IP Library › Patent Application 18335687

Patent Application

App. No. 18/335,687

DIHYDROOXADIAZINONE COMPOUND AND PHARMACEUTICAL USE THEREOF

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Patent No.: US None
App. No.: 18/335,687

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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. wherein each symbol is as defined in the description.

Claims (279)

1 . A compound represented by Formula [Ia] or a pharmaceutically acceptable salt thereof:

wherein

A a is CR 10a or N;

A 2a is CR 5a or O;

Cy a is

(1) C 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 1a is

(1) C 1-6 alkyl wherein the alkyl is optionally substituted by

(a) hydroxy,

(b) cyano,

(d) NHCOR 12 wherein R 12 is C 1-4 alkyl,

(2) C 2-4 alkenyl wherein the alkenyl is optionally substituted by 1 to 3 of

(a) NR 13 R 14 wherein R 13 and R 14 are each independently hydrogen or C 1-4 alkyl,

(b) halogen,

(d) CONR 36a R 37a wherein R 36a and R 37a are each independently hydrogen or C 1-4 alkyl, or

(e) a partial structural formula:

(3) C 1-4 haloalkyl wherein the haloalkyl is optionally substituted by hydroxy,

(4) C 1-6 alkoxy wherein the alkoxy is optionally substituted by phenyl,

(5) NR 15 R 16 wherein R 15 and R 16 are each independently

(a) hydrogen,

(b) C 1-4 alkyl wherein the alkyl is optionally substituted by

(i) phenyl wherein the phenyl is optionally substituted by halogen, or

(ii) pyridyl,

(d) C 3-4 cycloalkyl,

(6) COR 17a wherein R 17a is C 1-4 alkyl or hydroxy,

(7) CONR 18a R 19a wherein R 18a and R 19a are each independently

(a) hydrogen,

(b) C 1-4 alkyl wherein the alkyl is optionally substituted by hydroxy,

(d) C 5-8 bridged cycloalkyl,

(e) C 1-4 haloalkyl, or

(f) C 1-4 alkoxy,

(8) C 3-4 cycloalkyl wherein the cycloalkyl is optionally substituted by

(a) hydroxy,

(b) halogen, or

(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,

(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 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 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 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 1-4 alkyl;

R 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 3-4 cycloalkyl,

(5) C 2-4 alkenyl wherein the alkenyl is optionally substituted by C 1-4 alkoxy,

(6) C 1-4 haloalkyl,

(7) C 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 23a wherein R 23a is C 1-4 alkyl or C 1-4 haloalkyl,

(9) COR 24a wherein R 24a is

(a) hydroxy,

(b) C 1-4 alkyl, or

(10) CONR 25a R 26a wherein R 25a and R 26a are each independently

(a) hydrogen,

(b) C 1-6 alkyl, or

R 25a and R 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 2 R 27 wherein R 27 is C 1-6 alkyl,

(12) C 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 1-4 alkyl, and

(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 3a is

(1) hydrogen,

(2) C 1-4 alkyl, or

(3) C 1-4 haloalkyl;

R 4a is

(1) hydrogen,

(2) C 1-4 alkyl, or

(3) cyano;

R 5a is hydrogen or C 1-4 alkyl;

the combination of R 6a , R 7a and R 8a is

(1) a combination where R 6a is hydrogen or C 1-4 alkyl, and R 7a and R 8a are both hydrogens,

(2) a combination where R 6a is hydrogen or C 1-4 alkyl, and R 7a and R 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 6a and R 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 8a is hydrogen;

R 9a is

(1) hydrogen,

(2) CONHR 28 wherein R 28 is C 3-4 cycloalkyl, or

(3) C 1-4 alkyl;

R 10a is

(1) hydrogen,

(2) hydroxy,

(3) halogen,

(4) C 1-4 alkyl,

(5) cyano, or

(6) C 1-4 alkoxy;

one or two R 22a are each independently

(1) halogen,

(2) C 1-4 alkyl,

(3) C 1-4 haloalkyl,

(4) C 1-4 alkoxy,

(5) NHCOR 29 wherein R 29 is C 1-4 alkyl,

(6) SO 2 R 30 wherein R 30 is C 1-4 alkyl,

(7) cyano, or

(8) C 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]:

wherein

A a , Cy a , R 1a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 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]:

wherein

Cy a , R 1a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 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]:

wherein

R 1b is

(1) C 1-6 alkyl wherein the alkyl is optionally substituted by

(a) hydroxy,

(b) cyano,

(d) NHCOR 12 wherein R 12 is C 1-4 alkyl,

(2) C 2-4 alkenyl wherein the alkenyl is optionally substituted by 1 to 3 of

(a) NR 13 R 14 wherein R 13 and R 14 are each independently hydrogen or C 1-4 alkyl,

(b) halogen,

(d) CONR 36a R 37a wherein R 36a and R 37a are each independently hydrogen or C 1-4 alkyl, or

(e) a partial structural formula:

(3) C 1-6 alkoxy wherein the alkoxy is optionally substituted by phenyl,

(4) NR 15 R 16 wherein R 15 and R 16 are each independently

(a) hydrogen,

(b) C 1-4 alkyl wherein the alkyl is optionally substituted by

(i) phenyl wherein the phenyl is optionally substituted by halogen, or

(ii) pyridyl,

(d) C 3-4 cycloalkyl,

(5) CONR 18a R 19a wherein R 18a and R 19a are each independently

(a) hydrogen,

(b) C 1-4 alkyl wherein the alkyl is optionally substituted by hydroxy,

(d) C 5-8 bridged cycloalkyl,

(e) C 1-4 haloalkyl, or

(f) C 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 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 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 1-4 alkyl; and

Cy a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 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]:

wherein

Cy a , R 2a , R 3a , R 4a and m are as defined in claim 1 ; and

R 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]:

wherein

Cy b is

(1) C 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 1b is as defined in claim 4 ; and

R 2a , R 3a , R 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]:

wherein

Cy a , R 2a , R 3a , R 5a , R 6a , R 7a , R 8a and m are as defined in claim 1 ; and

R 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]:

wherein

Cy a , R 2a , R 3a and m are as defined in claim 1 ; and

R 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]:

wherein

Cy b is as defined in claim 6 ;

R 1b is as defined in claim 4 ; and

R 2a , R 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]:

wherein

Cy a , R 1a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 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]:

wherein

Cy a , R 1a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 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]:

wherein

R 1b is

(1) C 1-6 alkyl wherein the alkyl is optionally substituted by

(a) hydroxy,

(b) cyano,

(d) NHCOR 12 wherein R 12 is C 1-4 alkyl,

(2) C 2-4 alkenyl wherein the alkenyl is optionally substituted by 1 to 3 of

(a) NR 13 R 14 wherein R 13 and R 14 are each independently hydrogen or C 1-4 alkyl,

(b) halogen,

(d) CONR 36a R 37a wherein R 36a and R 37a are each independently hydrogen or C 1-4 alkyl, or

(e) a partial structural formula:

(3) C 1-6 alkoxy wherein the alkoxy is optionally substituted by phenyl,

(4) NR 15 R 16 wherein R 15 and R 16 are each independently

(a) hydrogen,

(b) C 1-4 alkyl wherein the alkyl is optionally substituted by

(i) phenyl wherein the phenyl is optionally substituted by halogen, or

(ii) pyridyl,

(d) C 3-4 cycloalkyl,

(5) CONR 18a R 19a wherein R 18a and R 19a are each independently

(a) hydrogen,

(b) C 1-4 alkyl wherein the alkyl is optionally substituted by hydroxy,

(d) C 5-8 bridged cycloalkyl,

(e) C 1-4 haloalkyl, or

(f) C 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,

Cy a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 10a , R 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]:

wherein

Cy a , R 2a , R 3a , R 4a , R 10a and m are as defined in claim 1 ; and

R 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]:

wherein

Cy b is

(1) C 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 1b is as defined in claim 12 ; and

R 2a , R 3a , R 4a , R 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]:

wherein

Cy a , R 2a , R 3a , R 5a , R 6a , R 7a , R 8a , R 10a and m are as defined in claim 1 ; and

R 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]:

wherein

Cy a , R 2a , R 3a , R 10a and m are as defined in claim 1 ; and

R 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]:

wherein

Cy b is as defined in claim 14 ;

R 1b is as defined in claim 12 ; and

R 2a , R 3a , R 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:

42 . A compound represented by the following formula, or a pharmaceutically acceptable salt thereof:

43 . A compound represented by the following formula, or a pharmaceutically acceptable salt thereof:

44 . A compound represented by the following formula, or a pharmaceutically acceptable salt thereof:

45 . A compound represented by the following formula, or a pharmaceutically acceptable salt thereof:

46 . A compound represented by the following formula, or a pharmaceutically acceptable salt thereof:

47 . A compound represented by the following formula, or a pharmaceutically acceptable salt thereof:

48 . A compound represented by the following formula, or a pharmaceutically acceptable salt thereof:

49 . A compound represented by the following formula, or a pharmaceutically acceptable salt thereof:

50 . A compound represented by the following formula:

51 . A compound represented by the following formula:

52 . A compound represented by the following formula:

53 . A compound represented by the following formula:

54 . A compound represented by the following formula:

55 . A compound represented by the following formula:

56 . A compound represented by the following formula:

57 . A compound represented by the following formula:

58 . A compound represented by the following formula:

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.

Assignments (2)

CHANGE OF NAME Recorded Mar 25, 2026

From: JAPAN TOBACCO INC.

To: SHIONOGI & CO., LTD.

Reel/Frame 075482/0570 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 23, 2024

From: YOKOTA, MASAHIRO; KAYA, TETSUDO; TORIZUKA, MAKOTO; NAKAYAMA, YASUAKI; IKENOGAMI, TAKU; MAEDA, KATSUYA; OTAKE, KAZUKI; SAKURAI, KENTARO

To: JAPAN TOBACCO INC.

Reel/Frame 066216/0122 →