US 8,895,580 B2Granted

Quinolinone-pyrazolone M1 receptor positive allosteric modulators

AssigneeMerck Sharp & Dohme Corp.

InventorsDouglas C. Beshore, Scott D. Kuduk, Robert M. DiPardo

Life of this patent

Estimating the term…

Abstract

The present invention is directed to quinolinone-pyrazolone compounds of formula (I) which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimer's disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds, and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor.

Claims17

Dependent claims

A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein
R1A and R1B are either hydrogen or selected from the group consisting of
(1) halogen,
(2) —C1-6 alkyl,
(3) —O—C1-6 alkyl,
(4) —CN;
R3 is selected from the group consisting of
(1) —C6-10 aryl,
(2) heteroaryl, wherein the heteroaryl is an aromatic cyclic group, having from five to ten ring atoms, said ring atoms selected from C, O, N, N→O, C(═O) or S, at least one of which is O, N, N→O or S,
(3) a heterocyclic group having 4 to 8 ring atoms selected from C, O, N, N→O, C(═O), SO2 or S, at least one of which is O, N, N→O, SO2 or S,
(4) —C3-8 cycloalkyl,
wherein each aryl, heteroaryl or heterocyclic is substituted with one or more of R5 group;
R5 is selected from the group consisting of
(1) halogen,
(2) —C2-8 alkenyl,
(3) —O—C1-6 alkyl,
(4) —C(═O)—(O)m—R7,
(5) —NH—C(═O)—R7,
(6) —C3-8 cycloalkyl,
(7) —S(═O)2—R7,
(8) —NH—S(═O)2—R7,
(9) —NO2,
(10) —CN;
(11) C6-10 aryl,
(12) heteroaryl, which is an aromatic cyclic or polycyclic group, having from five to ten ring atoms, said ring atoms selected from C, O, N, N→O, C(═O) or S, at least one of which is O, N, N→O or S,
(13) —NR9R10,
(14) —B(OH)2,
wherein said cycloalkyl, aryl or heteroaryl R5 group is optionally substituted with one or more
(a) halogen,
(b) —C1-6 alkyl,
(c) —C3-8 cycloalkyl,
(d) —NR11R12,
(e) —O—C1-6 alkyl,
(f) C6-10 aryl,
(g) CN,
(h) hydroxyl
(i) —C(═O)—O—R7,
(j) —NH—C(═O)—R7,
(k) —S(═O)2—R7,
(l) —NH—S(═O)2—R7,
wherein said alkyl or aryl is optionally substituted with one or more
(i) halogen,
(ii) hydroxyl,
(iii) —NR13R14;
R4 is selected from the group consisting of
(1) —C6-10 aryl,
(2) heteroaryl, which is an aromatic cyclic or polycyclic group, having from five to ten ring atoms, said ring atoms selected from C, O, N, N→O, C(═O) or S, at least one of which is O, N, N→O or S,
(3) a heterocyclic group having 4 to 8 ring atoms selected from C, O, N, N→O, C(═O), SO2 or S, at least one of which is O, N, N→O, SO2 or S,
wherein each aryl, heteroaryl or heterocyclic is optionally substituted with one or more R6 group;
R6 is selected from the group consisting of
(1) halogen,
(2) —C1-6 alkyl,
(3) —C2-8 alkenyl,
(4) —O—C1-6 alkyl,
(5) hydroxyl,
(6) —C(═O)—(O)m—R7,
(7) —C(═O)—NR9R10,
(8) —O—C(═O)—R7,
(9) —NH—C(═O)—R7,
(10) —NH—C(═O)—OR7,
(11) —C3-8 cycloalkyl,
(12) —S(═O)2—R7,
(13) —S(═O)2—OR7,
(14) —S(═O)2—NR9R10,
(15) —NH—S(═O)2—R7,
(16) —NO2,
(17) —CN;
(18) —C6-10 aryl,
(19) —O—C6-10 aryl,
(20) heteroaryl, which is an aromatic cyclic or polycyclic group, having from five to ten ring atoms, said ring atoms selected from C, O, N, N→O, C(═O) or S, at least one of which is O, N, N→O or S,
(21) —NR9R10,
wherein said alkyl, cycloalkyl, aryl or heteroaryl R5 group is optionally substituted with one or more
(a) halogen,
(b) —C1-6 alkyl,
(c) —NR11R12,
(d) —O—C1-6 alkyl,
(f) —C6-10 aryl,
(g) heteroaryl, which is an aromatic cyclic or polycyclic group, having from five to ten ring atoms, said ring atoms selected from C, O, N, N→O, C(═O) or S, at least one of which is O, N, N→O or S,
(h) CN,
(i) hydroxyl
wherein said alkyl, aryl or heteroaryl is optionally substituted with one or more
(i) halogen,
(ii) hydroxyl,
(iii) —NR13R14;
R7 is selected from the group consisting of
(1) hydrogen,
(2) —C1-6 alkyl;
(3) —C3-8 cycloalkyl;
(2) —C2-6 alkenyl;
(3) —C0-2 alkyl-C6-10 aryl,
(4) —C0-2 alkyl-heteroaryl group, wherein the heteroaryl is an aromatic cyclic or polycyclic group, having from five to ten ring atoms, said ring atoms selected from C, O, N, N→O, C(═O) or S, at least one of which is O, N, N→O or S, wherein said alkyl, alkenyl, aryl or heteroaryl R7 group is optionally substituted with one or more
(a) halogen,
(b) hydroxy,
(c) —O—C1-6 alkyl,
(d) —C1-6 alkyl, optionally substituted with halogen;
R9 and R10, or R11 and R12, or R13 and R14 are each independently selected from the group consisting of
(1) hydrogen,
(2) —C1-6 alkyl,
(3) —C3-8 cycloalkyl, or
(4) —C6-10 aryl,
wherein said alkyl, cycloalkyl or aryl is optionally substituted with one or more
(a) halogen,
(b) —C1-6 alkyl,
(c) —C3-8 cycloalkyl,
(d) —N(—C1-6 alkyl)2,
(e) —O—C1-6 alkyl,
(f) —C6-10 aryl,
(g) heteroaryl, which is an aromatic cyclic or polycyclic cyclic, having from five to ten ring atoms, said ring atoms selected from C, O, N, N→O, C(═O) or S, at least one of which is O, N, N→O or S,
(h) CN,
(i) hydroxyl
(i) —C(═O)—O—R7,
(j) —NH—C(═O)—R7,
(k) —S(═O)2—R7,
(l) —NH—S(═O)2—R7,
or R9 and R10, or R11 and R12, or R13 and R14 are linked together with the nitrogen to which they are both attached to form a 4-8 membered carbocyclic ring, wherein one or two of the ring carbon atoms is replaced by a nitrogen, oxygen or sulfur, and the carbocyclic is optionally substituted with one or more
(a) halogen,
(b) —C1-6 alkyl,
(c) —O—C1-6 alkyl, or
(d) —C6-10 aryl,
m is 0 or 1;
or a pharmaceutically acceptable salt thereof.

118 more elements

A compound which is selected from the group consisting of

2-(2-Fluorophenyl)-5-{[4-(methoxy)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-(2-Fluorophenyl)-5-(biphenyl-4-ylmethyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
5-(Biphenyl-4-ylmethyl)-2-phenyl-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
5-(Biphenyl-4-ylmethyl)-2-(phenylmethyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
6,9-Difluoro-2-(1-methyl-1H-imidazol-4-yl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
6,9-Difluoro-2-(1-iodophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
6,9-Difluoro-2-[2-(1H-pyrazol-1-yl)phenyl]-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
6,9-Difluoro-2-[2-(hydroxymethyl)phenyl]-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-{2-[(Ethylamino)methyl]phenyl-6,9-difluoro-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
6,9-Difluoro-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2-[3-(trifluoromethyl)pyridin-2-yl]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
5-[(4-Bromo-2-fluorophenyl)methyl-6,9-difluoro-2-(2-fluorophenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
6,9-Difluoro-2-(2-fluorophenyl)-5-{[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
5-[(4-Iodo-2-fluorophenyl)methyl-6,9-difluoro-2-(2-fluorophenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
6,9-Difluoro-2-(2-fluorophenyl)-5-{[2-fluoro-4-(1H-1,2,4-triazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
6,9-Difluoro-5-({2-fluoro-4-[1-(2-methylpropyl)-1H-pyrazol-4-yl]phenyl}methyl)-2-(2-fluorophenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
5-[(5-Bromo-3-fluoropyridin-2-yl)methyl]-6,9-difluoro-2-(2-fluorophenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
6,9-Difluoro-5-{[3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl]methyl}-2-(2-fluorophenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
6,9-Difluoro-5-[(5-fluoro-6′-morpholin-4-yl-3,3′-bipyridin-6-yl)methyl]-2-(2-fluorophenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
6,9-Difluoro-2-(2-fluorophenyl)-5-{3-fluoro-5-(1H-pyrazol-1-yl)pyridin-2-yl}methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-Fluorophenyl-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
5-{[4-(3-Methyl-1H-pyrazol-1-yl)phenyl]methyl}-2-phenyl-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-(2-Fluorophenyl)-5-(1H-indol-5-ylmethyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-(2-Fluorophenyl)-5-[(2-oxo-1-phenylpiperidin-4-yl)methyl]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
5{[2-Fluoro-4-(1H-indol-5-yl)phenyl]methyl}-2-(2-fluorophenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
5-[(6-Chloropyridin-3-yl)methyl]-2-(2-fluorophenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-(2-Fluorophenyl)-5-{[6-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-(2-Fluorophenyl)-5-[(2′-methyl-3,3′-bipyridin-6-yl)methyl]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-(2-Fluorophenyl)-5-{[5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
5-Ethyl-2-(2-fluorophenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-(2-Fluorophenyl)-5-{[4-(1,3-oxadiazol-2-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-(2-Fluorophenyl)-5-{[4-(1-methyl-1H-pyrazol-4-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-(2-Fluorophenyl)-5-{[4-(1-methyl-1H-pyrazol-4-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-(2,6-Difluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-(3-Oxo-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-3,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl)benzonitrile;
6-Fluoro-2-(2-fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
6-Fluoro-2-(2-fluoro-3-methylpyridin-4-yl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
9-Fluoro-2-(2-methylphenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
9-Bromo-6-fluoro-2-(2-fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-(3-Oxo-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-3,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl)benzoic acid;
N-Methyl-2-(3-oxo-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-3,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl)benzamide;
2-(2-Aminophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-[2-(Ethylamino)phenyl]-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
3-Methyl-N-[2-(3-oxo-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-3,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl)phenyl]butanamide;
5-{[4-(1H-Pyrazol-1-yl)phenyl]methyl}-2-[2-(pyrrolodin-1-ylmethyl)phenyl]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2,5-Bis {[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-[2-(Hydroxymethyl)phenyl]-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
(±)-2-[2-(Hydroxyethyl)phenyl]-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-[2-(1-Hydroxy-1-methylethyl)phenyl]-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
(±)-2-[2-(Hydroxypropyl)phenyl]-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-[2-(2-Hydroxyethyl)phenyl]-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-(2-Propanoylphenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
Methyl 2-(3-oxo-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-3,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl)benzoate;
2-[2-(Azidomethyl)phenyl]-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-[2-(Aminomethyl)phenyl]-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-(2-Fluorophenyl)-5-{[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-(2-Bromo-6-fluorophenyl)-5-{[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
3-Fluoro-2-(3-oxo-5-{[4-(1H-pyrazol-1-yl)phenyl]methy}-3,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl)benzonitrile;
2-(2-Fluoro-6-methylphenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-(2-Bromo-6-methylphenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-(2-Bromo-6-methylphenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-(3-Chloropyridin-4-yl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-(4-Methylpyridin-3-yl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
3-(3-Oxo-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-3,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl)pyridine-4-carbonitrile;
2-Piperidin-4-yl-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-(1-Acetylpiperidin-4-yl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-(3-Chloro-5-methylpyridin-4-yl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-(3,5-Dimethylpyridin-4-yl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
4-{[2-(2-Fluorophenyl)-3-oxo-2,3-dihydro-5H-pyrazolo[4,3-c]quinolin-5-yl]methyl}-N-methylpiperidine-1-carboxamide;
2-(2-Fluorophenyl)-5-{[2-(hydroxymethyl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
(3-Oxo-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-3,5-dihydro-2H-pyrazol[4,3-c]quinolin-2-yl)acetic acid;
N,N-Diethyl-2-(3-oxo-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-3,5-dihydro-2H-pyrazol[4,3-c]quinolin-2-yl)acetamide;
6-Bromo-9-fluoro-2-(2-methylphenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
9-Fluoro-6-methyl-2-(2-methylphenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
9-Fluoro-2-(2-methylphenyl)-3-oxo-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-3,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-carbonitrile;
5-{[3-Chloro-4-(6-morpholin-4-ylpyridin-3-yl)phenyl]methyl}-2-(2-fluorophenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
(±)-2-[trans-2-(Methyloxy)cyclohexyl]-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
(±)-2-(cis-2-Fluorocyclohexyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
(±)-2-(Cyclohex-2-en-1-yl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
(±)-2-(3-Oxo-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-3,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl)cyclohexyl acetate;
(±)-2-(2-Oxocyclohexyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
(±)-2-[trans-2-(Methylamino)cyclohexyl]-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
5-[(4-Iodophenyl)methyl]-9-(methyloxy)-2-(2-methylphenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
9-(Methyloxy)-2-(2-methylphenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
9-Hydroxy-2-(2-methylphenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-(2-Methylphenyl)-3-oxo-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-3,5-dihydro-2H-pyrazolo[4,3-c]quinolin-9-yl trifluoromethanesulfonate;
9-Methyl-2-(2-methylphenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-(2-Methylphenyl)-3-oxo-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-3,5-dihydro-2H-pyrazolo[4,3-c]quinolin-9-yl acetate;
9-Hydroxy-5-[(iodophenyl)methyl]-2-(2-methylphenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
9-Hydroxy-2-(2-methylphenyl)-5-{[4-(6-methylpyridin-3-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
9-(Methyloxy)-2-(2-methylphenyl)-5-{[4-(6-methylpyridin-3-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-[5-(Hydroxymethyl)-1-methyl-1H-imidazol-4-yl]-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-{1-Methyl-5-[(methylamino)methyl]-1H-imidazol-4-yl]-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
(±)-2-(3-Fluoro-4-methylpyridin-2-yl)-5-trans-2-[(3-fluoro-4-methylpyridin-2-yl)amino]cyclohexy}-9-({[4-(1H-pyrazol-1-yl)phenyl]methyl}amino)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
8-Fluoro-5-{[4-(methyloxy)phenyl]methyl}-2-(2-methylphenyl)-9-({[4-(1H-pyrazol-1-yl)phenyl]methyl}amino)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
(±)-2-(2-Fluorophenyl)-5-{trans-2-[(3-fluoropyridin-2-yl)amino]cyclohexyl}-9-({[4-(1H-pyrazol-1-yl)phenyl]methyl}amino)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
5-[(5-Bromopyridin-2-yl)methyl]-2-(2-methylphenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-(2-Methylphenyl)-5-[(5-phenylpyridin-2-yl)methyl]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-(2-Methylphenyl)-5-(pyridin-2-ylmethyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-(3,5-Dichloropyridin-4-yl)-5-[(pyridin-2-yl)methyl]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-(2-Methylphenyl)-5-[(5-methylpyridin-2-yl)methyl]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-(2-Methylphenyl)-5-(4-nitrobenzyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
5-(4-Aminobenzyl)-2-(2-methylphenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
5-[4-(Dimethylamino)benzyl]-2-(2-methylphenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
N-(4-{[2-(2-Methylphenyl)-3-oxo-2,3-dihydro-5H-pyrazolo[4,3-c]quinolin-5-yl]methyl}phenyl)methanesulfonamide;
2-Allyl-5-[(5-bromopyridin-2-yl)methyl]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-Allyl-5-(4-fluorobenzyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
5-(4-Fluorobenzyl)-2-pyridin-4-yl-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
5-(4-Fluorobenzyl)-2-piperidin-4-yl-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
Methyl 4-[5-(4-fluorobenzyl)-3-oxo-3,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl]piperidine-1-carboxylate;
5-[(4-Fluorophenyl)methyl]-2-(1-methylpiperidin-4-yl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
(±)-5-(4-Fluorobenzyl)-2-[2-(1-hydroxyethyl)phenyl]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
5-(4-Fluorobenzyl)-2-propyl-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
5-(4-Fluorobenzyl)-2-[2-(hydroxymethyl)phenyl]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one;
or a pharmaceutically acceptable salt thereof.

111 more elements

Dependencies are inferred from the claim text.

Facts

Application: 13/499,335Filed 1 Oct 2010 · us provisional application
Priority: 21 Oct 2009
Published: US 2012/0196845 A12 Aug 2012
Granted: 25 Nov 2014
Term ends: Not estimatedThe source records don’t support an estimate.

Classification20 codes

C07D 405/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
A61K 31/535
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having six-membered rings with at least one nitrogen and one oxygen as the…
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/18
Drugs for disorders of the nervous system: antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Family

Application61/253,629Us provisional application · filed 21 Oct 2009
US 2012/0196845 A1Pre-grant publication · published 2 Aug 2012
US 8,895,580 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein
R1A and R1B are either hydrogen or selected from the group consisting of
(1) halogen,
(2) —C1-6 alkyl,
(3) —O—C1-6 alkyl,
(4) —CN;
R3 is selected from the group consisting of
(1) —C6-10 aryl,
(2) heteroaryl, wherein the heteroaryl is an aromatic cyclic group, having from five to ten ring atoms, said ring atoms selected from C, O, N, N→O, C(═O) or S, at least one of which is O, N, N→O or S,
(3) a heterocyclic group having 4 to 8 ring atoms selected from C, O, N, N→O, C(═O), SO2 or S, at least one of which is O, N, N→O, SO2 or S,
(4) —C3-8 cycloalkyl,
wherein each aryl, heteroaryl or heterocyclic is substituted with one or more of R5 group;
R5 is selected from the group consisting of
(1) halogen,
(2) —C2-8 alkenyl,
(3) —O—C1-6 alkyl,
(4) —C(═O)—(O)m—R7,
(5) —NH—C(═O)—R7,
(6) —C3-8 cycloalkyl,
(7) —S(═O)2—R7,
(8) —NH—S(═O)2—R7,
(9) —NO2,
(10) —CN;
(11) C6-10 aryl,
(12) heteroaryl, which is an aromatic cyclic or polycyclic group, having from five to ten ring atoms, said ring atoms selected from C, O, N, N→O, C(═O) or S, at least one of which is O, N, N→O or S,
(13) —NR9R10,
(14) —B(OH)2,
wherein said cycloalkyl, aryl or heteroaryl R5 group is optionally substituted with one or more
(a) halogen,
(b) —C1-6 alkyl,
(c) —C3-8 cycloalkyl,
(d) —NR11R12,
(e) —O—C1-6 alkyl,
(f) C6-10 aryl,
(g) CN,
(h) hydroxyl
(i) —C(═O)—O—R7,
(j) —NH—C(═O)—R7,
(k) —S(═O)2—R7,
(l) —NH—S(═O)2—R7,
wherein said alkyl or aryl is optionally substituted with one or more
(i) halogen,
(ii) hydroxyl,
(iii) —NR13R14;
R4 is selected from the group consisting of
(1) —C6-10 aryl,
(2) heteroaryl, which is an aromatic cyclic or polycyclic group, having from five to ten ring atoms, said ring atoms selected from C, O, N, N→O, C(═O) or S, at least one of which is O, N, N→O or S,
(3) a heterocyclic group having 4 to 8 ring atoms selected from C, O, N, N→O, C(═O), SO2 or S, at least one of which is O, N, N→O, SO2 or S,
wherein each aryl, heteroaryl or heterocyclic is optionally substituted with one or more R6 group;
R6 is selected from the group consisting of
(1) halogen,
(2) —C1-6 alkyl,
(3) —C2-8 alkenyl,
(4) —O—C1-6 alkyl,
(5) hydroxyl,
(6) —C(═O)—(O)m—R7,
(7) —C(═O)—NR9R10,
(8) —O—C(═O)—R7,
(9) —NH—C(═O)—R7,
(10) —NH—C(═O)—OR7,
(11) —C3-8 cycloalkyl,
(12) —S(═O)2—R7,
(13) —S(═O)2—OR7,
(14) —S(═O)2—NR9R10,
(15) —NH—S(═O)2—R7,
(16) —NO2,
(17) —CN;
(18) —C6-10 aryl,
(19) —O—C6-10 aryl,
(20) heteroaryl, which is an aromatic cyclic or polycyclic group, having from five to ten ring atoms, said ring atoms selected from C, O, N, N→O, C(═O) or S, at least one of which is O, N, N→O or S,
(21) —NR9R10,
wherein said alkyl, cycloalkyl, aryl or heteroaryl R5 group is optionally substituted with one or more
(a) halogen,
(b) —C1-6 alkyl,
(c) —NR11R12,
(d) —O—C1-6 alkyl,
(f) —C6-10 aryl,
(g) heteroaryl, which is an aromatic cyclic or polycyclic group, having from five to ten ring atoms, said ring atoms selected from C, O, N, N→O, C(═O) or S, at least one of which is O, N, N→O or S,
(h) CN,
(i) hydroxyl
wherein said alkyl, aryl or heteroaryl is optionally substituted with one or more
(i) halogen,
(ii) hydroxyl,
(iii) —NR13R14;
R7 is selected from the group consisting of
(1) hydrogen,
(2) —C1-6 alkyl;
(3) —C3-8 cycloalkyl;
(2) —C2-6 alkenyl;
(3) —C0-2 alkyl-C6-10 aryl,
(4) —C0-2 alkyl-heteroaryl group, wherein the heteroaryl is an aromatic cyclic or polycyclic group, having from five to ten ring atoms, said ring atoms selected from C, O, N, N→O, C(═O) or S, at least one of which is O, N, N→O or S, wherein said alkyl, alkenyl, aryl or heteroaryl R7 group is optionally substituted with one or more
(a) halogen,
(b) hydroxy,
(c) —O—C1-6 alkyl,
(d) —C1-6 alkyl, optionally substituted with halogen;
R9 and R10, or R11 and R12, or R13 and R14 are each independently selected from the group consisting of
(1) hydrogen,
(2) —C1-6 alkyl,
(3) —C3-8 cycloalkyl, or
(4) —C6-10 aryl,
wherein said alkyl, cycloalkyl or aryl is optionally substituted with one or more
(a) halogen,
(b) —C1-6 alkyl,
(c) —C3-8 cycloalkyl,
(d) —N(—C1-6 alkyl)2,
(e) —O—C1-6 alkyl,
(f) —C6-10 aryl,
(g) heteroaryl, which is an aromatic cyclic or polycyclic cyclic, having from five to ten ring atoms, said ring atoms selected from C, O, N, N→O, C(═O) or S, at least one of which is O, N, N→O or S,
(h) CN,
(i) hydroxyl
(i) —C(═O)—O—R7,
(j) —NH—C(═O)—R7,
(k) —S(═O)2—R7,
(l) —NH—S(═O)2—R7,
or R9 and R10, or R11 and R12, or R13 and R14 are linked together with the nitrogen to which they are both attached to form a 4-8 membered carbocyclic ring, wherein one or two of the ring carbon atoms is replaced by a nitrogen, oxygen or sulfur, and the carbocyclic is optionally substituted with one or more
(a) halogen,
(b) —C1-6 alkyl,
(c) —O—C1-6 alkyl, or
(d) —C6-10 aryl,
m is 0 or 1;
or a pharmaceutically acceptable salt thereof.

118 more elements

Facts

Application

13/499,335Filed 1 Oct 2010 · us provisional application

Priority

21 Oct 2009

Published

US 2012/0196845 A12 Aug 2012

Granted

25 Nov 2014

Term ends

Not estimatedThe source records don’t support an estimate.

Classification20 codes

C07D 405/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
A61K 31/535
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having six-membered rings with at least one nitrogen and one oxygen as the…
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/18
Drugs for disorders of the nervous system: antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia