Granted Patent B2

US 10,208,048 · App. 15/570,054 · Granted Feb 19, 2019

Inventors: David Francis Alain Lançois (Issy-les-Moulineaux, FR); Jérôme Émile Georges Guillemont (Issy-les-Moulineaux, FR); Pierre Jean-Marie Bernard Raboisson (Beerse, BE); Dirk André Emmy Roymans (Beerse, BE); Boris Rogovoy (San Diego, CA); Vadim Bichko (San Diego, CA); Delphine Yvonne Raymonde Lardeau (Issy-les-Moulineaux, FR); Antoine Benjamin Michaut (Illkirch, FR); Anil Koul (Beerse, BE)

Assignee: Janssen Sciences Ireland UC

C07D487/04A61P31/14C07D519/00

Abstract

Claims (96)

1. A compound of formula (I)

and any stereochemically isomeric form thereof, wherein

X is N or CR 6 wherein R 6 is hydrogen, halo or C 1-4 alkyl;

R 1 is CH 3 or CH 2 CH 3 , and R 1′ is hydrogen; or R 1 and R 1′ are taken together with the carbon atom to which they are attached to form cyclopropyl; and R 2 is C 3-6 alkyl and R 3 is C 1-4 alkyl;

or the

moiety is a radical of formula:

wherein R 1 is CH 3 or CH 2 CH 3 , and R 1′ is hydrogen; or R 1′ is absent in radical (a-6); or R 1 and R 1′ are taken together with the carbon atom to which they are attached to form cyclopropyl; and radical (a-1) to (a-30) are optionally substituted with one or two substituents each independently selected from C 1-2 alkyl and halo;

R 4 is C 1-6 alkyl; C 3-6 alkenyl, polyhaloC 1-4 alkyl; C 1-4 alkyl substituted with one C 3-6 cycloalkyl; aminocarbonyl, mono- or di(C 1 -4alkyl)aminocarbonyl; oxetanyl optionally substituted with C 1-4 alkyl; Heteroaryl 1 ; C 3-6 cycloalkyl; C 3-6 cycloalkyl substituted with one or two substituents each individually selected from hydroxy, halo, cyano, C 1-4 alkyl, C 1-4 alkyloxy, polyhaloC 1-4 alkyl, and polyhaloC 1-4 alkyloxy; or

NR 7 R 8 wherein R 7 is selected from hydrogen and C 1-4 alkyl;

R 8 is C 1-4 alkyl or C 3-6 cycloalkyl;

or R 7 and R 8 are taken together with the nitrogen to which they are attached to form azetidinyl, pyrrolidinyl or piperidinyl;

R 5 is C 3-6 cycloalkyl;

Heteroaryl;

Bicycle;

naphthyl substituted with 1, 2 or 3 substituents each independently selected from halo and hydroxycarbonyl;

phenyl substituted with 1, 2 or 3 substituents each independently selected from

hydroxy;

halo;

C 1-6 alkyl;

C 1-6 alkyl substituted with one, two or three substituents each independently selected from halo, hydroxy, hydroxycarbonyl, aminocarbonyl, Heterocycle, C 3-6 cycloalkyl, C 3-6 cycloalkyl substituted with one or two substituents each independently selected from C 1-4 alkyl, halo, hydroxycarbonyl, and C 1-4 alkyl substituted with hydroxycarbonyl;

C 3-6 alkenyl;

C 3-6 alkenyl substituted with one or two substituents selected from C 1-6 alkyl, hydroxy, hydroxycarbonyl and aminocarbonyl;

C 3-6 alkynyl;

C 3-6 alkynyl substituted with one hydroxycarbonyl;

C 3-6 cycloalkyl;

C 3-6 cycloalkyl substituted with one, two or three substituents each independently selected from C 1-4 alkyl, halo, hydroxycarbonyl, and C 1-4 alkyl substituted with hydroxycarbonyl;

C 3-6 cycloalkenyl;

C 3-6 cycloalkenyl substituted with one hydroxycarbonyl;

C 1-6 alkyloxy optionally substituted with hydroxycarbonyl;

polyhaloC 1-4 alkyl;

polyhaloC 1-4 alkyloxy;

cyano;

nitro;

B(OH) 2 ;

hydroxycarbonyl;

CO—NHOH;

CO—NR 9 R 10 ;

CO—NH—NR 9 R 10 ;

NR 9 R 10 ;

NH—CO—R 11 ;

NH—CO—O—R 11 ;

NH—CO—NH—R 11 ;

NH—CS—NH—R 11 ;

NH—C═(N—CN)—NH—R 11 ;

aminosulfonyl; mono- or di(C 1-4 alkyl)aminosulfonyl;

Heterocycle; and

spiro[3.3]heptanyl optionally substituted with hydroxycarbonyl;

wherein

R 9 and R 10 are each independently selected from hydrogen; C 1-6 alkyl; SO 2 —R 12 ; and C 1-6 alkyl substituted with one or two substituents each independently selected from hydroxy, hydroxycarbonyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl substituted with hydroxycarbonyl, C 1-4 alkylcarbonylamino, mono- or di(C 1-4 alkyl)amino, and Heterocycle;

R 11 is C 1-6 alkyl; C 3-6 alkenyl; C 3-6 cycloalkyl; Aryl; Heterocycle; or C 1-6 alkyl substituted with one substituent selected from C 3-6 cycloalkyl, C 1-4 alkyloxy, hydroxy, cyano, hydroxycarbonyl, aminocarbonyl, mono- or di(C 1-4 alkyl)aminocarbonyl, C 1-4 alkylcarbonylamino, and Heterocycle;

R 12 is C 1-4 alkyl, C 3-6 cycloalkyl, or C 1-4 alkyl substituted with one C 3-6 cycloalkyl,

Heteroaryl is thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl, 1-benzopyrazolyl, 2,3-dihydro-1H-indolyl, 2-oxo-2,3-dihydro-1H-indolyl, quinolinyl, 2-oxo-quinolinyl, benzimidazolyl, cinnolinyl, or 2H-chromenyl, wherein each Heteroaryl is optionally substituted with one or two substituents each independently selected from C 1-4 alkyl, halo, amino, aminocarbonyl, and NH—CO—C 3-6 cycloalkyl;

Heteroaryl 1 is imidazolyl or pyrazolyl; wherein each Heteroaryl 1 is optionally substituted with one or two substituents each independently selected from C 1-4 alkyl, halo and hydroxycarbonyl;

Heterocycle is azetidinyl, tetrahydrofuranyl, pyrrolidinyl, furanyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 2,5-dihydro-1H-pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, 2-oxo-azepanyl, 2,5-dioxopyrrolidinyl, or 3-oxo-2,3-dihydro-1,2-oxazolyl; wherein each Heterocycle is optionally substituted with one or two substituents each independently selected from C 1-4 alkyl, C 3-6 cycloalkyl, halo, hydroxyC 1-4 alkyl, polyhaloC 1-4 alkyl, hydroxycarbonyl, and C 1-4 alkyl substituted with hydroxycarbonyl;

Aryl is phenyl substituted with one or two substituents each independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 alkyloxy, and trifluoromethyl;

Bicycle is 1,2,3,4-tetrahydronaphthalenyl, chromanyl or 2,3-dihydrobenzofuranyl; wherein each Bicycle is optionally substituted with one or two substituents each independently selected from C 1-4 alkyl, halo and hydroxycarbonyl;

with the proviso that [7-ethyl-2-(3-thienyl)pyrazolo[1,5-a]pyrimidin-5-yl] (2-methyl-1-piperidinyl)-methanone and [7-ethyl-2-(2-pyridinyl)pyrazolo[1,5-a]pyrimidin-5-yl](2-methyl-1-piperidinyl)-methanone are not included;

or a pharmaceutically acceptable acid addition salt thereof.

2. The compound as claimed in claim 1 , wherein

X is N or CR 6 wherein R 6 is hydrogen or halo;

R 1 is CH 3 or CH 2 CH 3 , and R 1′ is hydrogen; or R 1 and R 1′ are taken together with the carbon atom to which they are attached to form cyclopropyl; and R 2 is C 3-6 alkyl and R 3 is C 1-4 alkyl;

or the

moiety is a radical of formula:

wherein R 1 is CH 3 or CH 2 CH 3 , and R 1′ is hydrogen; or R 1′ is absent in radical (a-6); or R 1 and R 1′ are taken together with the carbon atom to which they are attached to form cyclopropyl; and radical (a-1) to (a-15) are optionally substituted with one or two substituents each independently selected from C 1-2 alkyl and halo;

R 4 is C 1-6 alkyl; polyhaloC 1-4 alkyl; C 3-6 cycloalkyl; C 1-4 alkyl substituted with one C 3-6 cycloalkyl; or NR 7 R 8 wherein R 7 is selected from hydrogen and C 1-4 alkyl; R 8 is C 1-4 alkyl or C 3-6 cycloalkyl; or R 7 and R 8 are taken together with the nitrogen to which they are attached to form pyrrolidinyl or piperidinyl;

R 5 is C 3-6 cycloalkyl; Heteroaryl; phenyl substituted with 1, 2 or 3 substituents each independently selected from hydroxy; halo; C 1-6 alkyl; C 1-6 alkyl substituted with one substituent selected from hydroxy, hydroxycarbonyl and aminocarbonyl; C 3-6 alkenyl substituted with one or two substituents selected from C 1-6 alkyl, hydroxy, hydroxycarbonyl and aminocarbonyl; C 3-6 cycloalkyl substituted with one hydroxycarbonyl; C 1-6 alkyloxy; cyano; B(OH) 2 ; hydroxycarbonyl; CO—NHOH; CO—NR 9 R 10 ; CO—NH—NR 9 R 10 ; NR 9 R 10 ; NH—CO—R 11 ; NH—CO—O—R 11 ; NH—CO—NH—R 11 ; NH—CS—NH—R 11 ; NH—C═(N—CN)—NH—R 11 ; aminosulfonyl; mono- or di(C 1-4 alkyl)aminosulfonyl; and Heterocycle;

wherein

R 9 and R 10 are each independently selected from hydrogen; C 1-6 alkyl; SO 2 —R 12 ; and C 1-6 alkyl substituted with C 3-6 cycloalkyl, mono- or di(C 1-4 alkyl)amino, or Heterocycle;

R 11 is C 1-6 alkyl; C 3-6 alkenyl; C 3-6 cycloalkyl; Aryl; Heterocycle; or C 1-6 alkyl substituted with one substituent selected from C 3-6 cycloalkyl, C 1-4 alkyloxy, hydroxy, cyano, hydroxycarbonyl, aminocarbonyl, mono- or di(C 1-4 alkyl)aminocarbonyl, C 1-4 alkylcarbonylamino, and Heterocycle;

R 12 is C 1-4 alkyl, or C 3-6 cycloalkyl;

Heteroaryl is thienyl, pyridinyl, 1-benzopyrazolyl, 2,3-dihydro-1H-indolyl, 2-oxo-2,3-dihydro-1H-indolyl, quinolinyl, 2-oxo-quinolinyl, benzimidazolyl, cinnolinyl, or 2H-chromenyl, wherein each Heteroaryl is optionally substituted with one or two substituents each independently selected from C 1-4 alkyl, halo, aminocarbonyl, and NH—CO—C 3-6 cycloalkyl;

Heterocycle is azetidinyl, tetrahydrofuranyl, pyrrolidinyl, furanyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 2-oxo-azepanyl, 2,5-dioxopyrrolidinyl, or 3-oxo-2,3-dihydro-1,2-oxazolyl; wherein each Heterocycle is optionally substituted with one or two substituents each independently selected from C 1-4 alkyl, C 3-6 cycloalkyl, halo and hydroxycarbonyl;

Aryl is phenyl substituted with one or two substituents each independently selected from hydrogen and halogen;

or a pharmaceutically acceptable acid addition salt thereof.

3. The compound as claimed in claim 1 , wherein X is N.

4. The compound as claimed in claim 3 , wherein R 1 is CH 3 or CH 2 CH 3 , and R 1′ is hydrogen, and R 2 is C 3-6 alkyl and R 3 is CH 3 .

5. The compound as claimed in claim 3 , wherein the

moiety is a radical of formula (a-1) to (a-15) wherein R 1 is CH 3 or CH 2 CH 3 , and R 1′ is hydrogen; or R 1′ is absent in radical (a-6); or R 1 and R 1′ are taken together with the carbon atom to which they are attached to form cyclopropyl; and radical (a-1) to (a-15) are optionally substituted with one or two substituents each independently selected from C 1-2 alkyl and halo.

6. The compound as claimed in claim 1 , wherein X is CR 6 wherein R 6 is hydrogen or halo.

7. The compound as claimed in claim 6 , wherein R 1 is CH 3 or CH 2 CH 3 , and R 1′ is hydrogen, and R 2 is C 3-6 alkyl and R 3 is CH 3 .

8. The compound as claimed in claim 6 , wherein the

moiety is a radical of formula (a-1) to (a-15) wherein R 1 is CH 3 or CH 2 CH 3 , and R 1 is hydrogen; or R 1 is absent in radical (a-6); or R 1 and R 1′ are taken together with the carbon atom to which they are attached to form cyclopropyl; and radical (a-1) to (a-15) are optionally substituted with one or two substituents each independently selected from C 1-2 alkyl and halo.

9. The compound as claimed in claim 1 , wherein R 5 is phenyl substituted with 1, 2 or 3 substituents each independently selected from halo; or C 1-6 alkyl substituted with one substituent selected from hydroxy, hydroxycarbonyl and aminocarbonyl.

10. The compound as claimed in claim 1 , wherein R 5 is phenyl substituted with 1, 2 or 3 substituents each independently selected from halo; or C 3-6 alkenyl substituted with one or two substituents selected from C 1-6 alkyl, hydroxy, hydroxycarbonyl and aminocarbonyl.

11. The compound according to claim 1 , wherein the compound is selected from

or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound as claimed in claim 1 .

13. The pharmaceutical composition according to claim 12 , which further comprises another antiviral agent.

14. The pharmaceutical composition according to claim 13 , wherein the other antiviral agent is a RSV inhibiting compound.

15. A process for preparing a pharmaceutical composition as claimed in claim 12 wherein a therapeutically active amount of a compound as claimed in any of claims 1 to 11 is intimately mixed with a pharmaceutically acceptable carrier.

16. A method of treating a respiratory syncytial virus (RSV) infection comprising administering to a subject in need thereof an anti-virally effective amount of a compound of formula (I) as defined in claim 1 .

17. The compound according to claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

18. The compound as claimed in claim 17 , wherein said compound has the (+) specific rotation measured in DMF as solvent.

19. The compound as claimed in claim 18 , wherein said compound has a specific optical rotation of [α] D 20 =+156.37° at a concentration of 0.259 (w/v %).

20. The pharmaceutical composition according to claim 13 , wherein the other antiviral agent is a RSV fusion inhibitor or a RSV polymerase inhibitor.

Assignments (9)

Continuity (3)