), 6.14 (3H, br s), 3.21-3.02 (1H, m), 2.99-2.86 (1H, m), 1.84-1.58 (7H, m), 1.37 (9H, s), 1.32-1.04 (5H, m), 1.03-0.96 (3H, m), 0.94-0.75 (2H, m).
(5) benzyl (S)-(1-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)propan-2-yl)carbamate
[1063] ##STR00086##
[1064] To a solution of tert-butyl (S)-(trans-4-(2-aminopropyl)cyclohexyl)carbamate acetate (obtained in the same manner as in (4)) (218 g) in DMF (1080 ml) was added triethylamine (100 ml) at room temperature, and the mixture was stirred. Under water-cooling, N-carbobenzoxyoxysuccinimide (179 g) was added thereto, and the mixture was stirred at room temperature for 6 hr. Under water-cooling, water (2160 ml) was added thereto, and the mixture was stirred for 1 hr. The obtained solid was collected by filtration, washed with water (1200 ml), and dried at room temperature for 48 hr to give seed crystals (257 g) of the title compound in 97% yield.
[1065] To a methanol solution obtained in (4) of tert-butyl (S)-(trans-4-(2-aminopropyl)cyclohexyl)carbamate acetate were added triethylamine (5.1 kg) and a solution of N-carbobenzoxyoxysuccinimide (5.8 kg) in acetonitrile (14 kg) at 10? C., and the mixture was stirred. The washing with acetonitrile (3.5 kg) is combined therewith, and the mixture was stirred for 3 hr. Water (8.9 kg) was added thereto, the seed crystals obtained in the same manner as above were added thereto, and the mixture was stirred for 2 hr. The obtained solid was collected by filtration, washed with 50% methanol aqueous solution (24 kg), and dried for 69 hr to give the title compound (8 kg) in 97% yield.
[1066] 1H-NMR (DMSO-D6) ?: 7.41-7.27 (5H, m), 7.06 (1H, d, J=8.2 Hz), 6.66 (1H, d, J=8.2 Hz), 5.03 (1H, d, J=12.0 Hz), 4.98 (1H, d, J=12.0 Hz), 3.66-3.52 (1H, m), 3.19-3.03 (1H, m), 1.80-1.51 (4H, m), 1.43-1.26 (1H, m), 1.37 (9H, s), 1.23-0.75 (6H, m), 1.01 (3H, d, J=6.7 Hz).
(6) benzyl (S)-(1-(trans-4-aminocyclohexyl)propan-2-yl)carbamate p-toluenesulfonate
[1067] ##STR00087##
[1068] A suspension of benzyl (S)-(1-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)propan-2-yl)carbamate (obtained in the same manner as in (5)) (257 g) in ethyl acetate (2570 ml) was heated to 80? C., p-toluenesulfonic acid monohydrate (188 g) was added thereto, and the mixture was stirred for 3 hr. After gradually cooling to room temperature, the mixture was allowed to stand all day. The obtained solid was collected by filtration, and washed with ethyl acetate (236 ml). The solid was dried at 50? C. for 8 hr dried under reduced pressure, and then dried under reduced pressure at room temperature all day to give seed crystals (281 g) of the title compound in 92% yield.
[1069] A suspension of benzyl (S)-(1-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)propan-2-yl)carbamate obtained in (5) (8 kg) in ethyl acetate (58 kg) was prepared, p-toluenesulfonic acid monohydrate (5.1 kg) was added thereto at room temperature, and the mixture was stirred. The washing with ethyl acetate (1.4 kg) is combined therewith, and the mixture was stirred for 1 hr. the seed crystals obtained in the same manner as above were added thereto, and the mixture was stirred for 1 hr, warmed to 55? C., and stirred for 4 hr. After gradually cooling to room temperature, the mixture was stirred for 14 hr. The obtained solid was collected by filtration, washed with ethyl acetate (22 kg), and dried at 50? C. for 23 hr to give the title compound (9 kg) in 96% yield.
[1070] 1H-NMR (DMSO-D6) ?: 7.67 (3H, br s), 7.47 (2H, d, J=8.2 Hz), 7.41-7.28 (5H, m), 7.14-7.06 (3H, m), 5.02 (1H, d, J=12.7 Hz), 4.98 (1H, d, J=12.7 Hz), 3.66-3.53 (1H, m), 2.98-2.83 (1H, m), 2.29 (3H, s), 1.95-1.60 (4H, m), 1.39-0.81 (7H, m), 1.02 (3H, d, J=6.7 Hz).
(7) benzyl (S)-(1-trans-(4-aminocyclohexyl)propan-2-yl) carbamate
[1071] ##STR00088##
[1072] To a solution of benzyl (S)-(1-(trans-4-aminocyclohexyl)propan-2-yl)carbamate p-toluenesulfonate obtained in (6) (30 g) in 2-methyl-tetrahydrofuran (120 ml) was added 4M aqueous sodium hydroxide solution (17 ml) at room temperature, and the mixture was stirred for 1.5 hr. Water (120 ml) was added thereto, the mixture was subjected to extraction, and the organic layer was washed with water (120 ml, twice) and saturated brine (120 ml), and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. Methanol (90 ml) was added thereto, and the mixture was concentrated under reduced pressure to give the title compound (18 g) in 96% yield.
[1073] 1H-NMR (DMSO-D6) ?: 7.41-7.25 (5H, m), 7.05 (1H, d, J=8.5 Hz), 5.03 (1H, d, J=12.5 Hz), 4.97 (1H, d, J=12.5 Hz), 3.68-3.50 (1H, m), 2.46-2.33 (1H, m), 1.81-0.71 (13H, m), 1.01 (3H, d, J=6.5 Hz).
(8) benzyl (S)-(1-(4-oxocyclohexyl)propan-2-yl)carbamate
[1074] ##STR00089##
[1075] To a solution of benzyl (S)-(1-trans-(4-aminocyclohexyl)propan-2-yl)carbamate obtained in (7) (18 g) in methanol (90 ml) was added 3,5-di-tert-butyl-1,2-benzoquinone (14 g) at room temperature, and the mixture was stirred for 1.5 hr. Water (18 ml), acetone (72 ml) and DOWEX (45 g) were added thereto, and the mixture was stirred for 1.5 hr. Additional DOWEX (9 g) was added thereto, and the mixture was stirred for 30 min. The mixture was filtered with ethyl acetate, and the filtrate was concentrated under reduced pressure. Ethyl acetate (72 ml) and water (36 ml) were added thereto, the mixture was subjected to extraction, and the organic layer was dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate (36 ml) and silica gel (18 g) were added thereto, and the mixture was stirred for 30 min. The mixture was filtered with ethyl acetate, and the filtrate was concentrated under reduced pressure. To the obtained residue was added diisopropyl ether (18 ml), and the mixture was warmed to an internal temperature of 48? C. Heptane (72 ml) was added dropwise thereto, and the mixture was stirred for 1.5 hr. The obtained solid was collected by filtration, washed with heptane, and dried under reduced pressure at 60? C. for 3 hr and then at room temperature all day to give the title compound (15 g) in 83% yield.
[1076] 1H-NMR (DMSO-D6) ?: 7.41-7.25 (5H, m), 7.15 (1H, d, J=8.6 Hz), 5.03 (1H, d, J=12.4 Hz), 4.99 (1H, d, J=12.4 Hz), 3.70-3.55 (1H, m), 2.40-2.10 (4H, m), 2.08-1.66 (3H, m), 1.49-1.18 (4H, m), 1.06 (3H, d, J=6.5 Hz).
(9) tert-butyl (S)-(1-(4-oxocyclohexyl)propan-2-yl) carbamate
[1077] ##STR00090##
[1078] To a solution of benzyl (S)-(1-(4-oxocyclohexyl)propan-2-yl)carbamate obtained in (8) (15 g) in methanol (145 ml) were added 10% PdC (1.5 g) and Boc.sub.2O (12 g) under argon atmosphere at room temperature. The mixture was stirred under hydrogen atmosphere (1 atm) for 4 hr. After purging with nitrogen, the 10% PdC was removed by Celite filtration, and washed with methanol. The filtrate was concentrated under reduced pressure, to the obtained residue was added acetone (27 ml), and the mixture was stirred at room temperature. Water (82 ml) was added thereto, and the mixture was stirred all day. The obtained solid was collected by filtration, washed with water, and dried under reduced pressure at 60? C. for 3 hr and then at room temperature all day to give the title compound (12 g) in 88% yield. The same procedures as in (7)-(9) above were performed with benzyl (S)-(1-(trans-4-aminocyclohexyl)propan-2-yl)carbamate p-toluenesulfonate (211 g) to give the title compound (60 g).
[1079] 1H-NMR (DMSO-D6) ?: 6.65 (1H, d, J=8.6 Hz), 3.63-3.46 (1H, m), 2.42-2.10 (4H, m), 2.08-1.97 (1H, m), 1.94-1.83 (1H, m), 1.80-1.66 (1H, m), 1.46-1.16 (4H, m), 1.38 (9H, s), 1.02 (3H, d, J=6.5 Hz).
[Production Example 2]: Synthesis of N.SUP.1.((S)-1-(cis-5-(2-bromo-4-cyanophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl) propan-2-yl)-N.SUP.2.-methyloxamide (Example 57)
[1080] ##STR00091##
(1) tert-butyl ((S)-1-(cis-4-(2-bromo-4-cyanobenzoyl)-4-((trimethylsilyl)oxy)cyclohexyl)propan-2-yl)carbamate
[1081] ##STR00092##
[1082] To a solution of 3-bromo-4-formylbenzonitrile (2.1 g) in THF (4 ml) were added lithium chloride (0.043 g) and trimethylsilylcyanide (1.5 ml) at room temperature, and the mixture was stirred at room temperature for 1 hr. THF (26 ml) was added thereto, and the mixture was cooled to ?78? C. 1M NaHMDS-THF solution (10.2 ml) was added thereto, and the mixture was stirred for 3 min. A solution of tert-butyl (S)-(1-(4-oxocyclohexyl)propan-2-yl)carbamate (obtained in the same manner as in (9) of [Production Example 1]) (2 g) in THF (10 ml) was added thereto, and the mixture was stirred for 30 min, and warmed to ?10? C. over 1 hr. Water and ethyl acetate were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction twice with ethyl acetate, and the combined organic layers were washed with saturated brine, and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane) to give the title compound (1.2 g) in 28% yield.
[1083] 1H-NMR (CDCl3) ?: 7.89 (1H, s), 7.62 (1H, d, J=8.1 Hz), 7.39 (1H, d, J=8.1 Hz), 4.30-4.15 (1H, m), 3.84-3.56 (1H, m), 2.01-1.92 (2H, m), 1.86-1.70 (3H, m), 1.64-1.52 (1H, m), 1.43 (9H, s), 1.40-1.18 (5H, m), 1.11 (3H, d, J=6.5 Hz), 0.04 (9H, s).
(2) tert-butyl ((S)-1-(cis-4-(2-bromo-4-cyanobenzoyl)-4-hydroxycyclohexyl)propan-2-yl)carbamate
[1084] ##STR00093##
[1085] To a solution of tert-butyl ((S)-1-(cis-4-(2-bromo-4-cyanobenzoyl)-4-((trimethylsilyl)oxy)cyclohexyl)propan-2-yl)carbamate obtained in (1) and the same compound obtained in the same manner as above (total 1.4 g) in THF (2.7 ml) were added acetic acid (0.42 ml) and 1M TBAF-THF solution (3.7 ml) at room temperature, and the mixture was stirred for 15 min. Saturated aqueous ammonium chloride solution, water and ethyl acetate were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction twice with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane) to give the title compound (1.1 g) in 93% yield.
[1086] 1H-NMR (CDCl3) ?: 7.89 (1H, s), 7.65 (1H, d, J=8.1 Hz), 7.32 (1H, d, J=7.5 Hz), 4.30-4.17 (1H, m), 3.84-3.67 (1H, m), 2.66 (1H, s), 1.93-1.74 (5H, m), 1.69-1.60 (1H, m), 1.50-1.22 (5H, m), 1.43 (9H, s), 1.10 (3H, d, J=5.9 Hz).
(3) 4-(cis-9-((S)-2-aminopropyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-5-yl)-3-bromobenzonitrile hydrochloride
[1087] ##STR00094##
[1088] To a solution of tert-butyl ((S)-1-(cis-4-(2-bromo-4-cyanobenzoyl)-4-hydroxycyclohexyl)propan-2-yl)carbamate obtained in (2) (1.1 g) in THF (11 ml) were added DBU (0.052 ml) and CDI (0.55 g) at room temperature, and the mixture was stirred for 1 hr. Hydrazine monohydrate was added thereto, and the mixture was stirred for 30 min. 10% Aqueous citric acid solution and ethyl acetate were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction twice with ethyl acetate, and the combined organic layers were washed with saturated brine, and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane, ethyl acetate/methanol). To the obtained solid were added THF (6.5 ml) and 6M hydrochloric acid (3.2 ml) at room temperature, and the mixture was stirred all day and then at 50? C. for 5 hr. The reaction solution was concentrated under reduced pressure, followed by azeotropy twice with THF (2 ml) to give the title compound (0.61 g).
[1089] 1H-NMR (DMSO-D6) ?: 11.37 (1H, s), 8.39 (1H, s), 7.99 (1H, d, J=8.1 Hz), 7.90-7.72 (3H, m), 7.70 (1H, d, J=8.1 Hz), 3.27-3.13 (1H, m), 2.23-2.10 (2H, m), 1.62-1.17 (9H, m), 1.13 (3H, d, J=5.4 Hz).
(4) N.SUP.1.((S)-1-(cis-5-(2-bromo-4-cyanophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-N.SUP.2.-methyloxamide
[1090] ##STR00095##
[1091] To a solution of 4-(cis-9-((S)-2-aminopropyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-5-yl)-3-bromobenzonitrile hydrochloride obtained in (3) (0.57 g) in DMF (8.4 ml) were added 2-methylamino-2-oxoacetic acid (0.24 g), HOAt (0.33 g) and N,N-diisopropylethylamine (1.0 ml) at room temperature. WSC (0.47 g) was added thereto, and the mixture was stirred at room temperature all day. Water, saturated aqueous sodium bicarbonate solution and ethyl acetate were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction twice with ethyl acetate, and the combined organic layers were washed with saturated brine, and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was subjected to azeotropy twice with toluene (10 ml), and the obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane), and then reverse-phase silica gel chromatography (developing solvent: acetonitrile/water). The obtained solid was subjected to recrystallization in ethyl acetate (8.4 ml)/isopropyl ether (8.4 ml) at 50? C., and the mixture was stirred at room temperature all day. The obtained suspension was filtered, and the obtained solid was washed three times with a mixed solvent (1 ml) of ice-cooled ethyl acetate:isopropyl ether=1:1, and dried under reduced pressure at 50? C. for 4 hr to give the title compound (0.30 g) in 57% yield.
[1092] 1H-NMR (CDCl3) ?: 8.24 (1H, s), 7.97 (1H, d, J=1.6 Hz), 7.68 (1H, dd, J=7.9, 1.6 Hz), 7.44-7.39 (1H, m), 7.33 (1H, d, J=7.9 Hz), 7.18-7.14 (1H, m), 4.08-4.00 (1H, m), 2.89 (3H, d, J=5.3 Hz), 2.34-2.28 (2H, m), 1.79-1.72 (1H, m), 1.60-1.51 (2H, m), 1.50-1.31 (5H, m), 1.30-1.21 (1H, m), 1.16 (3H, d, J=6.5 Hz).
[Production Example 3]: Synthesis of (S)N.SUP.1.-(1-(5-(2-bromo-4-fluorophenyl)-2-oxo-1-oxa-3,4,9-triazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-N.SUP.2.-methyloxamide (Example 179)
[1093] ##STR00096##
(1) tert-butyl 4-(2-bromo-4-fluorobenzoyl)-4-((trimethylsilyl)oxy)piperidine-1-carboxylate
[1094] ##STR00097##
[1095] To a solution of 2-bromo-4-fluorobenzaldehyde (1.2 ml) and DMAP (0.015 g) in acetonitrile (20 ml) was added trimethylsilylcyanide (1.5 ml) at room temperature, and the mixture was stirred for 3 hr. The reaction solution was concentrated, THF (18 ml) was added thereto, and the mixture was cooled to ?78? C. 1.1M LiHMDS-n-hexane solution (10 ml) was added thereto, and the mixture was stirred for 30 min. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (2 g) in THF (9 ml) was added thereto, and the mixture was stirred for 1 hr. 2M Hydrochloric acid (12 ml) was added thereto, and the mixture was stirred at room temperature all day. The reaction solution was ice-cooled, 2M aqueous sodium hydroxide solution (12.5 ml) was added thereto, and the mixture was stirred at room temperature for 30 min. Water and ethyl acetate were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction with ethyl acetate, and the combined organic layers were dried over magnesium sulfate. The magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane=15/85 to 35/65) to give the title compound (1.8 g) in 34% yield.
[1096] 1H-NMR (DMSO-D6) ?: 7.74 (1H, dd, J=8.7, 2.4 Hz), 7.62 (1H, dd, J=8.6, 6.0 Hz), 7.38 (1H, td, J=8.6, 2.5 Hz), 3.66 (2H, dt, J=13.9, 4.0 Hz), 3.24-3.14 (2H, m), 1.92-1.83 (2H, m), 1.82-1.75 (2H, m), 1.38 (9H, s), 0.06 (9H, s).
(2) tert-butyl 4-(2-bromo-4-fluorobenzoyl)-4-hydroxypiperidine-1-carboxylate
[1097] ##STR00098##
[1098] To a solution of tert-butyl 4-(2-bromo-4-fluorobenzoyl)-4-((trimethylsilyl)oxy)piperidine-1-carboxylate obtained in (1) (1.0 g) in THF (8.8 ml) was added 1M TBAF-THF solution (1.9 ml) at room temperature, and the mixture was stirred for 1 hr. Saturated aqueous ammonium chloride solution and ethyl acetate were added thereto, and the mixture was subjected to extraction. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane=20/80 to 40/60) to give the title compound (0.74 g) in 92% yield.
[1099] 1H-NMR (DMSO-D6) ?: 7.67 (1H, dd, J=8.8, 2.5 Hz), 7.58 (1H, dd, J=8.6, 6.0 Hz), 7.34 (1H, td, J=8.6, 2.4 Hz), 5.70 (1H, s), 3.84-3.73 (2H, m), 3.15-2.92 (2H, m), 1.81-1.66 (4H, m), 1.40 (9H, s).
(3) tert-butyl 5-(2-bromo-4-fluorophenyl)-2-oxo-1-oxa-3,4,9-triazaspiro[5.5]undec-4-ene-9-carboxylate
[1100] ##STR00099##
[1101] To a solution of tert-butyl 4-(2-bromo-4-fluorobenzoyl)-4-hydroxypiperidine-1-carboxylate obtained in (2) (0.74 g) in THF (6.9 ml) were added DBU (0.026 ml) and CDI (0.42 g) at room temperature, and the mixture was stirred for 1 hr. Hydrazine monohydrate (0.25 ml) was added thereto, and the mixture was stirred for 1 hr. 1M Hydrochloric acid and ethyl acetate were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over magnesium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. To the obtained residue were added THF (7.3 ml) and 6M hydrochloric acid (3.7 ml) at room temperature, and the mixture was stirred for 20 hr. The mixture was neutralized with 4M aqueous sodium hydroxide solution (6.0 ml), Boc.sub.2O (0.44 ml) was added thereto, and the mixture was stirred for 1 hr. Ethyl acetate was added thereto, and the mixture was subjected to extraction. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane=30/70 to 50/50) to give the title compound (0.60 g) in 79% yield.
[1102] 1H-NMR (DMSO-D6) ?: 11.35 (1H, s), 7.76 (1H, dd, J=8.6, 2.5 Hz), 7.57 (1H, dd, J=8.7, 5.9 Hz), 7.36 (1H, td, J=8.5, 2.6 Hz), 3.90-3.78 (2H, m), 3.10-2.91 (2H, m), 2.16-2.06 (2H, m), 1.59-1.46 (2H, m), 1.35 (9H, s).
(4) 5-(2-bromo-4-fluorophenyl)-1-oxa-3,4,9-triazaspiro[5.5]undec-4-en-2-one hydrochloride
[1103] ##STR00100##
[1104] To tert-butyl 5-(2-bromo-4-fluorophenyl)-2-oxo-1-oxa-3,4,9-triazaspiro[5,5]undec-4-ene-9-carboxylate obtained in (3) (0.60 g) was added 4M hydrogen chloride-CPME solution (5.6 ml) at room temperature, and the mixture was stirred for 3 hr. The obtained reaction solution was concentrated under reduced pressure to give the title compound (0.53 g) in 100% yield.
[1105] 1H-NMR (DMSO-D6) ?: 11.48 (1H, s), 8.87-8.70 (1H, m), 8.56-8.40 (1H, m), 7.81 (1H, dd, J=8.6, 2.5 Hz), 7.61 (1H, dd, J=8.7, 5.9 Hz), 7.44 (1H, td, J=8.5, 2.6 Hz), 3.28-3.20 (2H, m), 3.11-2.99 (2H, m), 2.36-2.26 (2H, m), 1.99-1.85 (2H, m).
(5) tert-butyl (S)-(1-(5-(2-bromo-4-fluorophenyl)-2-oxo-1-oxa-3,4,9-triazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)carbamate
[1106] ##STR00101##
[1107] To a solution of 5-(2-bromo-4-fluorophenyl)-1-oxa-3,4,9-triazaspiro[5.5]undec-4-en-2-one hydrochloride obtained in (4) (0.53 g) in methanol (5.3 ml) were added triethylamine (0.89 ml) and tert-butyl (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (0.36 g) under ice-cooled, and the mixture was stirred for 5 hr. The methanol was evaporated, THF (5.3 ml), water (5.3 ml) and potassium hydrogen sulfate (0.52 g) were added thereto, and the mixture was stirred at room temperature for 2 days. Saturated aqueous sodium bicarbonate solution and ethyl acetate were added thereto, and the mixture was subjected to extraction. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (developing solvent: ethyl acetate/n-hexane=67/33) to give the title compound (0.57 g) in 84% yield.
[1108] 1H-NMR (DMSO-D6) ?: 11.24 (1H, s), 7.75 (1H, dd, J=8.7, 2.7 Hz), 7.53 (1H, dd, J=8.6, 6.0 Hz), 7.36 (1H, td, J=8.5, 2.6 Hz), 6.45-6.38 (1H, m), 3.64-3.51 (1H, m), 2.81-2.71 (1H, m), 2.63-2.57 (1H, m), 2.35-2.24 (1H, m), 2.24-2.01 (5H, m), 1.68-1.44 (2H, m), 1.28 (9H, s), 0.94 (3H, d, J=6.5 Hz).
(6) (S)-9-(2-aminopropyl)-5-(2-bromo-4-fluorophenyl)-1-oxa-3,4,9-triazaspiro[5.5]undec-4-en-2-one dihydrochloride
[1109] ##STR00102##
[1110] To tert-butyl (S)-(1-(5-(2-bromo-4-fluorophenyl)-2-oxo-1-oxa-3,4,9-triazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)carbamate obtained in (5) (0.12 g) was added 4M hydrogen chloride-CPME solution (1.1 ml) at room temperature, and the mixture was stirred for 3 hr. The obtained reaction solution was concentrated under reduced pressure to give the title compound (0.13 g).
[1111] 1H-NMR (DMSO-D6) ?: 11.59-11.30 (1H, m), 10.86-10.59 (1H, m), 8.46-8.13 (2H, m), 7.79 (1H, dd, J=8.6, 2.5 Hz), 7.58 (1H, dd, J=8.6, 6.0 Hz), 7.41 (1H, td, J=8.5, 2.5 Hz), 3.90-3.53 (5H, m), 3.49-3.30 (1H, m), 2.44-2.10 (4H, m), 1.68-1.42 (2H, m), 1.31-1.13 (3H, m).
(7) (S)N.SUP.1.-(1-(5-(2-bromo-4-fluorophenyl)-2-oxo-1-oxa-3,4,9-triazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-N.SUP.2.-methyloxamide
[1112] ##STR00103##
[1113] To a solution of (S)-9-(2-aminopropyl)-5-(2-bromo-4-fluorophenyl)-1-oxa-3,4,9-triazaspiro[5.5]undec-4-en-2-one dihydrochloride obtained in (6) (0.04 g) in acetonitrile (0.34 ml) were added 2-methylamino-2-oxoacetic acid (0.014 g), HOAt (0.018 g) and N,N-diisopropylethylamine (0.059 ml) at room temperature. WSC (0.026 g) was added thereto, and the mixture was stirred at room temperature for 3 hr. Saturated aqueous sodium bicarbonate solution and ethyl acetate were added thereto, and the mixture was subjected to extraction. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (developing solvent: ethyl acetate) to give the title compound (0.029 g) in 87% yield.
[1114] 1H-NMR (DMSO-D6) ?: 11.25 (1H, s), 8.63 (1H, q, J=4.7 Hz), 8.35 (1H, d, J=8.8 Hz), 7.75 (1H, dd, J=8.6, 2.5 Hz), 7.54 (1H, dd, J=8.6, 5.8 Hz), 7.36 (1H, td, J=8.6, 2.5 Hz), 3.96-3.89 (1H, m), 2.72-2.60 (2H, m), 2.64 (3H, d, J=4.7 Hz), 2.42 (1H, dd, J=12.5, 8.3 Hz), 2.33-2.19 (3H, m), 2.10-2.02 (2H, m), 1.64-1.48 (2H, m), 1.04 (3H, d, J=6.5 Hz).
[Production Example 4]: Synthesis of N.SUP.1.((S)-1-(cis-5-(2-bromo-5-cyanophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-N.SUP.2.-methyloxamide (Example 198)
[1115] ##STR00104##
(1) tert-butyl ((S)-1-(cis-4-(2-bromo-5-cyanobenzoyl)-4-((trimethylsilyl)oxy)cyclohexyl)propan-2-yl)carbamate
[1116] ##STR00105##
[1117] To a solution of 4-bromo-3-formylbenzonitrile (54 g) and lithium chloride (1.1 g) in THF (350 ml) was added trimethylsilylcyanide (34 ml) under water-cooling, and the mixture was stirred for 1 hr. The mixture was cooled to ?78? C., 1.1M LiHMDS-n-hexane solution (225 ml) was added thereto, and the mixture was stirred for 2 hr. The mixture was warmed to ?60? C., a solution of tert-butyl (S)-(1-(4-oxocyclohexyl)propan-2-yl)carbamate (obtained in (9) of [Production Example 1]) (50 g) in THF (100 ml) was added thereto, and the mixture was stirred for 1.5 hr. Acetic acid (15 ml) was added thereto, the mixture was warmed to ?20? C., and water (250 ml) was added thereto. After stirring at room temperature for 10 min, water (250 ml) and toluene (500 ml) were added thereto, and the mixture was subjected to extraction. The organic layer was washed with water (500 ml, three times) and 20% brine (500 ml), and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure at room temperature to give the title compound (150 g) containing small amount of toluene.
[1118] 1H-NMR (DMSO-D6) ?: 8.01-7.98 (1H, m), 7.96 (1H, d, J=8.3 Hz), 7.89-7.85 (1H, m), 6.59 (1H, d, J=8.6 Hz), 3.62-3.48 (1H, m), 2.01-1.91 (2H, m), 1.77-1.50 (4H, m), 1.40-1.07 (5H, m), 1.36 (9H, s), 0.99 (3H, d, J=6.5 Hz), 0.00 (9H, s).
(2) tert-butyl ((S)-1-(cis-4-(2-bromo-5-cyanobenzoyl)-4-hydroxycyclohexyl)propan-2-yl)carbamate
[1119] ##STR00106##
[1120] To tert-butyl ((S)-1-(cis-4-(2-bromo-5-cyanobenzoyl)-4-((trimethylsilyl)oxy)cyclohexyl)propan-2-yl)carbamate obtained in (1) (150 g) were added THF (310 ml), acetic acid (14 ml) and 1M TBAF-THF solution (230 ml) at room temperature, and the mixture was stirred at room temperature for 1.5 hr. Water (500 ml) and toluene (500 ml) were added thereto, and the mixture was subjected to extraction. The obtained organic layer was washed with 5% aqueous sodium bicarbonate solution (500 ml), water (500 ml) and saturated brine (500 ml), and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. Methanol (150 ml) was added thereto, and the mixture was concentrated again under reduced pressure. To the obtained residue were added methanol (270 ml) and water (90 ml), and the mixture was stirred for two days. Under ice-cooled, the mixture was stirred again all day, and the obtained solid was collected by filtration. The solid was washed with a mixed solvent of ice-cooled methanol (68 ml) and water (22 ml), and dried under reduced pressure at 60? C. for 3 hr and then at room temperature all day to give the title compound (52 g) in 58% yield.
[1121] 1H-NMR (DMSO-D6) ?: 7.92-7.88 (2H, m), 7.83-7.79 (1H, m), 6.59 (1H, d, J=8.1 Hz), 5.28 (1H, s), 3.64-3.48 (1H, m), 1.88-1.78 (2H, m), 1.71-1.09 (9H, m), 1.38 (9H, s), 0.99 (3H, d, J=6.5 Hz).
(3) 3-(cis-9-((S)-2-aminopropyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-5-yl)-4-bromobenzonitrile
[1122] ##STR00107##
[1123] To a solution of tert-butyl ((S)-1-(cis-4-(2-bromo-5-cyanobenzoyl)-4-hydroxycyclohexyl)propan-2-yl)carbamate obtained in (2) (48 g) in THF (240 ml) were added DBU (2.4 ml) and CDI (25 g) at room temperature, and the mixture was stirred for 1 hr. Hydrazine monohydrate (10 ml) was added thereto, and the mixture was stirred for 30 min. Water (240 ml) and ethyl acetate (240 ml) were added thereto, and the mixture was subjected to extraction. The obtained organic layer was washed with 10% aqueous citric acid solution (240 ml), water (240 ml) and 20% brine (240 ml), and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. To the obtained residue was added ethyl acetate (530 ml), and the mixture was stirred at room temperature for 1 hr. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. To concentrate were added THF (240 ml) and 6M hydrochloric acid (120 ml) at room temperature, and the mixture was stirred at 50? C. for 5 hr. The mixture was gradually cooled to room temperature, water (242 ml) and 8M aqueous sodium hydroxide solution (91 ml) were added thereto, and the mixture was stirred for 5 min. THF (120 ml) and toluene (240 ml) were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction with THF (96 ml) and toluene (120 ml). The combined organic layers were washed with 20% brine (240 ml), and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate (144 ml) was added thereto, and the mixture was concentrated again under reduced pressure. To the obtained residue was added ethyl acetate (54 ml) at room temperature, and the mixture was stirred all day. The obtained solid was collected by filtration, washed with ice-cooled ethyl acetate (36 ml), and dried under reduced pressure 60? C. for 3 hr and then at room temperature all day to give the title compound (32 g) in 89% yield.
[1124] 1H-NMR (DMSO-D6) ?: 11.29 (1H, br s), 8.04-7.96 (2H, m), 7.91-7.84 (1H, m), 2.87-2.75 (1H, m), 2.19-2.05 (2H, m), 1.80-1.03 (11H, m), 0.92 (3H, d, J=5.9 Hz).
(4) N.SUP.1.((S)-1-(cis-5-(2-bromo-5-cyanophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-N.SUP.2.-methyloxamide
[1125] ##STR00108##
[1126] To a solution of 3-(cis-9-((S)-2-aminopropyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-5-yl)-4-bromobenzonitrile (obtained in the same manner as in (3)) (0.02 g) in DMF (0.5 ml) were added 2-methylamino-2-oxoacetic acid (0.008 g), HOAt (0.007 g), WSC (0.014 g) and N,N-diisopropylethylamine (0.026 ml) at room temperature, and the mixture was stirred all day. Water and ethyl acetate were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction with ethyl acetate. The combined organic layers were washed with water and saturated brine, and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography (developing solvent: ethyl acetate) to give the title compound (0.021 g) in 87% yield.
[1127] 1H-NMR (DMSO-D6) ?: 11.29 (1H, s), 8.65-8.59 (1H, m), 8.41 (1H, d, J=9.0 Hz), 8.00 (1H, d, J=1.8 Hz), 7.98 (1H, d, J=8.3 Hz), 7.86 (1H, dd, J=8.3, 1.8 Hz), 3.98-3.85 (1H, m), 2.64 (3H, d, J=4.9 Hz), 2.16-2.04 (2H, m), 1.69-1.59 (1H, m), 1.59-1.13 (8H, m), 1.06 (3H, d, J=6.5 Hz).
(5) crystal of N.SUP.1. ((S)-1-(cis-5-(2-bromo-5-cyanophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-N.SUP.2.-methyloxamide
[1128] ##STR00109##
[1129] Under nitrogen atmosphere, to a solution of 3-(cis-9-((S)-2-aminopropyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-5-yl)-4-bromobenzonitrile (obtained in the same manner as in (3)) (42 g), 2-methylamino-2-oxoacetic acid (13 g) and WSC (24 g) in DMF (210 ml) was added HOAt (7.1 g) at room temperature, and the mixture was stirred for 1 hr. 5% Aqueous sodium bicarbonate solution (420 ml) and ethyl acetate (420 ml) were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction with ethyl acetate (210 ml), and the combined organic layers were washed with 5% aqueous sodium bicarbonate solution (210 ml), water (210 ml?2) and saturated brine (210 ml). Sodium sulfate and activated carbon (1.3 g) were added thereto, the mixture was stirred for 1.5 hr, and the solid was removed by filtration. The obtained solution was concentrated under reduced pressure, and to the obtained amorphous solid was added DMF (115 ml). The obtained solution was concentrated under reduced pressure, the ethyl acetate was evaporated, and the obtained solution was subjected to dust removal filtration, followed by washing with DMF (139 ml). To the obtained DMF solution was added water (150 ml) at room temperature. After confirming the solid precipitation, water (612 ml) was added dropwise thereto, and the obtained suspension was stirred at room temperature for 5 days. The suspension was warmed to 50? C., stirred overnight, and allowed to cool to room temperature. The suspension was filtered, and the solid was washed with water. The obtained wet crystals were air-dried overnight, and then dried under reduced pressure at 60? C. for 3 hr to give the title compound (45 g).
[Production Example 5]: Synthesis of 1-((S)-1-(cis-5-(2-bromo-5-cyanophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-3-cyclopropylurea (Example 222)
[1130] ##STR00110##
(1) 1-((S)-1-(cis-5-(2-bromo-5-cyanophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-3-cyclopropylurea
[1131] ##STR00111##
[1132] To a solution of 3-(cis-9-((S)-2-aminopropyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-5-yl)-4-bromobenzonitrile (obtained in the same manner as in (3) of [Production Example 4]) (0.020 g) in THF (0.4 ml) was added cyclopropylisocyanate (0.005 ml) at room temperature, and the mixture was stirred for 3 hr. Water and ethyl acetate were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction with ethyl acetate, and the combined organic layers were washed with water and saturated brine, and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by thin layer chromatography (developing solvent: ethyl acetate) to give the title compound (0.019 g) in 79% yield.
[1133] 1H-NMR (DMSO-D6) ?: 11.30 (1H, s), 8.03 (1H, d, J=1.8 Hz), 7.99 (1H, d, J=8.3 Hz), 7.87 (1H, dd, J=8.4, 2.0 Hz), 5.89 (1H, d, J=2.8 Hz), 5.46 (1H, d, J=8.6 Hz), 3.72-3.61 (1H, m), 2.40-2.31 (1H, m), 2.19-2.07 (2H, m), 1.70-1.57 (1H, m), 1.56-1.06 (8H, m), 0.97 (3H, d, J=6.5 Hz), 0.56-0.46 (2H, m), 0.31-0.22 (2H, m).
[Production Example 6]: Synthesis of N.SUP.1.((S)-1-(cis-5-(4-chloro-6-methylpyridin-3-yl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-N.SUP.2.-methyloxamide (Example 230)
[1134] ##STR00112##
(1) tert-butyl ((S)-1-(cis-4-(4-chloro-6-methylnicotinoyl)-4-((trimethylsilyl)oxy)cyclohexyl)propan-2-yl)carbamate
[1135] ##STR00113##
[1136] To a mixture of 4-chloro-6-methylnicotinaldehyde (0.55 g) and lithium chloride (0.015 g) was added trimethylsilylcyanide (0.55 ml), and the mixture was stirred at room temperature for 10 min. THF (7 ml) was added thereto, and the mixture was cooled to ?78? C. 1M NaHMDS-THF solution (1.9 ml) was added thereto, and the mixture was stirred for 5 min. tert-Butyl (S)-(1-(4-oxocyclohexyl)propan-2-yl)carbamate (obtained in the same manner as in (9) of [Production Example 1]) (0.7 g) was added thereto, and the mixture was stirred for 30 min, and warmed to 0? C. over 1 hr. Water and ethyl acetate were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction twice with ethyl acetate, and the combined organic layers were washed with saturated brine, and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane) to give the title compound (1.1 g) in 83% yield.
[1137] 1H-NMR (CDCl3) ?: 8.58 (1H, s), 7.25 (1H, s), 4.32-4.15 (1H, m), 3.84-3.65 (1H, m), 2.57 (3H, s), 1.99-1.88 (2H, m), 1.83-1.68 (3H, m), 1.66-1.55 (1H, m), 1.43 (9H, s), 1.41-1.21 (5H, m), 1.11 (3H, d, J=6.5 Hz), 0.06 (9H, s).
(2) tert-butyl ((S)-1-(cis-4-(4-chloro-6-methylnicotinoyl)-4-hydroxycyclohexyl)propan-2-yl)carbamate
[1138] ##STR00114##
[1139] To a solution of tert-butyl ((S)-1-(cis-4-(4-chloro-6-methylnicotinoyl)-4-((trimethylsilyl)oxy)cyclohexyl)propan-2-yl)carbamate obtained in (1) (1.1 g) in THF (2.2 ml) were added acetic acid (0.39 ml) and 1M TBAF-THF solution (3.4 ml) at room temperature, and the mixture was stirred for 15 min, and allowed to stand all day. Saturated aqueous ammonium chloride solution, water and ethyl acetate were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction twice with ethyl acetate, and the combined organic layers were washed with saturated brine, and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane) to give the title compound (0.80 g) in 86% yield.
[1140] 1H-NMR (CDCl3) ?: 8.39 (1H, s), 7.26 (1H, s), 4.29-4.16 (1H, m), 3.83-3.65 (1H, m), 2.93 (1H, s), 2.58 (3H, s), 1.87-1.73 (5H, m), 1.67-1.59 (1H, m), 1.43 (9H, s), 1.41-1.22 (5H, m), 1.10 (3H, d, J=6.5 Hz).
(3) cis-9-((S)-2-aminopropyl)-5-(4-chloro-6-methylpyridin-3-yl)-1-oxa-3,4-diazaspiro[5.5]undec-4-en-2-one dihydrochloride
[1141] ##STR00115##
[1142] To a solution of tert-butyl ((S)-1-(cis-4-(4-chloro-6-methylnicotinoyl)-4-hydroxycyclohexyl)propan-2-yl)carbamate obtained in (2) (0.8 g) in THF (8 ml) were added DBU (0.044 ml) and CDI (0.47 g) at room temperature, and the mixture was stirred for 1 hr. Hydrazine monohydrate (0.19 ml) was added thereto, and the mixture was stirred for 1 hr. 10% Aqueous citric acid solution and ethyl acetate were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction twice with ethyl acetate, and the combined organic layers were washed with saturated brine, and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane). To the obtained solid were added THF (9.0 ml) and 6M hydrochloric acid (4.5 ml) at room temperature, and the mixture was stirred all day and then at 50? C. for 6 hr. The reaction solution was concentrated under reduced pressure, followed by azeotropy twice with THF (10 ml) to give the title compound (0.98 g).
[1143] 1H-NMR (DMSO-D6) ?: 11.40 (1H, s), 8.64 (1H, s), 8.08-7.97 (3H, m), 7.81 (1H, s), 3.25-3.14 (1H, m), 2.59 (3H, s), 2.18-2.08 (2H, m), 1.62-1.19 (9H, m), 1.15 (3H, d, J=6.5 Hz).
(4) N.SUP.1.((S)-1-(cis-5-(4-chloro-6-methylpyridin-3-yl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-N.SUP.2.-methyloxamide
[1144] ##STR00116##
[1145] To a solution of cis-9-((S)-2-aminopropyl)-5-(4-chloro-6-methylpyridin-3-yl)-1-oxa-3,4-diazaspiro[5.5]undec-4-en-2-one dihydrochloride obtained in (3) (0.1 g) in DMF (1.5 ml) were added 2-methylamino-2-oxoacetic acid (0.045 g), HOAt (0.062 g) and N,N-diisopropylethylamine (0.23 ml) at room temperature. WSC (0.087 g) was added thereto, and the mixture was stirred at room temperature for 15 min, and allowed to stand all day. Water, saturated aqueous sodium bicarbonate solution and ethyl acetate were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction twice with ethyl acetate, and the combined organic layers were washed with saturated brine, and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure, followed by azeotropy with toluene (5 ml). The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane) to give the title compound (0.067 g) in 71% yield.
[1146] 1H-NMR (DMSO-D6) ?: 11.28 (1H, s), 8.62 (1H, q, J=4.8 Hz), 8.48 (1H, s), 8.41 (1H, d, J=9.2 Hz), 7.58 (1H, s), 3.98-3.83 (1H, m), 2.64 (3H, d, J=4.8 Hz), 2.51 (3H, s), 2.15-2.02 (2H, m), 1.71-1.59 (1H, m), 1.57-1.15 (8H, m), 1.05 (3H, d, J=6.5 Hz).
[Production Example 7]: Synthesis of N((S)-1-(cis-5-(2-bromo-4-fluorophenyl)-9-hydroxy-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-3-methyl-1H-pyrazole-5-carboxamide (Example 320)
[1147] ##STR00117##
(1) 1,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate
[1148] ##STR00118##
[1149] A solution of 1,4-dioxaspiro[4.5]decan-8-one (5 g) in THF (50 ml) was cooled to ?78? C., 1.1M LiHMDS-n-hexane solution (31 ml) was added thereto, and the mixture was stirred for 10 min. The mixture was warmed to 0? C., stirred for 20 min, and cooled to ?78? C., and Comins reagent (14 g) was added thereto. The mixture was stirred for 30 min, warmed to 0? C., and stirred for additional 1.5 hr. Saturated aqueous sodium bicarbonate solution, water and ethyl acetate were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction with ethyl acetate, and the combined organic layers were washed with saturated brine, and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane) to give the title compound (7.5 g) in 81% yield.
[1150] 1H-NMR (CDCl3) ?: 5.69-5.65 (1H, m), 4.00 (4H, t, J=2.4 Hz), 2.54 (2H, t, J=6.5 Hz), 2.41 (2H, d, J=2.7 Hz), 1.91 (2H, t, J=6.7 Hz).
(2) (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate
[1151] ##STR00119##
[1152] To a solution of tert-butyl (S)-(1-hydroxypropan-2-yl)carbamate (10 g) in THF (100 ml) was added triethylamine (16 ml) at room temperature. The mixture was cooled to 0? C., methanesulfonic anhydride (11 g) was added thereto, and the mixture was stirred at room temperature for 15 min. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane) to give the title compound (13.7 g) in 95% yield.
[1153] 1H-NMR (CDCl3) ?: 4.68-4.49 (1H, m), 4.28-4.19 (1H, m), 4.15 (1H, dd, J=9.7, 4.3 Hz), 4.04-3.88 (1H, m), 3.04 (3H, s), 1.45 (9H, s), 1.24 (3H, d, J=7.0 Hz).
(3) tert-butyl (S)-(1-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)propan-2-yl) carbamate
[1154] ##STR00120##
[1155] To a solution of 1,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate obtained in (1) (5 g) in DMA (100 ml) were added (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate obtained in (2) (7.9 g), nickel(II) iodide (0.093 ml), 2,2:6,2-terpyridine (0.61 g), manganese (2.9 g) and sodium iodide (1.3 g) at room temperature, and the mixture was stirred at 80? C. for 1.5 hr. Water and ethyl acetate were added thereto at room temperature, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction twice with ethyl acetate, and the combined organic layers were washed with saturated brine, and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane) to give the title compound (1.9 g) in 37% yield.
[1156] 1H-NMR (CDCl3) ?: 5.34 (1H, s), 4.40-4.21 (1H, m), 3.97 (4H, s), 3.88-3.71 (1H, m), 2.30-1.98 (6H, m), 1.75 (2H, t, J=6.5 Hz), 1.43 (9H, s), 1.10 (3H, d, J=6.5 Hz).
(4) tert-butyl (S)-(1-(4-oxocyclohex-1-en-1-yl)propan-2-yl) carbamate
[1157] ##STR00121##
[1158] To a solution of tert-butyl (S)-(1-(1,4-dioxaspiro[4,5]dec-7-en-8-yl)propan-2-yl)carbamate obtained in (3) (0.5 g) in water (2 ml) was added acetic acid (8 ml) at room temperature, and the mixture was stirred for 15 min, and allowed to stand all day. The reaction solution was concentrated under reduced pressure, followed by azeotropy three times with toluene (2 ml), and the obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane) to give the title compound (0.37 g) in 87% yield.
[1159] 1H-NMR (CDCl3) ?: 5.49 (1H, s), 4.37-4.22 (1H, m), 3.91-3.76 (1H, m), 2.85 (2H, s), 2.60-2.30 (4H, m), 2.22-2.09 (2H, m), 1.42 (9H, s), 1.14 (3H, d, J=6.5 Hz).
(5) tert-butyl ((2S)-1-(4-(2-bromo-4-fluorobenzoyl)-4-((trimethylsilyl)oxy)cyclohex-1-en-1-yl)propan-2-yl)carbamate
[1160] ##STR00122##
[1161] To 2-bromo-4-fluorobenzaldehyde (0.16 g) and lithium chloride (0.003 g) was added trimethylcyanide (0.12 ml) at room temperature, and the mixture was stirred for 10 min. THF (1.5 ml) was added thereto, and the mixture was cooled to ?78? C. 1M NaHMDS-THF solution (0.77 ml) was added thereto, and the mixture was stirred for 5 min. tert-Butyl (S)-(1-(4-oxocyclohex-1-en-1-yl)propan-2-yl)carbamate obtained in (4) (0.15 g) was added to the reaction solution, and the mixture was stirred for 30 min. The mixture was warmed to 0? C. over 1 hr, water and ethyl acetate were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction twice with ethyl acetate, and the combined organic layers were washed with saturated brine, and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane) to give the title compound (0.22 g) in 66% yield.
[1162] 1H-NMR (CDCl3) ?: 7.65 (0.3H, dd, J=8.6, 6.5 Hz), 7.56 (0.7H, dd, J=8.1, 6.5 Hz), 7.36 (1H, d, J=8.1 Hz), 7.04 (1H, t, J=8.4 Hz), 5.36 (1H, s), 4.37-4.21 (1H, m), 3.88-3.74 (1H, m), 2.81-2.67 (1H, m), 2.34-1.92 (7H, m), 1.45 (3H, s), 1.43 (6H, s), 1.14 (2.1H, d, J=6.5 Hz), 1.12 (0.9H, d, J=6.5 Hz), 0.01 (6.3H, s), 0.00 (2.7H, s).
(6) tert-butyl ((2S)-1-(4-(2-bromo-4-fluorobenzoyl)-4-hydroxycyclohex-1-en-1-yl)propan-2-yl)carbamate
[1163] ##STR00123##
[1164] To a solution of tert-butyl ((2S)-1-(4-(2-bromo-4-fluorobenzoyl)-4-((trimethylsilyl)oxy)cyclohex-1-en-1-yl)propan-2-yl)carbamate obtained in (5) (0.22 g) in THF (0.41 ml) were added acetic acid (0.067 ml) and 1M TBAF-THF solution (0.59 ml) at room temperature, and the mixture was stirred for 15 min, and allowed to stand at room temperature all day. Saturated aqueous ammonium chloride solution, water and ethyl acetate were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction twice with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane) to give the title compound (0.17 g) in 66% yield.
[1165] 1H-NMR (CDCl3) ?: 7.50-7.41 (0.3H, m), 7.40-7.29 (1.7H, m), 7.12-6.96 (1H, m), 5.43-5.35 (1H, m), 4.37-4.18 (1H, m), 4.01 (0.3H, s), 3.90-3.73 (1H, m), 3.10 (0.7H, s), 2.82-2.50 (1H, m), 2.30-1.88 (7H, m), 1.39-1.38 (2.7H, s), 1.37-1.35 (6.3H, s), 1.14 (0.9H, d, J=7.5 Hz), 1.12 (2.1H, d, J=6.5 Hz).
(7) tert-butyl ((2S)-1-(5-(2-bromo-4-fluorophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undeca-4,8-dien-9-yl)propan-2-yl)carbamate
[1166] ##STR00124##
[1167] To a solution of tert-butyl ((2S)-1-(4-(2-bromo-4-fluorobenzoyl)-4-hydroxycyclohex-1-en-1-yl)propan-2-yl)carbamate obtained in (6) (0.17 g) in THF (1.7 ml) were added DBU (0.009 ml) and CDI (0.093 g) at room temperature, and the mixture was stirred for 30 min. Hydrazine monohydrate (0.037 ml) was added thereto, and the mixture was stirred at room temperature for 30 min. 10% Aqueous citric acid solution and ethyl acetate were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction twice with ethyl acetate, and the combined organic layers were washed with saturated brine, and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane). To the obtained solid were added THF (1.5 ml) and 6M hydrochloric acid (0.73 ml) at room temperature, and the mixture was stirred for 15 min, and allowed to stand all day. The mixture was stirred at 50? C. for 1.5 hr, and the reaction solution was concentrated under reduced pressure, followed by azeotropy twice with THF (2 ml). To the obtained solid were added saturated aqueous sodium bicarbonate solution (0.65 mL), THF (1.3 ml), water (0.65 ml) and Boc.sub.2O (0.19 ml) at room temperature, and the mixture was stirred all day. Water and ethyl acetate were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction twice with ethyl acetate, and the combined organic layers were washed with saturated brine, and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane) to give the title compound (0.12 g) in 88% yield.
[1168] 1H-NMR (CDCl3) ?: 8.13 (1H, s), 7.44-7.39 (1H, m), 7.24-7.16 (1H, m), 7.13-7.02 (1H, m), 5.31-5.18 (1H, m), 4.40-4.14 (1H, m), 3.86-3.67 (1H, m), 2.71-2.60 (1H, m), 2.44-2.08 (4H, m), 2.07-1.91 (2H, m), 1.78-1.66 (1H, m), 1.43 (2.7H, s), 1.32 (6.3H, s), 1.12 (0.9H, d, J=7.0 Hz), 1.07 (2.1H, d, J=7.0 Hz).
(8) tert-butyl ((S)-1-(cis-5-(2-bromo-4-fluorophenyl)-9-hydroxy-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)carbamate (cis isomer), and tert-butyl ((S)-1-(trans-5-(2-bromo-4-fluorophenyl)-9-hydroxy-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)carbamate (trans isomer)
[1169] ##STR00125##
[1170] To a solution of tert-butyl ((2S)-1-(5-(2-bromo-4-fluorophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undeca-4,8-dien-9-yl)propan-2-yl)carbamate obtained in (7) (0.12 g) in THF (1.8 ml) were added cobalt(II) acetyl acetone (0.063 g) and phenylsilane (0.30 ml) at room temperature, and the mixture was stirred under oxygen atmosphere all day. Saturated aqueous sodium thiosulfate solution, water and ethyl acetate were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction twice with ethyl acetate, and the combined organic layers were washed with saturated brine, and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane) to give a cis isomer (0.047 g) of the title compound in 27% yield, and a trans isomer (0.060 g) of the title compound in 30% yield.
(Cis Isomer)
[1171] 1H-NMR (CDCl3) ?: 8.22-8.08 (1H, m), 7.43 (1H, dd, J=8.1, 2.2 Hz), 7.27-7.22 (1H, m), 7.11 (1H, td, J=8.1, 2.5 Hz), 4.63 (1H, d, J=6.5 Hz), 3.81-3.67 (1H, m), 2.32-2.22 (2H, m), 2.19 (1H, s), 2.00-1.84 (3H, m), 1.84-1.48 (5H, m), 1.42 (9H, s), 1.15 (3H, d, J=6.5 Hz).
(Trans Isomer)
[1172] 1H-NMR (CDCl3) ?: 8.10 (1H, s), 7.40 (1H, dd, J=8.1, 2.2 Hz), 7.28-7.22 (1H, m), 7.10 (1H, t, J=8.6 Hz), 4.59-4.44 (1H, m), 3.99-3.81 (1H, m), 3.81-3.66 (1H, m), 2.19 (1H, s), 2.15-2.03 (1H, m), 2.03-1.89 (2H, m), 1.85-1.73 (2H, m), 1.73-1.50 (4H, m), 1.41 (9H, s), 1.17 (3H, d, J=7.0 Hz).
(9) cis-9-((S)-2-aminopropyl)-5-(2-bromo-4-fluorophenyl)-9-hydroxy-1-oxa-3,4-diazaspiro[5.5]undec-4-en-2-one
[1173] ##STR00126##
[1174] To a solution of tert-butyl ((S)-1-(cis-5-(2-bromo-4-fluorophenyl)-9-hydroxy-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)carbamate obtained in (8) (0.039 g) in chloroform (0.39 ml) was added trifluoroacetic acid (0.39 ml) at room temperature, and the mixture was stirred for 30 min. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (InertSep (registered trademark) SCX, developing solvent: methanol/2M ammonia-methanol solution) to give the title compound (0.030 g) in 85% yield.
[1175] 1H-NMR (DMSO-D6) ?: 11.30-11.21 (1H, m), 7.75 (1H, dd, J=8.6, 2.7 Hz), 7.56 (1H, dd, J=8.9, 5.7 Hz), 7.40-7.32 (1H, m), 2.97-2.85 (1H, m), 2.10-1.97 (2H, m), 1.81-1.27 (9H, m), 1.09-0.99 (2H, m), 0.96 (3H, d, J=6.5 Hz).
(10) N((S)-1-(cis-5-(2-bromo-4-fluorophenyl)-9-hydroxy-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-3-methyl-1H-pyrazole-5-carboxamide
[1176] ##STR00127##
[1177] To a solution of cis-9-((S)-2-aminopropyl)-5-(2-bromo-4-fluorophenyl)-9-hydroxy-1-oxa-3,4-diazaspiro[5.5]undec-4-en-2-one obtained in (9) (0.013 g) in DMF (0.2 ml) were added 3-methyl-1H-pyrazole-5-carboxylic acid (0.005 g), HOAt (0.006 g) and N,N-diisopropylethylamine (0.017 ml) at room temperature. WSC (0.008 g) was added thereto, and the mixture was stirred at room temperature for 15 min, and allowed to stand all day. Water, saturated aqueous sodium bicarbonate solution and ethyl acetate were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction twice with ethyl acetate, and the combined organic layers were washed with saturated brine, and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure, followed by azeotropy twice with toluene (2 ml). The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane) and then reverse-phase silica gel chromatography (developing solvent: acetonitrile/water) to give the title compound (0.004 g) in 26% yield.
[1178] 1H-NMR (DMSO-D6) ?: 12.81 (1H, s), 11.24 (1H, s), 7.90-7.79 (1H, m), 7.74 (1H, d, J=8.1 Hz), 7.59-7.48 (1H, m), 7.39-7.26 (1H, m), 6.29 (1H, s), 4.59 (1H, s), 4.07-3.93 (1H, m), 2.25 (3H, s), 2.11-1.94 (2H, m), 1.78-1.28 (8H, m), 1.12 (3H, d, J=5.9 Hz).
[Production Example 8]: Synthesis of N((S)-1-(trans-5-(2-bromo-4-fluorophenyl)-9-hydroxy-2-oxo-1-oxa-3,4-diazaspiro[5,5]undec-4-en-9-yl)propan-2-yl)-3-methyl-1H-pyrazole-5-carboxamide (Example 322)
[1179] ##STR00128##
(1) trans-9-((S)-2-aminopropyl)-5-(2-bromo-4-fluorophenyl)-9-hydroxy-1-oxa-3,4-diazaspiro[5.5]undec-4-en-2-one
[1180] ##STR00129##
[1181] To a solution of tert-butyl ((S)-1-(trans-5-(2-bromo-4-fluorophenyl)-9-hydroxy-2-oxo-1-oxa-3,4-diazaspiro[5,5]undec-4-en-9-yl)propan-2-yl)carbamate (obtained in (8) of [Production Example 7]) (0.056 g) in chloroform (0.44 ml) was added trifluoroacetic acid (0.44 ml) at room temperature, and the mixture was stirred for 30 min. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (InertSep (registered trademark) SCX, developing solvent: methanol/2M ammonia-methanol solution) to give the title compound (0.036 g) in 100% yield.
[1182] LC-MS (M+1): 414
(2) N((S)-1-(trans-5-(2-bromo-4-fluorophenyl)-9-hydroxy-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-3-methyl-1H-pyrazole-5-carboxamide
[1183] ##STR00130##
[1184] To a solution of trans-9-((S)-2-aminopropyl)-5-(2-bromo-4-fluorophenyl)-9-hydroxy-1-oxa-3,4-diazaspiro[5,5]undec-4-en-2-one obtained in (1) (0.016 g) in DMF (0.24 ml) were added 3-methyl-1H-pyrazole-5-carboxylic acid (0.006 g), HOAt (0.007 g) and N,N-diisopropylethylamine (0.020 ml) at room temperature. WSC (0.010 g) was added thereto, and the mixture was stirred at room temperature for 15 min, and allowed to stand all day. Water, saturated aqueous sodium bicarbonate solution and ethyl acetate were added thereto, and the mixture was subjected to extraction. The aqueous layer was subjected to re-extraction twice with ethyl acetate, and the combined organic layers were washed with saturated brine, and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure, followed by azeotropy twice with toluene (2 ml). The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane) and then reverse-phase silica gel chromatography (developing solvent: acetonitrile/water) to give the title compound (0.007 g) in 34% yield.
[1185] 1H-NMR (DMSO-D6) ?: 12.80 (1H, s), 11.18 (1H, s), 7.85 (1H, d, J=7.5 Hz), 7.74 (1H, dd, J=8.6, 2.7 Hz), 7.51 (1H, dd, J=8.6, 5.9 Hz), 7.37 (1H, ddd, J=8.6, 8.1, 2.7 Hz), 6.31 (1H, s), 4.25-4.08 (1H, m), 4.21 (1H, s), 2.24 (3H, s), 1.97-1.82 (2H, m), 1.82-1.66 (3H, m), 1.66-1.34 (5H, m), 1.12 (3H, d, J=6.5 Hz).
[Production Example 9]: Synthesis of N.SUP.1.((S)-1-(trans-5-(2-bromo-3-fluorophenyl)-9-cyano-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-N.SUP.2.-methyloxamide (Example 2-153)
[1186] ##STR00131##
(1) tert-butyl (S)-(1-(8-cyano-1,4-dioxaspiro[4.5]decan-8-yl)propan-2-yl)carbamate
[1187] ##STR00132##
[1188] A solution of 1,4-dioxaspiro[4.5]decane-8-carbonitrile (7.5 g) in THF (75 ml) was cooled to ?78? C., 1.11M LDA-THF/n-hexane solution (48.5 ml) was added thereto, and the mixture was stirred for 1 hr. tert-Butyl (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (12.8 g) was added thereto, and the mixture was warmed to 0? C., and stirred for 1 hr. 1M Hydrochloric acid (135 ml) was added thereto, and the mixture was stirred at room temperature for 30 min. Ethyl acetate and water were added thereto, and the mixture was subjected to extraction. The organic layer was washed with saturated brine, and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane=25/75 to 55/45), and the fractions were concentrated under reduced pressure to give the title compound (14.3 g) in 98% yield.
[1189] 1H-NMR (DMSO-D6) ?: 6.78 (1H, d, J=8.6 Hz), 3.87 (4H, s), 3.78-3.63 (1H, m), 2.06-1.44 (10H, m), 1.37 (9H, s), 1.06 (3H, d, J=6.5 Hz).
(2) tert-butyl (S)-(1-(1-cyano-4-oxocyclohexyl)propan-2-yl) carbamate
[1190] ##STR00133##
[1191] To a solution of tert-butyl (S)-(1-(8-cyano-1,4-dioxaspiro[4.5]decan-8-yl)propan-2-yl)carbamate obtained in (1) (10.9 g) in THF (54.5 ml) was added 6M hydrochloric acid (28 ml) at room temperature, and the mixture was stirred at 60? C. for 6 hr. After standing at room temperature for 3 days, 10M aqueous sodium hydroxide solution (16.8 ml) and Boc.sub.2O (23.4 ml) were added thereto, and the mixture was stirred for 2 hr. Ethyl acetate and water were added thereto, and the mixture was subjected to extraction. The organic layer was washed with saturated brine, and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane=30/70 to 65/35), and the fractions were concentrated under reduced pressure to give the title compound (5.59 g) in 59% yield.
[1192] 1H-NMR (DMSO-D6) ?: 6.84 (1H, d, J=9.2 Hz), 3.83-3.67 (1H, m), 2.55-2.39 (2H, m), 2.36-2.10 (4H, m), 1.92-1.75 (3H, m), 1.65 (1H, dd, J=14.3, 3.5 Hz), 1.38 (9H, s), 1.09 (3H, d, J=6.5 Hz).
(3) tert-butyl ((S)-1-(trans-4-(2-bromo-3-fluorobenzoyl)-1-cyano-4-((trimethylsilyl)oxy)cyclohexyl)propan-2-yl)carbamate
[1193] ##STR00134##
[1194] Under argon atmosphere, to a solution of 2-bromo-3-fluorobenzaldehyde (0.38 g) and lithium chloride (0.008 g) in THF (0.8 ml) was added trimethylsilylcyanide (0.27 ml) at room temperature, and the mixture was stirred for 30 min. THF (5.2 ml) was added thereto, and the mixture was cooled to ?78? C., and stirred for 5 min. 1.13M LiHMDS-n-hexane solution (1.6 ml) was added thereto, and the mixture was stirred for 10 min. tert-Butyl (S)-(1-(1-cyano-4-oxocyclohexyl)propan-2-yl)carbamate obtained in (2) (0.40 g) was added thereto, and the mixture was stirred for 30 min. Then, and the mixture was warmed to 0? C. over 1 hr, water and ethyl acetate were added thereto, and the mixture was subjected to extraction. The organic layer was washed with saturated brine, and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane=3/97 to 30/70), and the fractions were concentrated under reduced pressure to give the title compound (0.62 g) in 78% yield.
[1195] 1H-NMR (DMSO-D6) ?: 7.59-7.41 (2H, m), 7.39-7.33 (1H, m), 6.84 (1H, d, J=8.6 Hz), 3.82-3.67 (1H, m), 2.07-1.49 (10H, m), 1.37 (9H, s), 1.08 (3H, d, J=6.5 Hz), 0.04 (9H, s).
(4) tert-butyl ((S)-1-(trans-4-(2-bromo-3-fluorobenzoyl)-1-cyano-4-hydroxycyclohexyl)propan-2-yl)carbamate
[1196] ##STR00135##
[1197] To a solution of tert-butyl ((S)-1-(trans-4-(2-bromo-3-fluorobenzoyl)-1-cyano-4-((trimethylsilyl)oxy)cyclohexyl)propan-2-yl)carbamate obtained in (3) (0.62 g) in THF (3.1 ml) were added acetic acid (0.19 ml) and 1M TBAF-THF solution (1.7 ml) at room temperature, and the mixture was stirred for 2 hr. Saturated aqueous sodium bicarbonate solution and ethyl acetate were added thereto, the mixture was subjected to extraction, and the organic layer was dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane=30/70 to 60/40), and the fractions were concentrated under reduced pressure to give the title compound (0.25 g) in 46% yield.
[1198] 1H-NMR (DMSO-D6) ?: 7.55-7.39 (2H, m), 7.32-7.27 (1H, m), 6.81 (1H, d, J=8.6 Hz), 5.53 (1H, s), 3.83-3.69 (1H, m), 2.02-1.49 (10H, m), 1.37 (9H, s), 1.07 (3H, d, J=6.5 Hz).
(5) trans-9-((S)-2-aminopropyl)-5-(2-bromo-3-fluorophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-ene-9-carbonitrile hydrochloride
[1199] ##STR00136##
[1200] To a solution of tert-butyl ((S)-1-(trans-4-(2-bromo-3-fluorobenzoyl)-1-cyano-4-hydroxycyclohexyl)propan-2-yl)carbamate obtained in (4) (0.25 g) in THF (2.5 ml) were added CDI (0.13 g) and DBU (0.012 ml) at room temperature, and the mixture was stirred for 30 min. Hydrazine monohydrate (0.069 ml) was added, and the mixture was stirred for 30 min. 10% Aqueous citric acid solution and ethyl acetate were added thereto, and the mixture was subjected to extraction. The organic layer was dried over sodium sulfate, the sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane=50/50 to 90/10), and the fractions were concentrated under reduced pressure. To the obtained solid were added THF (2.3 ml) and 6M hydrochloric acid (1.1 ml), and the mixture was stirred at 50? C. for 2 hr. The reaction solution was concentrated under reduced pressure, followed by azeotropy with THF to give the title compound (0.17 g) in 72% yield.
[1201] 1H-NMR (DMSO-D6) ?: 11.45 (1H, s), 7.93 (3H, br s), 7.62-7.50 (2H, m), 7.42-7.36 (1H, m), 3.44-3.34 (1H, m), 2.31-2.19 (2H, m), 2.03-1.81 (4H, m), 1.78-1.58 (4H, m), 1.31 (3H, d, J=6.5 Hz).
(6) N.SUP.1.((S)-1-(trans-5-(2-bromo-3-fluorophenyl)-9-cyano-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-N.SUP.2.-methyloxamide
[1202] ##STR00137##
[1203] To a solution of trans-9-((S)-2-aminopropyl)-5-(2-bromo-3-fluorophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-ene-9-carbonitrile hydrochloride obtained in (5) (0.025 g) in DMF (0.4 ml) were added 2-methylamino-2-oxoacetic acid (0.007 g), N,N-diisopropylethylamine (0.048 ml) and HATU (0.025 g) at room temperature, and the mixture was stirred for 1 hr. The reaction solution was purified by reverse-phase silica gel chromatography (developing solvent: acetonitrile/water=5/95 to 70/30) and then thin layer chromatography (developing solvent: ethyl acetate), and the fractions were concentrated under reduced pressure to give the title compound (0.018 g) in 65% yield.
[1204] 1H-NMR (DMSO-D6) ?: 11.39 (1H, s), 8.72 (1H, d, J=9.2 Hz), 8.63-8.57 (1H, m), 7.58-7.47 (2H, m), 7.38-7.34 (1H, m), 4.17-4.04 (1H, m), 2.64 (3H, d, J=4.8 Hz), 2.27-1.95 (4H, m), 1.81-1.53 (6H, m), 1.12 (3H, d, J=6.5 Hz).
[Production Example 10]: Synthesis of N.SUP.1.((S)-1-(trans-5-(2-bromo-5-cyanophenyl)-9-methoxy-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-N.SUP.2.-methyloxamide (Example 2-123)
[1205] ##STR00138##
(1) 1-(8-methoxy-1,4-dioxaspiro[4.5]decan-8-yl)propan-2-one
[1206] ##STR00139##
[1207] To a solution of 1,4-dioxaspiro[4.5]decan-8-one (5.0 g) in methanol (50 ml) were added dimethyl (2-oxopropyl)phosphonate (5.9 g) and 28% sodium methoxide-methanol solution (23.5 ml) at room temperature, and the mixture was stirred all day. Water (20 ml) was added thereto, and the mixture was concentrated under reduced pressure to evaporate the methanol. The mixture was diluted with ethyl acetate, and washed with saturated brine. The obtained organic layer was dried over sodium sulfate, the sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane=20/80 to 50/50), and the fractions were concentrated under reduced pressure to give the title compound (2.1 g) in 28% yield.
[1208] 1H-NMR (DMSO-D6) ?: 3.83 (4H, s), 3.15 (3H, s), 2.57 (2H, s), 2.11 (3H, s), 1.78-1.68 (2H, m), 1.66-1.41 (6H, m).
(2) (S)-1-(8-methoxy-1,4-dioxaspiro[4.5]decan-8-yl)-N((S)-1-phenylethyl)propan-2-amine
[1209] ##STR00140##
[1210] To a solution of 1-(8-methoxy-1,4-dioxaspiro[4.5]decan-8-yl)propan-2-one obtained in (1) (2.1 g) in THF (31 ml) were added (S)-1-phenethylamine (1.3 ml), acetic acid (0.52 ml) and sodium triacetoxyborohydride (3.6 g) at room temperature, and the mixture was stirred for 3 hr. Under ice-cooled, 4M aqueous sodium hydroxide solution (11.3 ml) and water were added thereto, and the mixture was diluted with ethyl acetate. The obtained organic layer was washed with saturated brine. The organic layer was dried over sodium sulfate, the sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: methanol/ethyl acetate/n-hexane=0/25/75 to 0/100/0 to 5/95/0), and the fractions were concentrated under reduced pressure to give the title compound (1.4 g) in 46% yield.
[1211] 1H-NMR (DMSO-D6) ?: 7.36-7.23 (4H, m), 7.20-7.15 (1H, m), 3.82 (4H, s), 3.78 (1H, q, J=6.7 Hz), 3.04 (3H, s), 2.66-2.56 (1H, m), 1.89-1.29 (11H, m), 1.24-1.10 (3H, m), 0.90 (3H, d, J=6.6 Hz).
(3) tert-butyl (S)-(1-(8-methoxy-1.4-dioxaspiro[4.5]decan-8-yl)propan-2-yl)carbamate
[1212] ##STR00141##
[1213] To a solution of (S)-1-(8-methoxy-1,4-dioxaspiro[4.5]decan-8-yl)-N((S)-1-phenylethyl)propan-2-amine obtained in (2) (1.4 g) in THF (14 ml) were added acetic acid (0.48 ml) and 20% palladium hydroxide-activated carbon at room temperature, and the mixture was stirred under hydrogen atmosphere (1 atm) all day. The reaction solution was filtered through Celite, followed by washing with THF (14 ml). To the obtained THF solution were added water (4.8 ml), sodium bicarbonate (1.1 g) and Boc.sub.2O (1.1 ml) at room temperature, and the mixture was stirred for 2 hr. The mixture was diluted with ethyl acetate, and washed with saturated brine. The obtained organic layer was dried over sodium sulfate, the sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane=15/85 to 50/50), and the fractions were concentrated under reduced pressure to give the title compound (1.0 g) in 76% yield.
[1214] 1H-NMR (DMSO-D6) ?: 6.62 (1H, d, J=8.1 Hz), 3.83 (4H, s), 3.65-3.48 (1H, m), 3.02 (3H, s), 1.79-1.27 (10H, m), 1.36 (9H, s), 1.03 (3H, d, J=6.5 Hz).
(4) tert-butyl (S)-(1-(1-methoxy-4-oxocyclohexyl)propan-2-yl) carbamate
[1215] ##STR00142##
[1216] To a solution of tert-butyl (S)-(1-(8-methoxy-1.4-dioxaspiro[4.5]decan-8-yl)propan-2-yl)carbamate obtained in (3) (1.0 g) in a mixed solvent of acetone (10 ml) and water (4.2 ml) was added pyridinium p-toluenesulfonate (0.16 g) at room temperature, and the mixture was stirred at 60? C. for 6 hr. Saturated aqueous sodium bicarbonate solution (5 ml) was added thereto at room temperature, and the acetone was evaporated. Ethyl acetate was added thereto, and the mixture was subjected to extraction. The obtained organic layer was washed with saturated brine, and dried over sodium sulfate, the sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane=20/80 to 55/45), and the fractions were concentrated under reduced pressure to give the title compound (0.77 g) in 85% yield.
[1217] 1H-NMR (DMSO-D6) ?: 6.68 (1H, d, J=8.6 Hz), 3.70-3.54 (1H, m), 3.14 (3H, s), 2.48-2.31 (2H, m), 2.11-1.92 (4H, m), 1.78-1.54 (4H, m), 1.36 (9H, s), 1.06 (3H, d, J=6.5 Hz).
(5) tert-butyl ((S)-1-(trans-4-(2-bromo-5-cyanobenzoyl)-1-methoxy-4-((trimethylsilyl)oxy)cyclohexyl)propan-2-yl)carbamate
[1218] ##STR00143##
[1219] Under argon atmosphere, to a solution of 4-bromo-3-formylbenzonitrile (0.24 g) and lithium chloride (0.005 g) in THF (0.5 ml) was added trimethylsilylcyanide (0.16 ml), and the mixture was stirred at room temperature for 30 min. THF (3.3 ml) was added thereto, and the mixture was cooled to ?78? C., and stirred for 5 min. 1.13M LiHMDS-n-hexane solution (1.0 ml) was added thereto, and the mixture was stirred for 10 min. tert-Butyl (S)-(1-(1-methoxy-4-oxocyclohexyl)propan-2-yl)carbamate obtained in (4) (0.25 g) was added thereto, and the mixture was stirred for 30 min. Then the mixture was warmed to 0? C. over 1 hr, water and ethyl acetate were added thereto, and the mixture was subjected to extraction. The organic layer was washed with saturated brine, and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane=5/95 to 33/67), and the fractions were concentrated under reduced pressure to give the title compound (0.23 g) in 45% yield.
[1220] 1H-NMR (DMSO-D6) ?: 8.05-7.82 (3H, m), 6.69 (1H, d, J=8.1 Hz), 3.67-3.51 (1H, m), 3.00 (3H, s), 2.01-1.31 (10H, m), 1.36 (9H, s), 1.04 (3H, d, J=6.5 Hz), 0.00-0.03 (9H, m).
(6) tert-butyl ((S)-1-(trans-4-(2-bromo-5-cyanobenzoyl)-4-hydroxy-1-methoxycyclohexyl)propan-2-yl)carbamate
[1221] ##STR00144##
[1222] To a solution of tert-butyl ((S)-1-(trans-4-(2-bromo-5-cyanobenzoyl)-1-methoxy-4-((trimethylsilyl)oxy)cyclohexyl)propan-2-yl)carbamate obtained in (5) (0.22 g) in THF (2.2 ml) were added acetic acid (0.067 ml) and 1M TBAF-THF solution (0.58 ml) at room temperature, and the mixture was stirred for 2 hr. Saturated aqueous sodium bicarbonate solution and ethyl acetate were added thereto, and the mixture was subjected to extraction. The organic layer was washed with saturated brine, and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane=30/70 to 60/40), and the fractions were concentrated under reduced pressure to give the title compound (0.15 g) in 78% yield.
[1223] 1H-NMR (DMSO-D6) ?: 7.93-7.88 (2H, m), 7.84-7.79 (1H, m), 6.64 (1H, d, J=8.1 Hz), 5.31 (1H, s), 3.69-3.56 (1H, m), 3.04 (3H, s), 1.97-1.31 (10H, m), 1.36 (9H, s), 1.04 (3H, d, J=6.5 Hz).
(7) 3-(trans-9-((S)-2-aminopropyl)-9-methoxy-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-5-yl)-4-bromobenzonitrile hydrochloride
[1224] ##STR00145##
[1225] To a solution of tert-butyl ((S)-1-(trans-4-(2-bromo-5-cyanobenzoyl)-4-hydroxy-1-methoxycyclohexyl)propan-2-yl)carbamate obtained in (6) (0.15 g) in THF (1.5 ml) were added CDI (0.073 g) and DBU (0.007 ml), and the mixture was stirred at room temperature for 30 min. Hydrazine monohydrate (0.045 ml) was added thereto, and the mixture was stirred for 30 min. 10% Aqueous citric acid solution and ethyl acetate were added thereto, the mixture was subjected to extraction, and organic layer was dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane=50/50 to 90/10), and the fractions were concentrated under reduced pressure. To the obtained solid were added THF (1.6 ml) and 6M hydrochloric acid (0.8 ml), and the mixture was stirred at 50? C. for 2 hr. The mixture was allowed to cool to room temperature, and the reaction solution was concentrated, followed by azeotropy with THF to give the title compound (0.14 g) in 96% yield.
[1226] 1H-NMR (DMSO-D6) ?: 11.38 (1H, s), 8.12-8.08 (1H, m), 8.05-8.00 (1H, m), 7.93-7.86 (1H, m), 7.71 (3H, br s), 3.68-3.49 (1H, m), 2.98 (3H, s), 2.07-1.93 (2H, m), 1.84-1.45 (8H, m), 1.22 (3H, d, J=6.5 Hz).
(8) N.SUP.1.((S)-1-(trans-5-(2-bromo-5-cyanophenyl)-9-methoxy-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl)propan-2-yl)-N.SUP.2.-methyloxamide
[1227] ##STR00146##
[1228] To a solution of 3-(trans-9-((S)-2-aminopropyl)-9-methoxy-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-5-yl)-4-bromobenzonitrile hydrochloride obtained in (7) (0.050 g) in DMF (0.75 ml) were added 2-methylamino-2-oxoacetic acid (0.016 g), N,N-diisopropylethylamine (0.074 ml) and HATU (0.060 g) at room temperature, and the mixture was stirred for 1 hr. The reaction solution was purified by reverse-phase silica gel chromatography (developing solvent: acetonitrile/water=5/95 to 65/35) and then thin layer chromatography (developing solvent: ethyl acetate/n-hexane=67/33), and the fractions were concentrated under reduced pressure to give the title compound (0.049 g) in 89% yield.
[1229] 1H-NMR (DMSO-D6) ?: 11.32 (1H, s), 8.65-8.54 (2H, m), 8.09-8.05 (1H, m), 8.03-7.98 (1H, m), 7.91-7.86 (1H, m), 4.01-3.92 (1H, m), 2.92 (3H, s), 2.67-2.63 (3H, m), 1.99-1.42 (10H, m), 1.08 (3H, d, J=6.5 Hz).
[1230] The compounds of the other Examples were obtained by employing the same methods as in the above Production Methods or Production Examples, and, where necessary, known methods. The structural formulae and physical property data of the compounds of Examples 1 to 339 and 2-001 to 2-172 are shown in Table 1-1 to Table 1-61.
TABLE-US-00001 TABLE 1-1 Ex. MS MS No. Structure Notes 1H-NMR (400 MHz) (M + 1) (M ? 1) 1 [00147]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.65 (1H, s), 11.16 (1H, s), 8.17 (1H, d, J = 8.3 Hz), 7.44-7.37 (4H, m), 7.16 (2H, t, J = 8.3 Hz), 7.11 (1H, s), 7.04 (1H, td, J = 8.3, 2.6 Hz), 4.24-4.16 (1H, m), 2.82-2.71 (2H, m), 2.39- 2.30 (4H, m), 1.97 (2H, d, J = 13.6 Hz), 1.81 (2H, td, J = 13.6, 5.2 Hz), 1.15 (3H, d, J = 6.5 Hz). 482 480 2 [00148]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.63 (1H, s), 11.30 (1H, s), 8.20 (1H, d, J = 6.5 Hz), 7.73 (1H, d, J = 6.5 Hz), 7.51 (1H, t, J = 7.6 Hz), 7.42-7.36 (2H, m), 7.30 (1H, t, J = 8.9 Hz), 7.08 (1H, s), 7.03 (1H, t, J = 8.9 Hz), 4.29-4.18 (1H, m), 2.48- 2.35 (6H, m), 2.17-2.09 (2H, m), 1.69-1.57 (2H, m), 1.13 (3H, d, J = 6.7 Hz). 560 558 3 [00149]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.80 (1H, s), 11.26 (1H, s), 7.74 (1H, d, J = 8.0 Hz), 7.58 (1H, d, J = 7.4 Hz), 7.53 (1H, t, J = 7.4 Hz), 7.35 (1H, t, J = 8.0 Hz), 6.29 (1H, s), 4.12-4.02 (1H, m), 2.68 (2H, d, J = 12.3 Hz), 2.44-2.39 (1H, m), 2.33- 2.25 (3H, m), 2.24 (3H, s), 2.07 (2H, d, J = 12.3 Hz), 1.55 (2H, s), 1.07 (3H, d, J = 6.2 Hz). 507 505 4 [00150]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.62 (1H, s), 11.11 (1H, s), 8.20 (1H, d, J = 8.3 Hz), 7.50 (2H, dd, J = 8.8, 5.5 Hz), 7.42-7.36 (2H, m), 7.22 (2H, t, J = 8.8 Hz), 7.12 (1H, d, J = 1.6 Hz), 7.02 (1H, td, J = 8.8, 2.5 Hz), 4.21-4.12 (1H, m), 2.04-1.95 (2H, m), 1.78-1.70 (2H, tm), 1.68-1.61 (1H, m), 1.61-1.51 (2H, m), 1.48-1.23 (4H, m), 1.15 (3H, d, J = 6.5 Hz). 481 479 5 [00151]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.82 (1H, s), 11.11 (1H, s), 7.62 (1H, s), 7.51 (2H, dd, J = 8.6, 5.3 Hz), 7.23 (2H, dd, J = 8.6, 5.3 Hz), 6.33 (1H, s), 4.12-4.02 (1H, m), 2.24 (3H, s), 2.02- 1.95 (2H, m), 1.74-1.66 (2H, m), 1.66-1.60 (1H, m), 1.59- 1.50 (2H, m), 1.42-1.22 (4H, m), 1.10 (3H, d, J = 6.2 Hz). 428 426 6 [00152]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.11 (1H, s), 8.66 (1H, d, J = 5.3 Hz), 8.45 (1H, d, J = 9.2 Hz), 7.52 (2H, dd, J = 8.9, 5.3 Hz), 7.25 (2H, t, J = 8.9 Hz), 3.99- 3.89 (1H, m), 2.66 (3H, d, J = 5.3 Hz), 2.02-1.95 (2H, m), 1.74-1.46 (5H, m), 1.35-1.21 (4H, m), 1.08 (3H, d, J = 6.5 Hz). 405 403 7 [00153]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.12 (1H, s), 8.45 (1H, d, J = 8.3 Hz), 7.76 (1H, d, J = 8.3 Hz), 7.65 (1H, d, J = 8.3 Hz), 7.52 (1H, s), 7.51 (2H, t, J = 7.5 Hz), 7.46 (1H, t, J = 7.5 Hz), 7.33 (1H, t, J = 8.3 Hz), 7.22 (2H, t, J = 8.3 Hz), 4.20-4.10 (1H, m), 2.04-1.94 (2H, m), 1.74-1.53 (5H, m), 1.46-1.26 (4H, m), 1.16 (3H, d, J = 6.5 Hz). 464 462 8 [00154]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.62 (1H, s), 11.29 (1H, s), 8.20 (1H, d, J = 9.0 Hz), 7.93 (2H, d, J = 8.3 Hz), 7.74 (2H, d, J = 8.3 Hz), 7.42-7.36 (2H, m), 7.13 (1H, d, J = 2.1 Hz), 7.02 (1H, td, J = 9.0, 2.3 Hz), 4.21- 4.13 (1H, m), 3.24 (3H, s), 2.08-1.98 (2H, m), 1.78-1.30 (9H, m), 1.16 (3H, d, J = 6.5 Hz). 541 539
TABLE-US-00002 TABLE 1-2 9 [00155]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.83 (1H, s), 11.28 (1H, s), 7.94 (2H, d, J = 8.3 Hz), 7.74 (2H, d, J = 8.3 Hz), 7.63 (1H, d, J = 8.8 Hz), 6.32 (1H, s), 4.12-4.05 (1H, m), 3.25 (3H, s), 2.24 (3H, s), 2.06-1.98 (2H, m), 1.75-1.68 (2H, m), 1.65-1.54 (3H, m), 1.43-1.23 (4H, m), 1.10 (3H, d, J = 6.7 Hz). 488 486 10 [00156]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.29 (1H, s), 8.66 (1H, d, J = 5.1 Hz), 8.46 (1H, q, J = 5.1 Hz), 7.96 (2H, d, J = 8.3 Hz), 7.76 (2H, d, J = 8.3 Hz), 3.98-3.90 (1H, m), 3.27 (3H, s), 2.66 (3H, d, J = 5.1 Hz), 2.06-1.98 (2H, m), 1.77-1.50 (5H, m), 1.38-1.23 (4H, m), 1.08 (3H, d, J = 6.5 Hz). 465 463 11 [00157]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.20 (1H, s), 7.74 (1H, dd, J = 8.4, 2.4 Hz), 7.58-7.50 (2H, m), 7.35 (1H, td, J = 8.4, 2.4 Hz), 3.86-3.76 (1H, m), 2.16-2.08 (2H, m), 1.73 (3H, s), 1.65- 1.58 (1H, m), 1.51-1.14 (8H, m), 0.97 (3H, d, J = 6.5 Hz). 440 438 12 [00158]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.96 (0.18H, s), 12.81 (0.82H, s), 11.20 (1H, s), 7.97 (0.18H, d, J = 8.1 Hz), 7.71 (1H, dd, J = 8.6, 2.5 Hz), 7.60 (0.82H, d, J = 8.1 Hz), 7.51 (1H, dd, J = 8.6, 6.0 Hz), 7.31 (1H, td, J = 8.1, 2.5 Hz), 6.59 (0.18H, s), 6.31 (0.82H, s), 4.10-4.00 (1H, m), 2.23 (3H, s), 2.17-2.07 (2H, m), 1.73-1.65 (1H, m), 1.55-1.45 (2H, m), 1.40-1.20 (6H, m), 1.07 (3H, d, J = 6.5 Hz). 506 504 13 [00159]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.60 (1H, s), 11.20 (1H, s), 8.17 (1H, d, J = 8.7 Hz), 7.70 (1H, dd, J = 8.7, 2.7 Hz), 7.49 (1H, dd, J = 8.7, 6.1 Hz), 7.38 (1H, s), 7.40-7.32 (1H, m), 7.30 (1H, td, J = 8.7, 2.7 Hz), 7.10 (1H, s), 7.02 (1H, td, J = 9.2, 2.7 Hz), 4.20-4.08 (1H, m), 2.18-2.08 (2H, m), 1.78-1.70 (1H, m), 1.57-1.49 (2H, m), 1.43-1.23 (6H, m), 1.13 (3H, d, J = 6.5 Hz). 559 557 14 [00160]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.20 (1H, s), 8.64 (1H, q, J = 5.0 Hz), 8.43 (1H, d, J = 8.6 Hz), 7.73 (1H, dd, J = 8.6, 2.5 Hz), 7.52 (1H, dd, J = 8.6, 5.0 Hz), 7.34 (1H, td, J = 8.6, 2.5 Hz), 3.96-3.85 (1H, m), 2.64 (3H, d, J = 5.0 Hz), 2.17-2.05 (2H, m), 1.67-1.63 (1H, m), 1.55-1.15 (8H, m), 1.05 (3H, d, J = 6.5 Hz). 483 481 15 [00161]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.62 (1H, s), 11.25 (1H, s), 8.63 (1H, d, J = 2.4 Hz), 8.62 (1H, dd, J = 4.9, 1.8 Hz), 8.20 (1H, d, J = 8.3 Hz), 7.92 (1H, dt, J = 8.3, 1.8 Hz), 7.44-7.36 (3H, m), 7.12 (1H, d, J = 1.8 Hz), 7.02 (1H, td, J = 9.1, 2.4 Hz), 4.22-4.12 (1H, m), 2.06-1.98 (2H, m), 1.77-1.45 (6H, m), 1.41-1.28 (3H, m), 1.16 (3H, d, J = 6.5 Hz). 464 462 16 [00162]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.82 (1H, s), 11.24 (1H, s), 8.64 (1H, s), 8.63 (1H, dd, J = 4.7, 1.3 Hz), 7.93 (1H, d, J = 8.1 Hz), 7.65-7.58 (1H, m), 7.44 (1H, dd, J = 8.1, 4.7 Hz), 6.32 (1H, s), 4.14-4.04 (1H, m), 2.24 (3H, s), 2.06-1.99 (2H, m), 1.74-1.51 (5H, m), 1.46-1.23 (4H, m), 1.10 (3H, d, J = 6.0 Hz). 411 409
TABLE-US-00003 TABLE 1-3 17 [00163]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.24 (1H, s), 8.67-8.63 (3H, m), 8.44 (1H, d, J = 9.2 Hz), 7.94 (1H, dt, J = 8.0, 1.8 Hz), 7.46 (1H, dd, J = 8.0, 4.7 Hz), 3.97- 3.87 (1H, m), 2.65 (3H, d, J = 4.7 Hz), 2.04-1.97 (2H, m), 1.77-1.48 (5H, m), 1.35-1.24 (4H, m), 1.08 (3H, d, J = 6.7 Hz). 388 386 18 [00164]![embedded image]()
Mixture of two diastereo- mers due to 5- position of pyrroli- done ring 1H-NMR (DMSO-D6) ?: 11.21 (1H, s), 7.76-7.73 (2H, m), 7.68 (1H, dd, J = 8.6, 4.6 Hz), 7.53 (1H, dd, J = 8.6, 6.0 Hz), 7.36 (1H, tt, J = 8.6, 2.3 Hz), 3.92-3.86 (1H, m), 3.85-3.81 (1H, m), 2.20-2.02 (5H, m), 1.82-1.73 (1H, m), 1.63-1.58 (1H, m), 1.51-1.18 (8H, m), 1.01-0.98 (3H, m). 509 507 19 [00165]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.20 (1H, s), 8.41 (1H, d, J = 8.6 Hz), 7.75 (1H, d, J = 7.6 Hz), 7.70 (1H, dd, J = 8.6, 2.2 Hz), 7.63 (1H, d, J = 7.6 Hz), 7.50 (1H, dd, J = 8.6, 5.9 Hz), 7.49 (1H, s), 7.45 (1H, td, J = 7.6, 2.2 Hz), 7.33 (1H, t, J = 4.7 Hz), 7.31-7.27 (1H, m), 4.19- 4.09 (1H, m), 2.18-2.07 (2H, m), 1.75-1.67 (1H, m), 1.60- 1.50 (2H, m), 1.46-1.19 (6H, m), 1.13 (3H, d, J = 6.5 Hz). 542 540 20 [00166]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.20 (1H, s), 7.74 (1H, dd, J = 8.6, 2.5 Hz), 7.53 (1H, dd, J = 8.6, 6.0 Hz), 7.42 (1H, d, J = 8.4 Hz), 7.35 (1H, td, J = 8.4, 2.5 Hz), 3.86-3.76 (1H, m), 2.30- 2.23 (1H, m), 2.16-2.08 (2H, m), 1.63-1.56 (1H, m), 1.53- 1.46 (1H, m), 1.43-1.18 (7H, m), 0.97-0.92 (9H, m). 468 466 21 [00167]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.20 (1H, s), 7.77 (1H, d, J = 7.9 Hz), 7.74 (1H, dd, J = 8.7, 2.5 Hz), 7.54 (1H, dd, J = 8.7, 5.9 Hz), 7.35 (1H, td, J = 8.7, 2.5 Hz), 3.87-3.78 (1H, m), 2.17- 2.07 (2H, m), 1.64-1.56 (1H, m), 1.52-1.17 (9H, m), 0.98 (3H, d, J = 6.5 Hz), 0.62-0.56 (4H, m). 466 464 22 [00168]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.82 (1H, s), 11.15 (1H, s), 7.63- 7.59 (1H, m), 7.60 (2H, d, J = 8.6 Hz), 7.41 (2H, d, J = 8.6 Hz), 6.33 (1H, s), 4.07 (1H, s), 2.25 (3H, s), 2.01-1.96 (2H, m), 1.72-1.51 (5H, m), 1.40- 1.24 (4H, m), 1.10 (3H, d, J = 6.5 Hz). 488 486 23 [00169]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.15 (1H, s), 8.65 (1H, q, J = 4.9 Hz), 8.44 (1H, d, J = 9.2 Hz), 7.62 (2H, d, J = 8.6 Hz), 7.43 (2H, d, J = 8.6 Hz), 3.98-3.88 (1H, m), 2.66 (3H, d, J = 4.9 Hz), 2.02-1.95 (2H, m), 1.74- 1.47 (5H, m), 1.34-1.21 (4H, m), 1.08 (3H, d, J = 6.5 Hz). 465 463 24 [00170]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.16 (1H, s), 8.65 (1H, q, J = 4.5 Hz), 8.43 (1H, d, J = 9.0 Hz), 7.66 (1H, d, J = 7.5 Hz), 7.62 (1H, s), 7.50 (1H, d, J = 7.5 Hz), 7.39 (1H, t, J = 7.5 Hz), 3.98-3.88 (1H, m), 2.65 (3H, d, J = 4.5 Hz), 2.03-1.96 (2H, m), 1.83-1.48 (5H, m), 1.33- 1.21 (4H, m), 1.08 (3H, d, J = 6.7 Hz). 465 463
TABLE-US-00004 TABLE 1-4 25 [00171]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.81 (1H, s), 11.16 (1H, s), 7.66- 7.58 (3H, m), 7.48 (1H, d, J = 7.9 Hz), 7.38 (1H, d, J = 7.9 Hz), 6.32 (1H, s), 4.12-4.02 (1H, m), 2.24 (3H, s), 2.04-1.97 (2H, m), 1.78-1.48 (5H, m), 1.44-1.20 (4H, m), 1.10 (3H, d, J = 6.0 Hz). 488 486 26 [00172]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.16 (1H, s), 8.63 (1H, q, J = 4.8 Hz), 8.41 (1H, d, J = 8.6 Hz), 7.73 (1H, d, J = 8.6 Hz), 7.48- 7.37 (3H, m), 3.95-3.85 (1H, m), 2.63 (3H, d, J = 4.8 Hz), 2.18-2.08 (2H, m), 1.69-1.61 (1H, m), 1.54-1.13 (8H, m), 1.05 (3H, d, J = 6.7 Hz). 465 463 27 [00173]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.94 (0.18H, s), 12.80 (0.82H, s), 11.16 (1H, s), 7.94 (0.18H, d, J = 9.0 Hz), 7.72 (1H, d, J = 7.6 Hz), 7.58 (0.82H, d, J = 9.0 Hz), 7.44-7.38 (3H, m), 6.56 (0.18H, s), 6.30 (0.82H, s), 4.10-4.00 (1H, m), 2.23 (3H, s), 2.17-2.08 (2H, m), 1.75-1.63 (1H, m), 1.55-1.45 (2H, m), 1.39-1.20 (6H, m), 1.07 (3H, d, J = 6.0 Hz). 488 486 28 [00174]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.20 (1H, s), 7.74 (1H, dd, J = 8.6, 2.5 Hz), 7.53 (1H, dd, J = 8.6, 6.0 Hz), 7.35 (1H, td, J = 8.6, 2.5 Hz), 7.29 (1H, d, J = 8.6 Hz), 5.35 (1H, d, J = 5.3 Hz), 3.92-3.84 (2H, m), 2.16-2.09 (2H, m), 1.65-1.58 (1H, m), 1.52-1.18 (8H, m), 1.14 (3H, d, J = 6.7 Hz), 1.01 (3H, d, J = 6.5 Hz). 470 468 29 [00175]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.19 (1H, s), 7.74 (1H, dd, J = 8.8, 2.6 Hz), 7.53 (1H, dd, J = 8.6, 6.0 Hz), 7.35 (1H, td, J = 8.6, 2.6 Hz), 7.27 (1H, d, J = 8.8 Hz), 5.32 (1H, d, J = 5.1 Hz), 3.91-3.82 (2H, m), 2.17-2.09 (2H, m), 1.67-1.60 (1H, m), 1.51-1.19 (8H, m), 1.15 (3H, d, J = 6.7 Hz), 1.00 (3H, d, J = 6.5 Hz). 470 468 30 [00176]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.19 (1H, s), 8.27 (1H, d, J = 9.0 Hz), 7.73 (1H, dd, J = 8.6, 2.6 Hz), 7.52 (1H, dd, J = 8.6, 6.1 Hz), 7.34 (1H, td, J = 8.6, 2.6 Hz), 3.91-3.82 (1H, m), 2.30 (3H, s), 2.15-2.08 (2H, m), 1.64-1.59 (1H, m), 1.50-1.18 (8H, m), 1.04 (3H, d, J = 6.5 Hz). 468 466 31 [00177]![embedded image]()
1H-NMR (DMSO-D6) o: 12.80 (1H, s), 11.31 (1H, s), 8.23 (1H, d, J = 1.8 Hz), 7.95 (1H, dd, J = 8.2, 1.8 Hz), 7.74 (1H, d, J = 8.2 Hz), 7.61-7.56 (1H, m), 6.31-6.29 (1H, m), 4.10- 4.02 (1H, m), 3.33 (3H, s), 2.23 (3H, s), 2.20-2.10 (2H, m), 1.73-1.67 (1H, m), 1.55-1.46 (2H, m), 1.45-1.21 (6H, m), 1.07 (3H, d, J = 6.5 Hz). 566 564 32 [00178]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.58 (1H, s), 11.32 (1H, s), 8.22 (1H, d, J = 1.8 Hz), 8.16 (1H, d, J = 8.6 Hz), 7.94 (1H, dd, J = 8.0, 1.8 Hz), 7.72 (1H, d, J = 8.0 Hz), 7.40-7.34 (2H, m), 7.10-7.08 (1H, m), 7.04-6.98 (1H, m), 4.18-4.09 (1H, m), 3.31 (3H, s), 2.20-2.12 (2H, m), 1.77-1.71 (1H, m), 1.57- 1.49 (2H, m), 1.47-1.22 (6H, m), 1.13 (3H, d, J = 6.5 Hz). 619 617
TABLE-US-00005 TABLE 1-5 33 [00179]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.31 (1H, s), 8.65-8.60 (1H, m), 8.41 (1H, d, J = 9.2 Hz), 8.25 (1H, d, J = 1.8 Hz), 7.97 (1H, dd, J = 8.1, 1.8 Hz), 7.75 (1H, d, J = 8.1 Hz), 3.95-3.86 (1H, m), 3.34 (3H, s), 2.63 (3H, d, J = 4.9 Hz), 2.17-2.11 (2H, m), 1.69-1.63 (1H, m), 1.56- 1.44 (2H, m), 1.40-1.18 (6H, m), 1.05 (3H, d, J = 6.5 Hz). 543 541 34 [00180]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.20 (1H, s), 7.74 (1H, dd, J = 8.5, 2.5 Hz), 7.53 (1H, dd, J = 8.5, 6.0 Hz), 7.35 (1H, td, J = 8.5, 2.5 Hz), 6.56 (1H, d, J = 9.0 Hz), 3.55-3.45 (1H, m), 2.19- 2.08 (2H, m), 1.68-1.60 (1H, m), 1.50-1.12 (8H, m), 1.32 (9H, s), 0.96 (3H, d, J = 6.5 Hz). 498 496 35 [00181]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.20 (1H, s), 8.05 (1H, d, J = 8.4 Hz), 7.74 (1H, dd, J = 8.4, 2.5 Hz), 7.54 (1H, dd, J = 8.4, 6.1 Hz), 7.36 (1H, td, J = 8.4, 2.5 Hz), 4.00-3.92 (1H, m), 2.18- 2.09 (2H, m), 1.65-1.59 (1H, m), 1.51-1.19 (10H, m), 1.16- 1.10 (2H, m), 1.06 (3H, d, J = 6.7 Hz). 484 482 36 [00182]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.20 (1H, s), 7.74 (1H, dd, J = 8.7, 2.5 Hz), 7.54 (1H, dd, J = 8.7, 5.9 Hz), 7.42 (1H, d, J = 8.7 Hz), 7.36 (1H, td, J = 8.7, 2.5 Hz), 6.11 (1H, s), 3.93-3.85 (1H, m), 2.18-2.09 (2H, m), 1.66-1.59 (1H, m), 1.53-1.22 (8H, m), 1.03 (3H, d, J = 6.5 Hz), 0.96 (2H, q, J = 3.8 Hz), 0.77 (2H, q, J = 3.8 Hz). 482 480 37 [00183]![embedded image]()
1H-NMR (CDCl3) ?: 8.19 (1H, br s), 7.41 (1H, dd, J = 8.1, 2.5 Hz), 7.21-7.17 (1H, m), 7.12- 7.07 (1H, m), 6.87 (1H, s), 6.22-6.18 (1H, m), 4.31-4.21 (1H, m), 2.35-2.28 (2H, m), 1.82-1.77 (1H, m), 1.63-1.52 (2H, m), 1.51-1.36 (5H, m), 1.34-1.25 (1H, m), 1.23 (3H, d, J = 6.5 Hz). 527 525 38 [00184]![embedded image]()
Mixture of two diastereomers due to 1,2-positions of cyclopropane ring (relative configuration: trans) 1H-NMR (CDCl3) ?: 8.12-8.08 (1H, m), 7.43-7.40 (1H, m), 7.30-7.24 (2H, m), 7.23-7.16 (2H, m), 7.13-7.02 (3H, m), 5.29-5.23 (1H, m), 4.16-4.07 (1H, m), 2.47-2.40 (1H, m), 2.35-2.26 (2H, m), 1.80-1.75 (1H, m), 1.62-1.38 (7H, m), 1.37-1.17 (4H, m), 1.14-1.10 (3H, m). 542 540 39 [00185]![embedded image]()
Mixture of two diastereomers due to 1,2-positions of cyclopropane ring (relative configuration: cis) 1H-NMR (CDCl3) ?: 8.11 (1H, s), 7.50-7.41 (1H, m), 7.23- 7.09 (5H, m), 7.08-7.03 (1H, m), 6.90-6.86 (1H, m), 4.97- 4.89 (1H, m), 3.89-3.80 (1H, m), 2.44-2.35 (1H, m), 2.27- 2.12 (2H, m), 1.91-1.83 (1H, m), 1.69-1.61 (2H, m), 1.50- 1.00 (9H, m), 0.94-0.74 (3H, m). 542 540 40 [00186]![embedded image]()
1H-NMR (CDCl3) ?: 8.15 (1H, s), 7.74-7.71 (2H, m), 7.51- 7.38 (4H, m), 7.20-7.16 (1H, m), 7.10-7.05 (1H, m), 5.77 (1H, d, J = 9.0 Hz), 4.38-4.28 (1H, m), 2.33-2.27 (2H, m), 1.90-1.85 (1H, m), 1.62-1.52 (3H, m), 1.51-1.38 (4H, m), 1.37-1.28 (1H, m), 1.22 (3H, d, J = 6.5 Hz). 502 500
TABLE-US-00006 TABLE 1-6 41 [00187]![embedded image]()
1H-NMR (CDCl3) ?: 8.11 (1H, s), 7.42 (1H, dd, J = 8.1, 2.5 Hz), 7.23-7.19 (1H, m), 7.14-7.09 (1H, m), 5.74-5.70 (1H, m), 4.15-4.07 (1H, m), 3.33 (2H, s), 2.35-2.29 (2H, m), 1.78-1.73 (1H, m), 1.59-1.52 (2H, m), 1.50-1.37 (4H, m), 1.29-1.21 (2H, m), 1.16 (3H, d, J = 6.5 Hz). 465 463 42 [00188]![embedded image]()
1H-NMR (CDCl3) ?: 8.10 (1H, s), 7.41 (1H, dd, J = 8.1, 2.5 Hz), 7.22-7.18 (1H, m), 7.13-7.07 (1H, m), 5.08-5.02 (1H, m), 4.16-4.08 (1H, m), 2.32-2.27 (2H, m), 2.09 (2H, t, J = 7.5 Hz), 1.84-1.79 (1H, m), 1.67-1.59 (2H, m), 1.57-1.40 (5H, m), 1.33-1.23 (3H, m), 1.10 (3H, d, J = 6.5 Hz), 0.91 (3H, t, J = 7.5 Hz). 468 466 43 [00189]![embedded image]()
1H-NMR (CDCl3) ?: 8.12 (1H, s), 7.42 (1H, dd, J = 8.2, 2.7 Hz), 7.23-7.20 (1H, m), 7.13-7.09 (1H, m), 5.31-5.28 (1H, m), 4.15-4.07 (1H, m), 3.46-3.31 (2H, m), 2.91 (3H, s), 2.69-2.65 (2H, m), 2.33-2.27 (2H, m), 1.77-1.72 (1H, m), 1.56-1.42 (5H, m), 1.36-1.24 (3H, m), 1.12 (3H, d, J = 6.5 Hz). 532 530 44 [00190]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.20 (1H, s), 8.66-8.60 (1H, m), 8.41 (1H, d, J = 9.0 Hz), 7.59 (1H, dd, J = 8.8, 2.5 Hz), 7.53 (1H, dd, J = 8.6, 6.1 Hz), 7.30 (1H, td, J = 6.6, 2.8 Hz), 3.97-3.85 (1H, m), 2.64 (3H, d, J = 5.0 Hz), 2.09 (2H, d, J = 13.0 Hz), 1.70-1.12 (9H, m), 1.05 (3H, d, J = 6.5 Hz). 439 437 45 [00191]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.80 (1H, s), 11.19 (1H, s), 7.63- 7.47 (3H, m), 7.28 (1H, td, J = 8.5, 2.2 Hz), 6.30 (1H, s), 4.14-3.99 (1H, m), 2.29-2.04 (5H, m), 1.79-1.16 (9H, m), 1.07 (3H, d, J = 6.5 Hz). 462 460 46 [00192]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.20 (1H, s), 8.40 (1H, d, J = 8.5 Hz), 7.75 (1H, d, J = 7.8 Hz), 7.63 (1H, d, J = 8.3 Hz), 7.57 (1H, dd, J = 8.8, 2.5 Hz), 7.52 (1H, dd, J = 8.8, 6.0 Hz), 7.49 (1H, d, J = 0.8 Hz), 7.47-7.42 (1H, m), 7.32 (1H, t, J = 7.5 Hz), 7.26 (1H, td, J = 8.5, 2.6 Hz), 4.18-4.08 (1H, m), 2.16- 2.05 (2H, m), 1.75-1.66 (1H, m), 1.63-1.21 (8H, m), 1.13 (3H, d, J = 6.5 Hz). 498 496 47 [00193]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.20 (1H, s), 8.70-8.61 (2H, m), 7.74 (1H, dd, J = 8.0, 2.5 Hz), 7.53 (1H, dd, J = 8.0, 6.6 Hz), 7.36 (1H, td, J = 8.0, 2.5 Hz), 3.18-3.00 (2H, m), 2.64 (3H, d, J = 4.9 Hz), 2.17-2.09 (2H, m), 1.62-1.56 (2H, m), 1.45- 1.33 (4H, m), 1.28-1.20 (3H, m). 469 467 48 [00194]![embedded image]()
1H-NMR (CDCl3) ?: 8.24 (1H, d, J = 1.8 Hz), 8.21 (1H, s), 7.94 (1H, dd, J = 8.1, 1.8 Hz), 7.42 (1H, d, J = 8.1 Hz), 6.86 (1H, s), 6.20-6.17 (1H, m), 4.31-4.22 (1H, m), 3.11 (3H, s), 2.37-2.32 (2H, m), 1.87-1.80 (1H, m), 1.64-1.27 (8H, m), 1.23 (3H, d, J = 6.5 Hz). 587 585
TABLE-US-00007 TABLE 1-7 49 [00195]![embedded image]()
1H-NMR (CDCl3) ?: 8.23 (1H, d, J = 1.8 Hz), 8.18 (1H, s), 7.92 (1H, dd, J = 8.2, 1.8 Hz), 7.73-7.70 (2H, m), 7.52-7.48 (1H, m), 7.45-7.40 (3H, m), 5.78-5.73 (1H, m), 4.38-4.31 (1H, m), 3.10 (3H, s), 2.36-2.30 (2H, m), 1.96-1.90 (1H, m), 1.64-1.49 (2H, m), 1.48-1.26 (6H, m), 1.22 (3H, d, J = 6.7 Hz). 562 560 50 [00196]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.15 (1H, s), 8.43 (1H, d, J = 9.0 Hz), 7.76 (1H, d, J = 7.3 Hz), 7.65 (1H, d, J = 8.6 Hz), 7.59 (2H, d, J = 8.6 Hz), 7.51 (1H, s), 7.46 (1H, t, J = 7.3 Hz), 7.41 (2H, d, J = 8.6 Hz), 7.33 (1H, t, J = 7.3 Hz), 4.19-4.12 (1H, m), 2.04-1.96 (2H, m), 1.74-1.53 (5H, m), 1.47-1.24 (4H, m), 1.16 (3H, d, J = 6.5 Hz). 524 522 51 [00197]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.32 (1H, s), 8.65-8.58 (1H, m), 8.41 (1H, d, J = 9.0 Hz), 8.12 (1H, d, J = 1.8 Hz), 7.93 (1H, dd, J = 8.0, 1.8 Hz), 7.78 (1H, d, J = 8.0 Hz), 3.95-3.85 (1H, m), 3.34 (3H, s), 2.63 (3H, d, J = 4.8 Hz), 2.18-2.08 (2H, m), 1.69-1.61 (1H, m), 1.59-1.14 (8H, m), 1.05 (3H, d, J = 6.5 Hz). 499 497 52 [00198]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.32 (1H, s), 8.77 (1H, d, J = 8.5 Hz), 8.11 (1H, d, J = 1.8 Hz), 7.93 (1H, dd, J = 8.0, 1.8 Hz), 7.78 (1H, d, J = 8.0 Hz), 7.32 (1H, s), 4.12-4.00 (1H, m), 3.33 (3H, s), 2.14 (2H, d, J = 11.3 Hz), 1.66 (1H, d, J = 11.0 Hz), 1.56-1.19 (8H, m), 1.10 (3H, d, J = 6.5 Hz). 543 541 53 [00199]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.32 (1H, s), 8.40 (1H, d, J = 8.5 Hz), 8.09 (1H, d, J = 1.8 Hz), 7.90 (1H, dd, J = 8.0, 1.8 Hz), 7.75 (2H, t, J = 7.5 Hz), 7.62 (1H, d, J = 8.8 Hz), 7.48 (1H, s), 7.44 (1H, t, J = 7.3 Hz), 7.32 (1H, t, J = 7.3 Hz), 4.15 (1H, bs), 3.36 (3H, s), 2.14 (2H, t, J = 11.0 Hz), 1.71 (1H, d, J = 9.0 Hz), 1.60-1.30 (8H, m), 1.13 (3H, d, J = 6.5 Hz). 558 556 54 [00200]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.00 (1H, s), 8.64 (1H, q, J = 4.7 Hz), 8.42 (1H, d, J = 9.8 Hz), 7.21 (1H, dd, J = 8.4, 6.8 Hz), 7.01 (1H, dd, J = 9.8, 2.4 Hz), 6.81 (1H, td, J = 8.4, 2.4 Hz), 3.96-3.86 (1H, m), 3.79 (3H, s), 2.64 (3H, d, J = 4.7 Hz), 2.00-1.93 (2H, m), 1.68-1.60 (1H, m), 1.50-1.38 (4H, m), 1.28-1.13 (4H, m), 1.06 (3H, d, J = 6.8 Hz). 435 433 55 [00201]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.08 (1H, s), 8.62 (1H, q, J = 4.9 Hz), 8.41 (1H, d, J = 9.0 Hz), 7.32 (1H, dd, J = 8.6, 6.0 Hz), 7.17 (1H, dd, J = 10.3, 2.7 Hz), 7.06 (1H, td, J = 8.6, 2.7 Hz), 3.95-3.86 (1H, m), 2.64 (3H, d, J = 4.9 Hz), 2.23 (3H, s), 2.06-1.99 (2H, m), 1.68-1.15 (9H, m), 1.05 (3H, d, J = 6.5 Hz). 419 417 56 [00202]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.26 (1H, s), 8.64 (1H, q, J = 4.9 Hz), 8.43 (1H, d, J = 9.2 Hz), 7.80 (1H, dd, J = 9.2, 2.5 Hz), 7.71 (1H, dd, J = 8.8, 5.3 Hz), 7.65-7.58 (1H, m), 3.97-3.84 (1H, m), 2.65 (3H, d, J = 4.9 Hz), 2.07-1.88 (2H, m), 1.70- 1.60 (1H, m), 1.60-1.14 (8H, m), 1.06 (3H, d, J = 6.5 Hz). 473 471
TABLE-US-00008 TABLE 1-8 57 [00203]![embedded image]()
1H-NMR (CDCl3) ?: 8.24 (1H, s), 7.97 (1H, d, J = 1.6 Hz), 7.68 (1H, dd, J = 7.9, 1.6 Hz), 7.44-7.39 (1H, m), 7.33 (1H, d, J = 7.9 Hz), 7.18-7.14 (1H, m), 4.08-4.00 (1H, m), 2.89 (3H, d, J = 5.3 Hz), 2.34-2.28 (2H, m), 1.79-1.72 (1H, m), 1.60-1.51 (2H, m), 1.50-1.31 (5H, m), 1.30-1.21 (1H, m), 1.16 (3H, d, J = 6.5 Hz). 490 488 58 [00204]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.10 (1H, s), 8.65-8.60 (1H, m), 8.41 (1H, d, J = 9.5 Hz), 7.34 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 2.5 Hz), 7.01 (1H, dd, J = 8.6, 2.5 Hz), 3.95-3.85 (1H, m), 3.81 (3H, s), 2.64 (3H, d, J = 4.9 Hz), 2.14-2.05 (2H, m), 1.68-1.62 (1H, m), 1.56-1.11 (8H, m), 1.05 (3H, d, J = 6.5 Hz). 495 493 59 [00205]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.10 (1H, s), 8.77 (1H, d, J = 8.3 Hz), 7.34 (1H, d, J = 8.6 Hz), 7.32 (1H, s), 7.28 (1H, d, J = 2.5 Hz), 7.00 (1H, dd, J = 8.6, 2.8 Hz), 4.11-4.01 (1H, m), 3.80 (3H, s), 2.15-2.06 (2H, m), 1.69-1.61 (1H, m), 1.55- 1.20 (8H, m), 1.11 (3H, d, J = 6.5 Hz). 539 537 60 [00206]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.21 (1H, s), 8.62 (1H, q, J = 5.2 Hz), 8.41 (1H, d, J = 9.7 Hz), 8.02 (1H, d, J = 1.8 Hz), 7.66 (1H, dd, J = 8.3, 1.8 Hz), 7.41 (1H, d, J = 8.3 Hz), 3.95-3.86 (1H, m), 2.64 (3H, d, J = 5.2 Hz), 2.13-2.06 (2H, m), 1.68- 1.61 (1H, m), 1.53-1.15 (8H, m), 1.05 (3H, d, J = 6.5 Hz). 543 541 61 [00207]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.20 (1H, s), 8.46 (1H, d, J = 8.5 Hz), 7.66 (1H, dd, J = 9.0, 4.3 Hz), 7.57 (2H, dd, J = 8.8, 2.8 Hz), 7.52 (1H, dd, J = 8.6, 6.1 Hz), 7.49 (1H, s), 7.33-7.23 (2H, m), 4.18-4.07 (1H, m), 2.16-2.05 (2H, m), 1.75-1.66 (1H, m), 1.62-1.21 (8H, m), 1.13 (3H, d, J = 6.5 Hz). 516 514 62 [00208]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.07 (1H, s), 11.20 (1H, s), 8.34 (1H, d, J = 8.5 Hz), 8.24 (1H, s), 7.68 (1H, dd, J = 8.8, 1.8 Hz), 7.61-7.55 (2H, m), 7.51 (1H, dd, J = 8.6, 6.1 Hz), 7.33 (1H, d, J = 1.5 Hz), 7.26 (1H, td, J = 8.6, 2.6 Hz), 4.22-4.10 (1H, m), 3.17 (3H, s), 2.15-2.06 (2H, m), 1.77-1.69 (1H, m), 1.59-1.21 (8H, m), 1.15 (3H, d, J = 6.5 Hz). 575 573 63 [00209]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.20 (1H, s), 8.77 (1H, d, J = 8.3 Hz), 7.59 (1H, dd, J = 9.0, 2.5 Hz), 7.53 (1H, dd, J = 8.6, 6.1 Hz), 7.32 (1H, s), 7.29 (1H, td, J = 8.5, 2.5 Hz), 4.12-4.01 (1H, m), 2.10 (2H, d, J = 13.0 Hz), 1.69-1.60 (1H, m), 1.57- 1.20 (8H, m), 1.11 (3H, d, J = 6.8 Hz). 483 481 64 [00210]![embedded image]()
1H-NMR (CDCl3) ?: 8.09 (1H, s), 7.44-7.38 (1H, m), 7.18- 7.13 (1H, m), 7.08-7.04 (1H, m), 6.90-6.85 (1H, m), 6.52 (1H, dd, J = 10.6, 2.5 Hz), 4.08-3.98 (1H, m), 2.89 (3H, d, J = 5.3 Hz), 2.27-2.19 (2H, m), 1.89-1.82 (1H, m), 1.76-1.70 (1H, m), 1.54-1.35 (7H, m), 1.29-1.21 (1H, m), 1.16 (3H, d, J = 6.5 Hz), 1.06-1.02 (2H, m), 0.75-0.71 (2H, m). 445 443
TABLE-US-00009 TABLE 1-9 65 [00211]![embedded image]()
1H-NMR (CDCl3) ?: 8.07 (1H, s), 7.05 (1H, dd, J = 8.6, 5.8 Hz), 6.89-6.84 (2H, m), 6.52 (1H, dd, J = 10.4, 2.5 Hz), 6.20-6.16 (1H, m), 4.30-4.21 (1H, m), 2.28-2.22 (2H, m), 1.89-1.77 (2H, m), 1.60-1.39 (7H, m), 1.35-1.26 (1H, m), 1.23 (3H, d, J = 6.5 Hz), 1.06-1.02 (2H, m), 0.75-0.71 (2H, m). 489 487 66 [00212]![embedded image]()
1H-NMR (CDCl3) ?: 8.21 (1H, s), 8.18 (1H, d, J = 1.7 Hz), 7.88 (1H, dd, J = 8.0, 1.7 Hz), 7.43-7.39 (2H, m), 7.17-7.14 (1H, m), 4.11-4.01 (1H, m), 3.29-3.21 (1H, m), 2.89 (3H, d, J = 5.3 Hz), 2.36-2.29 (2H, m), 1.79-1.74 (1H, m), 1.58- 1.37 (7H, m), 1.35 (6H, d, J = 7.2 Hz), 1.29-1.21 (1H, m), 1.16 (3H, d, J = 6.5 Hz). 571 569 67 [00213]![embedded image]()
1H-NMR (CDCl3) ?: 8.19 (1H, s), 8.17 (1H, d, J = 1.8 Hz), 7.87 (1H, dd, J = 8.0, 1.8 Hz), 7.41 (1H, d, J = 8.0 Hz), 6.86 (1H, s), 6.21-6.17 (1H, m), 4.32-4.22 (1H, m), 3.27-3.20 (1H, m), 2.38-2.31 (2H, m), 1.86-1.77 (1H, m), 1.61-1.39 (7H, m), 1.34 (6H, d, J = 6.9 Hz), 1.29-1.21 (4H, m). 615 613 68 [00214]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.35 (1H, s), 8.68-8.63 (1H, m), 8.44 (1H, d, J = 9.2 Hz), 7.48 (1H, d, J = 1.8 Hz), 6.62 (1H, d, J = 2.1 Hz), 3.97-3.87 (1H, m), 3.81 (3H, s), 2.66 (3H, d, J = 5.1 Hz), 2.03-1.96 (2H, m), 1.77-1.46 (5H, m), 1.37- 1.17 (4H, m), 1.08 (3H, d, J = 6.5 Hz). 391 389 69 [00215]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.19 (1H, s), 8.58 (1H, d, J = 8.3 Hz), 7.72 (1H, dd, J = 8.7, 2.7 Hz), 7.52 (1H, dd, J = 8.6, 6.0 Hz), 7.33 (1H, td, J = 8.5, 2.5 Hz), 6.75 (1H, s), 4.09-3.99 (1H, m), 3.92 (3H, s), 2.16-2.07 (2H, m), 1.69-1.61 (1H, m), 1.55-1.20 (8H, m), 1.09 (3H, d, J = 6.7 Hz). 523 521 70 [00216]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.20 (1H, s), 8.68 (1H, d, J = 5.2 Hz), 8.41 (1H, d, J = 9.0 Hz), 7.60 (1H, dd, J = 8.6, 2.6 Hz), 7.53 (1H, dd, J = 9.0, 6.0 Hz), 7.30 (1H, td, J = 8.4, 2.6 Hz), 3.93-3.85 (1H, m), 2.77-2.70 (1H, m), 2.12-2.04 (2H, m), 1.68-1.61 (1H, m), 1.54-1.16 (8H, m), 1.05 (3H, d, J = 6.7 Hz), 0.64-0.58 (4H, m). 465 463 71 [00217]![embedded image]()
1H-NMR (CDCl3) ?: 8.17 (1H, s), 7.96 (1H, d, J = 1.6 Hz), 7.67 (1H, dd, J = 8.0, 1.6 Hz), 7.33 (1H, d, J = 8.0 Hz), 6.86 (1H, s), 6.19-6.15 (1H, m), 4.30-4.22 (1H, m), 2.35-2.31 (2H, m), 1.85-1.79 (1H, m), 1.60-1.25 (8H, m), 1.23 (3H, d, J = 6.5 Hz). 534 532 72 [00218]![embedded image]()
1H-NMR (DMSO-D6) ?: 14.40-14.28 (1H, m), 11.20 (1H, s), 8.30-8.25 (1H, m), 7.72 (1H, dd, J = 8.7, 2.7 Hz), 7.50 (1H, dd, J = 8.6, 6.0 Hz), 7.32 (1H, td, J = 8.4, 2.5 Hz), 7.26 (1H, s), 4.14-4.03 (1H, m), 2.16-2.07 (2H, m), 1.75-1.67 (1H, m), 1.54-1.21 (8H, m), 1.11 (3H, d, J = 6.5 Hz). 560 558
TABLE-US-00010 TABLE 1-10 73 [00219]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.06 (1H, s), 8.68 (1H, q, J = 5.2 Hz), 8.38 (1H, d, J = 9.0 Hz), 7.78 (2H, d, J = 7.6 Hz), 7.74 (1H, dd, J = 8.1, 2.0 Hz), 7.66 (1H, d, J = 2.0 Hz), 7.51-7.37 (9H, m), 3.90-3.80 (1H, m), 2.67 (3H, d, J = 5.0 Hz), 1.63- 1.07 (11H, m), 1.02 (3H, d, J = 6.7 Hz). 539 537 74 [00220]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.09 (1H, s), 8.63 (1H, q, J = 4.7 Hz), 8.41 (1H, d, J = 9.0 Hz), 7.46-7.36 (2H, m), 7.26-7.15 (2H, m), 3.95-3.85 (1H, m), 2.64 (3H, d, J = 4.7 Hz), 2.43 (3H, s), 2.16-2.07 (2H, m), 1.66-1.60 (1H, m), 1.53-1.37 (3H, m), 1.34-1.13 (5H, m), 1.05 (3H, d, J = 6.5 Hz). 433 431 75 [00221]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.12 (1H, s), 8.64 (1H, q, J = 4.6 Hz), 8.42 (1H, d, J = 8.8 Hz), 8.07 (1H, d, J = 7.8 Hz), 7.82- 7.75 (2H, m), 7.66 (1H, d, J = 7.8 Hz), 3.96-3.86 (1H, m), 3.24 (3H, s), 2.65 (3H, d, J = 4.6 Hz), 2.20-2.09 (2H, m), 1.66-1.45 (4H, m), 1.34-1.17 (5H, m), 1.06 (3H, d, J = 6.7 Hz). 465 463 76 [00222]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.12 (1H, s), 8.78 (1H, d, J = 8.1 Hz), 8.06 (1H, d, J = 7.6 Hz), 7.77 (2H, dt, J = 18.1, 7.5 Hz), 7.65 (1H, d, J = 6.5 Hz), 7.33 (1H, s), 4.07 (1H, s), 3.24 (3H, s), 2.21-2.06 (2H, m), 1.68-1.42 (4H, m), 1.39-1.20 (5H, m), 1.12 (3H, d, J = 6.2 Hz). 509 507 77 [00223]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.32 (1H, s), 8.66-8.59 (1H, m), 8.41 (1H, d, J = 9.3 Hz), 8.06 (1H, d, J = 1.8 Hz), 7.90 (1H, dd, J = 8.0, 1.8 Hz), 7.77 (1H, d, J = 8.0 Hz), 3.96-3.84 (1H, m), 3.45-3.39 (2H, m), 2.63 (3H, d, J = 5.3 Hz), 2.16-2.06 (2H, m), 1.69-1.13 (11H, m), 1.05 (3H, d, J = 6.5 Hz), 0.94 (3H, t, J = 7.5 Hz). 527 525 78 [00224]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.12 (1H, s), 8.78 (1H, d, J = 8.1 Hz), 8.06 (1H, d, J = 7.0 Hz), 7.82-7.72 (2H, m), 7.65 (1H, d, J = 7.0 Hz), 7.33 (1H, s), 4.10-4.02 (1H, m), 3.24 (3H, s), 2.21-2.06 (2H, m), 1.68-1.42 (4H, m), 1.39-1.20 (5H, m), 1.12 (3H, d, J = 6.2 Hz). 509 507 79 [00225]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.09 (1H, s), 8.76 (1H, d, J = 9.0 Hz), 7.45-7.37 (2H, m), 7.32 (1H, s), 7.25-7.18 (2H, m), 4.10-4.03 (1H, m), 2.43 (3H, s), 2.17-2.09 (2H, m), 1.66- 1.61 (1H, m), 1.54-1.21 (8H, m), 1.11 (3H, d, J = 6.5 H). 477 475 80 [00226]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.25 (1H, s), 8.66-8.60 (1H, m), 8.41 (1H, d, J = 9.2 Hz), 7.85-7.83 (1H, m), 7.61 (1H, d, J = 8.3 Hz), 7.51-7.46 (1H, m), 3.95-3.85 (1H, m), 2.64 (3H, d, J = 4.9 Hz), 2.16-2.08 (2H, m), 1.70-1.61 (1H, m), 1.56- 1.16 (8H, m), 1.05 (3H, d, J = 6.5 Hz). 549 547
TABLE-US-00011 TABLE 1-11 81 [00227]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.25 (1H, s), 8.77 (1H, d, J = 8.6 Hz), 7.85-7.83 (1H, m), 7.61 (1H, d, J = 8.6 Hz), 7.50-7.46 (1H, m), 7.33-7.31 (1H, m), 4.11-4.01 (1H, m), 2.18-2.09 (2H, m), 1.70-1.62 (1H, m), 1.57-1.21 (8H, m), 1.11 (3H, d, J = 6.5 Hz). 593 591 82 [00228]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.23 (1H, s), 8.71-8.65 (1H, m), 8.49 (1H, d, J = 9.5 Hz), 7.39 (1H, s), 7.03 (1H, s), 4.01- 3.90 (1H, m), 3.98 (2H, d, J = 7.6 Hz), 2.68 (3H, d, J = 4.9 Hz), 2.37-2.20 (2H, m), 1.93-1.82 (2H, m), 1.73-1.64 (1H, m), 1.62-1.45 (2H, m), 1.37-1.15 (5H, m), 1.09 (3H, d, J = 6.5 Hz), 0.52-0.45 (2H, m), 0.37-0.30 (2H, m). 431 429 83 [00229]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.24 (1H, s), 8.86-8.82 (1H, m), 7.38 (2H, d, J = 9.0 Hz), 7.01 (1H, s), 4.16-4.06 (1H, m), 3.98 (2H, d, J = 7.4 Hz), 2.37-2.22 (2H, m), 1.93-1.84 (2H, m), 1.72-1.65 (1H, m), 1.60-1.50 (2H, m), 1.44-1.17 (5H, m), 1.15 (3H, d, J = 6.9 Hz), 0.51-0.45 (2H, m), 0.37-0.31 (2H, m). 475 473 84 [00230]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.23 (1H, s), 8.47 (1H, d, J = 8.3 Hz), 7.79-7.75 (1H, m), 7.66 (1H, d, J = 8.6 Hz), 7.54 (1H, s), 7.50-7.43 (1H, m), 7.37 (1H, s), 7.34 (1H, t, J = 8.2 Hz), 6.98 (1H, s), 4.24-4.13 (1H, m), 3.97 (2H, d, J = 7.2 Hz), 2.38-2.21 (2H, m), 1.93-1.85 (2H, m), 1.79-1.69 (1H, m), 1.67-1.51 (2H, m), 1.48-1.14 (5H, m), 1.17 (3H, d, J = 6.2 Hz), 0.51-0.44 (2H, m), 0.36-0.29 (2H, m). 490 488 85 [00231]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.12 (1H, s), 8.67-8.59 (1H, m), 8.44-8.39 (1H, m), 7.41-7.35 (2H, m), 7.11-7.07 (1H, m), 6.55-6.23 (1H, m), 4.47-4.36 (2H, m), 3.98-3.82 (1H, m), 2.64 (3H, d, J = 4.9 Hz), 2.14-2.05 (2H, m), 1.71-1.61 (1H, m), 1.59-1.10 (8H, m), 1.05 (3H, d, J = 6.5 Hz). 545 543 86 [00232]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.14 (1H, d, J = 2.3 Hz), 8.65-8.60 (1H, m), 8.41 (1H, d, J = 9.0 Hz), 7.46 (1H, d, J = 2.8 Hz), 7.41 (1H, d, J = 8.1 Hz), 7.14 (1H, dd, J = 8.6, 2.5 Hz), 4.87 (2H, q, J = 8.8 Hz), 3.96-3.85 (1H, m), 2.64 (3H, d, J = 4.6 Hz), 2.15-2.05 (2H, m), 1.70-1.60 (1H, m), 1.58-1.09 (8H, m), 1.05 (3H, d, J = 6.5 Hz). 563 561 87 [00233]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.24 (1H, s), 8.40 (1H, d, J = 9.2 Hz), 7.82 (1H, d, J = 1.8 Hz), 7.74 (1H, d, J = 8.1 Hz), 7.63 (1H, d, J = 8.3 Hz), 7.59 (1H, d, J = 8.6 Hz), 7.49 (1H, d, J = 0.9 Hz), 7.47-7.42 (2H, m), 7.34-7.30 (1H, m), 4.18-4.07 (1H, m), 2.18-2.09 (2H, m), 1.75-1.66 (1H, m), 1.65-1.20 (8H, m), 1.13 (3H, d, J = 6.7 Hz). 608 606 88 [00234]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.09 (1H, s), 8.13 (1H, d, J = 8.3 Hz), 7.56-7.48 (2H, m), 7.36-7.30 (2H, m), 7.18 (1H, dd, J = 10.2, 2.8 Hz), 7.08 (1H, td, J = 8.6, 2.8 Hz), 4.08-4.00 (1H, m), 2.24 (3H, s), 2.10-2.02 (2H, m), 1.70-1.63 (1H, m), 1.56-1.23 (8H, m), 1.09 (3H, d, J = 6.5 Hz). 490 488
TABLE-US-00012 TABLE 1-12 89 [00235]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.08 (1H, s), 8.66 (1H, d, J = 2.3 Hz), 8.45 (1H, d, J = 9.2 Hz), 8.09 (1H, dd, J = 8.6, 2.3 Hz), 8.01 (1H, d, J = 8.6 Hz), 7.30 (1H, dd, J = 8.4, 5.9 Hz), 7.16 (1H, dd, J = 10.2, 2.5 Hz), 7.03 (1H, td, J = 8.4, 2.5 Hz), 4.16-4.07 (1H, m), 2.22 (3H, s), 2.08-1.98 (2H, m), 1.72-1.21 (9H, m), 1.13 (3H, d, J = 6.7 Hz). 473 471 90 [00236]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.26 (1H, s), 8.66-8.59 (1H, m), 8.35 (1H, d, J = 8.8 Hz), 7.62 (1H, dd, J = 9.0, 2.5 Hz), 7.56 (1H, dd, J = 8.6, 6.1 Hz), 7.33 (1H, td, J = 8.6, 2.6 Hz), 3.98-3.86 (1H, m), 2.74-2.59 (2H, m), 2.64 (3H, d, J = 5.0 Hz), 2.42 (1H, dd, J = 12.5, 8.3 Hz), 2.35-2.18 (3H, m), 2.10-2.00 (2H, m), 1.63-1.46 (2H, m), 1.04 (3H, d, J = 6.5 Hz). 440 438 91 [00237]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.25 (1H, s), 8.39 (1H, d, J = 8.3 Hz), 7.65 (1H, dd, J = 9.1, 4.1 Hz), 7.59 (1H, d, J = 2.5 Hz), 7.56 (1H, d, J = 2.5 Hz), 7.52 (1H, dd, J = 8.6, 5.9 Hz), 7.45 (1H, s), 7.31 (1H, td, J = 8.6, 2.7 Hz), 7.26 (1H, td, J = 8.6, 2.5 Hz), 4.20-4.09 (1H, m), 2.77-2.64 (2H, m), 2.49-2.43 (1H, m), 2.37-2.25 (3H, m), 2.06 (2H, d, J = 14.3 Hz), 1.61-1.48 (2H, m), 1.11 (3H, d, J = 6.8 Hz). 517 515 92 [00238]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.26 (1H, s), 8.72 (1H, d, J = 8.5 Hz), 7.61 (1H, dd, J = 9.0, 2.5 Hz), 7.54 (1H, dd, J = 8.6, 6.1 Hz), 7.34-7.28 (1H, m), 7.28 (1H, s), 4.14-4.04 (1H, m), 2.76-2.61 (2H, m), 2.42 (1H, dd, J = 12.5, 8.0 Hz), 2.37-2.23 (3H, m), 2.09-2.00 (2H, m), 1.60-1.48 (2H, m), 1.09 (3H, d, J = 6.8 Hz). 484 482 93 [00239]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.80 (1H, s), 11.25 (1H, s), 7.66- 7.50 (3H, m), 7.31 (1H, td, J = 8.5, 2.6 Hz), 6.28 (1H, s), 4.12-4.01 (1H, m), 2.75-2.61 (2H, m), 2.46-2.38 (1H, m), 2.35-2.14 (6H, m), 2.10-2.01 (2H, m), 1.63-1.49 (2H, m), 1.07 (3H, d, J = 6.5 Hz). 463 461 94 [00240]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.26 (1H, s), 8.41 (1H, s), 8.10 (1H, d, J = 8.5 Hz), 7.61 (1H, dd, J = 8.8, 2.5 Hz), 7.54 (1H, dd, J = 8.5, 6.0 Hz), 7.31 (1H, td, J = 8.5, 2.6 Hz), 4.16-4.01 (1H, m), 4.07 (3H, s), 2.75-2.65 (2H, m), 2.49- 2.42 (1H, m), 2.35-2.23 (3H, m), 2.10-2.00 (2H, m), 1.64- 1.48 (2H, m), 1.09 (3H, d, J = 6.5 Hz). 464 462 95 [00241]![embedded image]()
1H-NMR (DMSO-D6) ?: 14.62 (1H, br s), 11.26 (1H, s), 8.46-8.09 (1H, m), 7.95 (1H, s), 7.60 (1H, dd, J = 8.8, 2.5 Hz), 7.54 (1H, dd, J = 8.8, 6.0 Hz), 7.31 (1H, td, J = 8.8, 2.5 Hz), 4.17-4.04 (1H, m), 2.77-2.61 (2H, m), 2.54-2.43 (1H, m), 2.37-2.21 (3H, m), 2.10-2.00 (2H, m), 1.65-1.48 (2H, m), 1.10 (3H, d, J = 6.5 Hz). 450 448 96 [00242]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.14 (1H, s), 8.63 (1H, q, J = 4.7 Hz), 8.41 (1H, d, J = 9.7 Hz), 7.78 (1H, s), 7.50 (1H, d, J = 8.2 Hz), 7.36 (1H, d, J = 8.2 Hz), 5.23 (1H, s), 3.97-3.83 (1H, m), 2.64 (3H, d, J = 4.7 Hz), 2.19-2.05 (2H, m), 1.72- 1.61 (1H, m), 1.56-1.14 (8H, m), 1.43 (6H, s), 1.05 (3H, d, H = 6.7 Hz). 523 521
TABLE-US-00013 TABLE 1-13 97 [00243]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.14 (1H, s), 8.76 (1H, d, J = 9.0 Hz), 7.78 (1H, s), 7.49 (1H, d, J = 8.2 Hz), 7.35 (1H, d, J = 8.2 Hz), 7.32 (1H, s), 5.22 (1H, s), 4.11-3.99 (1H, m), 2.19- 2.07 (2H, m), 1.71-1.60 (1H, m), 1.57-1.20 (8H, m), 1.42 (6H, s), 1.11 (3H, d, J = 6.7 Hz). 567 565 98 [00244]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.25 (1H, s), 8.30 (1H, d, J = 8.5 Hz), 7.62 (1H, dd, J = 9.0, 2.5 Hz), 7.55 (1H, dd, J = 8.6, 6.1 Hz), 7.32 (1H, td, J = 8.5, 2.5 Hz), 6.42 (1H, s), 4.14-4.03 (1H, m), 2.74-2.61 (2H, m), 2.47-2.38 (1H, m), 2.44 (3H, s), 2.36-2.23 (3H, m), 2.10-2.00 (2H, m), 1.62-1.47 (2H, m), 1.07 (3H, d, J = 6.8 Hz). 464 462 99 [00245]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.51 (1H, s), 9.12-9.07 (1H, m), 7.83 (1H, s), 7.72-7.58 (2H, m), 7.45-7.36 (1H, m), 4.56- 4.32 (1H, m), 2.55-2.24 (6H, m), 2.12-1.81 (2H, m), 1.67- 1.43 (2H, m), 1.21 (3H, d, J = 6.5 Hz). 520 (M + 3) 516 100 [00246]![embedded image]()
1H-NMR (DMSO-D6) ?: 14.36 (1H, s), 11.26 (1H, s), 8.26 (1H, d, J = 8.0 Hz), 7.60 (1H, dd, J = 8.8, 2.5 Hz), 7.52 (1H, dd, J = 8.6, 6.1 Hz), 7.29 (1H, td, J = 8.6, 2.6 Hz), 7.23 (1H, s), 4.16-4.06 (1H, m), 2.78-2.64 (2H, m), 2.41 (1H, dd, J = 12.4, 7.6 Hz), 2.36-2.25 (3H, m), 2.05 (2H, d, J = 13.5 Hz), 1.62-1.50 (2H, m), 1.10 (3H, d, J = 6.5 Hz). 517 515 101 [00247]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.08 (1H, s), 7.34-7.24 (5H, m), 7.16 (1H, dd, J = 10.3, 2.7 Hz), 7.04 (1H, td, J = 8.5, 2.5 Hz), 5.88 (1H, d, J = 8.3 Hz), 4.60-4.50 (4H, m), 3.84-3.75 (1H, m), 2.23 (3H, s), 2.09-2.00 (2H, m), 1.69-1.61 (1H, m), 1.55-1.17 (8H, m), 1.04 (3H, d, J = 6.5 Hz). 479 477 102 [00248]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.17 (1H, s), 8.62 (1H, q, J = 4.5 Hz), 8.51 (1H, d, J = 5.2 Hz), 8.41 (1H, d, J = 9.0 Hz), 7.73 (1H, d, J = 7.5 Hz), 7.28 (1H, dd, J = 7.5, 5.2 Hz), 3.97-3.83 (1H, m), 2.64 (3H, d, J = 4.5 Hz), 2.41 (3H, s), 2.14-2.01 (2H, m), 1.71-1.60 (1H, m), 1.58-1.40 (3H, m), 1.40-1.15 (5H, m), 1.05 (3H, d, J = 6.7 Hz). 402 400 103 [00249]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.17 (1H, s), 8.77 (1H, d, J = 8.2 Hz), 8.50 (1H, d, J = 4.5 Hz), 7.72 (1H, d, J = 7.5 Hz), 7.32 (1H, s), 7.27 (1H, dd, J = 7.5, 4.5 Hz), 4.12-4.00 (1H, m), 2.41 (3H, s), 2.14-2.03 (2H, m), 1.71-1.61 (1H, m), 1.56- 1.21 (8H, m), 1.11 (3H, d, J = 6.0 Hz). 446 444 104 [00250]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.17 (1H, s), 8.48 (1H, d, J = 3.0 Hz), 8.40 (1H, d, J = 9.0 Hz), 7.74 (1H, d, J = 8.2 Hz), 7.71 (1H, dd, J = 8.2, 1.5 Hz), 7.63 (1H, d, J = 8.2 Hz), 7.49 (1H, s), 7.45 (1H, t, J = 7.5 Hz), 7.32 (1H, t, J = 7.5 Hz), 7.24 (1H, dd, J = 7.9, 4.9 Hz), 4.19-4.07 (1H, m), 2.41 (3H, s), 2.14-2.01 (2H, m), 1.75-1.66 (1H, m), 1.63-1.21 (8H, m), 1.13 (3H, d, J = 6.7 Hz). 461 459
TABLE-US-00014 TABLE 1-14 105 [00251]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.22 (1H, s), 8.63 (1H, q, J = 4.5 Hz), 8.42 (1H, d, J = 9.7 Hz), 7.64-7.58 (1H, m), 7.55-7.43 (3H, m), 3.97-3.83 (1H, m), 2.64 (3H, d, J = 4.5 Hz), 2.07- 1.96 (2H, m), 1.71-1.58 (1H, m), 1.58-1.14 (8H, m), 1.05 (3H, d, J = 6.7 Hz). 471 469 106 [00252]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.03 (1H, s), 8.70-8.65 (1H, m), 8.44 (1H, d, J = 9.0 Hz), 7.31 (1H, d, J = 6.9 Hz), 7.03 (1H, d, J = 7.6 Hz), 6.87 (1H, t, J = 7.5 Hz), 4.57-4.49 (2H, m), 4.00-3.87 (1H, m), 3.21 (2H, t, J = 8.4 Hz), 2.66 (3H, d, J = 4.9 Hz), 1.99-1.87 (2H, m), 1.79-1.42 (5H, m), 1.35- 1.14 (4H, m), 1.07 (3H, d, J = 6.7 Hz). 429 427 107 [00253]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.87-12.77 (1H, m), 11.02 (1H, s), 7.65-7.57 (1H, m), 7.31-7.27 (1H, m), 7.03-7.00 (1H, m), 6.85 (1H, t, J = 7.5 Hz), 6.35-6.29 (1H, m), 4.53-4.39 (2H, m), 4.13-4.02 (1H, m), 3.18 (2H, t, J = 8.7 Hz), 2.29- 2.16 (3H, m), 1.98-1.87 (2H, m), 1.76-1.43 (5H, m), 1.33- 1.17 (4H, m), 1.09 (3H, d, J = 6.5 Hz). 452 450 108 [00254]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.03 (1H, s), 8.80 (1H, d, J = 9.0 Hz), 7.35 (1H, s), 7.30 (1H, d, J = 7.4 Hz), 7.02 (1H, d, J = 7.4 Hz), 6.86 (1H, t, J = 7.5 Hz), 4.57-4.43 (2H, m), 4.13- 4.01 (1H, m), 3.20 (2H, t, J = 8.7 Hz), 1.99-1.90 (2H, m), 1.77-1.44 (5H, m), 1.37-1.16 (4H, m), 1.13 (3H, d, J = 6.5 Hz). 473 471 109 [00255]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.30 (1H, s), 8.33 (1H, d, J = 1.4 Hz), 7.92 (1H, dd, J = 7.9, 1.6 Hz), 7.67 (1H, d, J = 7.9 Hz), 7.32-7.25 (4H, m), 5.88 (1H, d, J = 8.1 Hz), 4.61-4.47 (4H, m), 3.86-3.75 (1H, m), 2.20-2.10 (2H, m), 1.73-1.60 (1H, m), 1.58-1.13 (8H, m), 1.04 (3H, d, J = 6.5 Hz). 550 548 110 [00256]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.80 (1H, s), 11.22 (1H, s), 7.63- 7.56 (2H, m), 7.53-7.49 (1H, m), 7.49-7.42 (2H, m), 6.30 (1H, s), 4.12-3.99 (1H, m), 2.23 (3H, s), 2.08-1.96 (2H, m), 1.74-1.62 (1H, m), 1.58-1.18 (8H, m), 1.07 (3H, d, J = 6.7 Hz). 494 492 111 [00257]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.22 (1H, s), 8.77 (1H, d, J = 8.2 Hz), 7.65-7.56 (1H, m), 7.55-7.42 (3H, m), 7.32 (1H, s), 4.13-3.99 (1H, m), 2.10-1.97 (2H, m), 1.71-1.61 (1H, m), 1.57-1.20 (8H, m), 1.11 (3H, d, J = 6.7 Hz). 515 513 112 [00258]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.20 (1H, s), 8.62 (1H, q, J = 4.5 Hz), 8.51-8.44 (2H, m), 8.41 (1H, d, J = 9.0 Hz), 7.35 (1H, d, J = 5.2 Hz), 3.98-3.83 (1H, m), 2.64 (3H, d, J = 4.5 Hz), 2.25 (3H, s), 2.13-2.00 (2H, m), 1.72-1.60 (1H, m), 1.58- 1.42 (3H, m), 1.42-1.17 (5H, m), 1.06 (3H, d, J = 6.0 Hz). 402 400
TABLE-US-00015 TABLE 1-15 113 [00259]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.21 (1H, s), 8.77 (1H, d, J = 8.2 Hz), 8.47 (1H, d, J = 5.2 Hz), 8.45 (1H, s), 7.35 (1H, d, J = 5.2 Hz), 7.32 (1H, s), 4.13-3.99 (1H, m), 2.25 (3H, s), 2.14-2.00 (2H, m), 1.71-1.59 (1H, m), 1.57-1.20 (8H, m), 1.11 (3H, d, J = 6.7 Hz). 446 444 114 [00260]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.21 (1H, s), 8.49-8.37 (3H, m), 7.74 (1H, d, J = 8.2 Hz), 7.63 (1H, d, J = 8.2 Hz), 7.49 (1H, s), 7.44 (1H, t, J = 7.9 Hz), 7.37-7.28 (2H, m), 4.21-4.05 (1H, m), 2.24 (3H, s), 2.15-2.02 (2H, m), 1.79-1.65 (1H, m), 1.65-1.20 (8H, m), 1.13 (3H, d, J = 6.7 Hz). 461 459 115 [00261]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.21 (1H, s), 8.40 (1H, d, J = 8.5 Hz), 7.66 (1H, dd, J = 9.0, 4.0 Hz), 7.58 (1H, dd, J = 8.6, 2.9 Hz), 7.46 (1H, s), 7.40 (1H, d, J = 1.8 Hz), 7.34 (1H, d, J = 8.3 Hz), 7.29 (1H, dd, J = 9.1, 2.9 Hz), 7.22 (1H, dd, J = 8.1, 1.9 Hz), 4.20-4.08 (1H, m), 3.32 (3H, s), 2.78-2.65 (2H, m), 2.49-2.41 (1H, m), 2.37-2.24 (3H, m), 2.09-1.99 (2H, m), 1.64-1.49 (2H, m), 1.11 (3H, d, J = 6.5 Hz). 545 543 116 [00262]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.37 (1H, s), 8.40 (1H, d, J = 8.5 Hz), 8.12 (1H, d, J = 1.8 Hz), 7.93 (1H, dd, J = 8.3, 1.8 Hz), 7.79 (1H, d, J = 7.8 Hz), 7.68- 7.63 (1H, m), 7.60-7.55 (1H, m), 7.44 (1H, s), 7.33-7.26 (1H, m), 4.19-4.08 (1H, m), 3.32 (3H, s), 2.80-2.65 (3H, m), 2.38-2.25 (3H, m), 2.15-2.05 (2H, m), 1.66-1.51 (2H, m), 1.11 (3H, d, J = 6.5 Hz). 577 575 117 [00263]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.32 (1H, s), 8.46 (1H, d, J = 8.8 Hz), 8.09 (1H, d, J = 1.8 Hz), 7.90 (1H, dd, J = 8.0, 1.8 Hz), 7.76 (1H, d, J = 8.0 Hz), 7.66 (1H, dd, J = 9.1, 4.1 Hz), 7.57 (1H, dd, J = 8.8, 2.5 Hz), 7.48 (1H, s), 7.29 (1H, td, J = 9.1, 2.7 Hz), 4.18-4.06 (1H, m), 3.31 (3H, s), 2.14 (2H, t, J = 9.9 Hz), 1.75-1.67 (1H, m), 1.62-1.21 (8H, m), 1.12 (3H, d, J = 6.5 Hz). 576 574 118 [00264]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.35 (1H, s), 8.63 (1H, q, J = 4.9 Hz), 8.44 (1H, d, J = 9.2 Hz), 7.51 (1H, dd, J = 6.2, 3.0 Hz), 7.31-7.25 (2H, m), 3.99-3.88 (1H, m), 2.65 (3H, d, J = 4.9 Hz), 2.07-1.98 (2H, m), 1.74-1.46 (5H, m), 1.36-1.18 (4H, m), 1.07 (3H, d, J = 6.5 Hz). 467 465 119 [00265]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.05 (1H, s), 8.63 (1H, q, J = 4.5 Hz), 8.41 (1H, d, J = 9.0 Hz), 7.38-7.18 (4H, m), 3.98- 3.82 (1H, m), 2.64 (3H, d, J = 4.5 Hz), 2.22 (3H, s), 2.10-1.97 (2H, m), 1.70- 1.60 (1H, m), 1.58-1.38 (3H, m), 1.38- 1.15 (5H, m), 1.05 (3H, d, J = 6.7 Hz). 401 399 120 [00266]![embedded image]()
Mixture (4:1) of two stereoisomers due to 1,4- posistions of cyclohexane ring (cis form is presumed to be major.) 1H-NMR (DMSO-D6) ?: 11.37 (0.2H, s), 11.34 (0.8H, s), 8.91 (0.2H, s), 8.88 (0.8H, s), 8.68-8.58 (2H, m), 8.47-8.43 (0.2H, m), 8.41 (0.8H, d, J = 9.0 Hz), 7.62 (0.2H, d, J = 4.5 Hz), 7.55 (0.8H, d, J = 5.2 Hz), 3.97-3.83 (0.8H, m), 3.82-3.70 (0.2H, m), 2.67-2.65 (0.6H, m), 2.64 (2.4H, d, J = 4.5 Hz), 2.18- 2.06 (1.6H, m), 1.91-1.82 (0.4H, m), 1.79-1.13 (9H, m), 1.05 (2.4H, d, J = 6.7 Hz), 1.05-1.01 (0.6H, m). 466 464
TABLE-US-00016 TABLE 1-16 121 [00267]![embedded image]()
Mixture (4:1) of two stereoisomers due to 1,4- posistions of cyclohexane ring (cis form is presumed to be major.) 1H-NMR (DMSO-D6) ?: 11.38 (0.2H, s), 11.35 (0.8H, s), 8.91 (0.2H, s), 8.88 (0.8H, s), 8.81-8.78 (0.2H, m), 8.77 (0.8H, d, J = 9.0 Hz), 8.66 (0.2H, d, J = 5.2 Hz), 8.62 (0.8H, d, J = 5.2 Hz), 7.62 (0.2H, d, J = 4.5 Hz), 7.55 (0.8H, d, J = 5.2 Hz), 7.32 (1H, s), 4.13-3.99 (0.8H, m), 3.99-3.85 (0.2H, m), 2.22-2.04 (1.6H, m), 1.93-1.84 (0.4H, m), 1.81-1.59 (2H, m), 1.58-1.19 (7H, m), 1.11 (2.4H, d, J = 6.0 Hz), 1.10-1.07 (0.6H, m). 510 508 122 [00268]![embedded image]()
Mixture (4:1) of two stereoisomers due to 1,4- posistions of cyclohexane ring (cis form is presumed to be major.) 1H-NMR (DMSO-D6) ?: 11.37 (0.2H, s), 11.34 (0.8H, s), 8.91 (0.2H, s), 8.85 (0.8H, s), 8.66 (0.2H, d, J = 4.5 Hz), 8.58 (0.8H, d, J = 5.2 Hz), 8.44-8.41 (0.2H, m), 8.41 (0.8H, d, J = 8.2 Hz), 7.78-7.75 (0.2H, m), 7.74 (0.8H, d, J = 6.7 Hz), 7.66-7.60 (1.2H, m), 7.54 (0.8H, d, J = 5.2 Hz), 7.51- 7.41 (2H, m), 7.36-7.29 (1H, m), 4.21-4.06 (0.8H, m), 4.06-3.93 (0.2H, m), 2.19-2.07 (1.6H, m), 1.94-1.84 (0.4H, m), 1.82-1.66 (2H, m), 1.62-1.20 (7H, m), 1.13 (2.4H, d, J = 6.7 Hz), 1.13-1.09 (0.6H, m). 525 523 123 [00269]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.20 (1H, s), 7.73 (1H, dd, J = 8.2, 2.2 Hz), 7.53 (1H, dd, J = 8.6, 5.6 Hz), 7.42 (1H, d, J = 9.0 Hz), 7.35 (1H, td, J = 8.6, 2.2 Hz), 6.66 (1H, s), 4.69 (1H, d, J = 6.0 Hz), 4.65 (1H, d, J = 6.0 Hz), 4.39 (2H, d, J = 6.0 Hz), 3.98-3.85 (1H, m), 2.17-2.07 (2H, m), 1.68-1.57 (1H, m), 1.53- 1.14 (8H, m), 1.01 (3H, d, J = 6.7 Hz). 498 496 124 [00270]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.20 (1H, s), 7.74 (1H, dd, J = 8.6, 2.6 Hz), 7.52 (1H, dd, J = 9.0, 6.0 Hz), 7.45 (1H, d, J = 9.0 Hz), 7.35 (1H, td, J = 8.6, 2.6 Hz), 4.63 (1H, d, J = 6.0 Hz), 4.59 (1H, d, J = 6.0 Hz), 4.31 (1H, d, J = 6.0 Hz), 4.30 (1H, d, J = 6.0 Hz), 3.97- 3.84 (1H, m), 2.99-2.81 (1H, m), 2.18-2.08 (2H, m), 2.05 (3H, s), 1.66-1.57 (1H, m), 1.54-1.16 (8H, m), 1.01 (3H, d, J = 6.0 Hz). 511 509 125 [00271]![embedded image]()
Mixture (4:1) of two stereoisomers due to 1,4- posistions of cyclohexane ring (cis form is presumed to be major.) 1H-NMR (DMSO-D6) ?: 11.28-11.19 (1H, m), 8.69-8.51 (2H, m), 8.51-8.37 (2H, m), 7.40-7.36 (0.2H, m), 7.36-7.31 (0.8H, m), 3.99-3.83 (0.8H, m), 3.83-3.70 (0.2H, m), 2.71-2.60 (3H, m), 2.23 (3H, s), 2.12-2.00 (1.6H, m), 1.89-1.17 (9.4H, m), 1.08-1.02 (3H, m). 402 400 126 [00272]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.02 (1H, s), 8.63 (1H, q, J = 4.5 Hz), 8.41 (1H, d, J = 9.0 Hz), 7.17 (1H, d, J = 7.5 Hz), 7.12 (1H, d, J = 7.5 Hz), 7.04 (1H, s), 3.98-3.83 (1H, m), 2.64 (3H, d, J = 4.5 Hz), 2.28 (3H, s), 2.16 (3H, s), 2.09-1.98 (2H, m), 1.71-1.58 (1H, m), 1.58- 1.39 (3H, m), 1.39-1.14 (5H, m), 1.06 (3H, d, J = 6.7 Hz). 415 413 127 [00273]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.80 (1H, s), 11.21 (1H, s), 7.61-7.53 (1H, m), 7.42 (1H, d, J = 1.8 Hz), 7.36 (1H, d, J = 8.3 Hz), 7.27 (1H, dd, J = 8.4, 1.9 Hz), 6.29 (1H, s), 4.12-3.99 (1H, m), 2.76-2.64 (2H, m), 2.53 (3H, s), 2.47- 2.37 (1H, m), 2.34-2.18 (6H, m), 2.09-2.00 (2H, m), 1.64-1.49 (2H, m), 1.07 (3H, d, J = 6.5 Hz). 491 489 128 [00274]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.80 (1H, s), 11.38 (1H, s), 8.13 (1H, d, J = 1.8 Hz), 7.95 (1H, dd, J = 8.0, 1.8 Hz), 7.80 (1H, d, J = 8.0 Hz), 7.30- 7.20 (1H, m), 6.29 (1H, s), 4.11-3.99 (1H, m), 3.34 (3H, s), 2.81-2.65 (2H, m), 2.48-2.40 (1H, m), 2.35-2.19 (6H, m), 2.13-2.05 (2H, m), 1.64- 1.50 (2H, m), 1.06 (3H, d, J = 6.5 Hz). 523 521
TABLE-US-00017 TABLE 1-17 129 [00275]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.02 (1H, s), 8.65-8.57 (1H, m), 8.40 (1H, d, J = 8.8 Hz), 7.22 (1H, d, J = 6.9 Hz), 7.13 (1H, t, J = 7.6 Hz), 7.05 (1H, d, J = 7.9 Hz), 3.97-3.83 (1H, m), 2.63 (3H, d, J = 4.9 Hz), 2.26 (3H, s), 2.11 (3H, s), 2.08-1.97 (2H, m), 1.68-1.60 (1H, m), 1.57-1.10 (8H, m), 1.05 (3H, d, J = 6.7 Hz). 415 413 130 [00276]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.10 (1H, s), 8.63 (1H, q, J = 4.9 Hz), 8.41 (1H, d, J = 8.8 Hz), 7.32 (1H, d, J = 8.8 Hz), 7.28 (1H, d, J = 2.5 Hz), 7.01 (1H, dd, J = 8.8, 2.5 Hz), 4.64 (1H, s), 3.95-3.86 (1H, m), 3.77 (2H, s), 2.64 (3H, d, J = 4.9 Hz), 2.13-2.05 (2H, m), 1.66-1.14 (9H, m), 1.19 (6H, s), 1.05 (3H, d, J = 6.5 Hz). 553 551 131 [00277]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.10 (1H, s), 8.77 (1H, d, J = 8.3 Hz), 7.33 (1H, s), 7.32 (1H, d, J = 8.3 Hz), 7.27 (1H, d, J = 2.5 Hz), 7.00 (1H, dd, J = 8.3, 2.5 Hz), 4.63 (1H, s), 4.10- 4.02 (1H, m), 3.76 (2H, s), 2.15-2.07 (2H, m), 1.68-1.62 (1H, m), 1.53-1.22 (8H, m), 1.19 (6H, s), 1.11 (3H, d, J = 6.5 Hz). 597 595 132 [00278]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.10 (1H, s), 8.40 (1H, d, J = 8.8 Hz), 7.75 (1H, d, J = 7.9 Hz), 7.63 (1H, d, J = 8.8 Hz), 7.49 (1H, s), 7.45 (1H, t, J = 8.3 Hz), 7.34-7.29 (2H, m), 7.25 (1H, d, J = 2.5 Hz), 6.97 (1H, dd, J = 8.3, 2.5 Hz), 4.61 (1H, s), 4.18-4.09 (1H, m), 3.74 (2H, s), 2.15-2.05 (2H, m), 1.74-1.66 (1H, m), 1.57-1.25 (8H, m), 1.17 (6H, s), 1.13 (3H, d, J = 6.5 Hz). 612 610 133 [00279]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.10 (1H, s), 8.62 (1H, q, J = 4.8 Hz), 8.41 (1H, d, J = 9.0 Hz), 7.30-7.25 (2H, m), 7.06 (1H, td, J = 8.5, 2.5 Hz), 3.95-3.85 (1H, m), 2.87-2.80 (1H, m), 2.64 (3H, d, J = 4.8 Hz), 2.05-1.93 (2H, m), 1.67-1.60 (1H, m), 1.52-1.18 (8H, m), 1.16 (6H, d, J = 6.5 Hz), 1.05 (3H, d, J = 6.5 Hz). 447 445 134 [00280]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.10 (1H, s), 8.77 (1H, d, J = 8.6 Hz), 7.32 (1H, s), 7.29-7.25 (2H, m), 7.05 (1H, td, J = 8.6, 2.5 Hz), 4.09-4.00 (1H, m), 2.87-2.80 (1H, m), 2.08-1.95 (2H, m), 1.68-1.61 (1H, m), 1.53-1.21 (8H, m), 1.16 (6H, d, J = 6.7 Hz), 1.11 (3H, d, J = 6.7 Hz). 491 489 135 [00281]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.18 (1H, s), 8.63 (1H, q, J = 4.7 Hz), 8.42 (1H, d, J = 9.0 Hz), 7.41 (1H, dd, J = 8.6, 5.6 Hz), 7.36 (1H, dd, J = 10.1, 2.6 Hz), 7.15 (1H, td, J = 8.6, 2.6 Hz), 3.97-3.84 (1H, m), 2.79-2.70 (2H, m), 2.64 (3H, d, J = 5.2 Hz), 2.61-2.52 (2H, m), 2.08-1.94 (2H, m), 1.71- 1.58 (1H, m), 1.58-1.17 (8H, m), 1.06 (3H, d, J = 6.7 Hz). 501 499 136 [00282]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.08 (1H, s), 7.33 (1H, dd, J = 8.6, 6.0 Hz), 7.18 (1H, dd, J = 10.2, 2.5 Hz), 7.07 (1H, td, J = 8.6, 2.5 Hz), 5.55 (1H, d, J = 8.3 Hz), 3.77-3.68 (1H, m), 3.18-3.11 (4H, m), 2.24 (3H, s), 2.08-2.00 (2H, m), 1.79-1.71 (4H, m), 1.65-1.58 (1H, m), 1.53-1.11 (8H, m), 0.99 (3H, d, J = 6.5 Hz). 431 429
TABLE-US-00018 TABLE 1-18 137 [00283]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.09 (1H, s), 7.36-7.17 (7H, m), 7.07 (1H, td, J = 8.6, 2.8 Hz), 5.66 (1H, d, J = 8.6 Hz), 3.80- 3.71 (1H, m), 3.67-3.61 (1H, m), 3.44-3.12 (4H, m), 2.24 (3H, s), 2.22-2.14 (1H, m), 2.09-2.02 (2H, m), 1.96-1.84 (1H, m), 1.67-1.60 (1H, m), 1.33 (8H, d, J = 158.6 Hz), 1.00 (3H, d, J = 6.5 Hz). 507 505 138 [00284]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.09 (1H, s), 7.36-7.16 (7H, m), 7.07 (1H, td, J = 8.5, 2.9 Hz), 5.67 (1H, d, J = 8.6 Hz), 3.80- 3.71 (1H, m), 3.67 (1H, dd, J = 9.8, 7.5 Hz), 3.47-3.40 (1H, m), 3.37-3.18 (2H, m), 3.14-3.08 (1H, m), 2.24 (3H, s), 2.22-2.13 (1H, m), 2.09-2.01 (2H, m), 1.96-1.84 (1H, m), 1.67-1.60 (1H, m), 1.53-1.13 (8H, m), 1.00 (3H, d, J = 6.5 Hz). 507 505 139 [00285]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.19 (1H, s), 8.67-8.60 (1H, m), 8.42 (1H, d, J = 9.5 Hz), 7.86 (1H, dd, J = 8.6, 2.5 Hz), 7.44 (1H, dd, J = 8.6, 5.8 Hz), 7.33 (1H, td, J = 8.4, 2.8 Hz), 3.97-3.83 (1H, m), 2.64 (3H, d, J = 4.9 Hz), 2.17-2.07 (2H, m), 1.70-1.59 (1H, m), 1.59-1.13 (8H, m), 1.05 (3H, d, J = 6.7 Hz). 531 529 140 [00286]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.20 (1H, s), 8.63 (1H, d, J = 5.1 Hz), 8.41 (1H, d, J = 9.0 Hz), 7.60 (1H, d, J = 2.3 Hz), 7.52 (1H, d, J = 8.6 Hz), 7.36 (1H, t, J = 74.3 Hz), 7.27 (1H, dd, J = 8.4, 2.4 Hz), 3.97-3.82 (1H, m), 2.64 (3H, d, J = 4.9 Hz), 2.15-2.07 (2H, m), 1.70-1.59 (1H, m), 1.59-1.13 (8H, m), 1.05 (3H, d, J = 6.7 Hz). 531 529 141 [00287]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.20 (1H, s), 7.61 (1H, d, J = 2.5 Hz), 7.57-7.53 (1H, m), 7.54 (1H, d, J = 8.6 Hz), 7.37 (1H, t, J = 74.0 Hz), 7.28 (1H, dd, J = 8.2, 2.4 Hz), 3.88-3.78 (1H, m), 2.19-2.06 (2H, m), 1.73 (3H, s), 1.67-1.59 (1H, m), 1.56-1.14 (8H, m), 0.97 (3H, d, J = 6.7 Hz). 488 486 142 [00288]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.51 (1H, s), 11.11 (1H, s), 9.77 (1H, s), 8.17 (1H, d, J = 8.6 Hz), 7.53-7.46 (2H, m), 7.41 (1H, d, J = 7.4 Hz), 7.27-7.06 (5H, m), 4.25-4.13 (1H, m), 2.12 (3H, s), 2.06-1.96 (2H, m), 1.83-1.23 (9H, m), 1.15 (3H, d, J = 6.5 Hz). 520 518 143 [00289]![embedded image]()
1H-NMR (DMSO-D6) ?: 13.22-13.09 (1H, m), 11.20 (1H, s), 7.82-7.67 (2H, m), 7.58 (1H, d, J = 2.3 Hz), 7.51 (1H, d, J = 8.3 Hz), 7.35 (1H, t, J = 73.1 Hz), 7.24 (1H, dd, J = 8.7, 2.7 Hz), 6.63-6.53 (1H, m), 4.14-4.00 (1H, m), 2.19-2.06 (2H, m), 1.77-1.63 (1H, m), 1.63-1.17 (8H, m), 1.09 (3H, d, J = 6.5 Hz). 540 538 144 [00290]![embedded image]()
1H-NMR (DMSO-D6) ?: 13.81-13.58 (1H, m), 11.20 (1H, s), 8.14 (1H, d, J = 8.6 Hz), 7.59 (1H, d, J = 2.3 Hz), 7.51 (1H, d, J = 8.3 Hz), 7.36 (1H, t, J = 72.8 Hz), 7.26 (1H, dd, J = 8.6, 2.3 Hz), 6.83 (1H, s), 4.13-3.98 (1H, m), 2.18-2.07 (2H, m), 1.73-1.63 (1H, m), 1.55-1.20 (8H, m), 1.10 (3H, d, J = 6.5 Hz). 574 572
TABLE-US-00019 TABLE 1-19 145 [00291]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.01 (1H, s), 8.65-8.60 (1H, m), 8.41 (1H, d, J = 9.2 Hz), 7.13 (1H, d, J = 7.6 Hz), 7.12-7.10 (1H, m), 7.04 (1H, d, J = 7.6 Hz), 3.95-3.83 (1H, m), 2.64 (3H, d, J = 4.9 Hz), 2.29 (3H, s), 2.18 (3H, s), 2.05-1.97 (2H, m), 1.68-1.60 (1H, m), 1.57-1.10 (8H, m), 1.05 (3H, d, J = 6.5 Hz). 415 413 146 [00292]![embedded image]()
1H-NMR (DMSO-D6) : 13.14 (1H, s), 11.20 (1H, s), 8.61 (1H, d, J = 6.7 Hz), 8.47-8.39 (2H, m), 7.68 (1H, d, J = 6.7 Hz), 7.50 (1H, d, J = 6.7 Hz), 7.34-7.20 (3H, m), 4.22-4.08 (1H, m), 2.23 (3H, s), 2.12-2.00 (2H, m), 1.80-1.69 (1H, m), 1.69- 1.57 (1H, m), 1.57-1.20 (7H, m), 1.16 (3H, d, J = 6.0 Hz). 461 459 147 [00293]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.14 (1H, s), 8.66 (1H, q, J = 4.5 Hz), 8.50-8.41 (2H, m), 7.75 (1H, d, J = 7.9 Hz), 7.35 (1H, dd, J = 7.9, 4.9 Hz), 4.00- 3.85 (1H, m), 2.66 (3H, d, J = 4.5 Hz), 2.31 (3H, s), 2.02-1.90 (2H, m), 1.88-1.42 (5H, m), 1.37- 1.16 (4H, m), 1.07 (3H, d, J = 6.0 Hz). 402 400 148 [00294]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.15 (1H, s), 8.80 (1H, d, J = 9.0 Hz), 8.43 (1H, d, J = 4.5 Hz), 7.75 (1H, d, J = 7.5 Hz), 7.39-7.31 (2H, m), 4.15-4.01 (1H, m), 2.30 (3H, s), 2.02-1.92 (2H, m), 1.87-1.71 (2H, m), 1.69-1.61 (1H, m), 1.58-1.46 (2H, m), 1.38-1.21 (4H, m), 1.13 (3H, d, J = 6.7 Hz). 446 444 149 [00295]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.15 (1H, s), 8.44 (1H, d, J = 8.2 Hz), 8.40 (1H, d, J = 4.5 Hz), 7.76 (1H, d, J = 8.2 Hz), 7.73 (1H, d, J = 8.2 Hz), 7.65 (1H, d, J = 8.2 Hz), 7.51 (1H, s), 7.46 (1H, t, J = 7.9 Hz), 7.38-7.28 (2H, m), 4.23-4.08 (1H, m), 2.30 (3H, s), 2.04-1.92 (2H, m), 1.88-1.65 (3H, m), 1.65-1.47 (2H, m), 1.41-1.21 (4H, m), 1.15 (3H, d, J = 6.0 Hz). 461 459 150 [00296]![embedded image]()
Mixture of three stereoisomers due to octahydro- 1H-isoindole moiety 1H-NMR (DMSO-D6) ?: 11.08 (1H, s), 7.34 (1H, dd, J = 8.7, 5.9 Hz), 7.18 (1H, dd, J = 10.1, 2.7 Hz), 7.07 (1H, td, J = 8.7, 2.7 Hz), 5.50 (1H, d, J = 8.6 Hz), 3.75-3.66 (1H, m), 3.44-3.35 (2H, m), 2.70-2.61 (2H, m), 2.24 (3H, s), 2.08-2.00 (2H, m), 1.84-1.68 (4H, m), 1.64-1.57 (1H, m), 1.52- 1.01 (14H, m), 0.97 (3H, d, J = 6.5 Hz). 485 483 151 [00297]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.32 (1H, s), 8.65-8.59 (1H, m), 8.60 (1H, s), 8.50 (1H, d, J = 5.5 Hz), 8.41 (1H, d, J = 9.0 Hz), 7.85 (1H, d, J = 5.3 Hz), 3.97-3.84 (1H, m), 2.63 (3H, d, J = 4.9 Hz), 2.17- 2.08 (2H, m), 1.71-1.60 (1H, m), 1.58-1.17 (8H, m), 1.05 (3H, d, J = 6.5 Hz). 466 464 152 [00298]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.21 (1H, s), 8.62 (1H, q, J = 5.2 Hz), 8.41 (1H, d, J = 8.3 Hz), 7.83 (1H, s), 7.71 (1H, d, J = 8.3 Hz), 7.51 (1H, d, J = 8.3 Hz), 3.95-3.85 (1H, m), 2.64 (3H, d, J = 5.2 Hz), 2.27 (3H, s), 2.09-2.01 (2H, m), 1.68-1.61 (1H, m), 1.54-1.37 (3H, m), 1.35-1.16 (5H, m), 1.05 (3H, d, J = 6.7 Hz). 426 424
TABLE-US-00020 TABLE 1-20 153 [00299]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.80 (1H, s), 11.20 (1H, s), 7.81 (1H, s), 7.68 (1H, d, J = 8.1 Hz), 7.58 (1H, d, J = 8.1 Hz), 7.50 (1H, d, J = 8.1 Hz), 6.30 (1H, s), 4.09-4.00 (1H, m), 2.26 (3H, s), 2.23 (3H, s), 2.10-2.01 (2H, m), 1.71-1.65 (1H, m), 1.55-1.20 (8H, m), 1.07 (3H, d, J = 6.2 Hz). 449 447 154 [00300]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.13 (1H, s), 8.63 (1H, q, J = 4.5 Hz), 8.41 (1H, d, J = 9.7 Hz), 8.07 (1H, s), 6.77 (1H, s), 3.98-3.83 (1H, m), 3.86 (3H, s), 2.64 (3H, d, J = 4.5 Hz), 2.19 (3H, s), 2.09-1.96 (2H, m), 1.72-1.59 (1H, m), 1.57- 1.16 (8H, m), 1.06 (3H, d, J = 6.7 Hz). 432 430 155 [00301]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.08 (1H, s), 7.31 (1H, dd, J = 8.6, 6.0 Hz), 7.21-7.04 (6H, m), 6.12 (1H, d, J = 8.3 Hz), 4.43 (2H, s), 3.84-3.73 (1H, m), 3.57-3.44 (2H, m), 2.75-2.66 (2H, m), 2.23 (3H, s), 2.05-1.97 (2H, m), 1.65-1.14 (9H, m), 1.01 (3H, d, J = 6.7 Hz). 493 491 156 [00302]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.09 (1H, s), 7.34 (1H, dd, J = 8.4, 5.9 Hz), 7.18 (1H, dd, J = 10.1, 2.7 Hz), 7.07 (1H, td, J = 8.4, 2.7 Hz), 6.88 (1H, d, J = 8.6 Hz), 3.59-3.43 (1H, m), 3.47 (3H, s), 2.24 (3H, s), 2.08-2.00 (2H, m), 1.63-1.12 (9H, m), 0.99 (3H, d, J = 6.5 Hz). 392 390 157 [00303]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.22 (1H, s), 8.65-8.59 (1H, m), 8.41 (1H, d, J = 9.0 Hz), 7.77 (1H, dd, J = 8.9, 5.2 Hz), 7.43 (1H, dd, J = 9.0, 3.0 Hz), 7.30 (1H, td, J = 8.6, 3.0 Hz), 3.97-3.83 (1H, m), 2.64 (3H, d, J = 4.9 Hz), 2.19-2.06 (2H, m), 1.70-1.16 (9H, m), 1.06 (3H, d, J = 6.7 Hz). 483 481 158 [00304]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.26 (1H, s), 8.65-8.59 (1H, m), 8.41 (1H, d, J = 9.2 Hz), 8.33 (1H, s), 7.54 (1H, s), 3.98- 3.86 (1H, m), 2.64 (3H, d, J = 4.9 Hz), 2.26 (3H, s), 2.10- 2.00 (2H, m), 1.70-1.61 (1H, m), 1.58-1.14 (8H, m), 1.06 (3H, d, J = 6.7 Hz). 436 434 159 [00305]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.02 (1H, s), 8.66-8.60 (1H, m), 8.41 (1H, d, J = 9.0 Hz), 7.90 (1H, s), 6.24 (1H, s), 3.98- 3.87 (1H, m), 3.94 (4H, t, J = 7.4 Hz), 2.65 (3H, d, J = 5.1 Hz), 2.36-2.27 (2H, m), 2.12 (3H, s), 2.03-1.94 (2H, m), 1.71-1.60 (1H, m), 1.57-1.14 (8H, m), 1.06 (3H, d, J = 6.5 Hz). 457 501 (formic acid adduct) 160 [00306]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.80 (1H, s), 11.13 (1H, s), 8.05 (1H, s), 7.58 (1H, d, J = 8.6 Hz), 6.76 (1H, s), 6.31 (1H, s), 4.14-3.98 (1H, m), 3.84 (3H, s), 2.23 (3H, s), 2.18 (3H, s), 2.07-1.99 (2H, m), 1.73-1.64 (1H, m), 1.57-1.16 (8H, m), 1.08 (3H, d, J = 6.5 Hz). 455 453
TABLE-US-00021 TABLE 1-21 161 [00307]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.11 (1H, s), 8.62 (1H, q, J = 4.7 Hz), 8.41 (1H, d, J = 9.2 Hz), 7.56 (1H, d, J = 1.8 Hz), 7.43 (1H, dd, J = 8.1, 1.8 Hz), 7.23 (1H, d, J = 8.1 Hz), 3.95-3.86 (1H, m), 2.64 (3H, d, J = 4.7 Hz), 2.22 (3H, s), 2.05-1.98 (2H, m), 1.68-1.63 (1H, m), 1.55- 1.36 (3H, m), 1.34-1.15 (5H, m), 1.05 (3H, d, J = 6.5 Hz). 479 477 162 [00308]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.64 (1H, s), 11.07 (1H, s), 8.64 (1H, q, J = 4.5 Hz), 8.42 (1H, d, J = 9.7 Hz), 7.36 (1H, s), 6.24 (1H, s), 3.99-3.85 (1H, m), 2.65 (3H, d, J = 4.5 Hz), 2.02 (3H, s), 2.02-1.93 (2H, m), 1.71-1.62 (1H, m), 1.59-1.38 (4H, m), 1.33-1.13 (4H, m), 1.07 (3H, d, J = 6.7 Hz). 418 416 163 [00309]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.07 (1H, s), 8.62 (1H, q, J = 4.7 Hz), 8.41 (1H, d, J = 9.2 Hz), 7.53 (1H, d, J = 1.8 Hz), 7.46 (1H, dd, J = 8.0, 1.8 Hz), 7.25 (1H, d, J = 8.0 Hz), 4.79 (1H, d, J = 2.8 Hz), 4.32 (1H, d, J = 2.8 Hz), 3.95-3.87 (1H, m), 3.90 (2H, q, J = 6.9 Hz), 2.64 (3H, d, J = 4.7 Hz), 2.24 (3H, s), 2.07-1.99 (2H, m), 1.69- 1.62 (1H, m), 1.53-1.39 (3H, m), 1.35 (3H, t, J = 6.9 Hz), 1.31-1.15 (5H, m), 1.06 (3H, d, J = 6.9 Hz). 471 469 164 [00310]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.04 (1H, s), 8.66-8.59 (1H, m), 8.41 (1H, d, J = 9.0 Hz), 7.99 (1H, s), 6.75 (1H, s), 3.97-3.85 (1H, m), 3.71-3.66 (4H, m), 3.50-3.43 (4H, m), 2.64 (3H, d, J = 4.9 Hz), 2.15 (3H, s), 2.04-1.96 (2H, m), 1.69-1.61 (1H, m), 1.57-1.17 (8H, m), 1.06 (3H, d, J = 6.7 Hz). 487 485 165 [00311]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.00 (1H, s), 8.65-8.60 (1H, m), 8.41 (1H, d, J = 9.2 Hz), 7.92 (1H, s), 6.33 (1H, s), 3.97-3.86 (1H, m), 3.41-3.35 (4H, m), 2.64 (3H, d, J = 4.9 Hz), 2.13 (3H, s), 2.04-1.90 (6H, m), 1.70-1.62 (1H, m), 1.58-1.15 (8H, m), 1.06 (3H, d, J = 6.5 Hz). 471 469 166 [00312]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.01 (1H, s), 8.66-8.61 (1H, m), 8.41 (1H, d, J = 9.0 Hz), 7.93 (1H, s), 6.71 (1H, s), 3.98-3.86 (1H, m), 3.57-3.49 (4H, m), 2.64 (3H, d, J = 4.9 Hz), 2.13 (3H, s), 2.03-1.95 (2H, m), 1.69-1.18 (15H, m), 1.06 (3H, d, J = 6.5 Hz). 485 483 167 [00313]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.15 (1H, s), 8.62 (1H, q, J = 4.8 Hz), 8.41 (1H, d, J = 9.2 Hz), 7.89 (1H, d, J = 1.7 Hz), 7.80 (1H, dd, J = 8.1, 1.7 Hz), 7.43 (1H, d, J = 8.1 Hz), 3.95-3.85 (1H, m), 2.63 (3H, d, J = 4.8 Hz), 2.59 (3H, s), 2.30 (3H, s), 2.10-2.02 (2H, m), 1.68-1.61 (1H, m), 1.54-1.41 (3H, m), 1.34-1.17 (5H, m), 1.05 (3H, d, J = 5.8 Hz). 443 441 168 [00314]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.37 (1H, s), 8.64-8.58 (1H, m), 8.33 (1H, d, J = 8.5 Hz), 8.23 (1H, d, J = 1.5 Hz), 7.93 (1H, dd, J = 8.0, 1.5 Hz), 7.72 (1H, d, J = 8.0 Hz), 3.98-3.87 (1H, m), 2.73-2.59 (2H, m), 2.64 (3H, d, J = 5.0 Hz), 2.42 (1H, dd, J = 12.5, 8.3 Hz), 2.35-2.18 (3H, m), 2.12-2.01 (2H, m), 1.63-1.47 (2H, m), 1.04 (3H, d, J = 6.5 Hz). 447 445
TABLE-US-00022 TABLE 1-22 169 [00315]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.79 (1H, s), 11.36 (1H, s), 8.22 (1H, d, J = 1.3 Hz), 7.91 (1H, dd, J = 8.0, 1.5 Hz), 7.71 (1H, d, J = 8.0 Hz), 7.55 (1H, d, J = 8.0 Hz), 6.28 (1H, s), 4.10-4.00 (1H, m), 2.74-2.64 (2H, m), 2.46-2.38 (1H, m), 2.35-2.14 (6H, m), 2.07 (2H, d, J = 14.3 Hz), 1.61-1.49 (2H, m), 1.06 (3H, d, J = 6.5 Hz). 470 468 170 [00316]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.18 (1H, s), 8.62 (1H, q, J = 4.9 Hz), 8.41 (1H, d, J = 9.2 Hz), 8.12 (1H, s), 6.97 (1H, s), 5.00 (2H, q, J = 8.9 Hz), 3.99-3.84 (1H, m), 2.64 (3H, d, J = 4.9 Hz), 2.23 (3H, s), 2.10-1.97 (2H, m), 1.71-1.59 (1H, m), 1.57-1.43 (3H, m), 1.42-1.14 (5H, m), 1.06 (3H, d, J = 6.7 Hz). 500 498 171 [00317]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.14 (1H, s), 8.63 (1H, q, J = 4.9 Hz), 8.40 (1H, d, J = 9.2 Hz), 8.25 (1H, s), 7.24 (1H, s), 3.97-3.84 (1H, m), 2.64 (3H, d, J = 4.9 Hz), 2.19 (3H, s), 2.11-1.97 (3H, m), 1.71-1.60 (1H, m), 1.56-1.41 (3H, m), 1.41-1.15 (5H, m), 1.06 (3H, d, J = 6.5 Hz), 0.99-0.89 (4H, m). 442 440 172 [00318]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.24 (1H, s), 8.62 (1H, q, J = 4.5 Hz), 8.41 (1H, d, J = 9.0 Hz), 8.25 (1H, s), 7.87 (1H, s), 3.98-3.84 (1H, m), 2.64 (3H, d, J = 4.5 Hz), 2.18 (3H, s), 2.09-1.97 (2H, m), 1.71-1.59 (1H, m), 1.57-1.15 (8H, m), 1.05 (3H, d, J = 6.7 Hz). 528 526 173 [00319]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.16 (1H, s), 8.66-8.59 (1H, m), 8.40 (1H, d, J = 9.0 Hz), 8.30 (1H, s), 7.21 (1H, s), 3.97- 3.83 (1H, m), 2.64 (3H, d, J = 4.9 Hz), 2.44 (3H, s), 2.20 (3H, s), 2.10-1.98 (2H, m), 1.70-1.60 (1H, m), 1.57-1.17 (8H, m), 1.05 (3H, d, J = 6.5 Hz). 416 414 174 [00320]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.33 (1H, s), 8.69 (1H, s), 8.63 (1H, q, J = 4.5 Hz), 8.41 (1H, d, J = 8.2 Hz), 7.93 (1H, s), 3.98-3.84 (1H, m), 2.64 (3H, d, J = 4.5 Hz), 2.37 (3H, s), 2.14-2.04 (2H, m), 1.72-1.61 (1H, m), 1.58-1.15 (8H, m), 1.06 (3H, d, J = 6.0 Hz). 470 468 175 [00321]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.32 (1H, s), 8.67-8.59 (1H, m), 8.42 (1H, d, J = 9.2 Hz), 8.22 (1H, d, J = 1.6 Hz), 7.91 (1H, dd, J = 8.1, 1.6 Hz), 7.70 (1H, d, J = 8.1 Hz), 3.95- 3.85 (1H, m), 2.64 (3H, d, J = 4.8 Hz), 2.10 (2H, d, J = 11.3 Hz), 1.69-1.62 (1H, m), 1.58-1.15 (8H, m), 1.05 (3H, d, J = 6.5 Hz). 446 444 176 [00322]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.79 (1H, s), 11.30 (1H, s), 8.19 (1H, s), 7.88 (1H, d, J = 8.3 Hz), 7.69 (1H, d, J = 7.8 Hz), 7.63-7.53 (1H, m), 6.30 (1H, s), 4.12-4.00 (1H, m), 2.27- 2.06 (5H, m), 1.90-1.83 (1H, m), 1.75-1.18 (8H, m), 1.07 (3H, d, J = 6.0 Hz). 469 467 7
TABLE-US-00023 TABLE 1-23 177 [00323]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.19 (1H, s), 8.68 (1H, d, J = 5.3 Hz), 8.42 (1H, d, J = 9.0 Hz), 7.86 (1H, dd, J = 8.4, 2.7 Hz), 7.44 (1H, dd, J = 8.7, 5.9 Hz), 7.33 (1H, td, J = 8.5, 2.6 Hz), 3.95-3.82 (1H, m), 2.78-2.70 (1H, m), 2.16-2.06 (2H, m), 1.69-1.60 (1H, m), 1.59-1.12 (8H, m), 1.05 (3H, d, J = 6.7 Hz), 0.65-0.56 (4H, m). 557 555 178 [00324]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.02 (1H, s), 8.63 (1H, q, J = 4.9 Hz), 8.41 (1H, d, J = 9.2 Hz), 7.38 (1H, d, J = 1.5 Hz), 7.31 (1H, dd, J = 8.1, 1.5 Hz), 7.17 (1H, d, J = 8.1 Hz), 5.01 (1H, s), 3.95-3.85 (1H, m), 2.63 (3H, d, J = 4.9 Hz), 2.21 (3H, s), 2.06-1.98 (2H, m), 1.68-1.62 (1H, m), 1.54-1.43 (3H, m), 1.42 (6H, s), 1.33-1.16 (5H, m), 1.05 (3H, d, J = 6.5 Hz). 459 457 179 [00325]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.25 (1H, s), 8.63 (1H, q, J = 4.7 Hz), 8.35 (1H, d, J = 8.8 Hz), 7.75 (1H, dd, J = 8.6, 2.5 Hz), 7.54 (1H, dd, J = 8.6, 5.8 Hz), 7.36 (1H, td, J = 8.6, 2.5 Hz), 3.96-3.89 (1H, m), 2.72-2.60 (2H, m), 2.64 (3H, d, J = 4.7 Hz), 2.42 (1H, dd, J = 12.5, 8.3 Hz), 2.33-2.19 (3H, m), 2.10-2.02 (2H, m), 1.64-1.48 (2H, m), 1.04 (3H, d, J = 6.5 Hz). 484 482 180 [00326]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.25 (1H, s), 8.68 (1H, d, J = 5.3 Hz), 8.35 (1H, d, J = 8.6 Hz), 7.75 (1H, dd, J = 8.6, 2.6 Hz), 7.54 (1H, dd, J = 8.6, 6.0 Hz), 7.36 (1H, td, J = 8.6, 2.6 Hz), 3.95-3.88 (1H, m), 2.75-2.57 (3H, m), 2.46-2.38 (1H, m), 2.33-2.19 (3H, m), 2.10-2.02 (2H, m), 1.62-1.49 (2H, m), 1.04 (3H, d, J = 6.5 Hz), 0.66-0.56 (4H, m). 510 508 181 [00327]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.19 (1H, s), 8.66-8.59 (1H, m), 8.41 (1H, d, J = 9.2 Hz), 7.71 (1H, s), 7.59 (1H, d, J = 7.6 Hz), 7.52 (1H, d, J = 7.9 Hz), 3.95-3.85 (1H, m), 2.63 (3H, d, J = 4.9 Hz), 2.31 (3H, s), 2.10-2.02 (2H, m), 1.70-1.60 (1H, m), 1.57-1.14 (8H, m), 1.05 (3H, d, J = 6.7 Hz). 557 555 182 [00328]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.02 (1H, s), 8.66-8.60 (1H, m), 8.41 (1H, d, J = 9.2 Hz), 7.90 (1H, s), 6.23 (1H, s), 4.06 (2H, t, J = 8.4 Hz), 3.96-3.87 (1H, m), 3.51 (2H, dd, J = 7.9, 5.5 Hz), 2.83-2.72 (1H, m), 2.64 (3H, d, J = 4.9 Hz), 2.11 (3H, s), 2.04-1.94 (2H, m), 1.72-1.60 (1H, m), 1.57- 1.14 (8H, m), 1.23 (3H, d, J = 6.7 Hz), 1.06 (3H, d, J = 6.7 Hz). 557 555 183 [00329]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.20 (1H, s), 7.87 (1H, dd, J = 8.4, 2.7 Hz), 7.46 (1H, dd, J = 8.7, 5.9 Hz), 7.34 (1H, td, J = 8.5, 2.6 Hz), 5.55 (1H, d, J = 8.6 Hz), 5.48 (1H, q, J = 4.5 Hz), 3.69-3.58 (1H, m), 2.50-2.48 (3H, m), 2.18-2.09 (2H, m), 1.67-1.58 (1H, m), 1.54-1.10 (8H, m), 0.96 (3H, d, J = 6.5 Hz). 503 501 184 [00330]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.23 (1H, s), 8.62 (1H, q, J = 4.5 Hz), 8.42 (1H, d, J = 9.0 Hz), 7.78 (1H, d, J = 9.0 Hz), 7.32 (1H, t, J = 73.7 Hz), 7.28 (1H, d, J = 3.0 Hz), 7.23 (1H, dd, J = 9.0, 3.0 Hz), 3.97-3.83 (1H, m), 2.64 (3H, d, J = 4.5 Hz), 2.19-2.07 (2H, m), 1.70-1.60 (1H, m), 1.57-1.15 (8H, m), 1.06 (3H, d, J = 6.0 Hz). 531 529
TABLE-US-00024 TABLE 1-24 185 [00331]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.18 (1H, s), 8.63 (1H, q, J = 4.5 Hz), 8.41 (1H, d, J = 9.0 Hz), 8.36 (1H, s), 7.59 (1H, s), 5.22 (1H, s), 3.98-3.82 (1H, m), 2.63 (3H, d, J = 4.5 Hz), 2.25 (3H, s), 2.11-2.00 (2H, m), 1.72-1.61 (1H, m), 1.56-1.17 (8H, m), 1.44 (6H, s), 1.06 (3H, d, J = 6.7 Hz). 460 458 186 [00332]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.20 (1H, s), 8.62 (1H, q, J = 4.9 Hz), 8.41 (1H, d, J = 9.2 Hz), 8.25 (1H, s), 7.81 (1H, s), 3.98-3.83 (1H, m), 2.63 (3H, d, J = 4.9 Hz), 2.25 (3H, s), 2.11-2.00 (2H, m), 1.72- 1.62 (1H, m), 1.56-1.38 (3H, m), 1.38-1.15 (5H, m), 1.05 (3H, d, J = 6.5 Hz). 446 444 187 [00333]![embedded image]()
1H-NMR (CD3OD) ?: 8.46 (1H, s), 8.04 (1H, s), 4.09-3.97 (1H, m), 2.78 (3H, s), 2.40 (3H, s), 2.25- 2.14 (2H, m), 1.80-1.72 (1H, m), 1.63-1.24 (8H, m), 1.14 (3H, d, J = 6.5 Hz). 445 443 188 [00334]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.34 (1H, s), 8.67 (1H, s), 8.61 (1H, q, J = 4.9 Hz), 8.41 (1H, d, J = 9.2 Hz), 8.07 (1H, s), 3.97-3.83 (1H, m), 2.64 (3H, d, J = 4.9 Hz), 2.32 (3H, s), 2.13-2.03 (2H, m), 1.69- 1.60 (1H, m), 1.58-1.14 (8H, m), 1.05 (3H, d, J = 6.7 Hz). 427 425 189 [00335]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.26 (1H, s), 7.76 (1H, dd, J = 8.6, 2.5 Hz), 7.56 (1H, dd, J = 8.6, 6.0 Hz), 7.38 (1H, td, J = 8.6, 2.5 Hz), 6.05 (1H, d, J = 1.8 Hz), 5.48 (1H, d, J = 7.2 Hz), 3.69-3.62 (1H, m), 2.70-2.61 (2H, m), 2.34-2.06 (7H, m), 1.69-1.50 (2H, m), 0.98 (3H, d, J = 6.5 Hz), 0.51-0.46 (2H, m), 0.26-0.21 (2H, m). 482 480 190 [00336]![embedded image]()
1H-NMR (DMSO-D6) ?: 8.36 (1H, d, J = 3.7 Hz), 7.80 (1H, dd, J = 8.6, 2.5 Hz), 7.62 (1H, dd, J = 8.6, 6.0 Hz), 7.41 (1H, td, J = 8.6, 2.5 Hz), 6.04 (1H, s), 5.48 (1H, d, J = 6.9 Hz), 3.68-3.62 (1H, m), 2.72- 2.65 (3H, m), 2.33-2.13 (7H, m), 1.70-1.56 (2H, m), 0.98 (3H, d, J = 6.5 Hz), 0.72-0.66 (2H, m), 0.56-0.46 (4H, m), 0.23-0.21 (2H, m). 565 609 (formic acid adduct) 191 [00337]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.03 (1H, s), 8.66-8.60 (1H, m), 8.41 (1H, d, J = 9.0 Hz), 7.92 (1H, s), 6.28 (1H, s), 4.71 (4H, s), 4.11 (4H, s), 3.96-3.86 (1H, m), 2.64 (3H, d, J = 4.9 Hz), 2.12 (3H, s), 2.02-1.93 (2H, m), 1.72-1.62 (1H, m), 1.59-1.14 (8H, m), 1.06 (3H, d, J = 6.5 Hz). 499 497 192 [00338]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.06 (1H, s), 8.65-8.60 (1H, m), 8.41 (1H, d, J = 9.0 Hz), 7.97 (1H, s), 6.39 (1H, s), 4.20 (2H, t, J = 8.9 Hz), 3.96 (2H, dd, J = 9.0, 4.5 Hz), 3.96-3.87 (1H, m), 3.80-3.65 (1H, m), 2.64 (3H, d, J = 4.9 Hz), 2.15 (3H, s), 2.04-1.95 (2H, m), 1.71-1.59 (1H, m), 1.59-1.13 (8H, m), 1.06 (3H, d, J = 6.5 Hz). 525 523
TABLE-US-00025 TABLE 1-25 193 [00339]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.30 (1H, s), 8.67-8.58 (2H, m), 8.41 (1H, d, J = 9.2 Hz), 7.91 (1H, s), 3.99-3.82 (1H, m), 2.70-2.59 (6H, m), 2.34 (3H, s), 2.15-2.02 (2H, m), 1.71- 1.60 (1H, m), 1.58-1.42 (3H, m), 1.42-1.16 (5H, m), 1.05 (3H, d, J = 6.5 Hz). 444 442 194 [00340]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.12 (1H, s), 8.62 (1H, q, J = 4.5 Hz), 8.41 (1H, d, J = 9.0 Hz), 7.35 (1H, d, J = 8.5 Hz), 7.24 (1H, t, J = 74.3 Hz), 7.15 (1H, d, J = 8.1 Hz), 7.06 (1H, s), 3.98-3.83 (1H, m), 2.63 (3H, d, J = 4.5 Hz), 2.19 (3H, s), 2.11-1.98 (2H, m), 1.71-1.59 (1H, m), 1.57-1.39 (3H, m), 1.39-1.16 (5H, m), 1.06 (3H, d, J = 6.7 Hz). 467 465 195 [00341]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.25 (1H, s), 7.86 (1H, d, J = 2.3 Hz), 7.63 (1H, d, J = 8.6 Hz), 7.50 (1H, d, J = 8.6 Hz), 5.88 (1H, d, J = 2.3 Hz), 5.45 (1H, d, J = 8.3 Hz), 3.70-3.62 (1H, m), 2.38-2.31 (1H, m), 2.18-2.10 (2H, m), 1.68-1.60 (1H, m), 1.53-1.13 (8H, m), 0.97 (3H, d, J = 6.2 Hz), 0.53- 0.49 (2H, m), 0.27-0.23 (2H, m). 547 545 196 [00342]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.41 (1H, s), 8.64-8.57 (1H, m), 8.35 (1H, d, J = 8.3 Hz), 7.68 (1H, dd, J = 8.6, 6.1 Hz), 7.60 (1H, dd, J = 8.8, 2.8 Hz), 7.31 (1H, td, J = 8.6, 2.7 Hz), 3.98-3.86 (1H, m), 2.80-2.72 (1H, m), 2.70-2.31 (7H, m), 2.64 (3H, d, J = 5.0 Hz), 1.63-1.49 (2H, m), 1.18-1.02 (1H, m), 1.07 (3H, d, J = 6.5 Hz), 0.99-0.82 (1H, m). 466 464 197 [00343]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.77 (1H, s), 11.40 (1H, s), 7.67 (1H, dd, J = 8.6, 6.1 Hz), 7.62-7.57 (2H, m), 7.30 (1H, td, J = 8.6, 2.5 Hz), 6.29 (1H, s), 4.11-3.98 (1H, m), 2.80-2.30 (8H, m), 2.22 (3H, s), 1.68-1.49 (2H, m), 1.18-1.02 (1H, m), 1.11 (3H, d, J = 6.5 Hz), 0.98-0.80 (1H, m). 489 487 198 [00344]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.29 (1H, s), 8.65-8.59 (1H, m), 8.41 (1H, d, J = 9.0 Hz), 8.00 (1H, d, J = 1.8 Hz), 7.98 (1H, d, J = 8.3 Hz), 7.86 (1H, dd, J = 8.3, 1.8 Hz), 3.98- 3.85 (1H, m), 2.64 (3H, d, J = 4.9 Hz), 2.16-2.04 (2H, m), 1.69-1.59 (1H, m), 1.59-1.13 (8H, m), 1.06 (3H, d, J = 6.5 Hz). 490 488 199 [00345]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.84-12.75 (1H, m), 11.30 (1H, s), 8.32 (1H, d, J = 1.6 Hz), 7.91 (1H, dd, J = 8.0, 1.6 Hz), 7.66 (1H, d, J = 8.1 Hz), 7.59 (1H, d, J = 9.2 Hz), 6.30 (1H, s), 4.11-3.96 (1H, m), 2.23 (3H, s), 2.19-2.07 (2H, m), 1.75-1.63 (1H, m), 1.61-1.15 (8H, m), 1.07 (3H, d, J = 6.5 Hz). 513 511 200 [00346]![embedded image]()
1H-NMR (DMSO-D6) ?: 10.94 (1H, s), 7.09 (1H, d, J = 8.5 Hz), 6.84 (1H, d, J = 2.3 Hz), 6.78 (1H, dd, J = 8.5, 2.3 Hz), 6.08 (1H, d, J = 7.9 Hz), 3.78-3.76 (1H, m), 3.73 (4H, t, J = 4.7 Hz), 3.49 (4H, t, J = 4.7 Hz), 3.20 (4H, t, J = 4.7 Hz), 3.14 (4H, t, J = 4.7 Hz), 2.18 (3H, s), 2.05-1.97 (2H, m), 1.62-1.56 (1H, m), 1.50-1.35 (4H, m), 1.27-1.14 (4H, m), 0.99 (3H, d, J = 6.5 Hz). 514 512
TABLE-US-00026 TABLE 1-26 201 [00347]![embedded image]()
1H-NMR (DMSO-D6) ?: 13.00-12.76 (2H, m), 11.14 (1H, s), 7.85 (1H, s), 7.76 (1H, d, J = 7.9 Hz), 7.68-7.56 (1H, m), 7.38 (1H, d, J = 7.9 Hz), 6.33 (1H, s), 4.10-3.98 (1H, m), 2.27 (3H, s), 2.21 (3H, s), 2.09-2.00 (2H, m), 1.71- 1.65 (1H, m), 1.52-1.21 (8H, m), 1.07 (3H, d, J = 6.5 Hz). 468 466 202 [00348]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.26 (1H, s), 9.15 (1H, s), 8.33 (1H, d, J = 9.0 Hz), 7.75 (1H, dd, J = 8.4, 2.5 Hz), 7.55 (1H, dd, J = 8.4, 6.1 Hz), 7.36 (1H, td, J = 8.4, 2.5 Hz), 3.94-3.87 (1H, m), 2.74-2.60 (2H, m), 2.44-2.38 (2H, m), 2.33-2.20 (3H, m), 2.09-2.03 (2H, m), 2.01 (6H, s), 1.63- 1.50 (2H, m), 1.03 (3H, d, J = 6.5 Hz). 536 534 203 [00349]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.19 (1H, s), 8.68 (1H, d, J = 5.3 Hz), 8.41 (1H, d, J = 8.9 Hz), 7.73 (1H, dd, J = 8.9, 2.4 Hz), 7.52 (1H, dd, J = 8.9, 6.2 Hz), 7.34 (1H, td, J = 8.9, 2.4 Hz), 3.95-3.85 (1H, m), 2.78-2.70 (1H, m), 2.16-2.06 (2H, m), 1.68-1.61 (1H, m), 1.57-1.17 (8H, m), 1.05 (3H, d, J = 6.2 Hz), 0.65-0.58 (4H, m). 509 507 204 [00350]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.95 (0.15H, s), 12.80 (0.85H, s), 11.11 (1H, s), 8.42 (1H, d, J = 3.9 Hz), 7.93 (0.15H, s), 7.71 (1H, s), 7.62-7.57 (1.85H, m), 7.33 (1H, d, J = 7.9 Hz), 6.56 (0.15H, s), 6.30 (0.85H, s), 4.10-4.00 (1H, m), 2.86-2.80 (1H, m), 2.25 (3H, s), 2.23 (3H, s), 2.08-2.01 (2H, m), 1.71- 1.65 (1H, m), 1.53-1.19 (8H, m), 1.07 (3H, d, J = 6.2 Hz), 0.71-0.66 (2H, m), 0.57-0.53 (2H, m). 507 505 205 [00351]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.25 (1H, s), 8.65 (1H, q, J = 4.9 Hz), 8.44 (1H, d, J = 9.0 Hz), 7.81 (1H, d, J = 8.1 Hz), 7.56 (1H, s), 7.48 (1H, dd, J = 8.1, 1.4 Hz), 3.98-3.87 (1H, m), 2.66 (3H, d, J = 4.9 Hz), 2.51 (3H, s), 2.04-1.94 (2H, m), 1.77-1.46 (5H, m), 1.40-1.19 (4H, m), 1.08 (3H, d, J = 6.5 Hz). 426 424 206 [00352]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.36 (1H, s), 8.65-8.57 (1H, m), 8.36 (1H, d, J = 1.5 Hz), 8.33 (1H, d, J = 8.8 Hz), 7.96 (1H, dd, J = 8.0, 1.5 Hz), 7.70 (1H, d, J = 8.0 Hz), 3.98- 3.87 (1H, m), 2.75-2.58 (2H, m), 2.64 (3H, d, J = 5.0 Hz), 2.42 (1H, dd, J = 12.4, 8.4 Hz), 2.35-2.20 (3H, m), 2.13- 2.04 (2H, m), 1.64-1.47 (2H, m), 1.04 (3H, d, J = 6.5 Hz). 491 489 207 [00353]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.79 (1H, s), 11.35 (1H, s), 8.35 (1H, d, J = 1.5 Hz), 7.95 (1H, dd, ] = 8.0, 1.5 Hz), 7.69 (1H, d, J = 7.8 Hz), 7.55 (1H, d, J = 8.5 Hz), 6.28 (1H, s), 4.10-4.00 (1H, m), 2.76-2.64 (2H, m), 2.46-2.37 (1H, m), 2.35-2.20 (6H, m), 2.09 (2H, d, J = 14.3 Hz), 1.63-1.47 (2H, m), 1.06 (3H, d, J = 6.8 Hz). 514 512 208 [00354]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.20 (1H, s), 8.88 (1H, s), 7.86 (1H, dd, J = 8.6, 2.5 Hz), 7.46 (1H, dd, J = 8.7, 5.9 Hz), 7.34 (1H, td, J = 8.6, 2.5 Hz), 6.49 (1H, d, J = 9.0 Hz), 3.84-3.70 (1H, m), 3.47 (3H, s), 2.19-2.06 (2H, m), 1.73- 1.61 (1H, m), 1.57-1.14 (8H, m), 1.03 (3H, d, J = 6.7 Hz). 519 517
TABLE-US-00027 TABLE 1-27 209 [00355]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.11 (1H, s), 8.68 (1H, d, J = 5.3 Hz), 8.41 (1H, d, J = 9.2 Hz), 7.56 (1H, d, J = 1.8 Hz), 7.43 (1H, dd, J = 8.2, 1.8 Hz), 7.23 (1H, d, J = 8.2 Hz), 3.93-3.84 (1H, m), 2.76-2.71 (1H, m), 2.22 (3H, s), 2.06-1.98 (2H, m), 1.68-1.60 (1H, m), 1.54-1.39 (3H, m), 1.36-1.16 (5H, m), 1.05 (3H, d, J = 6.5 Hz), 0.64-0.59 (4H, m). 505 503 210 [00356]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.12 (1H, s), 7.57 (1H, d, J = 1.6 Hz), 7.44 (1H, dd, J = 8.0, 1.6 Hz), 7.25 (1H, d, J = 8.0 Hz), 5.88 (1H, d, J = 2.3 Hz), 5.45 (1H, d, J = 8.0 Hz), 3.69-3.63 (1H, m), 2.38-2.32 (1H, m), 2.23 (3H, s), 2.08-2.00 (2H, m), 1.66-1.59 (1H, m), 1.51-1.13 (8H, m), 0.97 (3H, d, J = 6.5 Hz), 0.54-0.50 (2H, m), 0.28-0.24 (2H, m). 477 475 211 [00357]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.20 (1H, s), 8.52 (1H, d, J = 8.8 Hz), 7.73 (1H, dd, J = 8.8, 2.4 Hz), 7.53 (1H, dd, J = 8.8, 6.1 Hz), 7.35 (1H, td, J = 8.8, 2.4 Hz), 6.12 (1H, t, J = 53.8 Hz), 3.95-3.85 (1H, m), 2.18-2.09 (2H, m), 1.65-1.55 (1H, m), 1.51-1.18 (8H, m), 1.05 (3H, d, J = 6.5 Hz). 476 474 212 [00358]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.13 (1H, s), 8.63 (1H, q, J = 4.8 Hz), 8.41 (1H, d, J= 9.2 Hz), 7.53 (1H, dd, J = 8.2, 2.1 Hz), 7.46 (1H, d, J = 2.1 Hz), 7.27 (1H, d, J = 8.2 Hz), 3.94-3.87 (1H, m), 2.64 (3H, d, J = 4.8 Hz), 2.18 (3H, s), 2.09-2.01 (2H, m), 1.69-1.62 (1H, m), 1.53-1.17 (8H, m), 1.06 (3H, d, J = 6.5 Hz). 479 477 213 [00359]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.19 (1H, s), 7.96 (1H, t, J = 5.4 Hz), 7.74 (1H, dd, J = 9.4, 1.9 Hz), 7.60- 7.49 (2H, m), 7.35 (1H, td, J = 8.4, 2.7 Hz), 3.91- 3.78 (1H, m), 3.57 (2H, d, J = 5.4 Hz), 2.20-2.04 (2H, m), 1.79 (3H, s), 1.68-1.56 (1H, m), 1.52-1.12 (8H, m), 0.99 (3H, d, J = 7.0 Hz). 497 495 214 [00360]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.80 (1H, s), 11.22 (1H, s), 7.77 (1H, d, J = 8.6 Hz), 7.59 (1H, d, J = 9.2 Hz), 7.31 (1H, t, J = 73.5 Hz), 7.27 (1H, s), 7.21 (1H, dd, J = 9.2, 1.6 Hz), 6.30 (1H, s), 4.12-3.98 (1H, m), 2.23 (3H, s), 2.19-2.07 (2H, m), 1.75-1.63 (1H, m), 1.58-1.18 (8H, m), 1.07 (3H, d, J = 6.5 Hz). 554 552 215 [00361]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.79 (1H, s), 11.12 (1H, s), 7.59 (1H, d, J= 8.1 Hz), 7.34 (1H, d, J = 8.6 Hz), 7.22 (1H, t, J = 74.1 Hz), 7.13 (1H, d, J = 8.6 Hz), 7.06 (1H, s), 6.30 (1H, s), 4.14-3.98 (1H, m), 2.22 (3H, s), 2.19 (3H, s), 2.11-1.99 (2H, m), 1.75-1.61 (1H, m), 1.59-1.16 (8H, m), 1.08 (3H, d, J = 6.5 Hz). 490 488 216 [00362]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.16 (1H, s), 8.65-8.58 (1H, m), 8.34 (1H, d, J = 8.8 Hz), 7.43 (1H, s), 7.35-7.28 (2H, m), 4.01-3.84 (1H, m), 2.73-2.59 (2H, m), 2.64 (3H, d, J = 4.8 Hz), 2.42 (1H, dd, J = 12.6, 8.4 Hz), 2.35-2.19 (3H, m), 2.22 (3H, s), 2.03-1.95 (2H, m), 1.64-1.45 (2H, m), 1.04 (3H, d, J = 6.5 Hz). 436 434
TABLE-US-00028 TABLE 1-28 217 [00363]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.79 (1H, s), 11.16 (1H, s), 7.55 (1H, d, J = 7.5 Hz), 7.42 (1H, s), 7.33-7.25 (2H, m), 6.29 (1H, s), 4.12-3.99 (1H, m), 2.74-2.63 (2H, m), 2.41 (1H, dd, J = 12.3, 8.0 Hz), 2.35-2.14 (9H, m), 1.99 (2H, d, J = 13.5 Hz), 1.62-1.49 (2H, m), 1.07 (3H, d, J = 6.5 Hz). 459 457 218 [00364]![embedded image]()
1H-NMR (DMSO-D6) ?: 10.94 (1H, s), 8.69 (1H, d, J = 5.3 Hz), 8.41 (1H, d, J = 9.0 Hz), 7.08 (1H, d, J = 9.0 Hz), 6.83 (1H, d, J = 2.3 Hz), 6.78 (1H, dd, J = 9.0, 2.3 Hz), 3.94-3.85 (1H, m), 3.72 (4H, dd, J = 5.5, 4.2 Hz), 3.14 (4H, dd, J = 5.5, 4.2 Hz), 2.76-2.70 (1H, m), 2.17 (3H, s), 2.03-1.95 (2H, m), 1.68-1.61 (1H, m), 1.53-1.16 (8H, m), 1.05 (3H, d, J = 6.5 Hz), 0.63-0.58 (4H, m). 512 510 219 [00365]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.19 (1H, s), 8.06 (1H, s), 7.78 (1H, s), 7.72 (1H, dd, J = 8.6, 2.5 Hz), 7.65 (1H, d, J = 8.6 Hz), 7.51 (1H, dd, J = 8.6, 6.0 Hz), 7.32 (1H, td, J = 8.6, 2.5 Hz), 4.08-3.99 (1H, m), 3.82 (3H, s), 2.15-2.08 (2H, m), 1.70-1.63 (1H, m), 1.53- 1.20 (8H, m), 1.06 (3H, d, J = 6.5 Hz). 506 504 220 [00366]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.13 (1H, s), 8.68 (1H, d, J = 5.5 Hz), 8.41 (1H, d, J = 9.2 Hz), 8.07 (1H, s), 6.77 (1H, s), 3.95-3.83 (1H, m), 3.86 (3H, s), 2.78-2.69 (1H, m), 2.19 (3H, s), 2.07-1.97 (2H, m), 1.69-1.14 (9H, m), 1.06 (3H, d, J = 6.7 Hz), 0.66-0.56 (4H, m). 458 456 221 [00367]![embedded image]()
1H-NMR (DMSO-D6) ?: 13.01-12.72 (1H, m), 11.04 (1H, s), 7.97 (1H, s), 7.63-7.55 (1H, m), 6.73 (1H, s), 6.31 (1H, s), 4.13-4.00 (1H, m), 3.67 (4H, t, J = 4.7 Hz), 3.64-3.56 (1H, m), 3.46 (4H, t, J = 4.9 Hz), 2.26- 2.19 (2H, m), 2.14 (3H, s), 2.05-1.96 (2H, m), 1.75- 1.64 (1H, m), 1.56-1.20 (8H, m), 1.08 (3H, d, J = 6.5 Hz). 510 508 222 [00368]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.30 (1H, s), 8.03 (1H, d, J = 1.8 Hz), 7.99 (1H, d, J = 8.3 Hz), 7.87 (1H, dd, J = 8.4, 2.0 Hz), 5.89 (1H, d, J = 2.8 Hz), 5.46 (1H, d, J = 8.6 Hz), 3.72-3.61 (1H, m), 2.40-2.31 (1H, m), 2.19-2.07 (2H, m), 1.70-1.57 (1H, m), 1.56-1.06 (8H, m), 0.97 (3H, d, J = 6.5 Hz), 0.56-0.46 (2H, m), 0.31-0.22 (2H, m). 488 486 223 [00369]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.80 (1H, s), 11.30 (1H, s), 7.86 (1H, s), 7.63-7.54 (1H, m), 6.75 (1H, s), 6.31 (1H, s), 4.12-3.99 (1H, m), 3.71 (2H, t, J = 12.8 Hz), 3.49 (2H, t, J = 7.3 Hz), 2.60-2.51 (2H, m), 2.26-2.05 (1H, m), 2.23 (3H, s), 1.96-1.76 (1H, m), 1.74-1.62 (1H, m), 1.60-1.14 (8H, m), 1.08 (3H, d, J = 6.5 Hz). 550 548 224 [00370]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.80 (1H, s), 11.15 (1H, s), 8.10 (1H, s), 7.59 (1H, d, J = 8.3 Hz), 6.75 (1H, s), 6.30 (1H, s), 4.11-4.00 (1H, m), 3.86 (2H, t, J = 13.1 Hz), 3.65 (2H, t, J = 7.4 Hz), 2.60-2.50 (2H, m), 2.23 (3H, s), 2.11-1.98 (2H, m), 1.74-1.62 (1H, m), 1.59-1.12 (8H, m), 1.08 (3H, d, J = 6.5 Hz). 550 548
TABLE-US-00029 TABLE 1-29 225 [00371]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.80 (1H, s), 11.25 (1H, s), 7.96 (1H, s), 7.58 (1H, d, J = 8.3 Hz), 7.08 (1H, s), 6.30 (1H, s), 4.11-3.98 (1H, m), 3.61 (4H, t, J = 4.5 Hz), 3.18-3.05 (4H, m), 2.23 (3H, s), 2.13-1.99 (2H, m), 1.72-1.63 (1H, m), 1.55-1.14 (8H, m), 1.08 (3H, d, J = 6.5 Hz). 530 528 226 [00372]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.80 (1H, s), 11.15 (1H, s), 8.09 (1H, s), 7.59 (1H, d, J = 8.3 Hz), 7.00 (1H, s), 6.31 (1H, s), 4.11-3.99 (1H, m), 3.67 (4H, t, J = 4.7 Hz), 3.51 (4H, t, J = 4.9 Hz), 2.23 (3H, s), 2.10-2.00 (2H, m), 1.73-1.63 (1H, m), 1.57-1.15 (8H, m), 1.08 (3H, d, J = 6.5 Hz). 530 528 227 [00373]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.08 (1H, s), 8.66-8.60 (1H, m), 8.41 (1H, d, J = 9.2 Hz), 7.95 (1H, s), 6.46-6.37 (1H, m), 6.38 (1H, td, J = 56.4, 4.3 Hz), 4.10 (2H, t, J = 8.3 Hz), 3.97-3.86 (3H, m), 3.32- 3.14 (1H, m), 2.64 (3H, d, J = 4.9 Hz), 2.15 (3H, s), 2.05-1.95 (2H, m), 1.71-1.60 (1H, m), 1.59-1.14 (8H, m), 1.06 (3H, d, J = 6.5 Hz). 507 505 228 [00374]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.08 (1H, s), 8.66-8.60 (1H, m), 8.41 (1H, d, J = 9.2 Hz), 8.01 (1H, s), 6.50 (1H, s), 4.39 (4H, t, J = 12.5 Hz), 3.99-3.85 (1H, m), 2.64 (3H, d, J = 4.9 Hz), 2.16 (3H, s), 2.06-1.98 (2H, m), 1.70-1.60 (1H, m), 1.59-1.15 (8H, m), 1.06 (3H, d, J = 6.7 Hz). 507 505 229 [00375]![embedded image]()
1H-NMR (DMSO-D6) ?: 10.94 (1H, s), 7.09 (1H, d, J = 8.6 Hz), 6.84 (1H, d, J = 2.7 Hz), 6.78 (1H, dd, J = 8.6, 2.7 Hz), 5.88 (1H, d, J = 2.7 Hz), 5.46 (1H, d, J = 8.6 Hz), 3.73 (4H, dd, J = 5.8, 4.4 Hz), 3.69-3.64 (1H, m), 3.14 (4H, dd, J = 5.8, 4.4 Hz), 2.37-2.33 (1H, m), 2.18 (3H, s), 2.05-1.96 (2H, m), 1.65-1.58 (1H, m), 1.51-1.36 (3H, m), 1.31- 1.15 (5H, m), 0.97 (3H, d, J = 6.5 Hz), 0.54-0.50 (2H, m), 0.28-0.23 (2H, m). 484 482 230 [00376]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.28 (1H, s), 8.62 (1H, q, J = 4.8 Hz), 8.48 (1H, s), 8.41 (1H, d, J = 9.2 Hz), 7.58 (1H, s), 3.98-3.83 (1H, m), 2.64 (3H, d, J = 4.8 Hz), 2.51 (3H, s), 2.15-2.02 (2H, m), 1.71- 1.59 (1H, m), 1.57-1.15 (8H, m), 1.05 (3H, d, J = 6.5 Hz). 436 434 231 [00377]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.80 (1H, s), 11.28 (1H, s), 8.47 (1H, s), 7.65-7.51 (1H, m), 7.56 (1H, s), 6.31 (1H, s), 4.12-4.00 (1H, m), 2.50 (3H, s), 2.22 (3H, s), 2.14-2.02 (2H, m), 1.74-1.63 (1H, m), 1.55- 1.15 (8H, m), 1.07 (3H, d, J = 6.7 Hz). 459 457 232 [00378]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.75 (1H, s), 11.34 (1H, s), 8.21 (1H, s), 7.90 (1H, d, J = 7.5 Hz), 7.68 (1H, d, J = 8.0 Hz), 7.46 (1H, d, J = 8.0 Hz), 6.22 (1H, s), 4.03-3.91 (1H, m), 2.92-2.82 (1H, m), 2.80-2.71 (1H, m), 2.41-2.30 (3H, m), 2.25 (3H, s), 2.00-1.89 (2H, m), 1.83-1.75 (1H, m), 1.68-1.56 (1H, m), 1.08 (3H, d, J = 6.8 Hz), 1.05 (3H, d, J = 6.5 Hz). 484 482
TABLE-US-00030 TABLE 1-30 233 [00379]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.35 (1H, s), 8.60-8.53 (1H, m), 8.28-8.21 (2H, m), 7.92 (1H, dd, J = 8.0, 1.5 Hz), 7.71 (1H, d, J = 8.0 Hz), 3.90-3.76 (1H, m), 2.90-2.82 (1H, m), 2.77- 2.69 (1H, m), 2.64 (3H, d, J = 5.0 Hz), 2.40-2.29 (3H, m), 2.00-1.89 (2H, m), 1.85-1.75 (1H, m), 1.63-1.52 (1H, m), 1.07 (3H, d, J = 6.8 Hz), 1.03 (3H, d, J = 6.5 Hz). 461 459 234 [00380]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.14 (1H, s), 8.08 (1H, s), 7.25- 7.18 (2H, m), 7.14-7.08 (1H, m), 6.99-6.94 (1H, m), 6.81 (1H, s), 6.11 (1H, t, J = 6.1 Hz), 5.74 (1H, d, J = 8.8 Hz), 4.24 (1H, dd, J = 15.7, 6.1 Hz), 4.16 (1H, dd, J = 15.7, 6.1 Hz), 3.87 (3H, s), 3.74-3.66 (1H, m), 2.20 (3H, s), 2.10-1.99 (2H, m), 1.68-1.61 (1H, m), 1.52-1.13 (8H, m), 0.99 (3H, d, J = 6.5 Hz). 498 496 235 [00381]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.14 (1H, s), 8.07 (1H, s), 7.58 (1H, s), 6.78 (1H, s), 6.47 (1H, d, J = 8.1 Hz), 4.62 (2H, s), 4.31 (2H, t, J = 5.4 Hz), 3.85 (3H, s), 3.83-3.72 (3H, m), 2.19 (3H, s), 2.06-1.98 (2H, m), 1.63-1.15 (9H, m), 1.01 (3H, d, J = 6.5 Hz). 497 495 236 [00382]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.13 (1H, s), 8.06 (1H, s), 7.18- 7.05 (4H, m), 6.79 (1H, s), 6.12 (1H, d, J = 8.3 Hz), 4.44 (2H, s), 3.86 (3H, s), 3.83-3.73 (1H, m), 3.61-3.38 (2H, m), 2.81-2.66 (2H, m), 2.19 (3H, s), 2.05-1.96 (2H, m), 1.63- 1.56 (1H, m), 1.51-1.14 (8H, m), 1.01 (3H, d, J = 6.5 Hz). 506 504 237 [00383]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.13 (1H, s), 8.07 (1H, s), 7.36 (1H, d, J = 1.8 Hz), 6.78 (1H, s), 6.40 (1H, d, J = 8.1 Hz), 6.04 (1H, d, J = 1.8 Hz), 4.54 (2H, s), 4.02 (2H, t, J = 5.4 Hz), 3.86 (3H, s), 3.81-3.72 (3H, m), 2.19 (3H, s), 2.06-1.98 (2H, m), 1.63-1.15 (9H, m), 1.01 (3H, d, J = 6.5 Hz). 496 494 238 [00384]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.80 (1H, s), 11.04 (1H, s), 7.97 (1H, s), 7.63-7.55 (1H, m), 6.46 (1H, s), 6.31 (1H, s), 4.13- 4.00 (1H, m), 3.82 (2H, t, J = 13.4 Hz), 3.61 (2H, t, J = 7.3 Hz), 2.59-2.50 (2H, m), 2.23 (3H, s), 2.15 (3H, s), 2.04-1.97 (2H, m), 1.72-1.64 (1H, m), 1.57-1.19 (8H, m), 1.08 (3H, d, J = 6.5 Hz). 530 528 239 [00385]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.80 (1H, s), 11.13 (1H, s), 8.02 (1H, s), 7.63-7.54 (1H, m), 6.72 (1H, s), 6.31 (1H, s), 4.90 (1H, s), 4.67 (1H, s), 4.12-4.02 (1H, m), 3.76 (1H, d, J = 6.0 Hz), 3.64 (1H, d, J = 7.4 Hz), 3.44 (1H, d, J = 10.2 Hz), 3.32-3.28 (1H, m), 2.23 (3H, s), 2.11-2.00 (2H, m), 1.93- 1.82 (2H, m), 1.73-1.64 (1H, m), 1.56-1.16 (8H, m), 1.08 (3H, d, J = 6.5 Hz). 542 540 240 [00386]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.80 (1H, s), 11.13 (1H, s), 8.02 (1H, s), 7.59 (1H, d, J = 9.0 Hz), 6.80-6.65 (1H, m), 6.31 (1H, s), 4.90 (1H, s), 4.67 (1H, s), 4.13-3.98 (1H, m), 3.76 (1H, d, J = 6.0 Hz), 3.65 (1H, d, J = 7.4 Hz), 3.44 (1H, d, J = 9.0 Hz), 3.32-3.24 (1H, m), 2.23 (3H, s), 2.10-2.00 (2H, m), 1.93-1.81 (2H, m), 1.73-1.65 (1H, m), 1.55-1.15 (8H, m), 1.08 (3H, d, J = 6.5 Hz). 542 540
TABLE-US-00031 TABLE 1-31 241 [00387]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.16 (1H, s), 8.66-8.60 (1H, m), 8.41 (1H, d, J = 9.2 Hz), 8.11 (1H, s), 6.76 (1H, s), 3.95- 3.84 (1H, m), 3.88 (2H, t, J = 13.2 Hz), 3.66 (2H, t, J = 7.4 Hz), 2.64 (3H, d, J = 4.9 Hz), 2.61-2.52 (2H, m), 2.10-2.00 (2H, m), 1.71-1.57 (1H, m), 1.57-1.14 (8H, m), 1.06 (3H, d, J = 6.7 Hz). 527 525 242 [00388]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.15 (1H, s), 8.66-8.60 (1H, m), 8.41 (1H, d, J = 9.2 Hz), 8.10 (1H, s), 7.02 (1H, s), 3.99- 3.83 (1H, m), 3.68 (4H, t, J = 4.9 Hz), 3.53 (4H, t, J = 4.7 Hz), 2.64 (3H, d, J = 4.9 Hz), 2.08-2.00 (2H, m), 1.70-1.60 (1H, m), 1.58-1.16 (8H, m), 1.06 (3H, d, J = 6.7 Hz). 507 505 243 [00389]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.13 (1H, s), 8.67-8.60 (1H, m), 8.41 (1H, d, J = 9.0 Hz), 8.03 (1H, s), 6.79-6.69 (1H, m), 4.91 (1H, s), 4.68 (1H, s), 3.97-3.85 (1H, m), 3.77 (1H, d, J = 7.4 Hz), 3.65 (1H, d, J = 7.4 Hz), 3.48-3.43 (1H, m), 3.33-3.27 (1H, m), 2.64 (3H, d, J = 4.9 Hz), 2.09-1.99 (2H, m), 1.94-1.83 (2H, m), 1.71-1.62 (1H, m), 1.58-1.14 (8H, m), 1.06 (3H, d, J = 6.5 Hz). 519 563 (formic acid adduct) 244 [00390]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.13 (1H, s), 8.67-8.60 (1H, m), 8.41 (1H, d, J = 9.5 Hz), 8.03 (1H, s), 6.78-6.69 (1H, m), 4.91 (1H, s), 4.68 (1H, s), 3.97-3.85 (1H, m), 3.77 (1H, d, J = 7.4 Hz), 3.65 (1H, d, J = 7.4 Hz), 3.48-3.42 (1H, m), 3.32-3.28 (1H, m), 2.64 (3H, d, J = 4.9 Hz), 2.08-2.00 (2H, m), 1.92-1.83 (2H, m), 1.70-1.61 (1H, m), 1.58-1.16 (8H, m), 1.06 (3H, d, J = 6.5 Hz). 519 563 (formic acid adduct) 245 [00391]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.20 (1H, s), 7.87 (1H, dd, J = 8.4, 2.7 Hz), 7.46 (1H, dd, J = 8.6, 5.8 Hz), 7.34 (1H, td, J = 8.5, 2.6 Hz), 5.89 (1H, d, J = 2.8 Hz), 5.46 (1H, d, J = 8.3 Hz), 3.72-3.61 (1H, m), 2.40-2.31 (1H, m), 2.19-2.08 (2H, m), 1.69-1.57 (1H, m), 1.55-1.08 (8H, m), 0.97 (3H, d, J = 6.5 Hz), 0.55-0.48 (2H, m), 0.29-0.23 (2H, m). 529 527 246 [00392]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.14 (1H, s), 8.66-8.61 (1H, m), 8.41 (1H, d, J = 9.2 Hz), 8.07 (1H, s), 6.90 (1H, s), 4.45- 4.40 (2H, m), 3.97-3.81 (1H, m), 3.86 (2H, d, J = 11.6 Hz), 3.03-2.96 (1H, m), 2.64 (3H, d, J = 4.9 Hz), 2.09-1.99 (2H, m), 1.87-1.80 (2H, m), 1.75-1.17 (12H, m), 1.06 (3H, d, J = 6.5 Hz). 533 577 (formic acid adduct) 247 [00393]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.80 (1H, s), 11.14 (1H, s), 8.06 (1H, s), 7.63-7.55 (1H, m), 6.88 (1H, s), 6.31 (1H, s), 4.44- 4.39 (2H, m), 4.11-4.00 (1H, m), 3.85 (2H, d, J = 12.5 Hz), 3.02-2.95 (2H, m), 2.23 (3H, s), 2.09-2.01 (2H, m), 1.87- 1.64 (5H, m), 1.56-1.17 (8H, m), 1.08 (3H, d, J = 6.5 Hz). 556 554 248 [00394]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.04 (1H, s), 8.66-8.59 (1H, m), 8.41 (1H, d, J = 9.2 Hz), 7.98 (1H, s), 6.47 (1H, s), 3.96- 3.84 (1H, m), 3.84 (2H, t, J = 13.4 Hz), 3.63 (2H, t, J = 7.3 Hz), 2.64 (3H, d, J = 4.9 Hz), 2.60-2.52 (2H, m), 2.16 (3H, s), 2.04-1.96 (2H, m), 1.69-1.60 (1H, m), 1.58-1.14 (8H, m), 1.06 (3H, d, J = 6.7 Hz). 507 505
TABLE-US-00032 TABLE 1-32 249 [00395]![embedded image]()
1H-NMR (DMSO-D6) ?: 13.02-12.64 (1H, m), 11.04 (1H, s), 7.91 (1H, s), 7.79-7.49 (1H, m), 6.58-6.24 (2H, m), 4.86 (1H, s), 4.66 (1H, s), 4.13-4.00 (1H, m), 3.76 (1H, d, J = 7.2 Hz), 3.64 (1H, d, J = 7.2 Hz), 3.44 (1H, d, J = 10.2 Hz), 3.24 (1H, d, J = 10.2 Hz), 2.22 (3H, s), 2.13 (3H, s), 2.05-1.96 (2H, m), 1.93-1.80 (2H, m), 1.73-1.63 (1H, m), 1.56-1.16 (8H, m), 1.08 (3H, d, J = 6.5 Hz). 522 520 250 [00396]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.80 (1H, s), 11.02 (1H, s), 7.91 (1H, s), 7.63-7.54 (1H, m), 6.42 (1H, s), 6.31 (1H, s), 4.85 (1H, s), 4.65 (1H, s), 4.11-4.00 (1H, m), 3.76 (1H, d, J = 7.2 Hz), 3.63 (1H, d, J = 7.2 Hz), 3.43 (1H, d, J = 10.2 Hz), 3.22 (1H, d, J = 10.2 Hz), 2.23 (3H, s), 2.12 (3H, s), 2.05-1.95 (2H, m), 1.91-1.80 (2H, m), 1.72-1.63 (1H, m), 1.57-1.21 (8H, m), 1.08 (3H, d, J = 6.7 Hz). 522 520 251 [00397]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.80 (1H, s), 11.03 (1H, s), 7.95 (1H, s), 7.59 (1H, d, J = 8.1 Hz), 6.62 (1H, s), 6.31 (1H, s), 4.42 (2H, s), 4.12-3.98 (1H, m), 3.81 (2H, d, J = 12.3 Hz), 2.93 (2H, d, J = 12.3 Hz), 2.23 (3H, s), 2.13 (3H, s), 2.04- 1.95 (2H, m), 1.88-1.63 (5H, m), 1.57-1.18 (8H, m), 1.08 (3H, d, J = 6.5 Hz). 536 534 252 [00398]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.19 (1H, s), 8.84 (1H, d, J = 9.0 Hz), 8.05 (1H, d, J = 8.8 Hz), 7.73 (1H, d, J = 8.8 Hz), 7.70 (1H, dd, J = 8.8, 2.7 Hz), 7.50 (1H, dd, J = 8.8, 6.0 Hz), 7.30 (1H, td, J = 8.8, 2.7 Hz), 4.22-4.13 (1H, m), 2.69 (3H, s), 2.16-2.08 (2H, m), 1.75-1.60 (2H, m), 1.58-1.49 (1H, m), 1.42-1.23 (6H, m), 1.16 (3H, d, J = 6.5 Hz). 518 516 253 [00399]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.19 (1H, s), 9.01 (1H, d, J = 1.0 Hz), 8.58 (1H, d, J = 1.0 Hz), 8.50 (1H, d, J = 8.6 Hz), 7.71 (1H, dd, J = 8.6, 2.5 Hz), 7.50 (1H, dd, J = 8.6, 6.0 Hz), 7.31 (1H, td, J = 8.6, 2.5 Hz), 4.18-4.11 (1H, m), 2.58 (3H, s), 2.18-2.06 (2H, m), 1.73-1.68 (1H, m), 1.65-1.45 (2H, m), 1.43-1.22 (6H, m), 1.13 (3H, d, J = 6.7 Hz). 518 516 254 [00400]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.25 (1H, s), 8.05 (1H, s), 7.76 (1H, s), 7.74 (1H, dd, J = 8.6, 2.6 Hz), 7.64 (1H, d, J = 7.4 Hz), 7.54 (1H, dd, J = 8.6, 6.0 Hz), 7.35 (1H, td, J = 8.6, 2.6 Hz), 4.09-4.02 (1H, m), 3.82 (3H, s), 2.73-2.66 (2H, m), 2.40-2.21 (4H, m), 2.11-2.04 (2H, m), 1.63-1.51 (2H, m), 1.05 (3H, d, J = 6.7 Hz). 507 505 255 [00401]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.25 (1H, s), 8.85 (1H, s), 8.24 (1H, s), 8.03 (1H, d, J = 8.1 Hz), 7.74 (1H, dd, J = 8.6, 2.5 Hz), 7.53 (1H, dd, J = 8.6, 5.9 Hz), 7.34 (1H, td, J = 8.6, 2.5 Hz), 4.13-4.05 (1H, m), 2.75-2.65 (2H, m), 2.41-2.24 (4H, m), 2.12-2.03 (2H, m), 1.63-1.51 (2H, m), 1.08 (3H, d, J = 6.7 Hz). 561 559 256 [00402]![embedded image]()
1H-NMR (DMSO-D6) ?: 10.99 (1H, s), 8.63 (1H, q, J = 4.9 Hz), 8.41 (1H, d, J = 9.0 Hz), 7.14 (1H, d, J = 8.4 Hz), 6.91 (1H, dd, J = 8.4, 2.3 Hz), 6.70 (1H, d, J = 2.3 Hz), 3.95-3.85 (1H, m), 3.72 (4H, dd, J = 5.6, 4.6 Hz), 3.06 (4H, dd, J = 5.6, 4.6 Hz), 2.64 (3H, d, J = 4.9 Hz), 2.10 (3H, s), 2.09- 2.00 (2H, m), 1.69-1.61 (1H, m), 1.52-1.39 (3H, m), 1.32- 1.16 (5H, m), 1.06 (3H, d, J = 6.7 Hz). 486 484
TABLE-US-00033 TABLE 1-33 257 [00403]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.13 (1H, s), 8.07 (1H, s), 7.90 (1H, s), 6.78 (1H, s), 6.50 (1H, d, J = 8.1 Hz), 4.61 (2H, s), 4.09 (2H, t, J = 5.3 Hz), 3.88-3.71 (3H, m), 3.86 (3H, s), 2.19 (3H, s), 2.06-1.97 (2H, m), 1.63-1.14 (9H, m), 1.02 (3H, d, J = 6.5 Hz). 497 495 258 [00404]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.13 (1H, s), 8.33 (1H, dd, J = 4.7, 1.5 Hz), 8.06 (1H, s), 7.50 (1H, dd, J = 7.6, 1.5 Hz), 7.15 (1H, dd, J = 7.6, 4.7 Hz), 6.79 (1H, s), 6.27 (1H, d, J = 8.3 Hz), 4.49 (2H, s), 3.86 (3H, s), 3.83-3.74 (1H, m), 3.61-3.49 (2H, m), 2.76-2.70 (2H, m), 2.19 (3H, s), 2.05-1.97 (2H, m), 1.63-1.56 (1H, m), 1.52-1.15 (8H, m), 1.01 (3H, d, J = 6.5 Hz). 507 505 259 [00405]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.14 (1H, s), 8.06 (1H, s), 6.78 (1H, s), 6.55 (1H, d, J = 8.1 Hz), 4.75 (2H, s), 4.13-4.07 (2H, m), 3.85 (3H, s), 3.83-3.70 (3H, m), 2.19 (3H, s), 2.07- 1.98 (2H, m), 1.62-1.16 (9H, m), 1.02 (3H, d, J = 6.7 Hz). 565 563 260 [00406]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.13 (1H, s), 8.65 (1H, s), 8.06 (1H, s), 6.78 (1H, s), 6.32 (1H, d, J = 8.1 Hz), 4.41 (1H, d, J = 16.0 Hz), 4.36 (1H, d, J = 16.0 Hz), 3.86 (3H, s), 3.80- 3.71 (1H, m), 3.63-3.51 (2H, m), 2.70 (2H, t, J = 5.9 Hz), 2.19 (3H, s), 2.06-1.97 (2H, m), 1.62-1.55 (1H, m), 1.52- 1.14 (8H, m), 1.00 (3H, d, J = 6.7 Hz). 497 495 261 [00407]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.14 (1H, s), 8.46-8.41 (1H, m), 8.08 (1H, s), 7.59 (1H, td, J = 7.7, 1.8 Hz), 7.22-7.15 (2H, m), 6.81 (1H, s), 6.25 (1H, t, J = 5.9 Hz), 5.88 (1H, d, J = 8.3 Hz), 4.28 (1H, dd, J = 16.4, 5.9 Hz), 4.22 (1H, dd, J = 16.4, 5.9 Hz), 3.87 (3H, s), 3.74-3.64 (1H, m), 2.20 (3H, s), 2.10-1.98 (2H, m), 1.69-1.60 (1H, m), 1.54-1.13 (8H, m), 0.99 (3H, d, J = 6.5 Hz). 481 479 262 [00408]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.14 (1H, s), 8.08 (1H, s), 7.33- 7.21 (5H, m), 7.05 (1H, d, J = 8.6 Hz), 6.81 (1H, s), 5.02 (1H, d, J = 12.7 Hz), 4.93 (1H, d, J = 12.7 Hz), 3.87 (3H, s), 3.65-3.56 (1H, m), 2.20 (3H, s), 2.09-1.98 (2H, m), 1.67- 1.58 (1H, m), 1.54-1.13 (8H, m), 1.01 (3H, d, J = 6.5 Hz). 481 479 263 [00409]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.15 (1H, s), 8.07 (1H, s), 8.00 (1H, d, J = 8.1 Hz), 6.79 (1H, s), 3.88-3.76 (1H, m), 3.86 (3H, s), 3.57 (1H, d, J = 18.0 Hz), 3.50 (1H, d, J = 18.0 Hz), 2.20 (3H, s), 2.09-2.00 (2H, m), 1.63-1.57 (1H, m), 1.53- 1.15 (8H, m), 1.01 (3H, d, J = 6.5 Hz). 414 412 264 [00410]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.13 (1H, s), 8.31 (1H, dd, J = 4.9, 1.4 Hz), 8.06 (1H, s), 7.50 (1H, dd, J = 7.6, 1.4 Hz), 7.17 (1H, dd, J = 7.6, 4.9 Hz), 6.78 (1H, s), 6.24 (1H, d, J = 8.3 Hz), 4.47 (2H, s), 3.86 (3H, s), 3.82-3.73 (1H, m), 3.68-3.56 (2H, m), 2.81 (2H, t, J = 5.9 Hz), 2.19 (3H, s), 2.06-1.97 (2H, m), 1.64-1.56 (1H, m), 1.53-1.15 (8H, m), 1.01 (3H, d, J = 6.5 Hz). 507 505
TABLE-US-00034 TABLE 1-34 265 [00411]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.27 (1H, s), 8.63 (1H, q, J = 4.8 Hz), 8.413 (1H, d, J = 9.2 Hz), 8.412 (1H, s), 7.62 (1H, s), 3.99-3.83 (1H, m), 2.64 (3H, d, J = 4.8 Hz), 2.23-2.13 (1H, m), 2.13-2.01 (2H, m), 1.72-1.59 (1H, m), 1.57- 1.12 (8H, m), 1.05 (3H, d, J = 6.5 Hz), 1.05- 0.94 (4H, m). 462 460 266 [00412]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.80 (1H, s), 11.27 (1H, s), 8.41 (1H, s), 7.67-7.55 (1H, m), 7.61 (1H, s), 6.31 (1H, s), 4.14-3.98 (1H, m), 2.23 (3H, s), 2.21-2.01 (3H, m), 1.76-1.62 (1H, m), 1.58-1.15 (8H, m), 1.07 (3H, d, J = 6.5 Hz), 1.05-0.92 (4H, m). 485 483 267 [00413]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.02 (1H, s), 8.66- 8.61 (1H, m), 8.41 (1H, d, J = 9.5 Hz), 7.92 (1H, s), 6.43 (1H, s), 4.86 (1H, s), 4.66 (1H, s), 3.97- 3.87 (1H, m), 3.77 (1H, d, J = 7.4 Hz), 3.64 (1H, d, J = 7.4 Hz), 3.44 (1H, d, J = 10.4 Hz), 3.23 (1H, d, J = 10.4 Hz), 2.64 (3H, d, J = 4.9 Hz), 2.13 (3H, s), 2.04-1.95 (2H, m), 1.93-1.81 (2H, m), 1.73- 1.61 (1H, m), 1.58-1.16 (8H, m), 1.06 (3H, d, J = 6.5 Hz). 499 543 (formic acid adduct) 268 [00414]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.02 (1H, s), 8.66-8.60 (1H, m), 8.41 (1H, d, J = 9.2 Hz), 7.92 (1H, s), 6.44 (1H, s), 4.86 (1H, s), 4.66 (1H, s), 3.98-3.84 (1H, m), 3.77 (1H, d, J = 7.2 Hz), 3.63 (1H, d, J = 7.2 Hz), 3.44 (1H, d, J = 9.9 Hz), 3.23 (1H, d, J = 9.9 Hz), 2.64 (3H, d, J = 4.9 Hz), 2.13 (3H, s), 2.04-1.95 (2H, m), 1.92-1.81 (2H, m), 1.70- 1.61 (1H, m), 1.59-1.17 (8H, m), 1.06 (3H, d, J = 6.5 Hz). 499 N.D. 269 [00415]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.03 (1H, s), 8.66-8.60 (1H, m), 8.41 (1H, d, J = 9.0 Hz), 7.96 (1H, s), 6.63 (1H, s), 4.43 (2H, s), 3.98-3.84 (1H, m), 3.82 (2H, d, J = 12.0 Hz), 2.94 (2H, dd, J = 12.5, 2.3 Hz), 2.64 (3H, d, J = 4.9 Hz), 2.14 (3H, s), 2.03- 1.95 (2H, m), 1.87-1.61 (5H, m), 1.60-1.15 (8H, m), 1.06 (3H, d, J = 6.5 Hz). 513 N.D. 270 [00416]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.30 (1H, s), 8.36 (1H, d, J = 1.6 Hz), 7.96 (1H, dd, J = 7.9, 1.6 Hz), 7.67 (1H, d, J = 7.9 Hz), 7.36 (1H, d, J = 1.8 Hz), 6.39 (1H, d, J = 8.3 Hz), 6.04 (1H, d, J = 1.8 Hz), 4.53 (2H, s), 4.01 (2H, t, J = 5.4 Hz), 3.83-3.69 (3H, m), 2.16-2.06 (2H, m), 1.63-1.55 (1H, m), 1.54- 1.12 (8H, m), 1.00 (3H, d, J = 6.5 Hz). 554 552 271 [00417]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.31 (1H, s), 8.35 (1H, d, J = 1.6 Hz), 7.96 (1H, dd, J = 8.0, 1.5 Hz), 7.67 (1H, d, J = 8.1 Hz), 7.58 (1H, s), 6.47 (1H, d, J = 8.1 Hz), 4.67-4.56 (2H, m), 4.30 (2H, t, J = 5.4 Hz), 3.82-3.72 (3H, m), 2.16-2.08 (2H, m), 1.63-1.56 (1H, m), 1.51-1.13 (8H, m), 1.00 (3H, d, J = 6.5 Hz). 555 553 272 [00418]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.80 (1H, s), 11.29 (1H, s), 8.00 (1H, d, J = 2.0 Hz), 7.96 (1H, d, J = 8.4 Hz), 7.84 (1H, dd, J = 8.4, 2.0 Hz), 7.63-7.55 (1H, m), 6.31 (1H, s), 4.13-3.98 (1H, m), 2.23 (3H, s), 2.20-2.03 (2H, m), 1.74-1.62 (1H, m), 1.59-1.15 (8H, m), 1.08 (3H, d, J = 6.9 Hz). 513 511
TABLE-US-00035 TABLE 1-35 273 [00419]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.80 (1H, s), 11.08 (1H, s), 7.99 (1H, s), 7.63-7.55 (1H, m), 6.48 (1H, s), 6.31 (1H, s), 4.38 (4H, t, J = 12.5 Hz), 4.11-4.01 (1H, m), 2.23 (3H, s), 2.16 (3H, s), 2.07-1.98 (2H, m), 1.73- 1.65 (1H, m), 1.59-1.18 (8H, m), 1.08 (3H, d, J = 6.5 Hz). 516 514 274 [00420]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.16 (1H, s), 8.66-8.60 (1H, m), 8.41 (1H, d, J = 9.0 Hz), 8.10 (1H, s), 7.16 (1H, s), 3.97-3.86 (1H, m), 3.75 (4H, t, J = 5.7 Hz), 2.64 (3H, d, J = 4.9 Hz), 2.09-1.94 (6H, m), 1.70-1.62 (1H, m), 1.57-1.15 (8H, m), 1.06 (3H, d, J = 6.7 Hz). 541 539 275 [00421]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.15 (1H, s), 8.10 (1H, s), 7.36 (1H, d, J = 1.8 Hz), 7.03 (1H, s), 6.40 (1H, d, J = 8.3 Hz), 6.04 (1H, s), 4.54 (2H, s), 4.02 (2H, t, J = 5.3 Hz), 3.80-3.73 (3H, m), 3.71-3.65 (4H, m), 3.57- 3.49 (4H, m), 2.09-1.99 (2H, m), 1.64-1.55 (1H, m), 1.53- 1.14 (8H, m), 1.01 (3H, d, J = 6.7 Hz). 571 569 276 [00422]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.28 (1H, s), 8.48 (1H, s), 7.59 (1H, s), 7.35 (1H, d, J = 1.3 Hz), 6.39 (1H, d, J = 8.1 Hz), 6.03 (1H, d, J = 1.3 Hz), 4.53 (2H, s), 4.01 (2H, t, J = 5.4 Hz), 3.85- 3.68 (3H, m), 2.51 (3H, s), 2.16- 2.02 (2H, m), 1.66-1.54 (1H, m), 1.54-1.14 (8H, m), 1.01 (3H, d, J = 6.7 Hz). 500 498 277 [00423]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.26 (1H, s), 8.42 (1H, s), 7.64 (1H, s), 7.34 (1H, d, J = 0.9 Hz), 6.39 (1H, d, J = 8.1 Hz), 6.03 (1H, d, J = 0.9 Hz), 4.53 (2H, s), 4.01 (2H, t, J = 5.4 Hz), 3.86-3.68 (3H, m), 2.24-2.14 (1H, m), 2.14- 2.01 (2H, m), 1.64-1.54 (1H, m), 1.54-1.12 (8H, m), 1.08-0.95 (4H, m), 1.01 (3H, d, J = 6.3 Hz). 526 524 278 [00424]![embedded image]()
Mixture of two diastereomers due to chlorofluoromethyl moiety 1H-NMR (DMSO-D6) ?: 11.20 (1H, s), 8.42 (1H, d, J = 8.6 Hz), 7.74 (1H, dd, J = 8.6, 2.4 Hz), 7.53 (1H, dd, J = 8.6, 6.2 Hz), 7.35 (1H, td, J = 8.4, 2.4 Hz), 6.63 (1H, d, J = 49.5 Hz), 3.93- 3.84 (1H, m), 2.18-2.10 (2H, m), 1.65-1.56 (1H, m), 1.51-1.19 (8H, m), 1.05 (3H, dd, J = 6.2, 4.5 Hz). 492 490 279 [00425]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.20 (1H, s), 7.73 (2H, dd, J = 8.6, 2.5 Hz), 7.53 (1H, dd, J = 8.6, 6.0 Hz), 7.34 (1H, td, J = 8.6, 2.5 Hz), 6.49 (1H, dt, J = 15.5, 6.1 Hz), 5.96 (1H, d, J = 15.5 Hz), 3.95-3.85 (1H, m), 2.96 (2H, d, J = 6.1 Hz), 2.13 (6H, s), 2.11-2.09 (2H, m), 1.65- 1.59 (1H, m), 1.52-1.18 (8H, m), 1.01 (3H, d, J = 6.5 Hz). 509 507 280 [00426]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.35 (1H, s), 8.63-8.56 (1H, m), 8.30 (1H, d, J = 8.8 Hz), 8.23 (1H, d, J = 1.5 Hz), 7.93 (1H, dd, J = 8.0, 1.5 Hz), 7.73 (1H, d, J = 8.0 Hz), 3.84-3.74 (1H, m), 2.90-2.72 (2H, m), 2.65 (3H, d, J = 4.8 Hz), 2.42 (1H, dd, J = 12.6, 7.6 Hz), 2.35- 2.25 (2H, m), 2.00-1.89 (2H, m), 1.87-1.79 (1H, m), 1.69-1.59 (1H, m), 1.05 (3H, d, J = 6.8 Hz), 1.02 (3H, d, J = 6.5 Hz). 461 459
TABLE-US-00036 TABLE 1-36 281 [00427]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.78 (1H, s), 11.35 (1H, s), 8.21 (1H, d, J = 1.5 Hz), 7.91 (1H, d, J = 7.8 Hz), 7.71 (1H, d, J = 7.8 Hz), 7.55-7.47 (1H, m), 6.28 (1H, s), 3.99-3.87 (1H, m), 2.94-2.75 (2H, m), 2.44 (1H, dd, J = 12.6, 7.1 Hz), 2.38-2.13 (7H, m), 2.01-1.90 (2H, m), 1.87-1.79 (1H, m), 1.68-1.58 (1H, m), 1.07 (3H, d, J = 6.8 Hz), 1.05 (3H, d, J = 6.5 Hz). 484 482 282 [00428]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.19 (1H, s), 7.74 (1H, dd, J = 8.6, 2.5 Hz), 7.54 (1H, dd, J = 8.6, 6.1 Hz), 7.35 (1H, td, J = 8.6, 2.5 Hz), 5.56 (1H, d, J = 8.6 Hz), 3.76- 3.69 (1H, m), 3.35-3.31 (2H, m), 3.11-3.02 (2H, m), 2.15-2.10 (2H, m), 1.70 (2H, t, J = 6.8 Hz), 1.65-1.59 (1H, m), 1.52-1.13 (8H, m), 0.99 (3H, d, J = 6.5 Hz), 0.51 (4H, s). 521 519 283 [00429]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.20 (1H, s), 7.74 (1H, dd, J = 8.6, 2.5 Hz), 7.54 (1H, dd, J = 8.6, 6.1 Hz), 7.35 (1H, td, J = 8.6, 2.5 Hz), 6.02 (1H, d, J = 8.6 Hz), 3.80-3.73 (1H, m), 3.53 (2H, t, J = 4.7 Hz), 3.29-3.16 (4H, m), 2.17-2.09 (2H, m), 1.66-1.60 (1H, m), 1.51- 1.13 (8H, m), 0.98 (3H, d, J = 6.5 Hz), 0.60-0.57 (2H, m), 0.49-0.46 (2H, m). 537 535 284 [00430]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.26 (1H, s), 7.76 (1H, dd, J = 8.7, 2.5 Hz), 7.56 (1H, dd, J = 8.7, 5.9 Hz), 7.37 (1H, td, J = 8.7, 2.5 Hz), 5.52 (1H, d, J = 7.9 Hz), 3.79-3.70 (1H, m), 3.28 (2H, t, J = 6.8 Hz), 3.09-2.98 (2H, m), 2.70-2.62 (2H, m), 2.32-2.17 (4H, m), 2.14- 2.02 (2H, m), 1.67 (2H, q, J = 6.2 Hz), 1.61-1.54 (2H, m), 0.99 (3H, d, J = 6.2 Hz), 0.53-0.46 (4H, m). 522 520 285 [00431]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.30 (1H, s), 8.64 (1H, q, J = 4.8 Hz), 8.60 (1H, d, J = 9.2 Hz), 7.75 (1H, dd, J = 8.6, 2.7 Hz), 7.56 (1H, dd, J = 8.6, 5.9 Hz), 7.37 (1H, ddd, J = 8.6, 8.1, 2.7 Hz), 4.16-3.99 (1H, m), 2.65 (3H, d, J = 4.8 Hz), 2.16-1.97 (3H, m), 1.86- 1.52 (7H, m), 1.08 (3H, d, J = 6.5 Hz). 501 499 286 [00432]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.83 (1H, s), 11.29 (1H, s), 7.81 (1H, d, J = 8.6 Hz), 7.74 (1H, dd, J = 8.6, 2.7 Hz), 7.55 (1H, dd, J = 8.6, 5.9 Hz), 7.36 (1H, ddd, J = 8.6, 8.1, 2.7 Hz), 6.32 (1H, s), 4.29-4.16 (1H, m), 2.24 (3H, s), 2.14-1.95 (3H, m), 1.88-1.53 (7H, m), 1.11 (3H, d, J = 6.5 Hz). 524 522 287 [00433]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.19 (1H, s), 8.64 (1H, q, J = 4.8 Hz), 8.42 (1H, d, J = 9.2 Hz), 7.81 (1H, s), 7.80 (1H, d, J = 8.1 Hz), 7.53 (1H, d, J = 8.1 Hz), 3.95-3.86 (1H, m), 2.64 (3H, d, J = 4.8 Hz), 2.30 (3H, s), 2.08-2.00 (2H, m), 1.68-1.61 (1H, m), 1.55-1.44 (3H, m), 1.39-1.18 (5H, m), 1.06 (3H, d, J = 6.5 Hz). 426 424 288 [00434]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.67 (1H, s), 11.21 (1H, s), 7.71 (1H, d, J = 8.6 Hz), 7.50 (1H, d, J = 7.4 Hz), 7.38-7.31 (2H, m), 6.18 (1H, s), 3.78-3.70 (1H, m), 2.72-2.65 (2H, m), 2.58-2.53 (2H, m), 2.36-2.29 (1H, m), 2.26 (3H, s), 2.09-1.92 (2H, m), 1.58-1.48 (1H, m), 1.45-1.35 (1H, m), 1.09 (3H, d, J = 6.5 Hz), 0.92 (3H, d, J = 6.5 Hz). 521 519
TABLE-US-00037 TABLE 1-37 289 [00435]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.23 (1H, s), 8.56 (1H, d, J = 5.0 Hz), 8.27 (1H, d, J = 7.9 Hz), 7.74 (1H, dd, J = 8.6, 2.5 Hz), 7.47 (1H, dd, J = 8.6, 6.0 Hz), 7.33 (1H, td, J = 8.6, 2.5 Hz), 3.65-3.58 (1H, m), 2.72-2.65 (2H, m), 2.62 (3H, d, J = 5.0 Hz), 2.47-2.41 (2H, m), 2.36-2.28 (1H, m), 2.10-1.95 (2H, m), 1.60-1.40 (2H, m), 1.06 (3H, d, J = 6.5 Hz), 0.90 (3H, d, J = 6.5 Hz). 498 N.D. 290 [00436]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.83 (1H, s), 11.26 (1H, s), 7.77 (1H, dd, J = 8.6, 2.6 Hz), 7.65 (1H, d, J = 8.1 Hz), 7.57 (1H, dd, J = 8.6, 6.0 Hz), 7.39 (1H, td, J = 8.6, 2.6 Hz), 6.32 (1H, s), 3.98-3.91 (1H, m), 2.79-2.70 (1H, m), 2.60-2.54 (2H, m), 2.46-2.40 (2H, m), 2.24 (3H, s), 2.15-2.05 (2H, m), 1.70- 1.50 (2H, m), 1.06 (3H, d, J = 6.3 Hz), 0.86 (3H, d, J = 6.3 Hz). 521 519 291 [00437]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.26 (1H, s), 8.65 (1H, q, J = 4.9 Hz), 8.46 (1H, d, J = 9.5 Hz), 7.76 (1H, dd, J = 8.6, 2.4 Hz), 7.56 (1H, dd, J = 8.6, 6.0 Hz), 7.38 (1H, td, J = 8.6, 2.4 Hz), 3.82-3.74 (1H, m), 2.77-2.68 (1H, m), 2.65 (3H, d, J = 4.9 Hz), 2.61-2.38 (4H, m), 2.14-2.06 (2H, m), 1.68-1.48 (2H, m), 1.04 (3H, d, J = 6.6 Hz), 0.81 (3H, d, J = 6.6 Hz). 498 N.D. 292 [00438]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.30 (1H, s), 8.69 (1H, d, J = 5.1 Hz), 8.43 (1H, d, J = 9.2 Hz), 8.00 (1H, d, J = 1.8 Hz), 7.98 (1H, d, J = 8.5 Hz), 7.86 (1H, dd, J = 8.5, 1.8 Hz), 3.95-3.85 (1H, m), 2.76-2.70 (1H, m), 2.15-2.05 (2H, m), 1.68-1.61 (1H, m), 1.56-1.35 (4H, m), 1.33-1.14 (4H, m), 1.06 (3H, d, J = 6.7 Hz), 0.64-0.58 (4H, m). 516 514 293 [00439]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.31 (1H, s), 9.77 (1H, s), 8.79 (1H, d, J = 8.6 Hz), 8.01 (1H, d, J = 1.6 Hz), 7.97 (1H, d, J = 8.6 Hz), 7.85 (1H, dd, J = 8.4, 1.9 Hz), 4.16-4.05 (1H, m), 2.19-2.06 (2H, m), 1.72-1.64 (1H, m), 1.63-1.18 (8H, m), 1.12 (3H, d, J = 6.5 Hz). 501 499 294 [00440]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.27 (1H, s), 8.67-8.60 (1H, m), 8.43 (1H, d, J = 9.2 Hz), 7.88 (1H, d, J = 8.6 Hz), 7.56 (1H, d, J = 2.7 Hz), 7.48-7.42 (1H, m), 3.96-3.85 (1H, m), 2.63 (3H, d, J = 4.8 Hz), 2.19-2.08 (2H, m), 1.69-1.62 (1H, m), 1.59-1.12 (8H, m), 1.05 (3H, d, J = 6.5 Hz). 549 547 295 [00441]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.27 (1H, s), 8.69 (1H, d, J = 5.4 Hz), 8.43 (1H, d, J = 9.2 Hz), 7.88 (1H, d, J = 8.6 Hz), 7.56 (1H, d, J = 2.7 Hz), 7.48-7.42 (1H, m), 3.95-3.83 (1H, m), 2.76-2.70 (1H, m), 2.18-2.07 (2H, m), 1.69-1.60 (1H, m), 1.60-1.12 (8H, m), 1.05 (3H, d, J = 6.5 Hz), 0.66-0.53 (4H, m). 575 573 296 [00442]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.18 (1H, s), 8.67-8.59 (1H, m), 8.43 (1H, d, J = 9.2 Hz), 7.66 (1H, d, J = 9.2 Hz), 7.13- 7.08 (2H, m), 4.90-4.77 (2H, m), 3.97-3.85 (1H, m), 2.63 (3H, d, J = 4.8 Hz), 2.19-2.08 (2H, m), 1.69-1.60 (1H, m), 1.59-1.14 (8H, m), 1.05 (3H, d, J = 6.5 Hz). 563 561
TABLE-US-00038 TABLE 1-38 297 [00443]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.18 (1H, s), 8.69 (1H, d, J = 5.4 Hz), 8.43 (1H, d, J = 9.2 Hz), 7.69-7.64 (1H, m), 7.13- 7.07 (2H, m), 4.91-4.77 (2H, m), 3.97-3.83 (1H, m), 2.78- 2.68 (1H, m), 2.18-2.07 (2H, m), 1.69-1.61 (1H, m), 1.59- 1.14 (8H, m), 1.05 (3H, d, J = 6.5 Hz), 0.66-0.53 (4H, m). 589 587 298 [00444]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.80 (1H, s), 11.18 (1H, s), 7.65 (1H, d, J = 8.1 Hz), 7.60 (1H, d, J = 8.1 Hz), 7.12-7.06 (2H, m), 6.30 (1H, s), 4.88-4.76 (2H, m), 4.13-4.00 (1H, m), 2.23 (3H, s), 2.19-2.08 (2H, m), 1.73-1.63 (1H, m), 1.57-1.17 (8H, m), 1.07 (3H, d, J = 6.5 Hz). 586 584 299 [00445]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.21 (1H, s), 8.64-8.58 (1H, m), 8.39 (1H, d, J = 9.0 Hz), 7.91 (1H, s), 7.80 (2H, s), 7.75 (1H, s), 3.95-3.86 (1H, m), 2.63 (3H, d, J = 4.8 Hz), 2.17 (2H, d, J = 13.0 Hz), 1.71-1.64 (1H, m), 1.55-1.15 (8H, m), 1.38 (9H, s), 1.06 (3H, d, J = 6.5 Hz). 564 562 300 [00446]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.35 (1H, s), 8.64-8.58 (1H, m), 8.35 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 2.0 Hz), 8.00 (1H, d, J = 8.5 Hz), 7.88 (1H, dd, J = 8.3, 2.0 Hz), 3.99-3.87 (1H, m), 2.75-2.60 (2H, m), 2.64 (3H, d, J = 5.0 Hz), 2.43 (1H, dd, J = 12.6, 8.1 Hz), 2.35-2.20 (3H, m), 2.14-2.03 (2H, m), 1.75-1.48 (2H, m), 1.05 (3H, d, J = 6.8 Hz). 491 489 301 [00447]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.79 (1H, s), 11.34 (1H, s), 8.06 (1H, d, J = 1.8 Hz), 7.99 (1H, d, J = 8.3 Hz), 7.87 (1H, dd, J = 8.3, 2.0 Hz), 7.60-7.50 (1H, m), 6.28 (1H, s), 4.15-3.99 (1H, m), 2.70 (2H, t, J = 11.6 Hz), 2.43 (1H, dd, J = 12.3, 7.8 Hz), 2.35-2.15 (6H, m), 2.09 (2H, d, J = 12.8 Hz), 1.69- 1.54 (2H, m), 1.07 (3H, d, J = 6.5 Hz). 514 512 302 [00448]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.46-11.09 (2H, m), 8.06 (1H, d, J = 1.8 Hz), 7.99 (1H, d, J = 8.3 Hz), 7.87 (1H, dd, J = 8.4, 1.9 Hz), 7.64 (1H, d, J = 8.3 Hz), 6.74-6.71 (1H, m), 6.57 (1H, s), 4.12-4.02 (1H, m), 2.77-2.63 (2H, m), 2.39 (1H, dd, J = 12.4, 7.1 Hz), 2.35-2.21 (3H, m), 2.14-2.04 (2H, m), 1.72-1.56 (2H, m), 1.07 (3H, d, J = 6.5 Hz). 517 515 303 [00449]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.27 (1H, s), 8.05 (1H, s), 7.87 (1H, m), 7.77 (1H, s), 7.65 (1H, m), 7.56 (1H, m), 7.44 (1H, m), 4.04 (1H, s), 3.81 (3H, s), 2.14 (2H, d, J = 12.4 Hz), 1.67 (1H, d, J = 8.6 Hz), 1.52-1.24 (8H, m), 1.06 (3H, d, J = 6.5 Hz). 572 570 304 [00450]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.80 (1H, s), 11.27 (1H, s), 7.87 (1H, m), 7.60 (1H, d, J = 9.2 Hz), 7.55 (1H, m), 7.43 (1H, d, J = 9.2 Hz), 6.29 (1H, s), 4.05-4.03 (1H, m), 2.23 (3H, s), 2.14 (2H, d, J = 12.4 Hz), 1.70 (1H, s), 1.51-1.25 (8H, m), 1.07 (3H, d, J = 5.9 Hz). 572 570
TABLE-US-00039 TABLE 1-39 305 [00451]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.18 (1H, s), 8.05 (1H, s), 7.78 (1H, s), 7.67 (1H, s), 7.64 (1H, s), 7.11-7.08 (2H, m), 4.82 (2H, q, J = 8.8 Hz), 4.09-3.96 (1H, m), 3.81 (3H, s), 2.14 (2H, d, J = 11.9 Hz), 1.67 (1H, d, J = 9.7 Hz), 1.51-1.24 (8H, m), 1.06 (3H, d, J = 6.5 Hz). 586 584 306 [00452]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.23 (1H, s), 8.64 (1H, q, J = 4.7 Hz), 8.43 (1H, d, J = 9.2 Hz), 7.51 (1H, t, J = 7.8 Hz), 7.40 (1H, d, J = 8.1 Hz), 7.33 (1H, t, J = 73.8 Hz), 7.32 (1H, d, J = 6.5 Hz), 3.91-3.88 (1H, m), 2.63 (3H, d, J = 4.8 Hz), 2.13 (2H, d, J = 11.9 Hz), 1.64 (1H, s), 1.55-1.17 (8H, m), 1.05 (3H, d, J = 6.5 Hz). 531 529 307 [00453]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.81 (1H, s), 11.22 (1H, s), 7.61 (1H, d, J = 8.6 Hz), 7.51-7.48 (1H, m), 7.38 (1H, d, J = 8.1 Hz), 7.32 (1H, t, J = 73.3 Hz), 7.31 (1H, d, J = 7.3 Hz), 6.30 (1H, s), 4.05 (1H, m), 2.23 (3H, s), 2.13 (2H, d, J = 15.6 Hz), 1.69 (1H, s), 1.49-1.24 (8H, m), 1.07 (3H, d, J = 6.5 Hz). 554 552 308 [00454]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.23 (1H, s), 8.69 (1H, d, J = 5.4 Hz), 8.42 (1H, d, J = 9.2 Hz), 7.52 (1H, t, J = 8.1 Hz), 7.41 (1H, d, J = 8.1 Hz), 7.33 (1H, t, J = 73.3 Hz), 7.32 (1H, d, J = 7.5 Hz), 3.89 (1H, s), 2.74-2.72 (1H, m), 2.13 (2H, d, J = 10.8 Hz), 1.65 (1H, d, J = 7.0 Hz), 1.54-1.20 (8H, m), 1.05 (3H, d, J = 6.5 Hz), 0.62-0.60 (4H, m). 557 555 309 [00455]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.23 (1H, s), 8.05 (1H, s), 7.78 (1H, s), 7.65 (1H, d, J = 8.6 Hz), 7.52-7.48 (1H, m), 7.39 (1H, d, J = 8.6 Hz), 7.32 (1H, t, J = 73.3 Hz), 7.31 (1H, d, J = 3.2 Hz), 4.05-4.01 (1H, m), 3.81 (3H, s), 2.13 (2H, d, J = 9.7 Hz), 1.68 (1H, s), 1.52-1.25 (8H, m), 1.05 (3H, d, J = 6.5 Hz). 554 552 310 [00456]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.40 (1H, s), 8.64 (1H, q, J = 4.8 Hz), 8.61 (1H, d, J = 8.6 Hz), 8.10 (1H, s), 8.01 (1H, d, J = 8.6 Hz), 7.88 (1H, d, J = 8.6 Hz), 4.16-4.01 (1H, m), 2.65 (3H, d, J = 4.8 Hz), 2.16-1.98 (3H, m), 1.86-1.56 (7H, m), 1.08 (3H, d, J = 6.5 Hz). 508 506 311 [00457]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.82 (1H, s), 11.39 (1H, s), 8.09 (1H, s), 8.00 (1H, d, J = 8.6 Hz), 7.87 (1H, d, J = 8.6 Hz), 7.81 (1H, d, J = 8.6 Hz), 6.32 (1H, s), 4.30-4.15 (1H, m), 2.24 (3H, s), 2.15-1.97 (3H, m), 1.89-1.56 (7H, m), 1.11 (3H, d, J = 6.5 Hz). 531 529 312 [00458]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.35 (1H, br s), 10.95 (1H, s), 8.06 (1H, d, J = 1.8 Hz), 7.99 (1H, d, J = 8.3 Hz), 7.87 (1H, dd, J = 8.3, 2.0 Hz), 7.46 (1H, d, J = 8.3 Hz), 6.58 (1H, s), 6.52 (1H, s), 4.11-4.02 (1H, m), 2.78-2.68 (2H, m), 2.40 (1H, dd, J = 12.3, 7.3 Hz), 2.32-2.22 (3H, m), 2.14-2.04 (2H, m), 1.99 (3H, s), 1.73-1.53 (2H, m), 1.06 (3H, d, J = 6.5 Hz). 513 511
TABLE-US-00040 TABLE 1-40 313 [00459]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.24 (1H, s), 8.64 (1H, d, J = 7.2 Hz), 8.07 (1H, d, J = 9.0 Hz), 7.75 (1H, d, J = 9.0 Hz), 7.61-7.57 (2H, m), 7.53 (1H, dd, J = 9.0, 2.4 Hz), 7.27 (1H, dd, J = 9.0, 6.8 Hz), 7.01 (1H, t, J = 6.8 Hz), 6.94 (1H, s), 4.19-4.10 (1H, m), 2.17-2.07 (2H, m), 1.77-1.68 (1H, m), 1.63-1.21 (8H, m), 1.13 (3H, d, J = 6.7 Hz). 514 512 314 [00460]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.24 (1H, s), 8.64 (1H, q, J = 4.9 Hz), 8.42 (1H, d, J = 9.2 Hz), 7.65-7.55 (3H, m), 3.95- 3.86 (1H, m), 2.64 (3H, d, J = 4.9 Hz), 2.16-2.06 (2H, m), 1.71-1.61 (1H, m), 1.57-1.13 (8H, m), 1.06 (3H, d, J = 6.5 Hz). 455 453 315 [00461]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.32 (1H, s), 8.64 (1H, q, J = 4.8 Hz), 8.43 (1H, d, J = 8.6 Hz), 8.03 (1H, dd, J = 7.8, 1.3 Hz), 7.79 (1H, dd, J = 7.8, 1.3 Hz), 7.65 (1H, t, J = 7.8 Hz), 3.90-3.90 (1H, m), 2.63 (3H, d, J = 4.8 Hz), 2.12 (2H, d, J = 11.9 Hz), 1.64 (1H, s), 1.53-1.21 (8H, m), 1.05 (3H, d, J = 6.5 Hz). 490 488 316 [00462]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.32 (1H, s), 8.69 (1H, d, J = 5.4 Hz), 8.43 (1H, d, J = 9.2 Hz), 8.04 (1H, dd, J = 7.8, 1.3 Hz), 7.79 (1H, dd, J = 7.8, 1.3 Hz), 7.66 (1H, t, J = 7.8 Hz), 3.90-3.89 (1H, m), 2.75-2.72 (1H, m), 2.11 (2H, d, J = 9.2 Hz), 1.64 (1H, s), 1.55-1.21 (8H, m), 1.05 (3H, d, J = 6.5 Hz), 0.63-0.60 (4H, m). 516 514 317 [00463]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.81 (1H, s), 11.31 (1H, s), 8.01 (1H, dd, J = 7.8, 1.3 Hz), 7.78 (1H, dd, J = 7.8, 1.3 Hz), 7.63 (1H, br s), 7.61 (1H, s), 6.31 (1H, br s), 4.07-4.05 (1H, m), 2.22 (3H, s), 2.12 (2H, s), 1.69 (1H, d, J = 8.1 Hz), 1.49- 1.26 (8H, m), 1.07 (3H, d, J = 6.5 Hz). 513 511 318 [00464]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.32 (1H, s), 8.05 (1H, s), 8.02 (1H, m), 7.80-7.78 (2H, m), 7.67-7.61 (2H, m), 4.04-4.02 (1H, m), 3.81 (3H, s), 2.13 (2H, d, J = 11.9 Hz), 1.67 (1H, d, J = 9.2 Hz), 1.52-1.23 (8H, m), 1.05 (3H, d, J = 6.5 Hz). 513 511 319 [00465]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.25 (1H, s), 8.62 (1H, q, J = 4.8 Hz), 8.55 (1H, d, J = 8.1 Hz), 7.74 (1H, dd, J = 8.6, 2.7 Hz), 7.53 (1H, dd, J = 8.6, 5.9 Hz), 7.35 (1H, td, J = 8.6, 2.7 Hz), 4.57 (1H, s), 3.96-3.81 (1H, m), 2.66 (3H, d, J = 4.8 Hz), 2.11-1.94 (2H, m), 1.76-1.29 (8H, m), 1.08 (3H, d, J = 6.5 Hz). 499 497 320 [00466]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.81 (1H, s), 11.24 (1H, s), 7.90- 7.79 (1H, m), 7.74 (1H, d, J = 8.1 Hz), 7.59-7.48 (1H, m), 7.39-7.26 (1H, m), 6.29 (1H, s), 4.59 (1H, s), 4.07-3.93 (1H, m), 2.25 (3H, s), 2.11-1.94 (2H, m), 1.78-1.28 (8H, m), 1.12 (3H, d, J = 5.9 Hz). 522 520
TABLE-US-00041 TABLE 1-41 321 [00467]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.20 (1H, s), 8.63 (1H, q, J = 4.8 Hz), 8.56 (1H, d, J = 7.5 Hz), 7.75 (1H, dd, J = 8.6, 2.7 Hz), 7.52 (1H, dd, J = 8.6, 5.9 Hz), 7.37 (1H, ddd, J = 8.6, 8.1, 2.7 Hz), 4.17 (1H, s), 4.10-3.94 (1H, m), 2.65 (3H, d, J = 4.8 Hz), 1.97-1.85 (2H, m), 1.85-1.66 (3H, m), 1.63- 1.33 (5H, m), 1.08 (3H, d, J = 5.9 Hz). 499 497 322 [00468]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.80 (1H, s), 11.18 (1H, s), 7.85 (1H, d, J = 7.5 Hz), 7.74 (1H, dd, J = 8.6, 2.7 Hz), 7.51 (1H, dd, J = 8.6, 5.9 Hz), 7.37 (1H, ddd, J = 8.6, 8.1, 2.7 Hz), 6.31 (1H, s), 4.25-4.08 (1H, m), 4.21 (1H, s), 2.24 (3H, s), 1.97-1.82 (2H, m), 1.82-1.66 (3H, m), 1.66-1.34 (5H, m), 1.12 (3H, d, J = 6.5 Hz). 522 520 323 [00469]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.24 (1H, s), 8.22 (1H, dd, J = 7.0, 1.0 Hz), 7.91 (1H, d, J = 1.4 Hz), 7.81 (1H, d, J = 8.4 Hz), 7.61-7.57 (2H, m), 7.53 (1H, dd, J = 8.4, 2.4 Hz), 7.40 (1H, d, J = 9.2 Hz), 6.76 (1H, s), 6.70 (1H, ddd, J = 9.2, 6.5, 1.0 Hz), 6.57 (1H, td, J = 6.5, 1.4 Hz), 4.15-4.05 (1H, m), 2.17-2.08 (2H, m), 1.74-1.66 (1H, m), 1.58-1.21 (8H, m), 1.10 (3H, d, J = 6.5 Hz). 513 511 324 [00470]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.24 (1H, s), 8.55 (1H, dt, J = 6.9, 1.1 Hz), 8.31 (1H, d, J = 0.6 Hz), 7.97 (1H, d, J = 9.0 Hz), 7.61-7.51 (4H, m), 7.32 (1H, ddd, J = 9.0, 6.9, 1.1 Hz), 6.96 (1H, td, J = 6.9, 1.1 Hz), 4.18-4.08 (1H, m), 2.17-2.07 (2H, m), 1.76-1.68 (1H, m), 1.63-1.20 (8H, m), 1.13 (3H, d, J = 6.7 Hz). 514 512 325 [00471]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.30 (1H, s), 8.06 (1H, s), 8.00 (1H, d, J = 1.8 Hz), 7.97 (1H, d, J = 8.3 Hz), 7.85 (1H, dd, J = 8.3, 2.1 Hz), 7.78 (1H, d, J = 0.7 Hz), 7.66 (1H, d, J = 8.3 Hz), 4.10-3.96 (1H, m), 3.82 (3H, s), 2.18-2.05 (2H, m), 1.72-1.61 (1H, m), 1.59-1.16 (8H, m), 1.06 (3H, d, J = 6.5 Hz). 513 511 326 [00472]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.80 (1H, s), 11.43 (1H, s), 8.47 (1H, s), 8.23 (1H, d, J = 7.8 Hz), 7.87 (1H, d, J = 7.8 Hz), 7.62-7.54 (1H, m), 6.30 (1H, s), 4.11-4.01 (1H, m), 2.77- 2.66 (2H, m), 2.53-2.37 (1H, m), 2.36-2.16 (6H, m), 2.04- 1.88 (2H, m), 1.71-1.53 (2H, m), 1.08 (3H, d, J = 6.5 Hz). 504 502 327 [00473]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.43 (1H, s), 8.66-8.59 (1H, m), 8.48 (1H, s), 8.35 (1H, d, J = 8.5 Hz), 8.25 (1H, d, J = 8.0 Hz), 7.89 (1H, d, J = 8.0 Hz), 3.99-3.87 (1H, m), 2.76-2.61 (2H, m), 2.65 (3H, d, J = 4.8 Hz), 2.44 (1H, dd, J = 12.5, 8.0 Hz), 2.36-2.20 (3H, m), 2.03-1.90 (2H, m), 1.72-1.52 (2H, m), 1.05 (3H, d, J = 6.5 Hz). 481 479 328 [00474]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.34 (1H, s), 8.67-8.59 (1H, m), 8.35 (1H, d, J = 8.3 Hz), 8.09 (1H, s), 7.99 (1H, d, J = 8.3 Hz), 7.60 (1H, d, J = 8.3 Hz), 3.99-3.85 (1H, m), 2.74-2.60 (2H, m), 2.65 (3H, d, J = 4.8 Hz), 2.43 (1H, dd, J = 12.6, 7.9 Hz), 2.35-2.20 (3H, m), 2.01-1.84 (2H, m), 1.70-1.53 (2H, m), 1.05 (3H, d, J = 6.5 Hz). 534 532
TABLE-US-00042 TABLE 1-42 329 [00475]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.35 (1H, s), 8.66-8.59 (1H, m), 8.41-8.35 (2H, m), 7.97 (1H, dd, J = 7.9, 1.4 Hz), 7.70 (1H, d, J = 8.0 Hz), 3.17-3.00 (2H, m), 2.73 (1H, q, J = 7.5 Hz), 2.68-2.58 (3H, m), 2.65 (3H, d, J = 4.8 Hz), 2.41 (1H, t, J = 11.5 Hz), 2.16-2.06 (2H, m), 1.64-1.47 (2H, m), 0.87 (3H, d, J = 6.8 Hz). 491 489 330 [00476]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.35 (1H, s), 8.66-8.59 (1H, m), 8.41-8.35 (2H, m), 7.97 (1H, dd, J = 7.9, 1.4 Hz), 7.70 (1H, d, J = 8.0 Hz), 3.17-3.00 (2H, m), 2.73 (1H, q, J = 7.5 Hz), 2.68-2.58 (3H, m), 2.65 (3H, d, J = 4.8 Hz), 2.41 (1H, t, J = 11.5 Hz), 2.16-2.06 (2H, m), 1.64-1.47 (2H, m), 0.87 (3H, d, J = 6.8 Hz). 491 489 331 [00477]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.82 (1H, br s), 11.29 (1H, br s), 8.08 (1H, d, J = 1.8 Hz), 7.97 (1H, dd, J = 8.5, 1.5 Hz), 7.66-7.55 (1H, m), 7.58 (1H, d, J = 8.5 Hz), 6.34 (1H, s), 4.11-4.01 (1H, m), 2.75-2.65 (2H, m), 2.43 (1H, dd, J = 12.9, 7.6 Hz), 2.35-2.24 (3H, m), 2.24 (3H, s), 2.02-1.86 (2H, m), 1.70-1.54 (2H, m), 1.08 (3H, d, J = 6.5 Hz). 557 555 332 [00478]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.77 (1H, s), 11.35 (1H, s), 8.37 (1H, s), 7.97 (1H, d, J = 7.8 Hz), 7.68 (2H, d, J = 8.0 Hz), 6.28 (1H, s), 2.80-2.38 (7H, m), 2.25 (3H, s), 2.11 (2H, d, J = 13.3 Hz), 1.65-1.48 (2H, m), 0.90 (3H, d, J = 6.5 Hz). 514 512 333 [00479]![embedded image]()
1H-NMR (CDCl3) ?: 8.17 (1H, s), 7.47-7.37 (3H, m), 7.24- 7.20 (1H, m), 7.13 (1H, td, J = 8.2, 2.5 Hz), 4.00-3.93 (1H, m), 2.89 (3H, d, J = 5.5 Hz), 2.75-2.68 (1H, m), 2.67-2.61 (2H, m), 2.47 (1H, td, J = 12.1, 2.9 Hz), 2.25-2.16 (2H, m), 1.82-1.65 (2H, m), 1.18 (3H, d, J = 6.1 Hz). 486 484 334 [00480]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.26 (1H, s), 8.05 (1H, s), 7.77- 7.72 (2H, m), 7.65 (1H, d, J = 8.3 Hz), 7.54 (1H, dd, J = 8.6, 6.0 Hz), 7.35 (1H, td, J = 8.5, 2.6 Hz), 4.08-4.00 (1H, m), 3.82 (3H, s), 2.74-2.65 (2H, m), 2.35-2.23 (2H, m), 2.12- 2.02 (2H, m), 1.64-1.51 (2H, m), 1.05 (3H, d, J = 6.7 Hz). 509 507 335 [00481]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.77 (1H, s), 11.35 (1H, s), 8.37 (1H, s), 7.97 (1H, d, J = 7.8 Hz), 7.68 (2H, d, J = 8.0 Hz), 6.28 (1H, s), 2.80-2.38 (7H, m), 2.25 (3H, s), 2.11 (2H, d, J = 13.3 Hz), 1.65-1.48 (2H, m), 0.90 (3H, d, J = 6.5 Hz). 514 512 336 [00482]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.36 (1H, s), 8.36 (1H, s), 8.04 (1H, s), 7.95 (1H, d, J = 8.0 Hz), 7.76 (1H, s), 7.69 (1H, d, J = 7.8 Hz), 7.63 (1H, d, J = 8.0 Hz), 4.13-4.00 (1H, m), 3.83 (3H, s), 2.75-2.65 (2H, m), 2.42-2.20 (4H, m), 2.14- 2.05 (2H, m), 1.63-1.51 (2H, m), 1.05 (3H, d, J = 6.8 Hz). 514 512
TABLE-US-00043 TABLE 1-43 337 [00483]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.27 (1H, s), 8.19 (1H, s), 8.15 (1H, s), 8.03 (1H, s), 7.92 (1H, dd, J = 8.0, 1.3 Hz), 7.76 (1H, s), 7.66-7.53 (3H, m), 4.10-3.98 (1H, m), 3.82 (3H, s), 2.74-2.65 (2H, m), 2.41-2.20 (4H, m), 2.14-2.05 (2H, m), 1.65-1.53 (2H, m), 1.06-1.02 (3H, m). 532 530 338 [00484]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.30 (1H, s), 8.67-8.61 (1H, m), 8.43 (1H, d, J = 9.2 Hz), 8.04-7.97 (2H, m), 7.89-7.85 (1H, m), 3.85-3.75 (1H, m), 2.65 (3H, d, J = 4.3 Hz), 2.24-2.06 (2H, m), 1.59-1.21 (8H, m), 1.02 (3H, d, J = 6.5 Hz), 0.77 (3H, d, J = 7.0 Hz). 504 502 339 [00485]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.30 (1H, s), 8.07 (1H, s), 8.03- 7.96 (2H, m), 7.88-7.83 (1H, m), 7.80 (1H, s), 7.68 (1H, d, J = 8.1 Hz), 4.06-3.97 (1H, m), 3.82 (3H, s), 2.23-2.09 (2H, m), 1.61-1.21 (8H, m), 1.00 (3H, d, J = 7.0 Hz), 0.80 (3H, d, J = 7.0 Hz). 527 525
TABLE-US-00044 TABLE 1-44 2-001 [00486]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.35 (1H, s), 8.58 (1H, s), 8.35 (1H, d, J = 8.8 Hz), 8.07 (1H, d, J = 2.0 Hz), 8.00 (1H, d, J = 8.5 Hz), 7.88 (1H, dd, J = 8.4, 1.9 Hz), 3.99-3.86 (1H, m), 2.75-2.60 (2H, m), 2.43 (1H, dd, J = 12.4, 8.1 Hz), 2.34-2.20 (3H, m), 2.13-2.02 (2H, m), 1.72-1.48 (2H, m), 1.05 (3H, d, J = 6.5 Hz). 494 492 2-002 [00487]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.35 (2H, s), 8.07 (1H, d, J = 1.8 Hz), 8.00 (1H, d, J = 8.3 Hz), 7.88 (1H, dd, J = 8.4, 1.9 Hz), 7.81 (1H, d, J = 7.8 Hz), 6.31 (1H, s), 4.34-4.22 (1H, m), 3.96-3.83 (1H, m), 2.73-2.63 (2H, m), 2.36- 2.22 (4H, m), 2.18 (1H, dd, J = 12.4, 7.1 Hz), 2.14-2.04 (2H, m), 1.72-1.58 (2H, m), 0.99 (3H, d, J = 6.8 Hz). 546 544 2-003 [00488]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.35 (1H, s), 8.29 (1H, d, J = 7.8 Hz), 8.08 (1H, d, J = 1.8 Hz), 8.00 (1H, d, J = 8.3 Hz), 7.88 (1H, dd, J = 8.4, 1.9 Hz), 6.72-6.69 (2H, m), 4.02-3.90 (1H, m), 2.74-2.63 (2H, m), 2.37-2.20 (4H, m), 2.14-2.05 (2H, m), 1.69-1.55 (2H, m), 1.04 (3H, d, J = 6.5 Hz). 528 526 2-004 [00489]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.36 (1H, s), 8.59 (1H, s), 8.35 (1H, d, J = 8.3 Hz), 8.19 (1H, d, J = 6.8 Hz), 8.15 (1H, d, J = 9.3 Hz), 4.00- 3.89 (1H, m), 2.75-2.60 (3H, m), 2.49-2.40 (1H, m), 2.34-2.20 (2H, m), 2.13-2.00 (2H, m), 1.81-1.59 (2H, m), 1.05 (3H, d, J = 6.5 Hz). 512 510 2-005 [00490]![embedded image]()
mixture of two stereo- isomers 1H-NMR (DMSO-D6) ?: 11.33 (1H, s), 8.67 (1H, d, J = 4.9 Hz), 8.37 (1H, d, J = 7.9 Hz), 7.75 (1H, dd, J = 8.4, 2.4 Hz), 7.60 (1H, dd, J = 8.6, 5.8 Hz), 7.39 (1H, td, J = 8.4, 2.6 Hz), 3.81-3.74 (1H, m), 3.09 (1H, br s), 2.92-2.80 (2H, br m), 2.66 (3H, d, J = 5.1 Hz), 2.59- 2.47 (4H, m), 1.99 (1H, br s), 1.80 (1H, br s), 1.64-1.62 (1H, br m), 1.09-1.07 (3H, m). 496 494 2-006 [00491]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.35 (1H, s), 8.64- 8.58 (1H, m), 8.35 (1H, d, J = 8.5 Hz), 8.11 (1H, d, J = 2.0 Hz), 7.99 (1H, dd, J = 8.4, 1.9 Hz), 7.84 (1H, d, J = 8.3 Hz), 3.98-3.86 (1H, m), 2.75-2.60 (2H, m), 2.64 (3H, d, J = 6.5 Hz), 2.43 (1H, dd, J = 12.4, 8.1 Hz), 2.36- 2.18 (3H, m), 2.15-1.98 (2H, m), 1.68-1.49 (2H, m), 1.05 (3H, d, J = 6.5 Hz). 447 445 2-007 [00492]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.78 (1H, s), 11.35 (1H, s), 8.10 (1H, d, J = 2.0 Hz), 7.98 (1H, dd, J = 8.3, 2.0 Hz), 7.83 (1H, d, J = 8.5 Hz), 7.55 (1H, d, J = 8.3 Hz), 6.28 (1H, s), 4.13-4.01 (1H, m), 2.76-2.64 (2H, m), 2.42 (1H, dd, J = 12.3, 7.5 Hz), 2.34-2.26 (3H, m), 2.23 (3H, s), 2.12-2.02 (2H, m), 1.68-1.49 (2H, m), 1.07 (3H, d, J = 6.5 Hz). 470 468 2-008 [00493]![embedded image]()
1H-NMR (DMSO) ?: 11.35 (1H, s, ), 8.58 (1H, s, ), 8.34 (1H, d, J = 8.8 Hz, ), 8.11 (1H, d, J = 1.8 Hz, ), 7.99 (1H, dd, J = 8.5, 2.0 Hz, ), 7.84 (1H, d, J = 8.5 Hz, ), 3.96-3.88 (1H, m, ), 2.75-2.59 (2H, m, ), 2.43 (1H, dd, J = 12.6, 8.1 Hz, ), 2.34-2.19 (3H, m, ), 2.12-2.01 (2H, m, ), 1.69-1.48 (2H, m, ), 1.05 (3H, d, J = 6.5 Hz, ). 450 448 2-009 [00494]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.33 (1H, s), 8.05 (1H, d, J = 1.8 Hz), 7.99 (1H, dd, J = 8.3, 2.0 Hz), 7.84 (1H, d, J = 8.3 Hz), 7.77 (1H, d, J = 8.8 Hz), 7.05 (1H, d, J = 6.8 Hz), 4.44-4.34 (1H, m), 4.03-3.92 (1H, m), 2.75- 2.66 (1H, m), 2.63-2.55 (1H, m), 2.38-1.98 (6H, m), 1.67-1.42 (2H, m), 1.01 (3H, d, J = 6.8 Hz). 488 486 2-010 [00495]![embedded image]()
mixture of two diastereomers 1H-NMR (DMSO-D6) ?: 11.34 (0.5H, s), 11.31 (0.5H, s), 8.93 (0.5H, d, J = 9.7 Hz), 8.77 (0.5H, q, J = 4.9 Hz), 8.65 (0.5H, q, J = 4.9 Hz), 8.52 (0.5H, d, J = 9.5 Hz), 7.78-7.74 (1H, m), 7.58 (0.5H, dd, J = 8.6, 6.0 Hz), 7.49 (0.5H, dd, J = 8.6, 6.0 Hz), 7.41-7.31 (1H, m), 4.21-4.09 (1H, m), 3.84 (1H, t, J = 10.6 Hz), 2.80- 2.54 (6H, m), 2.41-2.30 (1H, m), 2.18- 2.07 (2H, m), 1.75-1.60 (1H, m), 1.58- 1.40 (1H, m), 1.24 (1.5H, d, J = 6.7 Hz), 1.07 (1.5H, d, J = 6.7 Hz). 509 507
TABLE-US-00045 TABLE 1-45 2-011 [00496]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.26 (1H, s), 8.63 (1H, d, J = 4.9 Hz), 8.36 (1H, d, J = 8.8 Hz), 7.75 (1H, dd, J = 8.6, 2.5 Hz), 7.54 (1H, dd, J = 8.6, 6.0 Hz), 7.36 (1H, td, J = 8.5, 2.6 Hz), 3.96-3.89 (1H, m), 2.72-2.59 (6H, m), 2.44- 2.20 (3H, m), 2.10-2.03 (2H, m), 1.59-1.52 (2H, m), 1.04 (3H, d, J = 6.7 Hz). 484 482 2-012 [00497]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.80 (1H, s), 11.25 (1H, s), 7.74 (1H, dd, J = 8.6, 2.5 Hz), 7.59-7.51 (2H, m), 7.35 (1H, td, J = 8.4, 2.8 Hz), 6.29 (1H, s), 4.11-4.02 (1H, m), 2.75-2.65 (3H, m), 2.46-2.39 (1H, m), 2.33-2.22 (5H, m), 2.11-2.04 (2H, br m), 1.61-1.51 (2H, br m), 1.07 (3H, d, J = 6.5 Hz). 507 505 2-013 [00498]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.27 (1H, s), 8.69-8.62 (2H, m), 8.48-8.41 (1H, m), 8.26-8.21 (1H, m), 7.47-7.42 (1H, m), 3.97-3.85 (1H, m), 2.65 (3H, d, J = 4.8 Hz), 2.08-2.00 (2H, m), 1.69-1.44 (5H, m), 1.34-1.14 (4H, m), 1.06 (3H, d, J = 6.5 Hz). 466 464 2-014 [00499]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.18 (1H, s), 8.69-8.63 (1H, m), 8.45 (1H, d, J = 9.2 Hz), 7.62 (1H, d, J = 9.2 Hz), 7.04-6.96 (2H, m), 4.65 (1H, s), 3.99-3.89 (1H, m), 3.78 (2H, s), 2.67 (3H, d, J = 4.9 Hz), 2.22-2.14 (2H, m), 1.73-1.17 (15H, m), 1.09 (3H, d, J = 6.7 Hz). 553 551 2-015 [00500]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.30 (1H, s), 8.65-8.58 (1H, m), 8.35 (1H, d, J = 8.8 Hz), 7.95 (1H, d, J = 7.3 Hz), 7.81 (1H, d, J = 8.5 Hz), 3.98-3.88 (1H, m), 2.76-2.62 (2H, m), 2.64 (3H, d, J = 5.0 Hz), 2.43 (1H, dd, J = 12.5, 8.0 Hz), 2.35- 2.18 (3H, m), 2.12-1.98 (2H, m), 1.68-1.49 (2H, m), 1.05 (3H, d, J = 6.5 Hz). 518 516 2-016 [00501]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.79 (1H, s), 11.30 (1H, s), 7.95 (1H, d, J = 7.3 Hz), 7.80 (1H, d, J = 8.8 Hz), 7.61-7.50 (1H, m), 6.28 (1H, s), 4.12-4.01 (1H, m), 2.76-2.65 (2H, m), 2.45-2.38 (1H, m), 2.34-2.18 (6H, m), 2.10-2.02 (2H, m), 1.65-1.50 (2H, m), 1.07 (3H, d, J = 6.5 Hz). 541 539 2-017 [00502]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.38 (1H, s), 9.23 (1H, d, J = 9.0 Hz), 8.78 (1H, q, J = 4.9 Hz), 8.07 (1H, d, J = 1.8 Hz), 8.00 (1H, d, J = 8.3 Hz), 7.88 (1H, dd, J = 8.4, 2.0 Hz), 4.65-4.55 (1H, m), 2.95 (1H, dd, J = 13.1, 9.8 Hz), 2.74- 2.58 (7H, m), 2.33-2.26 (1H, m), 2.14-2.05 (2H, br m), 1.68-1.47 (2H, br m). 545 543 2-018 [00503]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.44 (1H, s), 8.67-8.60 (1H, m), 8.37 (1H, d, J = 8.1 Hz), 7.67-7.62 (1H, m), 7.54-7.41 (2H, m), 3.97-3.87 (1H, m), 2.76-2.60 (2H, m), 2.64 (3H, d, J = 4.8 Hz), 2.46-2.02 (6H, m), 1.72-1.46 (2H, m), 1.05 (3H, d, J = 6.5 Hz). 484 N.D. 2-019 [00504]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.30 (1H, s), 8.66-8.60 (1H, m), 8.42 (1H, d, J = 9.2 Hz), 7.87-7.82 (1H, m), 7.66-7.61 (3H, m), 3.96-3.86 (1H, m), 2.64 (3H, d, J = 4.8 Hz), 2.08-1.99 (2H, m), 1.72-1.11 (9H, m), 1.06 (3H, d, J = 6.5 Hz). 487 485 2-020 [00505]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.30 (1H, s), 8.06 (1H, s), 7.87- 7.81 (1H, m), 7.78 (1H, s), 7.68-7.59 (4H, m), 4.09-3.98 (1H, m), 3.82 (3H, s), 2.09-2.01 (2H, m), 1.73-1.21 (9H, m), 1.06 (3H, d, J = 6.5 Hz). 510 508
TABLE-US-00046 TABLE 1-46 2-021 [00506]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.36 (1H, s), 8.71-8.59 (1H, m), 8.42-8.33 (1H, m), 7.93-7.83 (1H, m), 7.73-7.61 (3H, m), 4.02-3.87 (1H, m), 2.78-2.60 (2H, m), 2.64 (3H, d, J = 4.8 Hz), 2.43-2.19 (4H, m), 2.10-1.95 (2H, m), 1.75-1.54 (2H, m), 1.15- 1.01 (3H, m). 488 486 2-022 [00507]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.34 (1H, s), 8.07 (1H, d, J = 2.0 Hz), 8.01 (1H, d, J = 8.5 Hz), 7.89 (1H, dd, J = 8.3, 2.0 Hz), 7.41 (1H, d, J = 8.3 Hz), 5.56 (1H, s, ), 3.96-3.86 (1H, m), 2.76-2.63 (2H, m), 2.34-2.21 (3H, m), 2.19-2.03 (3H, m), 1.98 (3H, s), 1.74 (3H, s), 1.69-1.51 (2H, m), 0.98 (3H, d, J = 6.5 Hz). 488 486 2-023 [00508]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.34 (1H, s), 8.07 (1H, d, J = 2.0 Hz), 8.01 (1H, d, J = 8.5 Hz), 7.89 (1H, dd, J = 8.3, 2.0 Hz), 7.41 (1H, d, J = 8.3 Hz), 5.56 (1H, s), 3.96-3.86 (1H, m), 2.76-2.63 (2H, m), 2.34-2.21 (3H, m), 2.19-2.03 (3H, m), 1.98 (3H, s), 1.74 (3H, s), 1.69-1.51 (2H, m), 0.98 (3H, d, J = 6.5 Hz). 530 528 2-024 [00509]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.35 (1H, s), 8.36 (1H, d, J = 1.5 Hz), 7.95 (1H, dd, J = 8.0, 1.5 Hz), 7.82 (1H, d, J = 8.5 Hz), 7.70-7.66 (2H, m), 7.47 (1H, d, J = 1.0 Hz), 4.13-4.00 (1H, m), 3.73 (3H, s), 3.48-3.40 (1H, m), 2.75-2.65 (2H, m), 2.40-2.22 (3H, m), 2.14- 2.03 (2H, m), 1.64-1.48 (2H, m), 1.08-1.03 (3H, m). 518 516 2-025 [00510]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.47 (1H, s), 8.68-8.60 (1H, m), 8.53-8.48 (0.5H, m), 8.40-8.35 (0.5H, m), 8.13-8.09 (1H, m), 8.04-7.99 (1H, m), 7.93-7.87 (1H, m), 4.24-4.11 (1H, m), 4.10-3.98 (1H, m), 3.90-3.73 (1H, m), 2.92-2.58 (7H, m), 2.27-2.18 (1H, m), 1.97-1.84 (1H, m), 1.11-1.03 (3H, m). 493 491 2-026 [00511]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.15 (1H, s), 8.65-8.59 (1H, m), 8.41 (1H, d, J = 9.2 Hz), 7.63 (1H, d, J = 9.2 Hz), 7.47-7.40 (2H, m), 5.19 (1H, s), 3.96- 3.82 (1H, m), 2.63 (3H, d, J = 5.4 Hz), 2.20-2.09 (2H, m), 1.71-1.11 (9H, m), 1.41 (6H, s), 1.06 (3H, d, J = 6.5 Hz). 523 521 2-027 [00512]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.15 (1H, s), 8.04 (1H, s), 7.76 (1H, s), 7.67-7.60 (2H, m), 7.48-7.37 (2H, m), 5.18 (1H, s), 4.09-3.96 (1H, m), 3.81 (3H, s), 2.21-2.09 (2H, m), 1.73-1.15 (9H, m), 1.39 (6H, s), 1.06 (3H, d, J = 4.3 Hz). 546 544 2-028 [00513]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.36 (1H, s), 8.71-8.65 (2H, m), 8.43-8.39 (1H, m), 8.30-8.27 (1H, m), 7.52-7.47 (1H, m), 4.02-3.92 (1H, m), 2.78-2.61 (2H, m), 2.69 (3H, d, J = 4.9 Hz), 2.55-2.24 (4H, m), 2.06-1.77 (4H, m), 1.09 (3H, d, J = 6.5 Hz). 467 N.D. 2-029 [00514]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.35 (1H, s), 8.17 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 2.0 Hz), 8.01 (1H, d, J = 8.5 Hz), 7.89 (1H, dd, J = 8.5, 2.0 Hz), 7.73 (1H, d, J = 7.5 Hz), 7.70-7.58 (2H, m), 7.41 (1H, d, J = 7.3 Hz), 4.14-4.03 (1H, m), 2.81-2.74 (1H, m), 2.71-2.64 (1H, m), 2.42-2.21 (4H, m), 2.17- 2.07 (2H, m), 1.74-1.53 (2H, m), 1.06 (3H, d, J = 6.5 Hz). 578 576 2-030 [00515]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.30 (1H, s), 8.62 (1H, d, J = 5.1 Hz), 8.35 (1H, d, J = 8.8 Hz), 7.56-7.47 (2H, m), 7.32 (1H, dd, J = 7.3, 1.7 Hz), 3.96-3.88 (1H, m), 2.73-2.60 (5H, m), 2.42 (1H, dd, J = 12.5, 8.1 Hz), 2.33-2.21 (3H, m), 2.11-2.03 (2H, br m), 1.63-1.50 (2H, m), 1.04 (3H, d, J = 6.7 Hz). 484 482
TABLE-US-00047 TABLE 1-47 2-031 [00516]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.79 (1H, s), 11.30 (1H, s), 7.58- 7.46 (3H, m), 7.31 (1H, dd, J = 6.8, 2.0 Hz), 6.28 (1H, s), 4.09-4.02 (1H, m), 2.74-2.65 (2H, br m), 2.42 (1H, dd, J = 12.5, 7.4 Hz), 2.33-2.24 (6H, m), 2.11-2.04 (2H, br m), 1.63-1.53 (2H, br m), 1.06 (3H, d, J = 6.7 Hz). 507 505 2-032 [00517]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.25 (1H, s), 8.65-8.59 (1H, m), 8.43-8.38 (1H, m), 7.94-7.90 (2H, m), 7.86-7.83 (1H, m), 3.96-3.83 (1H, m), 3.87 (3H, s), 2.63 (3H, d, J = 4.8 Hz), 2.21-2.12 (2H, m), 1.71-1.15 (9H, m), 1.05 (3H, d, J = 6.5 Hz). 523 521 2-033 [00518]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.32 (1H, s), 8.65-8.58 (1H, m), 8.39-8.33 (1H, m), 7.95-7.92 (2H, m), 7.89-7.86 (1H, m), 3.97-3.85 (1H, m), 3.87 (3H, s), 2.75-2.60 (2H, m), 2.62 (3H, d, J = 4.8 Hz), 2.46-2.07 (6H, m), 1.63-1.46 (2H, m), 1.04 (3H, d, J = 7.0 Hz). 524 522 2-034 [00519]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.20 (1H, s), 8.64-8.58 (1H, m), 8.38-8.33 (1H, m), 7.67-7.63 (1H, m), 7.50-7.45 (1H, m), 7.43-7.40 (1H, m), 5.21 (1H, s), 3.97-3.87 (1H, m), 2.74- 2.60 (2H, m), 2.63 (3H, d, J = 4.8 Hz), 2.46-2.02 (6H, m), 1.65-1.48 (2H, m), 1.41 (6H, s), 1.04 (3H, d, J = 6.5 Hz). 524 522 2-035 [00520]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.23 (1H, s), 8.65-8.57 (2H, m), 8.43-8.38 (1H, m), 7.87-7.80 (2H, m), 7.78-7.76 (1H, m), 3.96-3.84 (1H, m), 2.78 (3H, d, J = 4.3 Hz), 2.63 (3H, d, J = 4.8 Hz), 2.20-2.10 (2H, m), 1.71-1.17 (9H, m), 1.05 (3H, d, J = 6.5 Hz). 522 520 2-036 [00521]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.21 (1H, s), 8.66-8.60 (1H, m), 8.44-8.38 (1H, m), 7.82-7.78 (1H, m), 7.48-7.45 (1H, m), 7.43-7.39 (1H, m), 3.96-3.85 (1H, m), 2.97 (3H, s), 2.87 (3H, s), 2.64 (3H, d, J = 4.8 Hz), 2.19-2.09 (2H, m), 1.71- 1.13 (9H, m), 1.05 (3H, d, J = 6.5 Hz). 536 534 2-037 [00522]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.29 (1H, s), 8.65-8.57 (2H, m), 8.38-8.34 (1H, m), 7.88-7.83 (2H, m), 7.81-7.78 (1H, m), 3.98-3.89 (1H, m), 2.79 (3H, d, J = 4.3 Hz), 2.75-2.62 (2H, m), 2.63 (3H, d, J = 4.8 Hz), 2.47-2.06 (6H, m), 1.71-1.51 (2H, m), 1.04 (3H, d, J = 6.5 Hz). 523 521 2-038 [00523]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.27 (1H, s), 8.67-8.58 (1H, m), 8.37-8.31 (1H, m), 7.85-7.80 (1H, m), 7.51-7.48 (1H, m), 7.45-7.40 (1H, m), 3.98-3.87 (1H, m), 2.98 (3H, s), 2.87 (3H, s), 2.74-2.60 (2H, m), 2.64 (3H, d, J = 4.8 Hz), 2.47- 2.03 (6H, m), 1.67-1.49 (2H, m), 1.04 (3H, d, J = 6.5 Hz). 537 535 2-039 [00524]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.30 (1H, s), 8.77 (1H, d, J = 6.9 Hz), 8.61 (1H, t, J = 4.9 Hz), 8.36 (1H, d, J = 8.6 Hz), 8.04 (1H, d, J = 2.3 Hz), 7.28 (1H, dd, J = 6.9, 0.9 Hz), 6.95 (1H, t, J = 7.1 Hz), 6.60 (1H, dd, J = 2.3, 0.9 Hz), 3.96-3.89 (1H, m), 2.73-2.60 (5H, m), 2.42 (1H, dd, J = 12.5, 8.1 Hz), 2.35-2.24 (3H, m), 2.08-2.04 (2H, br m), 1.79-1.66 (2H, m), 1.04 (3H, d, J = 6.7 Hz). 428 426 2-040 [00525]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.44 (1H, s), 8.72 (1H, d, J = 9.0 Hz), 8.59 (1H, d, J = 4.9 Hz), 8.14 (1H, d, J = 1.8 Hz), 8.03 (1H, d, J = 8.6 Hz), 7.90 (1H, dd, J = 8.3, 2.1 Hz), 4.11 (1H, d, J = 9.7 Hz), 2.64 (3H, d, J = 4.9 Hz), 2.23 (2H, t, J = 11.8 Hz), 2.10-2.04 (1H, m), 2.01-1.97 (1H, m), 1.79- 1.56 (6H, m), 1.12 (3H, d, J = 6.7 Hz). 515 513
TABLE-US-00048 TABLE 1-48 2-041 [00526]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.35 (1H, s), 8.31-8.24 (1H, m), 8.15 (1H, d, J = 8.0 Hz), 8.08 (1H, d, J = 2.0 Hz), 8.00 (1H, d, J = 8.3 Hz), 7.87 (1H, dd, J = 8.3, 2.0 Hz), 6.77 (1H, d, J = 15.3 Hz), 6.72 (1H, d, J = 15.3 Hz), 4.02-3.89 (1H, m), 2.71-2.65 (1H, m), 2.67 (3H, d, J = 5.0 Hz), 2.36-2.16 (5H, m), 2.15-2.03 (2H, m), 1.71-1.53 (2H, m), 1.02 (3H, d, J = 6.5 Hz). 517 515 2-042 [00527]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.35 (1H, s), 8.53-8.45 (1H, m), 8.08 (1H, d, J = 1.8 Hz), 8.00 (1H, d, J = 8.5 Hz), 7.87 (1H, dd, J = 8.4, 2.1 Hz), 7.27 (1H, d, J = 15.5 Hz), 6.77 (1H, d, J = 15.5 Hz), 4.06-3.94 (1H, m), 2.77 (4H, s), 2.73-2.64 (1H, m), 2.41-2.22 (5H, m), 2.18-2.03 (2H, m), 1.71-1.57 (2H, m), 1.06 (3H, d, J = 6.5 Hz). 601 599 2-043 [00528]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.11 (1H, s), 8.68-8.62 (1H, m), 8.47-8.41 (1H, m), 8.00 (1H, s), 3.99-3.82 (1H, m), 3.85 (3H, s), 2.65 (3H, d, J = 4.8 Hz), 1.97- 1.87 (2H, m), 1.81-1.43 (5H, m), 1.35-1.16 (4H, m), 1.07 (3H, d, J = 6.5 Hz). 517 515 2-044 [00529]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.27 (1H, s), 8.70-8.63 (1H, m), 8.48-8.42 (1H, m), 7.99 (1H, d, J = 8.4 Hz), 7.53 (1H, d, J = 2.4 Hz), 7.32 (1H, dd, J = 8.4, 2.4 Hz), 4.00-3.89 (1H, m), 2.68 (3H, d, J = 4.9 Hz), 2.22-2.13 (2H, m), 1.74-1.17 (9H, m), 1.10 (3H, d, J = 6.5 Hz). 547 545 2-045 [00530]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.14 (1H, s), 8.70-8.65 (1H, m), 8.44-8.38 (1H, m), 7.66-7.61 (1H, m), 7.48-7.43 (1H, m), 7.42-7.39 (1H, m), 5.19 (1H, s), 3.94-3.84 (1H, m), 2.76-2.67 (1H, m), 2.20-2.09 (2H, m), 1.71-1.11 (9H, m), 1.41 (6H, s), 1.05 (3H, d, J = 6.5 Hz), 0.66-0.55 (4H, m). 549 547 2-046 [00531]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.11 (1H, s), 8.80 (1H, d, J = 8.1 Hz), 7.99 (1H, s), 7.34 (1H, s), 4.14-4.01 (1H, m), 3.84 (3H, s), 1.98-1.20 (11H, m), 1.13 (3H, d, J = 6.5 Hz). 561 559 2-047 [00532]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.35 (1H, s), 8.07 (1H, d, J = 2.0 Hz), 8.00 (1H, d, J = 8.5 Hz), 7.87 (1H, dd, J = 8.5, 2.0 Hz), 6.13 (1H, d, J = 12.8 Hz), 6.07-5.98 (1H, m), 3.97-3.89 (1H, m), 2.74-2.67 (2H, m), 2.40-2.20 (4H, m), 2.14-2.04 (2H, m), 1.73-1.58 (2H, m), 1.04 (3H, d, J = 6.5 Hz). 504 502 2-048 [00533]![embedded image]()
Mixture of two diastereomers due to 2-position of furan ring 1H-NMR (DMSO-D6) ?: 11.34-11.34 (1H, m), 8.09-8.07 (1H, m), 8.04-7.99 (1H, m), 7.92-7.87 (1H, m), 7.37 (0.5H, d, J = 8.8 Hz), 7.23 (0.5H, d, J = 8.8 Hz), 4.16-4.05 (1H, m), 3.97-3.61 (3H, m), 2.76-2.54 (2H, m), 2.41-1.87 (7H, m), 1.81- 1.35 (5H, m), 1.00 (3H, d, J = 6.5 Hz). 504 502 2-049 [00534]![embedded image]()
Mixture of two diastereomers due to 2-position of dioxane ring 1H-NMR (DMSO-D6) ?: 11.36-11.32 (1H, m), 8.09-8.06 (1H, m), 8.03-7.98 (1H, m), 7.91-7.85 (1H, m), 7.44 (0.5H, d, J = 8.6 Hz), 7.36 (0.5H, d, J = 8.6 Hz), 4.00-3.19 (8H, m), 2.73-2.58 (2H, m), 2.40-2.01 (6H, m), 1.72-1.41 (2H, m), 1.00 (3H, d, J = 6.5 Hz). 520 518 2-050 [00535]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.18 (1H, s), 8.66-8.59 (1H, m), 8.44-8.38 (1H, m), 7.44-7.36 (1H, m), 7.25-7.19 (1H, m), 3.95-3.84 (4H, m), 2.64 (3H, d, J = 4.8 Hz), 2.16-2.06 (2H, m), 1.69-1.12 (9H, m), 1.05 (3H, d, J = 6.5 Hz). 513 511
TABLE-US-00049 TABLE 1-49 2-051 [00536]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.30 (1H, s), 8.77 (1H, d, J = 6.9 Hz), 8.61 (1H, t, J = 4.9 Hz), 8.36 (1H, d, J = 8.6 Hz), 8.04 (1H, d, J = 2.3 Hz), 7.28 (1H, dd, J = 6.9, 0.9 Hz), 6.95 (1H, t, J = 7.1 Hz), 6.60 (1H, dd, J = 2.3, 0.9 Hz), 3.96-3.89 (1H, m), 2.73-2.60 (5H, m), 2.42 (1H, dd, J = 12.5, 8.1 Hz), 2.35-2.24 (3H, m), 2.08-2.04 (2H, br m), 1.79-1.66 (2H, m), 1.04 (3H, d, J = 6.7 Hz). 428 426 2-052 [00537]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.44 (1H, s), 8.72 (1H, d, J = 9.0 Hz), 8.59 (1H, d, J = 4.9 Hz), 8.14 (1H, d, J = 1.8 Hz), 8.03 (1H, d, J = 8.6 Hz), 7.90 (1H, dd, J = 8.3, 2.1 Hz), 4.11 (1H, d, J = 9.7 Hz), 2.64 (3H, d, J = 4.9 Hz), 2.23 (2H, t, J = 11.8 Hz), 2.10-2.04 (1H, m), 2.01-1.97 (1H, m), 1.79-1.56 (6H, m), 1.12 (3H, d, J = 6.7 Hz). 515 513 2-053 [00538]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.34 (1H, s), 8.06 (1H, d, J = 2.0 Hz), 8.00 (1H, d, J = 8.3 Hz), 7.87 (1H, dd, J = 8.3, 2.0 Hz), 7.83 (1H, d, J = 8.3 Hz), 7.67 (1H, s), 7.48 (1H, d, J = 1.0 Hz), 4.13-4.04 (1H, m), 3.73 (3H, s), 2.77-2.65 (2H, m), 2.41-2.23 (4H, m), 2.14-2.05 (2H, m), 1.68-1.52 (2H, m), 1.07 (3H, d, J = 6.5 Hz). 514 512 2-054 [00539]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.34 (1H, s), 8.06 (1H, d, J = 2.2 Hz), 8.00 (1H, d, J = 8.5 Hz), 7.90-7.85 (1H, m), 7.58 (1H, s), 7.54 (1H, d, J = 1.0 Hz), 7.48 (1H, d, J = 8.3 Hz), 4.08-4.00 (1H, m), 3.67 (3H, s), 2.74-2.64 (2H, m), 2.43 (1H, dd, J = 12.3, 7.8 Hz), 2.34-2.23 (3H, m), 2.13-2.03 (2H, m), 1.70-1.53 (2H, m), 1.08 (3H, d, J = 6.5 Hz). 514 N.D. 2-055 [00540]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.37 (1H, s), 8.75-8.70 (1H, m), 8.63-8.57 (1H, m), 7.85-7.80 (1H, m), 7.50-7.30 (2H, m), 7.29-7.24 (1H, m), 4.17-4.07 (1H, m), 2.64 (3H, d, J = 4.8 Hz), 2.28-1.96 (4H, m), 1.81-1.53 (6H, m), 1.12 (3H, d, J = 6.5 Hz). 556 554 2-056 [00541]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.22 (1H, s), 8.67-8.57 (1H, m), 8.46-8.37 (1H, m), 7.86-7.79 (1H, m), 7.63-7.51 (2H, m), 3.97-3.82 (3H, m), 3.74-3.61 (2H, m), 2.63 (3H, d, J = 4.8 Hz), 2.55-2.36 (2H, m), 2.20-2.09 (2H, m), 1.71-1.14 (9H, m), 1.05 (3H, d, J = 6.5 Hz). 598 596 2-057 [00542]![embedded image]()
1H-NMR (CDCl3) ?: 8.27 (1H, s), 7.77-7.72 (1H, m), 7.53-7.49 (2H, m), 7.46-7.40 (1H, m), 7.20-7.14 (1H, m), 4.60- 4.50 (4H, m), 4.09-3.98 (1H, m), 2.88 (3H, d, J = 5.4 Hz), 2.37-2.27 (2H, m), 1.80-1.33 (9H, m), 1.16 (3H, d, J = 6.5 Hz). 584 582 2-058 [00543]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.17 (1H, s), 8.69-8.62 (1H, m), 8.49-8.41 (1H, m), 8.09 (1H, s), 6.55-6.23 (1H, m), 4.70- 4.58 (2H, m), 3.99-3.87 (1H, m), 2.65 (3H, d, J = 4.8 Hz), 1.98-1.88 (2H, m), 1.84-1.41 (5H, m), 1.35-1.17 (4H, m), 1.07 (3H, d, J = 6.5 Hz). 567 565 2-059 [00544]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.35 (1H, s), 8.36 (1H, d, J = 1.5 Hz), 7.95 (1H, dd, J = 8.0, 1.5 Hz), 7.82 (1H, d, J = 8.5 Hz), 7.70-7.66 (2H, m), 7.47 (1H, d, J = 1.2 Hz), 4.10-4.01 (1H, m), 3.73 (3H, s), 2.76-2.64 (2H, m), 2.42-2.22 (4H, m), 2.15-2.05 (2H, m), 1.63-1.47 (2H, m), 1.09-1.00 (3H, m). 514 512 2-060 [00545]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.36 (1H, s), 8.35 (1H, d, J = 1.5 Hz), 7.96 (1H, dd, J = 8.0, 1.5 Hz), 7.69 (1H, d, J = 8.0 Hz), 7.59 (1H, s), 7.54 (1H, d, J = 1.0 Hz), 7.48 (1H, d, J = 8.3 Hz), 4.09-3.97 (1H, m), 3.67 (3H, s), 2.73-2.64 (2H, m), 2.43 (1H, dd, J = 12.4, 7.9 Hz), 2.35-2.22 (3H, m), 2.12-2.03 (2H, m), 1.64-1.48 (2H, m), 1.07 (3H, d, J = 6.5 Hz). 514 512
TABLE-US-00050 TABLE 1-50 2-061 [00546]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.36 (1H, s), 8.71 (1H, d, J = 8.3 Hz), 8.35 (1H, d, J = 1.5 Hz), 7.94 (1H, dd, J = 7.9, 1.6 Hz), 7.68 (1H, d, J = 8.0 Hz), 7.28 (1H, s), 4.14-4.04 (1H, m), 2.76-2.61 (2H, m), 2.46-2.23 (4H, m), 2.12-2.07 (2H, m), 1.58-1.51 (2H, m), 1.09 (3H, d, J = 6.5 Hz). 535 533 2-062 [00547]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.36 (1H, s), 8.51 (1H, d, J = 8.5 Hz), 8.35 (1H, d, J = 1.5 Hz), 7.95 (1H, dd, J = 8.0, 1.5 Hz), 7.68 (1H, d, J = 8.0 Hz), 6.82 (1H, s), 4.13-4.01 (1H, m), 2.76-2.61 (2H, m), 2.46-2.38 (1H, m), 2.36-2.24 (3H, m), 2.28 (3H, s), 2.12-2.05 (2H, m), 1.61-1.46 (2H, m), 1.08 (3H, d, J = 6.5 Hz). 515 513 2-063 [00548]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.35 (1H, s), 8.32-7.83 (6H, m), 6.75 (1H, d, J = 5.0 Hz), 4.00-3.84 (1H, m), 2.73-2.64 (1H, m), 2.67 (3H, d, J = 4.8 Hz), 2.35-2.02 (7H, m), 1.70-1.56 (2H, m), 1.02 (3H, d, J = 6.5 Hz). 517 515 2-064 [00549]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.36 (1H, s), 8.67 (1H, d, J = 5.3 Hz), 8.38-8.31 (2H, m), 7.96 (1H, dd, J = 8.0, 1.5 Hz), 7.70 (1H, d, J = 8.0 Hz), 3.97-3.86 (1H, m), 2.76-2.67 (2H, m), 2.65-2.59 (1H, m), 2.42 (1H, dd, J = 12.5, 8.3 Hz), 2.36- 2.19 (3H, m), 2.16-2.03 (2H, m), 1.64-1.48 (2H, m), 1.04 (3H, d, J = 6.5 Hz), 0.68-0.53 (4H, m). 517 515 2-065 [00550]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.46 (1H, s), 8.73 (1H, d, J = 9.2 Hz), 8.60 (1H, d, J = 4.8 Hz), 8.39 (1H, s), 8.01 (1H, d, J = 8.1 Hz), 7.75 (1H, d, J = 8.1 Hz), 4.12 (1H, br s), 2.64 (3H, d, J = 4.8 Hz), 2.24 (2H, t, J = 10.5 Hz), 2.07 (1H, dd, J = 13.7, 11.0 Hz), 1.99 (1H, br s), 1.79-1.53 (6H, m), 1.12 (3H, d, J = 6.5 Hz). 515 513 2-066 [00551]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.43 (1H, s), 8.75-8.69 (1H, m), 8.62-8.57 (1H, m), 8.06-8.01 (1H, m), 7.94 (1H, s), 7.83- 7.78 (1H, m), 4.16-4.05 (1H, m), 2.65-2.62 (3H, m), 2.33- 2.19 (2H, m), 2.11-1.96 (2H, m), 1.81-1.52 (6H, m), 1.12 (3H, d, J = 6.5 Hz). 558 556 2-067 [00552]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.34 (1H, s), 8.75-8.69 (1H, m), 8.63-8.57 (1H, m), 7.65-7.62 (1H, m), 7.60-7.55 (1H, m), 7.41-7.20 (2H, m), 4.18-4.06 (1H, m), 2.66-2.62 (3H, m), 2.27-1.97 (4H, m), 1.82-1.54 (6H, m), 1.12 (3H, d, J = 6.5 Hz). 556 554 2-068 [00553]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.44 (1H, s), 9.01 (1H, d, J = 8.6 Hz), 8.16-8.13 (1H, m), 8.04-8.00 (1H, m), 7.91-7.88 (1H, m), 7.30-7.28 (1H, m), 4.35-4.24 (1H, m), 2.32-2.17 (2H, m), 2.07-1.97 (2H, m), 1.87-1.54 (6H, m), 1.20-1.16 (3H, m). 559 557 2-069 [00554]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.91 (0.25H, s), 12.85 (0.75H, s), 11.29 (1H, s), 8.01-7.93 (2.5H, m), 7.86-7.81 (1H, m), 7.61- 7.54 (0.5H, m), 6.49 (0.25H, s), 6.22 (0.75H, s), 4.10-4.00 (1H, m), 2.19-1.79 (3H, m), 1.74-1.14 (9H, m), 1.07 (3H, d, J = 6.5 Hz), 0.98-0.55 (4H, m). 539 537 2-070 [00555]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.29 (1H, s), 8.01-7.94 (2H, m), 7.86-7.81 (1H, m), 7.74-7.71 (1H, m), 7.68-7.63 (1H, m), 6.57-6.54 (1H, m), 4.12-4.02 (1H, m), 3.88-3.86 (3H, m), 2.17-2.06 (2H, m), 1.73-1.18 (9H, m), 1.08 (3H, d, J = 6.5 Hz). 513 511
TABLE-US-00051 TABLE 1-51 2-071 [00556]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.28 (1H, s), 8.01-7.94 (2H, m), 7.86-7.81 (1H, m), 7.61-7.59 (1H, m), 7.55-7.53 (1H, m), 7.47-7.41 (1H, m), 4.09-3.99 (1H, m), 3.66 (3H, s), 2.16- 2.06 (2H, m), 1.74-1.18 (9H, m), 1.07 (3H, d, J = 7.0 Hz). 513 511 2-072 [00557]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.95-12.82 (1H, m), 11.30 (1H, s), 8.34-8.31 (1H, m), 7.94-7.89 (1H, m), 7.69-7.64 (1H, m), 7.61-7.54 (1H, m), 6.54-6.18 (1H, m), 4.12-3.98 (1H, m), 2.17-2.07 (2H, m), 1.95-1.64 (2H, m), 1.57-1.12 (8H, m), 1.07 (3H, d, J = 5.9 Hz), 0.98-0.56 (4H, m). 539 537 2-073 [00558]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.28 (1H, s), 8.59 (1H, s), 8.40 (1H, d, J = 9.0 Hz), 8.00 (1H, d, J = 1.8 Hz), 7.98 (1H, d, J = 8.3 Hz), 7.85 (1H, dd, J = 8.3, 1.8 Hz), 3.98-3.85 (1H, m), 2.16-2.04 (2H, m), 1.69-1.59 (1H, m), 1.59-1.13 (8H, m), 1.06 (3H, d, J = 6.5 Hz). 493 491 2-074 [00559]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.30 (1H, s), 8.65-8.60 (1H, m), 8.47-8.38 (2H, m), 7.00 (1H, s), 3.96-3.84 (1H, m), 3.88 (3H, s), 2.64 (3H, d, J = 4.8 Hz), 2.15-2.06 (2H, m), 1.70- 1.15 (9H, m), 1.05 (3H, d, J = 6.5 Hz). 496 494 2-075 [00560]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.43 (1H, s), 9.09 (1H, s), 8.65- 8.58 (1H, m), 8.43-8.38 (1H, m), 8.08 (1H, s), 3.96-3.84 (1H, m), 2.63 (3H, d, J = 4.8 Hz), 2.20-2.11 (2H, m), 1.69- 1.16 (9H, m), 1.05 (3H, d, J = 6.5 Hz). 534 532 2-076 [00561]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.44 (1H, s), 8.72 (1H, d, J = 9.2 Hz), 8.63-8.55 (1H, m), 8.00-7.95 (1H, m), 7.85-7.80 (1H, m), 7.76-7.69 (1H, m), 4.19-4.04 (1H, m), 2.64 (3H, d, J = 4.8 Hz), 2.37-1.92 (4H, m), 1.84-1.35 (6H, m), 1.12 (3H, d, J = 6.5 Hz). 558 556 2-077 [00562]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.46 (1H, s), 8.75-8.70 (1H, m), 8.63-8.57 (1H, m), 8.49 (1H, s), 7.11 (1H, s), 4.17-4.06 (1H, m), 3.90-3.87 (3H, m), 2.64 (3H, d, J = 3.8 Hz), 2.27-1.97 (4H, m), 1.82-1.53 (6H, m), 1.12 (3H, d, J = 6.5 Hz). 521 519 2-078 [00563]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.36 (1H, s), 7.86-7.79 (2H, m), 7.61 (1H, s), 7.56 (1H, s), 7.49-7.10 (3H, m), 4.32-4.21 (1H, m), 3.66 (3H, s), 2.29-1.96 (4H, m), 1.88-1.54 (6H, m), 1.14 (3H, d, J = 6.5 Hz). 579 577 2-079 [00564]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.42 (1H, s), 8.06-8.01 (1H, m), 7.96-7.91 (1H, m), 7.85-7.76 (2H, m), 7.61 (1H, s), 7.55 (1H, s), 4.32-4.20 (1H, m), 3.66 (3H, s), 2.33-1.95 (4H, m), 1.88-1.50 (6H, m), 1.14 (3H, d, J = 7.0 Hz). 581 579 2-080 [00565]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.41 (1H, s), 8.75-8.70 (1H, m), 8.63-8.57 (1H, m), 7.95-7.90 (1H, m), 7.67-7.64 (1H, m), 7.51-7.46 (1H, m), 4.17-4.05 (1H, m), 2.64 (3H, d, J = 4.8 Hz), 2.30-1.94 (4H, m), 1.81-1.52 (6H, m), 1.12 (3H, d, J = 7.0 Hz). 574 572
TABLE-US-00052 TABLE 1-52 2-081 [00566]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.29 (1H, s), 8.71-8.64 (1H, m), 8.44-8.37 (1H, m), 8.01-7.95 (2H, m), 7.89-7.82 (1H, m), 3.96-3.85 (1H, m), 3.18-3.06 (2H, m), 2.16-2.05 (2H, m), 1.69-1.16 (9H, m), 1.09-0.99 (6H, m). 504 502 2-082 [00567]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.37 (1H, s), 8.75-8.69 (1H, m), 8.68-8.62 (1H, m), 7.85-7.80 (1H, m), 7.50-7.10 (3H, m), 4.17-4.05 (1H, m), 3.21-3.04 (2H, m), 2.29-1.96 (4H, m), 1.82-1.56 (6H, m), 1.12 (3H, d, J = 6.5 Hz), 1.02 (3H, t, J = 7.3 Hz). 570 568 2-083 [00568]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.32 (1H, s), 8.66-8.58 (2H, m), 8.45-8.38 (1H, m), 7.10 (1H, s), 6.56-6.24 (1H, m), 4.63- 4.51 (2H, m), 3.97-3.84 (1H, m), 2.64 (3H, d, J = 3.8 Hz), 2.16-2.07 (2H, m), 1.71-1.13 (9H, m), 1.06 (3H, d, J = 6.5 Hz). 594 592 2-084 [00569]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.32 (1H, s), 8.66-8.60 (1H, m), 8.47 (1H, s), 8.44-8.38 (1H, m), 7.14 (1H, s), 6.56-6.24 (1H, m), 4.64-4.52 (2H, m), 3.96-3.85 (1H, m), 2.64 (3H, d, J = 4.8 Hz), 2.15-2.07 (2H, m), 1.70-1.16 (9H, m), 1.05 (3H, d, J = 6.5 Hz). 546 544 2-085 [00570]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.32 (1H, s), 8.46 (1H, s), 7.60 (1H, s), 7.54 (1H, s), 7.45 (1H, d, J = 9.2 Hz), 7.14 (1H, s), 6.57-6.21 (1H, m), 4.63-4.50 (2H, m), 4.11-3.96 (1H, m), 3.66 (3H, s), 2.17-2.07 (2H, m), 1.76-1.15 (9H, m), 1.07 (3H, d, J = 6.5 Hz). 569 567 2-086 [00571]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.31 (1H, s), 8.59 (1H, s), 7.61 (1H, s), 7.54 (1H, s), 7.45 (1H, d, J = 8.6 Hz), 7.10 (1H, s), 6.55-6.21 (1H, m), 4.61-4.50 (2H, m), 4.09-3.98 (1H, m), 3.66 (3H, s), 2.17-2.06 (2H, m), 1.75-1.14 (9H, m), 1.07 (3H, d, J = 6.5 Hz). 617 615 2-087 [00572]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.31 (1H, s), 8.64-8.58 (1H, m), 8.43-8.38 (1H, m), 8.07-8.02 (1H, m), 7.92-7.88 (2H, m), 3.96-3.84 (1H, m), 3.32 (3H, s), 2.63 (3H, d, J = 4.8 Hz), 2.21-2.12 (2H, m), 1.71-1.13 (9H, m), 1.05 (3H, d, J = 6.5 Hz). 543 541 2-088 [00573]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.34 (1H, s), 8.75-8.69 (1H, m), 8.63-8.57 (1H, m), 7.80-7.75 (1H, m), 7.61-7.55 (1H, m), 7.43-7.36 (1H, m), 4.18-4.06 (1H, m), 2.64 (3H, d, J = 4.8 Hz), 2.26-1.95 (4H, m), 1.81-1.53 (6H, m), 1.12 (3H, d, J = 6.5 Hz). 508 506 2-089 [00574]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.33 (1H, s), 8.03 (1H, s), 7.86 (1H, d, J = 9.2 Hz), 7.78-7.73 (2H, m), 7.60-7.54 (1H, m), 7.41-7.34 (1H, m), 4.32-4.20 (1H, m), 3.82 (3H, s), 2.27- 2.15 (2H, m), 2.03-1.51 (8H, m), 1.12 (3H, d, J = 6.5 Hz). 531 529 2-090 [00575]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.37 (1H, s), 8.03 (1H, s), 7.90- 7.78 (2H, m), 7.76 (1H, s), 7.50-7.08 (3H, m), 4.32-4.20 (1H, m), 3.82 (3H, s), 2.29-2.16 (2H, m), 2.04-1.54 (8H, m), 1.12 (3H, d, J = 6.5 Hz). 579 577
TABLE-US-00053 TABLE 1-53 2-091 [00576]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.31 (1H, s), 8.59 (1H, s), 8.05 (1H, s), 7.78 (1H, s), 7.64 (1H, d, J = 8.1 Hz), 7.10 (1H, s), 6.56-6.21 (1H, m), 4.63-4.49 (2H, m), 4.09-3.94 (1H, m), 3.81 (3H, s), 2.17-2.07 (2H, m), 1.73-1.14 (9H, m), 1.06 (3H, d, J = 5.9 Hz). 617 615 2-092 [00577]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.45 (1H, s), 8.75-8.70 (1H, m), 8.67-8.63 (1H, m), 8.15-8.13 (1H, m), 8.05-8.01 (1H, m), 7.93-7.88 (1H, m), 4.16-4.04 (1H, m), 2.78-2.69 (1H, m), 2.29-1.94 (4H, m), 1.82-1.53 (6H, m), 1.12 (3H, d, J = 6.5 Hz), 0.64-0.56 (4H, m). 541 539 2-093 [00578]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.46 (1H, s), 8.75-8.69 (1H, m), 8.67-8.63 (1H, m), 8.49 (1H, s), 7.11 (1H, s), 4.15-4.02 (1H, m), 3.89 (3H, s), 2.77-2.68 (1H, m), 2.27-1.96 (4H, m), 1.82-1.53 (6H, m), 1.12 (3H, d, J = 6.5 Hz), 0.66-0.54 (4H, m). 547 545 2-094 [00579]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.44 (1H, s), 8.14 (1H, s), 8.04- 8.00 (2H, m), 7.91-7.83 (2H, m), 7.76 (1H, s), 4.35-4.19 (1H, m), 3.82 (3H, s), 2.31-2.16 (2H, m), 2.04-1.54 (8H, m), 1.13 (3H, d, J = 6.5 Hz). 538 536 2-095 [00580]![embedded image]()
1H-NMR (CDCl3) ?: 8.49 (1H, s), 8.34 (1H, s), 7.81 (1H, s), 7.75 (1H, s), 6.62 (1H, s), 5.68 (1H, d, J = 9.7 Hz), 4.59- 4.47 (1H, m), 3.92 (3H, s), 3.89 (3H, s), 2.37-2.27 (2H, m), 2.18-1.69 (8H, m), 1.27 (3H, d, J = 6.5 Hz). 544 542 2-096 [00581]![embedded image]()
1H-NMR (DMSO-D6) ?: 8.35 (1H, d, J = 1.5 Hz), 7.95 (1H, dd, J = 8.0, 1.5 Hz), 7.70 (1H, d, J = 8.0 Hz), 7.42-7.35 (2H, m), 4.10-3.98 (1H, m), 2.74-2.65 (2H, m), 2.46-2.38 (1H, m), 2.34-2.21 (4H, m), 2.24 (3H, s), 2.15-2.04 (2H, m), 1.65-1.51 (2H, m), 1.06 (3H, d, J = 6.5 Hz). 514 512 2-097 [00582]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.43 (1H, s), 8.02 (1H, s), 7.98- 7.94 (1H, m), 7.88-7.79 (2H, m), 7.76 (1H, s), 7.73-7.68 (1H, m), 4.33-4.20 (1H, m), 3.83-3.80 (3H, m), 2.36-2.13 (2H, m), 2.04-1.60 (8H, m), 1.12 (3H, d, J = 6.5 Hz). 581 579 2-098 [00583]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.38 (1H, s), 8.75-8.70 (1H, m), 8.63-8.57 (1H, m), 7.84-7.79 (1H, m), 7.56-7.51 (1H, m), 7.38-7.30 (1H, m), 4.17-4.06 (1H, m), 2.64 (3H, d, J = 4.8 Hz), 2.27-1.95 (4H, m), 1.81-1.53 (6H, m), 1.12 (3H, d, J = 6.5 Hz). 508 506 2-099 [00584]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.49 (1H, s), 8.77-8.68 (1H, m), 8.63-8.56 (1H, m), 8.52 (1H, s), 7.25 (1H, s), 6.58-6.24 (1H, m), 4.67-4.54 (2H, m), 4.07-3.97 (1H, m), 2.66 (3H, d, J = 3.8 Hz), 2.08-1.55 (10H, m), 1.11 (3H, d, J = 6.5 Hz). 571 569 2-100 [00585]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.38 (1H, s), 8.72 (1H, d, J = 9.2 Hz), 8.65 (1H, d, J = 5.4 Hz), 7.84-7.79 (1H, m), 7.56-7.51 (1H, m), 7.38-7.31 (1H, m), 4.16-4.04 (1H, m), 2.78-2.69 (1H, m), 2.27-1.94 (4H, m), 1.82-1.54 (6H, m), 1.12 (3H, d, J = 6.5 Hz), 0.65-0.55 (4H, m). 534 532
TABLE-US-00054 TABLE 1-54 2-101 [00586]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.49 (1H, s), 8.75-8.68 (1H, m), 8.67-8.60 (1H, m), 8.51 (1H, s), 7.25 (1H, s), 6.58-6.24 (1H, m), 4.67-4.55 (2H, m), 4.07-3.94 (1H, m), 2.80-2.69 (1H, m), 2.08-1.54 (10H, m), 1.10 (3H, d, J = 6.5 Hz), 0.69-0.55 (4H, m). 597 595 2-102 [00587]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.40 (1H, s), 8.77-8.67 (1H, m), 8.66-8.56 (1H, m), 7.67-7.50 (2H, m), 7.27 (1H, t, J = 71.9 Hz), 4.19-4.05 (1H, m), 2.66-2.62 (3H, m), 2.31-1.93 (4H, m), 1.82-1.50 (6H, m), 1.12 (3H, d, J = 6.5 Hz). 574 572 2-103 [00588]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.40 (1H, s), 8.72 (1H, d, J = 9.7 Hz), 8.65 (1H, d, J = 4.8 Hz), 7.66-7.59 (1H, m), 7.57-7.51 (1H, m), 7.27 (1H, t, J = 72.2 Hz), 4.17-4.04 (1H, m), 2.77- 2.69 (1H, m), 2.27-1.93 (4H, m), 1.82-1.50 (6H, m), 1.12 (3H, d, J = 6.5 Hz), 0.68-0.53 (4H, m). 600 598 2-104 [00589]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.38 (1H, s), 8.97-8.90 (1H, m), 8.88-8.82 (1H, m), 7.85-7.80 (1H, m), 7.50-7.10 (3H, m), 6.20-5.87 (1H, m), 4.20-4.07 (1H, m), 3.65-3.40 (2H, m), 2.30-1.95 (4H, m), 1.83-1.54 (6H, m), 1.13 (3H, d, J = 6.5 Hz). 606 604 2-105 [00590]![embedded image]()
1H-NMR (CDCl3) ?: 9.73 (1H, s), 8.34 (1H, s), 7.66 (1H, d, J = 9.2 Hz), 7.39-7.33 (1H, m), 7.15-7.10 (1H, m), 7.02 (1H, d, J = 2.7 Hz), 6.51 (1H, t, J = 72.7 Hz), 4.35-4.22 (1H, m), 3.82 (3H, s), 2.41-2.29 (2H, m), 2.10-1.70 (8H, m), 1.30 (3H, d, J = 6.5 Hz). 572 570 2-106 [00591]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.46 (1H, s), 8.96-8.91 (1H, m), 8.88-8.82 (1H, m), 8.49 (1H, s), 7.11 (1H, s), 6.21-5.86 (1H, m), 4.18-4.07 (1H, m), 3.88 (3H, s), 3.66-3.39 (2H, m), 2.29-1.95 (4H, m), 1.81-1.55 (6H, m), 1.13 (3H, d, J = 6.5 Hz). 571 569 2-107 [00592]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.38 (1H, s), 8.75-8.69 (1H, m), 8.67-8.63 (1H, m), 7.85-7.81 (1H, m), 7.52-7.11 (3H, m), 4.16-4.01 (1H, m), 2.78-2.67 (1H, m), 2.29-1.93 (4H, m), 1.86-1.52 (6H, m), 1.12 (3H, d, J = 6.5 Hz), 0.67-0.54 (4H, m). 582 580 2-108 [00593]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.22 (1H, s), 8.38 (1H, d, J = 8.6 Hz), 7.98 (1H, s), 7.81-7.76 (1H, m), 7.71 (1H, s), 7.53-7.12 (3H, m), 3.95-3.80 (1H, m), 2.21-2.08 (2H, m), 1.70-1.14 (9H, m), 1.05 (3H, d, J = 6.5 Hz). 517 515 2-109 [00594]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.36 (1H, s), 8.75-8.69 (1H, m), 8.63-8.57 (1H, m), 7.59-7.52 (1H, m), 7.46-7.42 (1H, m), 7.39-7.34 (2H, m), 4.16-4.05 (1H, m), 2.66-2.61 (3H, m), 2.29-1.94 (4H, m), 1.81-1.57 (6H, m), 1.11 (3H, d, J = 4.8 Hz). 556 554 2-110 [00595]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.37 (1H, s), 8.74-8.69 (1H, m), 8.67-8.63 (1H, m), 7.59-7.53 (1H, m), 7.47-7.42 (1H, m), 7.39-7.35 (2H, m), 4.16-4.03 (1H, m), 2.78-2.68 (1H, m), 2.29-1.93 (4H, m), 1.82-1.55 (6H, m), 1.12 (3H, d, J = 6.5 Hz), 0.67-0.56 (4H, m). 582 580
TABLE-US-00055 TABLE 1-55 2-111 [00596]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.37 (1H, s), 8.97-8.90 (1H, m), 8.88-8.82 (1H, m), 7.59-7.52 (1H, m), 7.47-7.42 (1H, m), 7.39-7.35 (2H, m), 6.20-5.87 (1H, m), 4.20-4.07 (1H, m), 3.64-3.38 (2H, m), 2.30-1.94 (4H, m), 1.83-1.53 (6H, m), 1.13 (3H, d, J = 6.5 Hz). 606 604 2-112 [00597]![embedded image]()
1H-NMR (DMSO-D6) ?: 8.66-8.59 (1H, m), 8.46-8.38 (1H, m), 8.04-7.96 (2H, m), 7.90-7.84 (1H, m), 3.96-3.85 (1H, m), 3.32 (3H, s), 2.64 (3H, d, J = 4.8 Hz), 2.16-2.05 (2H, m), 1.70-1.38 (4H, m), 1.31-1.14 (5H, m), 1.05 (3H, d, J = 7.0 Hz). 504 N.D. 2-113 [00598]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.38 (1H, s), 8.72 (1H, d, J = 9.2 Hz), 8.57 (1H, s), 7.85-7.81 (1H, m), 7.50-7.11 (3H, m), 4.16-4.05 (1H, m), 2.28-1.95 (4H, m), 1.81-1.57 (6H, m), 1.12 (3H, d, J = 7.0 Hz). 559 557 2-114 [00599]![embedded image]()
1H-NMR (CDCl3) ?: 9.77 (1H, s), 8.49 (1H, s), 7.83-7.79 (1H, m), 7.57-7.51 (1H, m), 7.43-7.38 (2H, m), 4.36-4.23 (1H, m), 3.81 (3H, s), 2.45-2.35 (2H, m), 2.09-1.70 (8H, m), 1.29 (3H, d, J = 7.0 Hz). 574 572 2-115 [00600]![embedded image]()
1H-NMR (CDCl3) ?: 9.84 (1H, s), 8.53 (1H, s), 7.48-7.39 (2H, m), 7.35-7.30 (1H, m), 7.14-7.09 (1H, m), 6.58 (1H, t, J = 72.7 Hz), 4.35-4.22 (1H, m), 3.81 (3H, s), 2.43-2.30 (2H, m), 2.09-1.68 (8H, m), 1.29 (3H, d, J = 7.0 Hz). 572 570 2-116 [00601]![embedded image]()
1H-NMR (CDCl3) ?: 9.96 (1H, s), 8.77 (1H, s), 8.35 (1H, s), 7.56 (1H, d, J = 9.7 Hz), 6.64 (1H, s), 4.36-4.24 (1H, m), 3.93 (3H, s), 3.82 (3H, s), 2.36-2.29 (2H, m), 2.08-1.70 (8H, m), 1.29 (3H, d, J = 6.5 Hz). 537 535 2-117 [00602]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.44 (1H, s), 8.74-8.69 (1H, m), 8.67-8.63 (1H, m), 8.00-7.95 (1H, m), 7.85-7.80 (1H, m), 7.76-7.70 (1H, m), 4.16-4.04 (1H, m), 2.78-2.69 (1H, m), 2.34-1.93 (4H, m), 1.84-1.60 (6H, m), 1.12 (3H, d, J = 6.5 Hz), 0.66-0.53 (4H, m). 584 582 2-118 [00603]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.44 (1H, s), 8.74-8.69 (1H, m), 8.56 (1H, s), 7.99-7.95 (1H, m), 7.84-7.80 (1H, m), 7.75- 7.69 (1H, m), 4.15-4.04 (1H, m), 2.33-1.95 (4H, m), 1.81- 1.59 (6H, m), 1.11 (3H, d, J = 6.5 Hz). 561 559 2-119 [00604]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.01 (1H, s), 11.42 (1H, s), 8.86- 8.80 (1H, m), 7.96-7.90 (1H, m), 7.67-7.64 (1H, m), 7.51- 7.47 (1H, m), 4.17-4.04 (1H, m), 3.59 (3H, s), 2.31-1.95 (4H, m), 1.83-1.52 (6H, m), 1.12 (3H, d, J = 6.6 Hz). 590 588 2-120 [00605]![embedded image]()
1H-NMR (DMSO-D6) ?: 12.02 (1H, s), 11.23 (1H, s), 8.53 (1H, d, J = 8.1 Hz), 7.79 (1H, d, J = 9.2 Hz), 7.53-7.12 (3H, m), 3.98-3.85 (1H, m), 3.60 (3H, s), 2.20-2.08 (2H, m), 1.70-1.14 (9H, m), 1.05 (3H, d, J = 6.5 Hz). 547 545
TABLE-US-00056 TABLE 1-56 2-121 [00606]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.30 (1H, s), 8.44 (1H, s), 8.42- 8.34 (1H, m), 7.99 (1H, s), 7.72 (1H, s), 7.01 (1H, s), 3.94- 3.82 (1H, m), 3.88 (3H, s), 2.17-2.06 (2H, m), 1.69-1.15 (9H, m), 1.05 (3H, d, J = 6.5 Hz). 482 480 2-122 [00607]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.32 (1H, s), 8.47 (1H, s), 8.41- 8.34 (1H, m), 7.99 (1H, s), 7.72 (1H, s), 7.15 (1H, s), 6.57- 6.25 (1H, m), 4.66-4.52 (2H, m), 3.96-3.82 (1H, m), 2.19- 2.07 (2H, m), 1.71-1.15 (9H, m), 1.05 (3H, d, J = 6.5 Hz). 532 530 2-123 [00608]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.32 (1H, s), 8.65-8.54 (2H, m), 8.09-8.05 (1H, m), 8.03-7.98 (1H, m), 7.91-7.86 (1H, m), 4.01-3.92 (1H, m), 2.92 (3H, s), 2.67-2.63 (3H, m), 1.99- 1.42 (10H, m), 1.08 (3H, d, J = 6.5 Hz). 520 518 2-124 [00609]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.31 (1H, s), 8.65-8.51 (2H, m), 8.00-7.92 (1H, m), 7.80-7.66 (2H, m), 4.04-3.91 (1H, m), 2.90 (3H, s), 2.65 (3H, d, J = 4.8 Hz), 2.01-1.40 (10H, m), 1.08 (3H, d, J = 6.5 Hz). 563 561 2-125 [00610]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.33 (1H, s), 8.66-8.53 (2H, m), 8.46 (1H, s), 7.03 (1H, s), 4.03-3.91 (1H, m), 3.89 (3H, s), 2.93 (3H, s), 2.65 (3H, d, J = 4.8 Hz), 1.97-1.68 (4H, m), 1.65-1.41 (6H, m), 1.08 (3H, d, J = 6.5 Hz). 526 524 2-126 [00611]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.33 (1H, s), 8.68-8.64 (1H, m), 8.59-8.54 (1H, m), 8.06 (1H, s), 8.03-7.98 (1H, m), 7.90- 7.86 (1H, m), 4.02-3.92 (1H, m), 2.92 (3H, s), 2.78-2.69 (1H, m), 2.00-1.69 (4H, m), 1.64-1.43 (6H, m), 1.08 (3H, d, J = 6.5 Hz), 0.68-0.57 (4H, m). 546 544 2-127 [00612]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.38 (1H, s), 8.97-8.95 (1H, m), 8.69-8.66 (1H, m), 8.56-8.52 (1H, m), 8.16-8.12 (1H, m), 7.81 (1H, d, J = 8.8 Hz), 7.50-7.46 (1H, m), 7.40-7.38 (1H, m), 7.28 (1H, t, J = 73.6 Hz), 7.27-7.23 (1H, m), 4.41-4.32 (1H, m), 2.31-2.19 (2H, m), 2.08-1.99 (2H, m), 1.88-1.57 (6H, m), 1.20-1.16 (3H, m). 576 574 2-128 [00613]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.36 (1H, s), 8.78-8.73 (1H, m), 8.64-8.60 (1H, m), 8.03-7.93 (2H, m), 7.82-7.78 (1H, m), 7.60-7.55 (1H, m), 7.39-7.36 (1H, m), 7.28 (1H, t, J = 73.5 Hz), 7.27-7.21 (1H, m), 4.40-4.30 (1H, m), 2.29-1.99 (4H, m), 1.85-1.54 (6H, m), 1.20 (3H, d, J = 6.5 Hz). 576 574 2-129 [00614]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.31 (1H, s), 8.59-8.53 (2H, m), 7.97-7.93 (1H, m), 7.78-7.66 (2H, m), 4.03-3.90 (1H, m), 2.90 (3H, s), 2.01-1.41 (10H, m), 1.07 (3H, d, J = 6.5 Hz). 566 564 2-130 [00615]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.33 (1H, s), 8.60-8.54 (2H, m), 8.38-8.35 (1H, m), 8.00-7.95 (1H, m), 7.70-7.66 (1H, m), 4.03-3.90 (1H, m), 2.91 (3H, s), 1.99-1.68 (4H, m), 1.62- 1.44 (6H, m), 1.08 (3H, d, J = 6.5 Hz). 523 521
TABLE-US-00057 TABLE 1-57 2-131 [00616]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.25 (1H, s), 8.60-8.52 (2H, m), 7.83-7.76 (1H, m), 7.49-7.43 (1H, m), 7.35-7.28 (1H, m), 4.02-3.91 (1H, m), 2.92 (3H, s), 1.99-1.67 (4H, m), 1.64- 1.41 (6H, m), 1.08 (3H, d, J = 6.5 Hz). 516 514 2-132 [00617]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.41 (1H, s), 8.73 (1H, d, J = 9.2 Hz), 8.58 (1H, s), 7.92 (1H, d, J = 8.8 Hz), 7.67-7.64 (1H, m), 7.51-7.46 (1H, m), 4.16-4.03 (1H, m), 2.30-1.94 (4H, m), 1.84-1.51 (6H, m), 1.12 (3H, d, J = 6.6 Hz). 577 575 2-133 [00618]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.38 (1H, s), 8.73 (1H, d, J = 9.7 Hz), 8.58 (1H, s), 7.85-7.79 (1H, m), 7.58-7.50 (1H, m), 7.40-7.30 (1H, m), 4.19-4.06 (1H, m), 2.29-1.95 (4H, m), 1.83-1.53 (6H, m), 1.12 (3H, d, J = 6.6 Hz). 511 509 2-134 [00619]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.34 (1H, s), 8.72 (1H, d, J = 9.2 Hz), 8.57 (1H, s), 7.82-7.74 (1H, m), 7.62-7.54 (1H, m), 7.44-7.36 (1H, m), 4.17-4.05 (1H, m), 2.27-2.14 (2H, m), 2.13-1.96 (2H, m), 1.81-1.53 (6H, m), 1.12 (3H, d, J = 6.5 Hz). 511 509 2-135 [00620]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.22 (1H, s), 8.62-8.52 (2H, m), 7.78-7.70 (1H, m), 7.56-7.47 (1H, m), 7.41-7.33 (1H, m), 4.03-3.91 (1H, m), 2.93-2.89 (3H, m), 1.96-1.79 (3H, m), 1.75-1.66 (1H, m), 1.63-1.42 (6H, m), 1.08 (3H, d, J = 6.5 Hz). 516 514 2-136 [00621]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.23 (1H, s), 9.31 (1H, s), 9.04 (1H, d, J = 4.8 Hz), 8.87 (1H, d, J = 8.6 Hz), 8.00 (1H, d, J = 5.4 Hz), 7.81-7.75 (1H, m), 7.48-7.42 (1H, m), 7.35-7.27 (1H, m), 4.28-4.14 (1H, m), 2.95 (3H, s), 2.02-1.86 (3H, m), 1.80-1.73 (1H, m), 1.69-1.46 (6H, m), 1.17 (3H, d, J = 6.5 Hz). 534 532 2-137 [00622]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.23 (1H, s), 9.40-9.37 (1H, m), 9.10 (1H, d, J = 8.6 Hz), 8.20-8.16 (1H, m), 7.91-7.86 (1H, m), 7.81-7.75 (1H, m), 7.47-7.42 (1H, m), 7.34-7.27 (1H, m), 4.34-4.22 (1H, m), 2.96 (3H, s), 2.04-1.48 (10H, m), 1.20 (3H, d, J = 6.5 Hz). 534 532 2-138 [00623]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.40 (1H, s), 8.73 (1H, d, J = 9.2 Hz), 8.57 (1H, s), 7.67-7.59 (1H, m), 7.57-7.51 (1H, m), 7.27 (1H, t, J = 72.2 Hz), 4.18-4.05 (1H, m), 2.29-1.93 (4H, m), 1.83-1.50 (6H, m), 1.12 (3H, d, J = 6.5 Hz). 577 575 2-139 [00624]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.40 (1H, s), 8.73 (1H, d, J = 9.7 Hz), 8.63-8.57 (1H, m), 8.08-8.01 (1H, m), 7.88-7.81 (1H, m), 4.17-4.06 (1H, m), 2.64 (3H, d, J = 4.8 Hz), 2.27-2.15 (2H, m), 2.13-1.96 (2H, m), 1.81-1.55 (6H, m), 1.12 (3H, d, J = 6.5 Hz). 526 524 2-140 [00625]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.40 (1H, s), 8.73 (1H, d, J = 9.7 Hz), 8.57 (1H, s), 8.08-8.01 (1H, m), 7.88-7.81 (1H, m), 4.18-4.06 (1H, m), 2.28-1.93 (4H, m), 1.84-1.55 (6H, m), 1.12 (3H, d, J = 6.5 Hz). 529 527
TABLE-US-00058 TABLE 1-58 2-141 [00626]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.36 (1H, s), 9.30 (1H, s), 9.06- 9.00 (2H, m), 8.01-7.97 (1H, m), 7.82-7.76 (1H, m), 7.55- 7.49 (1H, m), 7.35-7.28 (1H, m), 4.44-4.28 (1H, m), 2.31- 2.01 (4H, m), 1.86-1.52 (6H, m), 1.21 (3H, d, J = 6.5 Hz). 529 527 2-142 [00627]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.36 (1H, s), 9.38 (1H, d, J = 5.4 Hz), 9.27 (1H, d, J = 9.7 Hz), 8.20-8.15 (1H, m), 7.90-7.85 (1H, m), 7.82-7.77 (1H, m), 7.55- 7.49 (1H, m), 7.35-7.28 (1H, m), 4.50-4.36 (1H, m), 2.31- 2.03 (4H, m), 1.87-1.54 (6H, m), 1.24 (3H, d, J = 6.5 Hz). 529 527 2-143 [00628]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.36 (1H, s), 8.94 (2H, d, J = 4.8 Hz), 8.89 (1H, d, J = 9.2 Hz), 7.83-7.77 (1H, m), 7.67-7.63 (1H, m), 7.55-7.50 (1H, m), 7.35- 7.28 (1H, m), 4.41-4.30 (1H, m), 2.31-2.01 (4H, m), 1.87- 1.55 (6H, m), 1.20 (3H, d, J = 7.0 Hz). 529 527 2-144 [00629]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.25 (1H, s), 8.65-8.53 (2H, m), 7.84-7.76 (1H, m), 7.49-7.42 (1H, m), 7.36-7.28 (1H, m), 4.02-3.91 (1H, m), 2.92 (3H, d, J = 1.1 Hz), 2.65 (3H, dd, J = 4.8, 1.1 Hz), 1.98-1.66 (4H, m), 1.63-1.40 (6H, m), 1.08 (3H, d, J = 6.5 Hz). 513 511 2-145 [00630]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.21 (1H, s), 8.65-8.53 (2H, m), 7.76-7.71 (1H, m), 7.55-7.48 (1H, m), 7.40-7.33 (1H, m), 4.03-3.91 (1H, m), 2.91 (3H, d, J = 1.1 Hz), 2.65 (3H, d, J = 4.3 Hz), 1.96-1.67 (4H, m), 1.64- 1.41 (6H, m), 1.08 (3H, d, J = 6.5 Hz). 513 511 2-146 [00631]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.36 (1H, s), 9.16 (1H, s), 8.92 (1H, d, J = 9.7 Hz), 8.86-8.83 (1H, m), 8.72-8.69 (1H, m), 7.83-7.77 (1H, m), 7.55-7.49 (1H, m), 7.35-7.29 (1H, m), 4.45-4.32 (1H, m), 2.35-2.03 (4H, m), 1.85-1.55 (6H, m), 1.21 (3H, d, J = 6.5 Hz). 529 527 2-147 [00632]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.37 (1H, s), 9.89-9.80 (1H, m), 8.30-8.24 (1H, m), 8.04-7.99 (1H, m), 7.83-7.76 (1H, m), 7.56-7.50 (1H, m), 7.36-7.29 (1H, m), 6.50-6.43 (1H, m), 4.38-4.24 (1H, m), 3.54 (3H, s), 2.29-2.16 (2H, m), 2.09- 1.54 (8H, m), 1.21-1.15 (3H, m). 558 556 2-148 [00633]![embedded image]()
racemate 1H-NMR (DMSO-D6) ?: 11.32 (1H, s), 8.64-8.58 (1H, m), 8.46 (1H, d, J = 9.2 Hz), 8.10 (1H, s), 8.03-7.99 (1H, m), 7.91-7.86 (1H, m), 3.83-3.73 (1H, m), 2.66 (3H, d, J = 4.8 Hz), 1.94-1.55 (7H, m), 1.47- 1.15 (4H, m), 1.04 (3H, d, J = 6.6 Hz). 490 488 2-149 [00634]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.32 (1H, s), 8.64-8.58 (1H, m), 8.46 (1H, d, J = 9.2 Hz), 8.10 (1H, s), 8.03-7.99 (1H, m), 7.91-7.86 (1H, m), 3.83-3.73 (1H, m), 2.66 (3H, d, J = 4.8 Hz), 1.94-1.55 (7H, m), 1.47- 1.15 (4H, m), 1.04 (3H, d, J = 6.6 Hz). 490 488 2-150 [00635]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.32 (1H, s), 8.64-8.58 (1H, m), 8.46 (1H, d, J = 9.2 Hz), 8.10 (1H, s), 8.03-7.99 (1H, m), 7.91-7.86 (1H, m), 3.83-3.73 (1H, m), 2.66 (3H, d, J = 4.8 Hz), 1.94-1.55 (7H, m), 1.47- 1.15 (4H, m), 1.04 (3H, d, J = 6.6 Hz). 490 488
TABLE-US-00059 TABLE 1-59 2-151 [00636]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.27 (1H, s), 8.65-8.52 (2H, m), 8.05-7.97 (1H, m), 7.80-7.72 (1H, m), 4.02-3.91 (1H, m), 2.93 (3H, s), 2.65 (3H, d, J = 4.8 Hz), 1.96-1.69 (4H, m), 1.64-1.41 (6H, m), 1.08 (3H, d, J = 6.5 Hz). 531 529 2-152 [00637]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.39 (1H, s), 8.72 (1H, d, J = 9.2 Hz), 8.57 (1H, s), 7.59-7.48 (2H, m), 7.39-7.34 (1H, m), 4.17-4.05 (1H, m), 2.28-2.15 (2H, m), 2.13-1.95 (2H, m), 1.82-1.52 (6H, m), 1.12 (3H, d, J = 6.5 Hz). 511 509 2-153 [00638]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.39 (1H, s), 8.72 (1H, d, J = 9.2 Hz), 8.63-8.57 (1H, m), 7.58-7.47 (2H, m), 7.38-7.34 (1H, m), 4.17-4.04 (1H, m), 2.64 (3H, d, J = 4.8 Hz), 2.27-1.95 (4H, m), 1.81-1.53 (6H, m), 1.12 (3H, d, J = 6.5 Hz). 508 506 2-154 [00639]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.38 (1H, s), 9.40-9.36 (1H, m), 9.27 (1H, d, J = 9.2 Hz), 8.19-8.15 (1H, m), 7.91-7.85 (1H, m), 7.55-7.45 (2H, m), 7.36-7.31 (1H, m), 4.48-4.35 (1H, m), 2.30-2.03 (4H, m), 1.88-1.52 (6H, m), 1.23 (3H, d, J = 7.0 Hz). 529 527 2-155 [00640]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.36 (1H, s), 9.39-9.36 (1H, m), 9.27 (1H, d, J = 9.2 Hz), 8.19-8.16 (1H, m), 7.88 (1H, dd, J = 8.6, 4.8 Hz), 7.80 (1H, d, J = 8.6 Hz), 7.39-7.36 (1H, m), 7.28 (1H, t, J = 73.5 Hz), 7.27-7.22 (1H, m), 4.48-4.36 (1H, m), 2.31-2.02 (4H, m), 1.87-1.55 (6H, m), 1.24 (3H, d, J = 6.5 Hz). 577 575 2-156 [00641]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.33 (1H, s), 9.39-9.36 (1H, m), 9.27 (1H, d, J = 9.2 Hz), 8.20-8.15 (1H, m), 7.88 (1H, dd, J = 8.6, 4.8 Hz), 7.75 (1H, dd, J = 8.6, 2.7 Hz), 7.59-7.53 (1H, m), 7.40-7.33 (1H, m), 4.48-4.36 (1H, m), 2.29-2.02 (4H, m), 1.86-1.52 (6H, m), 1.23 (3H, d, J = 6.5 Hz). 529 527 2-157 [00642]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.39 (1H, s), 9.40-9.36 (1H, m), 9.27 (1H, d, J = 9.7 Hz), 8.19-8.15 (1H, m), 8.05-7.99 (1H, m), 7.90-7.79 (2H, m), 4.47-4.38 (1H, m), 2.29-2.04 (4H, m), 1.86-1.56 (6H, m), 1.24 (3H, d, J = 6.5 Hz). 547 545 2-158 [00643]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.27 (1H, s), 8.64-8.53 (2H, m), 7.57-7.46 (2H, m), 7.30 (1H, d, J = 7.0 Hz), 4.04-3.91 (1H, m), 2.91 (3H, s), 2.65 (3H, d, J = 4.8 Hz), 1.96-1.67 (4H, m), 1.65-1.41 (6H, m), 1.08 (3H, d, J = 6.5 Hz). 513 511 2-159 [00644]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.38 (1H, s), 8.76 (1H, d, J = 9.2 Hz), 8.62 (1H, d, J = 4.3 Hz), 8.03-7.93 (2H, m), 7.59-7.45 (3H, m), 7.36-7.32 (1H, m), 4.41-4.29 (1H, m), 2.29-2.01 (4H, m), 1.87-1.53 (6H, m), 1.20 (3H, d, J = 7.0 Hz). 528 526 2-160 [00645]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.30 (1H, s), 8.64-8.56 (2H, m), 8.08 (1H, d, J = 1.6 Hz), 8.01-7.97 (1H, m), 7.89-7.85 (1H, m), 4.06-3.96 (1H, m), 2.65 (3H, d, J = 4.8 Hz), 2.03-1.89 (2H, m), 1.76-1.43 (4H, m), 1.27-1.17 (4H, m), 1.06 (3H, d, J = 6.5 Hz), 0.76 (3H, s). 504 502
TABLE-US-00060 TABLE 1-60 2-161 [00646]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.31 (1H, s), 8.64-8.57 (2H, m), 8.07-7.94 (4H, m), 7.89-7.85 (1H, m), 7.60-7.55 (1H, m), 4.24-4.14 (1H, m), 2.96 (3H, s), 1.98-1.47 (10H, m), 1.17 (3H, d, J = 6.5 Hz). 540 538 2-162 [00647]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.33 (1H, s), 8.64-8.53 (2H, m), 8.36 (1H, d, J = 1.6 Hz), 8.00- 7.96 (1H, m), 7.68 (1H, d, J = 8.1 Hz), 4.02-3.91 (1H, m), 2.91 (3H, s), 2.65 (3H, d, J = 4.8 Hz), 1.98-1.79 (3H, m), 1.77- 1.68 (1H, m), 1.62-1.42 (6H, m), 1.08 (3H, d, J = 7.0 Hz). 520 518 2-163 [00648]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.31 (1H, s), 8.71 (1H, d, J = 9.7 Hz), 8.63-8.56 (1H, m), 7.77 (1H, d, J = 7.5 Hz), 7.51-7.47 (2H, m), 7.45-7.40 (1H, m), 4.17-4.04 (1H, m), 2.64 (3H, d, J = 4.8 Hz), 2.27-2.16 (2H, m), 2.11-1.95 (2H, m), 1.81- 1.52 (6H, m), 1.12 (3H, d, J = 6.5 Hz). 490 488 2-164 [00649]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.31 (1H, s), 8.71 (1H, d, J = 9.2 Hz), 8.57 (1H, s), 7.77 (1H, d, J = 8.1 Hz), 7.54-7.38 (3H, m), 4.19-4.03 (1H, m), 2.27- 2.16 (2H, m), 2.12-1.93 (2H, m), 1.82-1.52 (6H, m), 1.12 (3H, d, J = 6.5 Hz). 493 491 2-165 [00650]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.30 (1H, s), 9.09 (1H, d, J = 2.2 Hz), 8.99 (1H, d, J = 9.2 Hz), 8.50-8.46 (1H, m), 8.14 (1H, d, J = 8.1 Hz), 7.75 (1H, d, J = 7.5 Hz), 7.48-7.44 (2H, m), 7.43-7.37 (1H, m), 4.41-4.31 (1H, m), 2.29-2.01 (4H, m), 1.84-1.53 (6H, m), 1.20 (3H, d, J = 6.5 Hz). 535 533 2-166 [00651]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.38 (1H, s), 9.10-9.08 (1H, m), 8.99 (1H, d, J = 9.7 Hz), 8.50- 8.46 (1H, m), 8.14 (1H, d, J = 8.1 Hz), 7.55-7.46 (2H, m), 7.36-7.32 (1H, m), 4.41-4.31 (1H, m), 2.28-2.01 (4H, m), 1.83-1.52 (6H, m), 1.20 (3H, d, J = 6.5 Hz). 553 551 2-167 [00652]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.33 (1H, s), 9.09 (1H, d, J = 2.2 Hz), 8.99 (1H, d, J = 9.7 Hz), 8.50-8.46 (1H, m), 8.16-8.13 (1H, m), 7.75 (1H, dd, J = 8.6, 2.2 Hz), 7.58-7.53 (1H, m), 7.40-7.33 (1H, m), 4.42-4.31 (1H, m), 2.28-2.01 (4H, m), 1.83-1.51 (6H, m), 1.20 (3H, d, J = 7.0 Hz). 553 551 2-168 [00653]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.29 (1H, s), 8.75 (1H, d, J = 9.7 Hz), 8.61 (1H, d, J = 3.8 Hz), 8.03-7.93 (2H, m), 7.75 (1H, d, J = 8.1 Hz), 7.59-7.54 (1H, m), 7.48-7.44 (2H, m), 7.43- 7.36 (1H, m), 4.40-4.29 (1H, m), 2.32-2.01 (4H, m), 1.87- 1.52 (6H, m), 1.20 (3H, d, J = 6.5 Hz). 510 508 2-169 [00654]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.29 (1H, s), 8.65-8.59 (1H, m), 8.41 (1H, d, J = 9.0 Hz), 8.00 (1H, d, J = 1.8 Hz), 7.98 (1H, d, J = 8.3 Hz), 7.86 (1H, dd, J = 8.3, 1.8 Hz), 3.98-3.85 (1H, m), 2.64 (3H, d, J = 4.9 Hz), 2.16-2.04 (2H, m), 1.69-1.59 (1H, m), 1.59-1.13 (8H, m), 1.06 (3H, d, J = 6.5 Hz). 490 488 2-170 [00655]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.30 (1H, s), 8.39 (1H, d, J = 8.6 Hz), 8.02-7.95 (3H, m), 7.88-7.83 (1H, m), 7.72 (1H, br s), 3.94-3.82 (1H, m), 2.16-2.06 (2H, m), 1.68-1.60 (1H, m), 1.56-1.12 (8H, m), 1.05 (3H, d, J = 6.5 Hz). 476 474
TABLE-US-00061 TABLE 1-61 2-171 [00656]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.30 (1H, s), 8.07-7.80 (4H, m), 3.84-3.74 (1H, m), 2.21-2.01 (2H, m), 1.70-1.10 (9H, m), 1.01 (3H, d, J = 6.6 Hz). 477 475 2-172 [00657]![embedded image]()
1H-NMR (DMSO-D6) ?: 11.30 (1H, s), 9.11 (1H, t, J = 6.7 Hz), 8.52 (1H, d, J = 9.2 Hz), 8.00 (1H, d, J = 2.2 Hz), 7.98 (1H, d, J = 8.6 Hz), 7.86 (1H, dd, J = 8.6, 2.2 Hz), 5.65 (1H, t, J = 6.7 Hz), 4.54 (2H, t, J = 6.7 Hz), 3.98-3.86 (1H, m), 2.16-2.06 (2H, m), 1.68-1.16 (9H, m), 1.06 (3H, d, J = 6.5 Hz). 488 (M-17) 504
Experimental Example 1: Evaluation of Human PLD1 Enzyme Inhibitory Activity
[1231] A method for measuring human PLD1 enzyme inhibitory activity using an enzyme in which a FLAG-tag is added to the N-terminus of full-length human PLD1 (1-1036 amino acids) is shown below.
1. Production of Full-Length Human PLD1-Expression Plasmid
[1232] DNA fragment in which a FLAG-tag sequence is added to the 5-end of full-length human PLD1 was amplified by PCR method, using commercially available human PLD1 gene (Promega KK) as a template. The amplified DNA fragment was fused with vector pVL1393 for baculovirus production (Pharmingen) digested with BamHI and EcoRI, using In-Fusion HD Cloning Kit (Takara Bio). The full-length human PLD1-expression plasmid DNA for baculovirus was isolated from Escherichia coli DH5a (TOYOBO) transformed with the obtained In-Fusion reaction product. Next, DNA fragment in which a FLAG-tag sequence is added to the 5-end of full-length human PLD1 was amplified by PCR method, using the full-length human PLD1-expression plasmid DNA for baculovirus as a template. The amplified DNA fragment was fused with a DNA fragment in which a linker sequence is introduced into pcDNA3.4-TOPO (Life Technologies), using In-Fusion HD Cloning Kit (Takara Bio). The full-length human PLD1-expression plasmid DNA for animal cells was isolated from Escherichia coli DH5a transformed with the obtained In-Fusion reaction product. The base sequence of the full-length human PLD1 cloned into vector was determined by a Dye Terminator method using BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems). The determined sequence was a sequence in which the FLAG-tag sequence was inserted at the 5-end of the full-length human PLD1 (GenBank Accession Number: NM_001130081).
2. Production of Full-Length Human PLD1 Protein in Expi293F Cell Expression System
[1233] Expi293F cells (Life Technologies) were cultured with shaking using Expi293 Expression Medium (Life Technologies) as a medium at 37? C. in the presence of 8% CO.sub.2. The gene introduction reagent PEI was prepared by dissolving Polyethylenimine Max (nominally MW 40,000) (Polysciences) in MilliQ water, adjusting the pH of the solution to 7.0 with NaOH to obtain a 1 mg/mL solution, and then filtering the solution through 0.22 ?m filter. The full-length human PLD1-expression plasmid DNA for animal cells was transfected into Expi293F cells using PEI, and after 48 hours of shaking culture, the cells were collected and stored at ?80? C.
3. Purification of Full-Length Human PLD1 Protein
[1234] To the full-length human PLD1-expressed cells was added a Homogenate buffer (20 mmol/L Na-phosphate pH 7.5, 250 mmol/L NaCl, 1 mmol/L MgCl.sub.2, 1% ?-OG, 0.05 mmol/L DTT+complete EDTA-free (Roche Diagnostics K.K.)), and the cells were lysed by Microfluidizer Processor M-110EH (Mizuho Kogyo Co., Ltd.). The lysate was centrifuged at 10,100?g at 4? C. for 15 minutes, and the supernatant was collected and filtered through 0.45 ?m filter. To the centrifuged supernatant was added ANTI-FLAG M2 Affinity Gel (SIGMA-Aldrich) resin equilibrated with a Homogenate buffer, and the mixed solution was stirred at 4? C. for 1 hr or more. The mixed solution was loaded onto Poly-Prep column, and the resin was washed with a Wash buffer (20 mmol/L Na-phosphate pH 7.5, 150 mmol/L NaCl, 1 mmol/L MgCl.sub.2, 0.02% Triton, 0.05 mmol/L DTT). A Wash buffer containing 400 ?g/mL DYKDDDDK Peptide (Scrum Inc.) was added to the column to elute the protein bound to the resin. The eluted fractions were subjected to SDS-PAGE followed by CBB staining to identify the fractions containing the full-length human PLD1. The eluted fractions of the full-length human PLD1 were collected and concentrated using Amicon Ultra-15 100k (Merck Millipore). The concentrated fractions were collected, flash-frozen in liquid nitrogen and stored at ?80? C.
4. Evaluation Human PLD1 Inhibitory Activity
[1235] A DMSO or test substance solution (the DMSO final concentration: 5%) prepared by diluting DMSO or test substance with an Assay buffer (50 mmol/L HEPES pH 7.5, 80 mmol/L KCl, 3 mmol/L EGTA, 3.6 mmol/L MgCl.sub.2, 0.01% NP-40, 0.1% BSA), and the solution was added to a 384 well Assay Plate (Black, Polystyrene, Non-Treated, Cat No. 3573, Corning) by 5 ?L/well. A full-length human PLD1 enzyme solution (6 nmol/L) diluted with an Assay buffer was added thereto by 5 ?L/well (the Assay buffer was added to blank wells). A 1,2-diheptanoyl-sn-glycero-3-phosphocholine (Avanti Polar Lipids) substrate solution (6 mmol/L) diluted with an Assay buffer was added thereto by 5 ?L/well, and enzymatic reaction was carried out at room temperature for 60 minutes. Immediately before stopping the reaction, a detection solution (200 ?mol/L AmplexRed (Thermofisher), 0.1 U/mL Choline Oxidase (Sigma-Aldrich), 4 U/mL Horseradish peroxidase (Thermofisher)) containing 4 ?mol/L of 5-fluoro-2-indolyl deschlorohalopemide (R&D Systems) as a reaction terminator was prepared with an Assay buffer, the detection solution was added thereto at 5 ?L/well to terminate the enzymatic reaction. Immediately after stopping the reaction and 30 minutes after incubation at room temperature, the fluorescence values at Ex: 531 nm/Em: 590 nm were measured by ARVO X5 (PerkinElmer). The inhibition rate was calculated from the change in the fluorescence values immediately after stopping the reaction and after 30 minutes. Data were obtained by subtracting the average fluorescence value of the blank wells from the average fluorescence value of the treated wells. The inhibition rate at each concentration of the test substance was calculated from the following formula:
100?(B/A)?100 [1236] A: data of solvent control [1237] B: data of test substance-treatment
[1238] The IC.sub.50 value (50% inhibitory concentration) of the test substance was calculated by fitting the inhibition rate at each concentration of the test substance to a logistic curve. The results of the compounds of each example are shown in Tables 2-1 to 2-14 below. For Examples 34, 186, 2-047, 2-099, 2-101, 2-150 and 2-171, the inhibition rate of PLD1 at 10 ?M compound is shown, and Example 34 gave 36% inhibition, Example 186 gave 33% inhibition, Example 2-047 gave 32% inhibition, Example 2-099 gave 21% inhibition, Example 2-101 gave 13% inhibition, Examples 2-150 gave 25% inhibition, and Example 2-171 gave 12% inhibition.
Experimental Example 2: Evaluation of Human PLD2 Enzyme Inhibitory Activity
[1239] A method for measuring human PLD2 enzyme inhibitory activity using an enzyme in which a FLAG-tag is added to the N-terminus of full-length human PLD2 (1-933 amino acids) is shown below.
1. Production of Full-Length Human PLD2-Expression Plasmid
[1240] DNA fragment in which a FLAG-tag sequence is added to the 5-end of full-length human PLD2 was amplified by PCR method, using commercially available human PLD2 gene (Promega KK) as a template. The amplified DNA fragment was fused with vector pVL1393 for baculovirus production (Pharmingen) digested with BamHI and EcoRI, using In-Fusion HD Cloning Kit (Takara Bio). The full-length human PLD2-expression plasmid DNA for baculovirus was isolated from Escherichia coli DH5a (TOYOBO) transformed with the obtained In-Fusion reaction product. Next, DNA fragment in which a FLAG-tag sequence is added to the 5-end of full-length human PLD2 was amplified by PCR method, using the full-length human PLD2-expression plasmid DNA for baculovirus as a template. The amplified DNA fragment was fused with a DNA fragment in which a linker sequence is introduced into pcDNA3.4-TOPO (Life Technologies), using In-Fusion HD Cloning Kit (Takara Bio). The full-length human PLD2-expression plasmid DNA for animal cells was isolated from Escherichia coli DH5a transformed with the obtained In-Fusion reaction product. The base sequence of the full-length human PLD2 cloned into vector was determined by a Dye Terminator method using BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems). The determined sequence was a sequence in which the FLAG-tag sequence was inserted at the 5-end of the full-length human PLD2 (GenBank Accession Number: NM 002663).
2. Production of Full-Length Human PLD2 Protein in Expi293F Cell Expression System
[1241] Expi293F cells (Life Technologies) were cultured with shaking using Expi293 Expression Medium (Life Technologies) as a medium at 37? C. in the presence of 8% CO.sub.2. The gene introduction reagent PEI was prepared by dissolving Polyethylenimine Max (nominally MW 40,000) (Polysciences) in MilliQ water, adjusting the pH of the solution to 7.0 with NaOH to obtain a 1 mg/mL solution, and then filtering the solution through 0.22 ?m filter. The full-length human PLD2-expression plasmid DNA for animal cells was transfected into Expi293F cells using PEI, and after 48 hours of shaking culture, the cells were collected and stored at ?80? C.
3. Purification of Full-Length Human PLD2 Protein
[1242] To the full-length human PLD2-expressed cells was added a Homogenate buffer (20 mmol/L Na-phosphate pH 7.5, 250 mmol/L NaCl, 1 mmol/L MgCl.sub.2, 1% ?-OG, 0.05 mmol/L DTT+complete EDTA-free (Roche Diagnostics K.K.)), and the cells were lysed by Microfluidizer Processor M-110EH (Mizuho Kogyo Co., Ltd.). The lysate was centrifuged at 10,100?g at 4? C. for 15 minutes, and the supernatant was collected and filtered through 0.45 ?m filter. To the centrifuged supernatant was added ANTI-FLAG M2 Affinity Gel (SIGMA-Aldrich) resin equilibrated with a Homogenate buffer, and the mixed solution was stirred at 4? C. for 1 hr or more. The mixed solution was loaded onto Poly-Prep column, and the resin was washed with a Wash buffer (20 mmol/L Na-phosphate pH 7.5, 150 mmol/L NaCl, 1 mmol/L MgCl.sub.2, 0.02% Triton, 0.05 mmol/L DTT). A Wash buffer containing 400 ?g/mL DYKDDDDK Peptide (Scrum Inc.) was added to the column to elute the protein bound to the resin. The eluted fractions were subjected to SDS-PAGE followed by CBB staining to identify the fractions containing the full-length human PLD2. The eluted fractions of the full-length human PLD2 were collected and concentrated using Amicon Ultra-15 100k (Merck Millipore). The concentrated fractions were collected, flash-frozen in liquid nitrogen and stored at ?80? C.
4. Evaluation Human PLD2 Inhibitory Activity
[1243] A DMSO or test substance solution (the DMSO final concentration: 5%) prepared by diluting DMSO or test substance with an Assay buffer (50 mmol/L HEPES pH 7.5, 80 mmol/L KCl, 3 mmol/L EGTA, 3.6 mmol/L MgCl.sub.2, 0.01% NP-40, 0.1% BSA), and the solution was added to a 384 well Assay Plate (Black, Polystyrene, Non-Treated, Cat No. 3573, Corning) by 5 ?L/well. A full-length human PLD2 enzyme solution (6 nmol/L) diluted with an Assay buffer was added thereto by 5 ?L/well (the Assay buffer was added to blank wells). A 1,2-diheptanoyl-sn-glycero-3-phosphocholine (Avanti Polar Lipids) substrate solution (6 mmol/L) diluted with an Assay buffer was added thereto by 5 ?L/well, and enzymatic reaction was carried out at room temperature for 60 minutes. Immediately before stopping the reaction, a detection solution (200 ?mol/L AmplexRed (Thermofisher), 0.1 U/mL Choline Oxidase (Sigma-Aldrich), 4 U/mL Horseradish peroxidase (Thermofisher)) containing 4 ?mol/L of 5-fluoro-2-indolyl deschlorohalopemide (R&D Systems) as a reaction terminator was prepared with an Assay buffer, the detection solution was added thereto at 5 ?L/well to terminate the enzymatic reaction. Immediately after stopping the reaction and 30 minutes after incubation at room temperature, the fluorescence values at Ex: 531 nm/Em: 590 nm were measured by ARVO X5 (PerkinElmer). The inhibition rate was calculated from the change in the fluorescence values immediately after stopping the reaction and after 30 minutes. Data were obtained by subtracting the average fluorescence value of the blank wells from the average fluorescence value of the treated wells. The inhibition rate at each concentration of the test substance was calculated from the following formula:
100?(B/A)?100 [1244] A: data of solvent control [1245] B: data of test substance-treatment
[1246] The IC.sub.50 value (50% inhibitory concentration) of the test substance was calculated by fitting the inhibition rate at each concentration of the test substance to a logistic curve. The results of the compounds of each example are shown in Tables 2-1 to 2-14 below. For Examples 34, 186, 2-047, 2-101, 2-112, 2-150 and 2-171, the inhibition rate of PLD2 at 10 ?M compound is shown, and Example 34 gave 17% inhibition, Example 186 gave 18% inhibition, Example 2-047 gave Example 34% inhibition, Example 2-101 gave 28% inhibition, Example 2-112 gave 39% inhibition, Example 2-150 gave 30% inhibition, and Example 2-171 gave 23% inhibition.
TABLE-US-00062 TABLE 2-1 Example No. PLD1 IC.sub.50 (?M) PLD2 IC.sub.50 (?M) 1 0.033 <0.010 2 0.020 <0.010 3 0.027 <0.010 4 0.036 0.011 5 0.164 0.171 6 0.069 0.120 7 0.030 0.044 8 0.030 0.010 9 0.083 0.056 10 0.092 0.106 11 0.228 0.394 12 <0.010 <0.010 13 0.036 <0.010 14 0.010 <0.010 15 0.025 <0.010 16 0.926 0.968 17 0.816 1.044 18 0.852 0.157 19 0.017 0.010 20 1.646 3.769 21 0.307 0.346 22 0.066 0.049 23 0.039 0.051 24 0.041 0.031 25 0.108 0.101 26 <0.010 <0.010 27 0.014 0.013 28 0.341 0.303 29 0.999 1.715 30 0.123 0.153 31 0.024 <0.010 32 0.032 <0.010 33 0.025 <0.010 34 36% inhibition 17% inhibition at 10 ?M at 10 ?M 35 0.257 0.367 36 0.221 0.137 37 <0.010 <0.010 38 0.035 0.088 39 0.093 0.024 40 0.013 <0.010
TABLE-US-00063 TABLE 2-2 41 0.229 0.500 42 0.247 0.261 43 0.221 0.184 44 0.018 <0.010 45 0.027 0.023 46 0.012 <0.010 47 0.119 <0.010 48 0.014 <0.010 49 0.031 0.011 50 0.033 0.051 51 0.033 0.016 52 0.021 <0.010 53 0.019 <0.010 54 0.020 <0.010 55 0.015 <0.010 56 0.026 0.017 57 0.016 <0.010 58 0.014 <0.010 59 <0.010 <0.010 60 <0.010 <0.010 61 0.014 0.011 62 0.140 0.223 63 <0.010 <0.010 64 0.018 <0.010 65 <0.010 <0.010 66 0.016 <0.010 67 <0.010 <0.010 68 2.028 4.659 69 <0.010 <0.010 70 0.028 0.020 71 <0.010 <0.010 72 0.034 0.024 73 0.023 0.015 74 <0.010 <0.010 75 1.628 1.992 76 0.017 0.017 77 0.026 <0.010 78 0.350 0.252 79 <0.010 <0.010 80 <0.010 <0.010
TABLE-US-00064 TABLE 2-3 81 0.012 <0.010 82 0.421 0.358 83 0.259 0.221 84 0.070 0.053 85 0.012 <0.010 86 0.013 <0.010 87 0.039 <0.010 88 0.056 0.065 89 0.038 0.037 90 0.045 0.018 91 0.023 0.015 92 0.026 0.013 93 0.032 <0.010 94 0.068 0.060 95 8.056 6.165 96 0.018 <0.010 97 <0.010 <0.010 98 0.057 0.078 99 0.241 0.373 100 0.041 0.033 101 <0.010 <0.010 102 0.288 0.666 103 0.170 0.379 104 0.075 0.217 105 0.027 0.041 106 0.026 0.048 107 0.085 0.139 108 0.025 0.038 109 0.012 <0.010 110 0.083 0.099 111 0.017 0.021 112 0.031 0.020 113 0.017 0.013 114 0.013 <0.010 115 0.015 <0.010 116 0.043 0.037 117 0.021 0.018 118 0.050 0.073 119 0.011 <0.010 120 0.012 0.011
TABLE-US-00065 TABLE 2-4 121 <0.010 <0.010 122 <0.010 <0.010 123 0.202 0.502 124 0.638 2.736 125 0.040 0.057 126 0.013 <0.010 127 0.025 <0.010 128 0.186 0.060 129 0.018 <0.010 130 0.018 <0.010 131 0.010 <0.010 132 0.014 <0.010 133 0.029 0.031 134 0.021 0.030 135 0.086 0.033 136 0.155 0.170 137 0.505 1.586 138 0.774 1.396 139 <0.010 <0.010 140 <0.010 <0.010 141 0.141 0.164 142 0.022 <0.010 143 0.027 0.025 144 0.011 <0.010 145 0.017 <0.010 146 0.020 <0.010 147 0.032 0.032 148 0.020 0.018 149 0.012 <0.010 150 0.880 0.640 151 0.018 <0.010 152 0.023 0.013 153 0.027 0.028 154 0.027 0.014 155 0.014 <0.010 156 0.236 0.412 157 <0.010 <0.010 158 0.027 0.015 159 0.028 <0.010 160 0.026 0.017
TABLE-US-00066 TABLE 2-5 161 0.020 0.013 162 0.322 0.536 163 <0.010 <0.010 164 0.038 <0.010 165 0.019 <0.010 166 0.019 <0.010 167 0.020 <0.010 168 0.056 0.035 169 0.034 0.020 170 0.019 <0.010 171 0.013 <0.010 172 0.023 0.012 173 0.029 0.010 174 0.042 0.017 175 0.021 0.015 176 0.029 0.029 177 0.010 <0.010 178 0.014 0.017 179 0.025 <0.010 180 0.028 0.012 181 0.013 <0.010 182 0.019 <0.010 183 0.042 0.107 184 <0.010 <0.010 185 0.068 0.064 186 33% inhibition 18% inhibition at 10 ?M at 10 ?M 187 0.222 0.455 188 0.044 0.033 189 0.130 0.140 190 0.642 0.776 191 0.038 <0.010 192 0.021 <0.010 193 0.055 0.046 194 <0.010 <0.010 195 0.039 0.067 196 0.027 <0.010 197 0.026 <0.010 198 0.011 <0.010 199 0.010 <0.010 200 0.103 0.082
TABLE-US-00067 TABLE 2-6 201 0.328 0.371 202 0.832 1.247 203 0.012 <0.010 204 0.123 0.146 205 0.035 0.102 206 0.036 0.013 207 0.025 <0.010 208 0.045 0.224 209 0.018 0.018 210 0.296 1.087 211 0.102 0.429 212 <0.010 <0.010 213 0.086 0.115 214 <0.010 <0.010 215 <0.010 <0.010 216 0.029 0.019 217 0.017 <0.010 218 0.023 0.013 219 <0.010 <0.010 220 0.042 0.033 221 0.016 <0.010 222 0.059 0.171 223 0.396 0.246 224 0.013 <0.010 225 0.513 0.203 226 0.018 <0.010 227 0.019 <0.010 228 0.028 <0.010 229 0.197 0.310 230 0.021 <0.010 231 0.024 0.012 232 2.580 2.132 233 1.861 1.796 234 0.247 0.474 235 0.035 0.013 236 0.015 <0.010 237 0.034 <0.010 238 0.012 <0.010 239 0.018 <0.010 240 0.013 <0.010
TABLE-US-00068 TABLE 2-7 241 0.017 <0.010 242 0.016 <0.010 243 0.024 <0.010 244 0.019 <0.010 245 0.040 0.107 246 0.015 <0.010 247 0.014 <0.010 248 0.017 <0.010 249 0.025 <0.010 250 0.022 <0.010 251 0.017 <0.010 252 0.174 0.335 253 0.252 0.324 254 0.029 <0.010 255 0.032 0.014 256 0.027 <0.010 257 0.262 0.215 258 0.186 0.249 259 1.450 2.499 260 0.031 <0.010 261 0.168 0.313 262 0.015 <0.010 263 2.777 4.499 264 0.036 <0.010 265 0.013 <0.010 266 0.015 <0.010 267 0.026 <0.010 268 0.030 <0.010 269 0.018 <0.010 270 0.017 <0.010 271 0.018 <0.010 272 0.015 <0.010 273 0.019 <0.010 274 0.017 <0.010 275 0.025 <0.010 276 0.021 <0.010 277 0.017 <0.010 278 0.246 1.176 279 0.086 0.044 280 0.147 0.316
TABLE-US-00069 TABLE 2-8 281 0.169 0.232 282 0.097 0.146 283 0.043 0.048 284 0.061 0.040 285 <0.010 <0.010 286 0.014 <0.010 287 0.013 <0.010 288 0.026 <0.010 289 0.018 <0.010 290 0.122 0.046 291 0.150 0.234 292 0.023 <0.010 293 0.127 0.325 294 0.011 <0.010 295 <0.010 <0.010 296 0.013 <0.010 297 0.013 <0.010 298 0.015 <0.010 299 0.025 <0.010 300 0.038 <0.010 301 0.030 <0.010 302 0.017 <0.010 303 0.011 <0.010 304 <0.010 <0.010 305 0.015 <0.010 306 <0.010 <0.010 307 0.013 <0.010 308 0.015 <0.010 309 0.015 <0.010 310 0.014 <0.010 311 0.015 <0.010 312 0.029 <0.010 313 0.023 0.025 314 <0.010 <0.010 315 0.025 0.024 316 0.046 0.061 317 0.071 0.065 318 0.037 0.041 319 2.092 0.744 320 3.881 1.577
TABLE-US-00070 TABLE 2-9 321 0.042 <0.010 322 0.030 <0.010 323 0.010 <0.010 324 0.020 0.022 325 0.015 <0.010 326 0.054 0.038 327 0.110 0.051 328 0.048 0.034 329 0.051 <0.010 330 3.151 0.026 331 0.032 0.022 332 2.595 0.015 333 0.025 <0.010 334 0.026 <0.010 335 0.126 <0.010 336 0.033 <0.010 337 0.074 0.028 338 0.024 <0.010 339 0.039 0.010
TABLE-US-00071 TABLE 2-10 2-001 0.041 <0.010 2-002 1.254 1.865 2-003 0.038 0.012 2-004 0.068 <0.010 2-005 0.433 0.035 2-006 0.056 0.011 2-007 0.028 <0.010 2-008 0.062 0.011 2-009 2.154 1.037 2-010 1.015 1.258 2-011 2.110 2.943 2-012 2.044 0.245 2-013 0.012 <0.010 2-014 0.022 <0.010 2-015 0.026 0.012 2-016 0.019 <0.010 2-017 0.099 0.045 2-018 0.022 <0.010 2-019 0.012 <0.010 2-020 0.021 0.016 2-021 0.027 0.015 2-022 0.738 0.388 2-023 0.102 0.064 2-024 0.046 0.028 2-025 0.219 0.205 2-026 0.012 <0.010 2-027 0.013 <0.010 2-028 0.045 0.032 2-029 1.507 8.407 2-030 0.031 0.018 2-031 0.019 <0.010 2-032 0.011 <0.010 2-033 0.035 <0.010 2-034 0.031 0.010 2-035 0.021 <0.010 2-036 0.017 <0.010 2-037 0.043 0.013 2-038 0.060 0.011 2-039 0.153 0.264 2-040 0.021 <0.010
TABLE-US-00072 TABLE 2-11 2-041 0.148 0.103 2-042 3.018 0.383 2-043 0.033 0.152 2-044 <0.010 <0.010 2-045 0.018 <0.010 2-046 0.024 0.118 2-047 32% inhibition 34% inhibition at 10 ?M at 10 ?M 2-048 0.644 1.014 2-049 1.743 1.443 2-050 0.012 <0.010 2-051 0.025 <0.010 2-052 0.021 <0.010 2-053 0.676 0.245 2-054 0.037 <0.010 2-055 0.011 <0.010 2-056 0.017 <0.010 2-057 0.018 <0.010 2-058 0.026 0.066 2-059 0.731 0.505 2-060 0.027 0.011 2-061 0.014 <0.010 2-062 0.025 0.025 2-063 0.173 0.106 2-064 0.027 0.011 2-065 0.021 <0.010 2-066 0.015 <0.010 2-067 0.015 <0.010 2-068 <0.010 <0.010 2-069 <0.010 <0.010 2-070 0.068 0.038 2-071 0.013 <0.010 2-072 0.014 0.024 2-073 0.014 0.002 2-074 0.011 <0.010 2-075 0.016 <0.010 2-076 0.011 <0.010 2-077 0.015 <0.010 2-078 <0.010 <0.010 2-079 0.011 0.010 2-080 <0.010 <0.010
TABLE-US-00073 TABLE 2-12 2-081 <0.010 <0.010 2-082 <0.010 <0.010 2-083 <0.010 <0.010 2-084 0.013 <0.010 2-085 0.022 <0.010 2-086 0.015 <0.010 2-087 0.012 <0.010 2-088 0.019 <0.010 2-089 0.018 <0.010 2-090 0.013 <0.010 2-091 <0.010 <0.010 2-092 0.026 <0.010 2-093 0.038 0.013 2-094 0.026 <0.010 2-095 0.035 0.012 2-096 0.055 0.031 2-097 0.020 <0.010 2-098 0.013 <0.010 2-099 21% inhibition 6.889 at 10 ?M 2-100 0.015 <0.010 2-101 13% inhibition 28% inhibition at 10 ?M at 10 ?M 2-102 0.014 <0.010 2-103 0.023 <0.010 2-104 0.021 0.011 2-105 0.017 <0.010 2-106 0.073 0.127 2-107 0.011 <0.010 2-108 <0.010 <0.010 2-109 0.011 <0.010 2-110 0.021 <0.010 2-111 0.025 0.029 2-112 3.590 39% inhibition at 10 ?M 2-113 0.014 <0.010 2-114 0.052 <0.010 2-115 0.038 <0.010 2-116 0.081 0.017 2-117 0.030 <0.010 2-118 0.019 <0.010 2-119 0.034 <0.010 2-120 0.021 <0.010
TABLE-US-00074 TABLE 2-13 2-121 0.026 0.021 2-122 0.014 <0.010 2-123 0.026 <0.010 2-124 0.022 <0.010 2-125 0.043 0.016 2-126 0.035 0.014 2-127 <0.010 <0.010 2-128 <0.010 <0.010 2-129 0.025 <0.010 2-130 0.032 <0.010 2-131 0.015 <0.010 2-132 0.011 <0.010 2-133 0.014 <0.010 2-134 0.018 <0.010 2-135 0.020 <0.010 2-136 0.017 0.015 2-137 0.029 0.033 2-138 0.014 <0.010 2-139 0.014 <0.010 2-140 0.017 <0.010 2-141 <0.010 <0.010 2-142 0.012 <0.010 2-143 0.262 0.738 2-144 0.012 <0.010 2-145 0.014 <0.010 2-146 0.019 0.016 2-147 0.136 0.152 2-148 0.140 0.046 2-149 0.045 0.023 2-150 25% inhibition 30% inhibition at 10 ?M at 10 ?M 2-151 0.024 <0.010 2-152 0.016 <0.010 2-153 0.016 <0.010 2-154 0.021 0.017 2-155 <0.010 <0.010 2-156 0.013 <0.010 2-157 0.017 <0.010 2-158 0.016 <0.010 2-159 0.015 <0.010 2-160 0.011 <0.010
TABLE-US-00075 TABLE 2-14 2-161 0.014 <0.010 2-162 0.021 <0.010 2-163 <0.010 <0.010 2-164 <0.010 <0.010 2-165 <0.010 <0.010 2-166 0.011 <0.010 2-167 0.011 <0.010 2-168 <0.010 <0.010 2-169 0.045 0.100 2-170 0.009 0.002 2-171 12% inhibition 23% inhibition at 10 ?M at 10 ?M 2-172 0.020 0.003
[1247] The formulation examples of the present invention include the following formulations. However, the present invention is not limited by such formulation examples.
Formulation Example 1 (Production of Capsule)
[1248]
TABLE-US-00076 1) Compound of Example 1 30 mg 2) Microcrystalline cellulose 10 mg 3) Lactose 19 mg 4) Magnesium stearate 1 mg
[1249] 1), 2), 3) and 4) are mixed and filled in a gelatin capsule.
Formulation Example 2 (Production of Tablet)
[1250]
TABLE-US-00077 1) Compound of Example 1 10 g 2) Lactose 50 g 3) Corn starch 15 g 4) Carmellose calcium 44 g 5) Magnesium stearate 1 g
[1251] The total amount of 1), 2), 3) and 30 g of 4) are kneaded with water, vacuum dried and then granulated. The granulated powder is mixed with 14 g of 4) and 1 g of 5), and the mixture is tableted by a tableting machine. In this way, 1000 tablets containing 10 mg of the compound of Example 1 per tablet are obtained.
INDUSTRIAL APPLICABILITY
[1252] Since Compound [I] or Compound [Ia] or a pharmaceutically acceptable salt thereof of the present invention has a PLD inhibitory activity, it may be useful for the treatment or prophylaxis of thrombosis and cancer.
