SUBSTITUTED PYRAZOLOAZEPIN-4-ONES AND THEIR USE AS PHOSPHODIESTERASE INHIBITORS
The present invention relates to novel substituted pyrazoloazepin-4-ones with phosphodiesterase inhibitory activity, as well as to their use as therapeutic agents in the treatment of inflammatory diseases and conditions.
1 - 17 . (canceled)
18 . A method for treatment or alleviation of a disease or a disorder or a condition responsive to PDE4 inhibitory activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of general formula (I):
wherein
R 1 and R 4 are independently selected from the group consisting of hydrogen and (C 1 -C 4 )alkyl;
R 2 and R 3 are independently selected from the group consisting of hydrogen and (C 1 -C 4 )alkyl: or R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl ring;
n=0, 1, or 2; and when n is 0, R 4 does not exist;
Q is selected from the group consisting of —O—C(O)—R 5 and —O—C(O)—(C 1 -C 6 )alkyl-R 5 ;
R 5 is selected from the group consisting of heteroaryl and heterocycloalkyl, wherein said heteroaryl and heterocycloalkyl are optionally substituted with one or more substituents independently selected from R 6 ;
R 6 consists of halogen, cyano, hydroxyl, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkyloxy, —S(O) 2 R x , —S(O) 2 NR a R b , —OR x , —C(O)NR a R b , —C(O)OR a , —C(O)R a , cycloalkyl, aryl, and heteroaryl;
R x is (C 1 -C 4 )alkyl;
R a and R b are independently selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl, phenyl-(C 1 -C 4 )alkyl, or
R a and R b together with the nitrogen to which they are attached form a 4-6 membered heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one or more (C 1 -C 4 )alkyl;
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
19 - 20 . (canceled)
21 . The method according to claim 18 , wherein each of R 1 , R 2 , and R 3 is hydrogen, n is 0, and Q is selected from the group consisting of —O—C(O)—R 5 and —O—C(O)—(C 1 -C 5 )alkyl-R 5 ;
wherein R 5 is selected from the group consisting of a (5-6) membered heteroaryl, and a (4-6) membered heterocycloalkyl, and
wherein said heteroaryl and heterocycloalkyl are optionally substituted with one or more substituents independently selected from (C 1 -C 4 )alkyl, (C 1 -C 4 )alkyloxy, —C(O)R a , and (C 3 -C 6 )cycloalkyl; wherein R a is (C 1 -C 4 )alkyl.
22 . The method according to claim 18 wherein each of R 1 , R 2 , R 3 , and R 4 is hydrogen, n is 1, and Q is —O—C(O)—R 5 ;
wherein R 5 is selected from the group consisting of a (5-6) membered heteroaryl, a (9-10) membered heteroaryl, and a (4-6) membered heterocycloalkyl,
wherein said heteroaryl and heterocycloalkyl are optionally substituted with one or more substituents independently selected from Re; and
wherein Re is selected from the group consisting of hydroxyl, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkyloxy, —OR x , —C(O)NR a R b , —C(O)OR a , —C(O)R a , and (C 3 -C 6 )cycloalkyl, wherein R x , R a , and R b are all (C 1 -C 4 )alkyl.
23 . The method according to claim 18 wherein R 1 and R 4 are both hydrogen, one of R 2 and R 3 is hydrogen and the other one of R 2 and R 3 is (C 1 -C 4 )alkyl, n is 1, and Q is —O—C(O)—R 5 , wherein R 5 is a (4-6) membered heterocycloalkyl.
24 . The method according to claim 18 wherein R 1 and R 4 are both hydrogen; R 2 and R 3 are both (C 1 -C 4 )alkyl; n is 1 and Q is —O—C(O)—R 5 ; wherein R 5 is a (4-6) membered heterocycloalkyl.
25 . The method according to claim 18 wherein each of R 1 , R 2 , R 3 , and R 4 is hydrogen, n is 2, and Q is —O—C(O)—R 5 ;
wherein R 5 is selected from the group consisting of a (5-6) membered heteroaryl and a (4-6) membered heterocycloalkyl, and
wherein said heteroaryl is optionally substituted with one or more of (C 1 -C 4 )alkyl.
26 . The method according to claim 18 , wherein the compound of general formula (I) is selected from the group consisting of:
(i) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl isoxazole-5-carboxylate;
(ii) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl oxazole-4-carboxylate;
(iii) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 1-methylpyrazole-4-carboxylate;
(iv) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 5-methylisoxazole-3-carboxylate;
(v) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 2-methyloxazole-4-carboxylate;
(vi) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 2-methyloxazole-5-carboxylate;
(vii) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl thiazole-4-carboxylate;
(viii) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl tetrahydropyran-4-carboxylate;
(ix) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 2-(1-methylpyrrol-2-yl)acetate;
(x) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 1,5-dimethylpyrazole-3-carboxylate;
(xi) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 2-(5-methylisoxazol-3-yl)acetate;
(xii) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 2-(3-methylisoxazol-5-yl)acetate;
(xiii) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 3-methylisothiazole-5-carboxylate;
(xiv) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 4-methylthiazole-2-carboxylate;
(xv) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 2-(2-methylthiazol-4-yl)acetate;
(xvi) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 1-acetylpiperidine-4-carboxylate;
(xvii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1H-imidazole-4-carboxylate;
(xviii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1H-pyrazole-3-carboxylate;
(xix) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1H-imidazole-2-carboxylate;
(xx) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1H-pyrazole-4-carboxylate;
(xxi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl isoxazole-3-carboxylate;
(xxii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl isoxazole-5-carboxylate;
(xxiii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl oxazole-4-carboxylate;
(xxiv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl oxazole-5-carboxylate;
(xxv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1H-triazole-4-carboxylate;
(xxvi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1H-1,2,4-triazole-3-carboxylate;
(xxvii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1,2,5-oxadiazole-3-carboxylate;
(xxviii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl tetrahydrofuran-3-carboxylate;
(xxix) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl pyridazine-3-carboxylate;
(xxx) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl pyridazine-4-carboxylate;
(xxxi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl pyrimidine-2-carboxylate;
(xxxii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1-methylpyrazole-3-carboxylate;
(xxxiii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 5-methyl-1H-pyrazole-3-carboxylate;
(xxxiv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3-methyl-1H-pyrazole-5-carboxylate;
(xxxv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-methylpyrazole-3-carboxylate;
(xxxvi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-methyl-1H-imidazole-4-carboxylate;
(xxxvii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-methyl-1H-imidazole-5-carboxylate;
(xxxviii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1-methylpyrazole-4-carboxylate;
(xxxix) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1-methylimidazole-4-carboxylate;
(xl) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1-methylimidazole-2-carboxylate;
(xli) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3-methylimidazole-4-carboxylate;
(xlii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 4-methylisoxazole-5-carboxylate;
(xliii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3-methylisoxazole-5-carboxylate;
(xliv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 5-methylisoxazole-3-carboxylate;
(xlv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3-methylisoxazole-4-carboxylate;
(xlvi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-methyloxazole-4-carboxylate;
(xlvii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 4-methyloxazole-5-carboxylate;
(xlviii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-methyloxazole-5-carboxylate;
(xlix) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3-methyltriazole-4-carboxylate;
(l) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 5-methyl-4H-1,2,4-triazole-3-carboxylate;
(li) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 4-methyl-1,2,5-oxadiazole-3-carboxylate;
(lii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3-hydroxyisoxazole-5-carboxylate;
(liii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl isothiazole-3-carboxylate;
(liv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl isothiazole-5-carboxylate;
(lv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl isothiazole-4-carboxylate;
(lvi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl thiazole-5-carboxylate;
(lvii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl thiadiazole-4-carboxylate;
(lviii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl tetrahydropyran-3-carboxylate;
(lix) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl tetrahydropyran-4-carboxylate;
(lx) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl tetrahydrothiophene-3-carboxylate;
(lxi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 5-methylpyridine-2-carboxylate;
(lxii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3-methylpyridine-2-carboxylate;
(lxiii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 4-methylpyridine-2-carboxylate;
(lxiv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 6-methylpyridine-2-carboxylate;
(lxv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-methylpyridine-3-carboxylate;
(lxvi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 5-methylpyrimidine-2-carboxylate;
(lxvii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3-methylpyridazine-4-carboxylate;
(lxviii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-methylpyrimidine-4-carboxylate;
(lxix) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 4-methylpyrimidine-2-carboxylate;
(lxx) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-methylpyrimidine-5-carboxylate;
(lxxi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2,5-dimethylpyrazole-3-carboxylate;
(lxxii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1,5-dimethylpyrazole-3-carboxylate;
(lxxiii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2,3-dimethylimidazole-4-carboxylate;
(lxxiv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 4,5-dimethylisoxazole-3-carboxylate;
(lxxv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3,5-dimethylisoxazole-4-carboxylate;
(lxxvi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2,5-dimethyloxazole-4-carboxylate;
(lxxvii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1-acetylazetidine-3-carboxylate;
(lxxviii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3-methylisothiazole-5-carboxylate;
(lxxix) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 5-methylisothiazole-4-carboxylate;
(lxxx) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 5-methylthiazole-4-carboxylate;
(lxxxi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 4-methylthiazole-5-carboxylate;
(lxxxii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-methylthiazole-5-carboxylate;
(lxxxiii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 4-methylthiadiazole-5-carboxylate;
(lxxxiv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl tetrahydrothiopyran-3-carboxylate;
(lxxxv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl tetrahydrothiopyran-4-carboxylate;
(lxxxvi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2,6-dimethylpyridine-4-carboxylate;
(lxxxvii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2,6-dimethylpyridine-3-carboxylate;
(lxxxviii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3,6-dimethylpyridazine-4-carboxylate;
(lxxxix) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-cyclopropyloxazole-4-carboxylate;
(xc) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-ethyl-5-methyl-pyrazole-3-carboxylate;
(xci) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1,3,5-trimethylpyrazole-4-carboxylate;
(xcii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3-ethyl-5-methyl-isoxazole-4-carboxylate;
(xciii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1-acetylpyrrolidine-3-carboxylate;
(xciv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 4,5-dimethylthiazole-2-carboxylate;
(xcv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2,4-dimethylthiazole-5-carboxylate;
(xcvi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1,1-dioxothiolane-3-carboxylate;
(xcvii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3,5-diethylisoxazole-4-carboxylate;
(xcviii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1-acetylpiperidine-3-carboxylate;
(xcix) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1-acetylpiperidine-4-carboxylate;
(c) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-methoxy-4-methyl-thiazole-5-carboxylate;
(ci) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3-methylbenzimidazole-5-carboxylate;
(cii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1,1-dioxothiane-3-carboxylate;
(ciii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1,1-dioxothiane-4-carboxylate;
(civ) 03-[3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl] 01-methyl piperidine-1,3-dicarboxylate;
(cv) 04-[3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl] 01-methyl piperidine-1,4-dicarboxylate;
(cvi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1-(dimethylcarbamoyl)piperidine-3-carboxylate;
(cvii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1-(dimethylcarbamoyl)piperidine-4-carboxylate;
(cviii) [(2R)-3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)-2-methyl-propyl] tetrahydrofuran-3-carboxylate;
(cix) [(2R)-3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)-2-methyl-propyl] tetrahydropyran-4-carboxylate;
(cx) [3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)-2,2-dimethyl-propyl] tetrahydrofuran-3-carboxylate;
(cxi) [3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)-2,2-dimethyl-propyl] tetrahydropyran-4-carboxylate;
(cxii) 4-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)butyl 2-methyloxazole-5-carboxylate;
(cxiii) 4-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)butyl isothiazole-4-carboxylate;
(cxiv) 4-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)butyl thiazole-4-carboxylate;
(cxv) 4-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)butyl tetrahydropyran-4-carboxylate;
or a pharmaceutically acceptable salt, hydrate or solvate thereof.
27 . The method according to claim 18 , wherein the compound of general formula (I) is administered to said subject in the form of a pharmaceutical composition comprising the compound and one or more pharmaceutically acceptable vehicles or excipients and/or pharmaceutically acceptable carriers.
28 . The method of claim 27 , wherein the pharmaceutical composition further comprises one or more other therapeutically active compounds.
29 . A method of treating or ameliorating one or more dermal diseases or conditions, comprising administering to a person suffering from at least one of said diseases an effective amount of one or more compounds of general formula (I):
wherein
R 1 and R 4 are independently selected from the group consisting of hydrogen and (C 1 -C 4 )alkyl;
R 2 and R 3 are independently selected from the group consisting of hydrogen and (C 1 -C 4 )alkyl; or R 2 and R a together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl ring;
n=0, 1, or 2; and when n is 0, R 4 does not exist;
Q is selected from the group consisting of —O—C(O)—R 5 and —O—C(O)—(C 1 -C 5 )alkyl-R 5 ;
R 5 is selected from the group consisting of heteroaryl and heterocycloalkyl, wherein said heteroaryl and heterocycloalkyl are optionally substituted with one or more substituents independently selected from Re;
R 6 consists of halogen, cyano, hydroxyl, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkyloxy, —S(O) 2 R x , —S(O) 2 NR a R b , —OR x , —C(O)NR a R b , —C(O)OR a , —C(O)R a , cycloalkyl, aryl, and heteroaryl;
R x is (C 1 -C 4 )alkyl;
R a and R b are independently selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl, and phenyl-(C 1 -C 4 )alkyl, or
R a and R b together with the nitrogen to which they are attached form a 4-6 membered heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one or more (C 1 -C 4 )alkyl;
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
30 . The method of claim 29 , wherein the compound of general formula (I) is selected from the group consisting of:
(i) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl isoxazole-5-carboxylate;
(ii) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl oxazole-4-carboxylate;
(iii) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 1-methylpyrazole-4-carboxylate;
(iv) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 5-methylisoxazole-3-carboxylate;
(v) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 2-methyloxazole-4-carboxylate;
(vi) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 2-methyloxazole-5-carboxylate;
(vii) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl thiazole-4-carboxylate;
(viii) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl tetrahydropyran-4-carboxylate;
(ix) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 2-(1-methylpyrrol-2-yl)acetate;
(x) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 1,5-dimethylpyrazole-3-carboxylate;
(xi) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 2-(5-methylisoxazol-3-yl)acetate;
(xii) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 2-(3-methylisoxazol-5-yl)acetate;
(xiii) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 3-methylisothiazole-5-carboxylate;
(xiv) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 4-methylthiazole-2-carboxylate;
(xv) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 2-(2-methylthiazol-4-yl)acetate;
(xvi) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 1-acetylpiperidine-4-carboxylate;
(xvii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1H-imidazole-4-carboxylate;
(xviii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1H-pyrazole-3-carboxylate;
(xix) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1H-imidazole-2-carboxylate;
(xx) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1H-pyrazole-4-carboxylate;
(xxi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl isoxazole-3-carboxylate;
(xxii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl isoxazole-5-carboxylate;
(xxiii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl oxazole-4-carboxylate;
(xxiv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl oxazole-5-carboxylate;
(xxv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1H-triazole-4-carboxylate;
(xxvi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1H-1,2,4-triazole-3-carboxylate;
(xxvii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1,2,5-oxadiazole-3-carboxylate;
(xxviii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl tetrahydrofuran-3-carboxylate;
(xxix) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl pyridazine-3-carboxylate;
(xxx) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl pyridazine-4-carboxylate;
(xxxi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl pyrimidine-2-carboxylate;
(xxxii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1-methylpyrazole-3-carboxylate;
(xxxiii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 5-methyl-1H-pyrazole-3-carboxylate;
(xxxiv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3-methyl-1H-pyrazole-5-carboxylate;
(xxxv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-methylpyrazole-3-carboxylate;
(xxxvi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-methyl-1H-imidazole-4-carboxylate;
(xxxvii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-methyl-1H-imidazole-5-carboxylate;
(xxxviii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1-methylpyrazole-4-carboxylate;
(xxxix) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1-methylimidazole-4-carboxylate;
(xl) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1-methylimidazole-2-carboxylate;
(xli) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3-methylimidazole-4-carboxylate;
(xlii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 4-methylisoxazole-5-carboxylate;
(xliii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3-methylisoxazole-5-carboxylate;
(xliv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 5-methylisoxazole-3-carboxylate;
(xlv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3-methylisoxazole-4-carboxylate;
(xlvi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-methyloxazole-4-carboxylate;
(xlvii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 4-methyloxazole-5-carboxylate;
(xlviii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-methyloxazole-5-carboxylate;
(xlix) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3-methyltriazole-4-carboxylate;
(l) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 5-methyl-4H-1,2,4-triazole-3-carboxylate;
(li) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 4-methyl-1,2,5-oxadiazole-3-carboxylate;
(lii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3-hydroxyisoxazole-5-carboxylate;
(liii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl isothiazole-3-carboxylate;
(liv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl isothiazole-5-carboxylate;
(lv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl isothiazole-4-carboxylate;
(lvi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl thiazole-5-carboxylate;
(lvii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl thiadiazole-4-carboxylate;
(lviii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl tetrahydropyran-3-carboxylate;
(lix) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl tetrahydropyran-4-carboxylate;
(Ix) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl tetrahydrothiophene-3-carboxylate;
(lxi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 5-methylpyridine-2-carboxylate;
(lxii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3-methylpyridine-2-carboxylate;
(lxiii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 4-methylpyridine-2-carboxylate;
(lxiv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 6-methylpyridine-2-carboxylate;
(lxv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-methylpyridine-3-carboxylate;
(lxvi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 5-methylpyrimidine-2-carboxylate;
(lxvii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3-methylpyridazine-4-carboxylate;
(lxviii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-methylpyrimidine-4-carboxylate;
(lxix) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 4-methylpyrimidine-2-carboxylate;
(lxx) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-methylpyrimidine-5-carboxylate;
(lxxi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2,5-dimethylpyrazole-3-carboxylate;
(lxxii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1,5-dimethylpyrazole-3-carboxylate;
(lxxiii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2,3-dimethylimidazole-4-carboxylate;
(lxxiv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 4,5-dimethylisoxazole-3-carboxylate;
(lxxv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3,5-dimethylisoxazole-4-carboxylate;
(lxxvi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2,5-dimethyloxazole-4-carboxylate;
(lxxvii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1-acetylazetidine-3-carboxylate;
(lxxviii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3-methylisothiazole-5-carboxylate;
(lxxix) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 5-methylisothiazole-4-carboxylate;
(lxxx) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 5-methylthiazole-4-carboxylate;
(lxxxi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 4-methylthiazole-5-carboxylate;
(lxxxii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-methylthiazole-5-carboxylate;
(lxxxiii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 4-methylthiadiazole-5-carboxylate;
(lxxxiv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl tetrahydrothiopyran-3-carboxylate;
(lxxxv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl tetrahydrothiopyran-4-carboxylate;
(lxxxvi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2,6-dimethylpyridine-4-carboxylate;
(lxxxvii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2,6-dimethylpyridine-3-carboxylate;
(lxxxviii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3,6-dimethylpyridazine-4-carboxylate;
(lxxxix) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-cyclopropyloxazole-4-carboxylate;
(xc) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-ethyl-5-methyl-pyrazole-3-carboxylate;
(xci) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1,3,5-trimethylpyrazole-4-carboxylate;
(xcii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3-ethyl-5-methyl-isoxazole-4-carboxylate;
(xciii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1-acetylpyrrolidine-3-carboxylate;
(xciv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 4,5-dimethylthiazole-2-carboxylate;
(xcv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2,4-dimethylthiazole-5-carboxylate;
(xcvi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1,1-dioxothiolane-3-carboxylate;
(xcvii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3,5-diethylisoxazole-4-carboxylate;
(xcviii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1-acetylpiperidine-3-carboxylate;
(xcix) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1-acetylpiperidine-4-carboxylate;
(c) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-methoxy-4-methyl-thiazole-5-carboxylate;
(ci) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3-methylbenzimidazole-5-carboxylate;
(cii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1,1-dioxothiane-3-carboxylate;
(ciii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1,1-dioxothiane-4-carboxylate;
(civ) 03-[3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl] 01-methyl piperidine-1,3-dicarboxylate;
(cv) 04-[3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl] 01-methyl piperidine-1,4-dicarboxylate;
(cvi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1-(dimethylcarbamoyl)piperidine-3-carboxylate;
(cvii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1-(dimethylcarbamoyl)piperidine-4-carboxylate;
(cviii) [(2R)-3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)-2-methyl-propyl] tetrahydrofuran-3-carboxylate;
(cix) [(2R)-3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)-2-methyl-propyl] tetrahydropyran-4-carboxylate;
(cx) [3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)-2,2-dimethyl-propyl] tetrahydrofuran-3-carboxylate;
(cxi) [3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)-2,2-dimethyl-propyl] tetrahydropyran-4-carboxylate;
(cxii) 4-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)butyl 2-methyloxazole-5-carboxylate;
(cxiii) 4-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)butyl isothiazole-4-carboxylate;
(cxiv) 4-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)butyl thiazole-4-carboxylate;
(cxv) 4-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)butyl tetrahydropyran-4-carboxylate;
or a pharmaceutically acceptable salt, hydrate or solvate thereof.
31 . The method according to claim 29 , wherein the dermal disease or condition is selected from the group consisting of proliferative and inflammatory skin disorders, dermatitis, atopic dermatitis, seborrheic dermatitis, contact dermatitis, psoriasis, cancer, epidermal inflammation, alopecia, alopecia areata, skin atrophy, steroid induced skin atrophy, skin ageing, photo skin ageing, acne, urticaria, pruritis, and eczema.
32 . The method according to claim 30 , wherein the dermal disease or condition is selected from the group consisting of proliferative and inflammatory skin disorders, dermatitis, atopic dermatitis, seborrheic dermatitis, contact dermatitis, psoriasis, cancer, epidermal inflammation, alopecia, alopecia areata, skin atrophy, steroid induced skin atrophy, skin ageing, photo skin ageing, acne, urticaria, pruritis, and eczema.
33 . A method of treating or ameliorating one or more dermal diseases or conditions, comprising administering to a person suffering from at least one of said diseases a therapeutically effective amount of a pharmaceutical composition, wherein said pharmaceutical composition comprises a compound of general formula (I) and one or more pharmaceutically acceptable vehicles or excipients and/or pharmaceutically acceptable carriers:
wherein
R 1 and R 4 are independently selected from the group consisting of hydrogen and (C 1 -C 4 )alkyl;
R 2 and R 3 are independently selected from the group consisting of hydrogen and (C 1 -C 4 )alkyl; or R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl ring;
n=0, 1, or 2; and when n is 0, R 4 does not exist;
Q is selected from the group consisting of —O—C(O)—R 5 and —O—C(O)—(C 1 -C 5 )alkyl-R 5 ;
R 5 is selected from the group consisting of heteroaryl and heterocycloalkyl, wherein said heteroaryl and heterocycloalkyl are optionally substituted with one or more substituents independently selected from R 6 ;
R 6 consists of halogen, cyano, hydroxyl, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkyloxy, —S(O) 2 R x , —S(O) 2 NR a R b , —OR x , —C(O)NR a R b , —C(O)OR a , —C(O)R a , cycloalkyl, aryl, and heteroaryl;
R x is (C 1 -C 4 )alkyl;
R a and R b are independently selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl, and phenyl-(C 1 -C 4 )alkyl, or
R a and R b together with the nitrogen to which they are attached form a 4-6 membered heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one or more (C 1 -C 4 )alkyl;
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
34 . The method of claim 33 , wherein the compound of general formula (I) is selected from the group consisting of:
(i) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl isoxazole-5-carboxylate;
(ii) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl oxazole-4-carboxylate;
(iii) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 1-methylpyrazole-4-carboxylate;
(iv) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 5-methylisoxazole-3-carboxylate;
(v) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 2-methyloxazole-4-carboxylate;
(vi) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 2-methyloxazole-5-carboxylate;
(vii) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl thiazole-4-carboxylate;
(viii) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl tetrahydropyran-4-carboxylate;
(ix) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 2-(1-methylpyrrol-2-yl)acetate;
(x) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 1,5-dimethylpyrazole-3-carboxylate;
(xi) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 2-(5-methylisoxazol-3-yl)acetate;
(xii) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 2-(3-methylisoxazol-5-yl)acetate;
(xiii) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 3-methylisothiazole-5-carboxylate;
(xiv) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 4-methylthiazole-2-carboxylate;
(xv) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 2-(2-methylthiazol-4-yl)acetate;
(xvi) 2-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)ethyl 1-acetylpiperidine-4-carboxylate;
(xvii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1H-imidazole-4-carboxylate;
(xviii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1H-pyrazole-3-carboxylate;
(xix) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1H-imidazole-2-carboxylate;
(xx) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1H-pyrazole-4-carboxylate;
(xxi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl isoxazole-3-carboxylate;
(xxii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl isoxazole-5-carboxylate;
(xxiii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl oxazole-4-carboxylate;
(xxiv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl oxazole-5-carboxylate;
(xxv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1H-triazole-4-carboxylate;
(xxvi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1H-1,2,4-triazole-3-carboxylate;
(xxvii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1,2,5-oxadiazole-3-carboxylate;
(xxviii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl tetrahydrofuran-3-carboxylate;
(xxix) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl pyridazine-3-carboxylate;
(xxx) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl pyridazine-4-carboxylate;
(xxxi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl pyrimidine-2-carboxylate;
(xxxii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1-methylpyrazole-3-carboxylate;
(xxxiii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 5-methyl-1H-pyrazole-3-carboxylate;
(xxxiv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3-methyl-1H-pyrazole-5-carboxylate;
(xxxv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-methylpyrazole-3-carboxylate;
(xxxvi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-methyl-1H-imidazole-4-carboxylate;
(xxxvii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-methyl-1H-imidazole-5-carboxylate;
(xxxviii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1-methylpyrazole-4-carboxylate;
(xxxix) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1-methylimidazole-4-carboxylate;
(xl) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1-methylimidazole-2-carboxylate;
(xli) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3-methylimidazole-4-carboxylate;
(xlii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 4-methylisoxazole-5-carboxylate;
(xliii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3-methylisoxazole-5-carboxylate;
(xliv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 5-methylisoxazole-3-carboxylate;
(xlv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3-methylisoxazole-4-carboxylate;
(xlvi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-methyloxazole-4-carboxylate;
(xlvii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 4-methyloxazole-5-carboxylate;
(xlviii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-methyloxazole-5-carboxylate;
(xlix) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3-methyltriazole-4-carboxylate;
(l) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 5-methyl-4H-1,2,4-triazole-3-carboxylate;
(li) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 4-methyl-1,2,5-oxadiazole-3-carboxylate;
(lii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3-hydroxyisoxazole-5-carboxylate;
(liii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl isothiazole-3-carboxylate;
(liv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl isothiazole-5-carboxylate;
(lv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl isothiazole-4-carboxylate;
(lvi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl thiazole-5-carboxylate;
(lvii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl thiadiazole-4-carboxylate;
(lviii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl tetrahydropyran-3-carboxylate;
(lix) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl tetrahydropyran-4-carboxylate;
(lx) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl tetrahydrothiophene-3-carboxylate;
(lxi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 5-methylpyridine-2-carboxylate;
(lxii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3-methylpyridine-2-carboxylate;
(lxiii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 4-methylpyridine-2-carboxylate;
(lxiv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 6-methylpyridine-2-carboxylate;
(lxv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-methylpyridine-3-carboxylate;
(lxvi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 5-methylpyrimidine-2-carboxylate;
(lxvii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3-methylpyridazine-4-carboxylate;
(lxviii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-methylpyrimidine-4-carboxylate;
(lxix) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 4-methylpyrimidine-2-carboxylate;
(lxx) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-methylpyrimidine-5-carboxylate;
(lxxi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2,5-dimethylpyrazole-3-carboxylate;
(lxxii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1,5-dimethylpyrazole-3-carboxylate;
(lxxiii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2,3-dimethylimidazole-4-carboxylate;
(lxxiv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 4,5-dimethylisoxazole-3-carboxylate;
(lxxv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3,5-dimethylisoxazole-4-carboxylate;
(lxxvi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2,5-dimethyloxazole-4-carboxylate;
(lxxvii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1-acetylazetidine-3-carboxylate;
(lxxviii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3-methylisothiazole-5-carboxylate;
(lxxix) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 5-methylisothiazole-4-carboxylate;
(lxxx) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 5-methylthiazole-4-carboxylate;
(lxxxi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 4-methylthiazole-5-carboxylate;
(lxxxii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-methylthiazole-5-carboxylate;
(lxxxiii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 4-methylthiadiazole-5-carboxylate;
(lxxxiv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl tetrahydrothiopyran-3-carboxylate;
(lxxxv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl tetrahydrothiopyran-4-carboxylate;
(lxxxvi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2,6-dimethylpyridine-4-carboxylate;
(lxxxvii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2,6-dimethylpyridine-3-carboxylate;
(lxxxviii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3,6-dimethylpyridazine-4-carboxylate;
(lxxxix) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-cyclopropyloxazole-4-carboxylate;
(xc) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-ethyl-5-methyl-pyrazole-3-carboxylate;
(xci) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1,3,5-trimethylpyrazole-4-carboxylate;
(xcii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3-ethyl-5-methyl-isoxazole-4-carboxylate;
(xciii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1-acetylpyrrolidine-3-carboxylate;
(xciv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 4,5-dimethylthiazole-2-carboxylate;
(xcv) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2,4-dimethylthiazole-5-carboxylate;
(xcvi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1,1-dioxothiolane-3-carboxylate;
(xcvii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3,5-diethylisoxazole-4-carboxylate;
(xcviii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1-acetylpiperidine-3-carboxylate;
(xcix) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1-acetylpiperidine-4-carboxylate;
(c) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 2-methoxy-4-methyl-thiazole-5-carboxylate;
(ci) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 3-methylbenzimidazole-5-carboxylate;
(cii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1,1-dioxothiane-3-carboxylate;
(ciii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1,1-dioxothiane-4-carboxylate;
(civ) 03-[3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl] 01-methyl piperidine-1,3-dicarboxylate;
(cv) 04-[3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl] 01-methyl piperidine-1,4-dicarboxylate;
(cvi) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1-(dimethylcarbamoyl)piperidine-3-carboxylate;
(cvii) 3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)propyl 1-(dimethylcarbamoyl)piperidine-4-carboxylate;
(cviii) [(2R)-3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)-2-methyl-propyl] tetrahydrofuran-3-carboxylate;
(cix) [(2R)-3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)-2-methyl-propyl] tetrahydropyran-4-carboxylate;
(cx) [3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)-2,2-dimethyl-propyl] tetrahydrofuran-3-carboxylate;
(cxi) [3-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)-2,2-dimethyl-propyl] tetrahydropyran-4-carboxylate;
(cxii) 4-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)butyl 2-methyloxazole-5-carboxylate;
(cxiii) 4-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)butyl isothiazole-4-carboxylate;
(cxiv) 4-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)butyl thiazole-4-carboxylate;
(cxv) 4-(3-ethyl-4-oxo-spiro[6,8-dihydro-5H-pyrazolo[4,3-c]azepine-7,4′-tetrahydropyran]-1-yl)butyl tetrahydropyran-4-carboxylate;
or a pharmaceutically acceptable salt, hydrate or solvate thereof.
35 . The method of claim 33 , wherein the pharmaceutical composition further comprises one or more other therapeutically active compounds.