US 8,557,832 B2Granted

Aryl methyl benzoquinazolinine M1 receptor positive allosteric modulators

AssigneeMerck Sharp & Dohme Corp.

InventorsScott D. Kuduk, Douglas C. Beshore, Christina Ng Di Marco, Thomas J. Greshock

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Abstract

The present invention is directed to benzoquinazilinone 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.

Claims25

Dependent claims

A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein
X, Y and Z are each CH and Q is C, or one of X, Y, Q and Z is N and the others are CH or C, or X and Y are CH and Q, R1 and Z are linked together to form a naphthyl group;
R1 is selected from the group consisting of
(1) hydrogen,
(2) aryl,
(3) a heteroaryl group which is a cyclic or polycyclic group, having from five to twelve ring atoms, said ring atoms selected from C, O, N or S, at least one of which is O, N or S,
(4) halogen,
(5) —CN,
(6) —O—C1-6 alkyl,
(7) —C1-6 alkyl,
(8) —C2-6 alkenyl
(9) —S(═O)n—R4,
(10) —NR5AR5B,
wherein said aryl, heteroaryl, alkyl and alkenyl moiety is optionally substituted with one or more
(a) halogen,
(b) hydroxy,
(c) —O—C1-6 alkyl,
(d) —C1-6 alkyl,
(e) —C(═O)—(O)m—R6,
(f) —N(R5AR5B),
(g) —S(═O)n—R8, or
(h) oxo,
provided that when Q is N then R1 is absent;
R2 is selected from the group consisting of
(1) hydrogen,
(2) aryl,
(3) a heteroaryl group which is a cyclic or polycyclic group, having from five to twelve ring atoms, said ring atoms selected from C, O, N or S, at least one of which is O, N or S,
(4) a heterocyclic group, which is a non-aromatic cyclic or polycyclic group having from five to twelve ring atoms selected from C, O, N or S, at least one of which is O, N or S,
(5) —O—C1-6 alkyl,
(6) —C1-6 alkyl,
(7) —C2-6 alkenyl,
(8) —S(═O)n—R4,
(9) —C3-8 cycloalkyl,
(10) —C5-8 cycloalkenyl,
(11) —NR5AR5B,
wherein said aryl, heteroaryl, heterocyclyl, alkyl, alkenyl, cycloalkyl and cycloalkenyl moiety is optionally substituted with one or more
(a) halogen,
(b) hydroxy,
(c) —O—C1-6 alkyl,
(d) —C1-6 alkyl,
(e) —S(═O)n—R8,
(f) —C2-6 alkenyl,
(g) —CN,
(h) —C(═O)—(O)m—R6,
(i) —NR5AR5B,
(j) oxo,
(k) aryl,
(l) a heteroaryl group which is a cyclic or polycyclic group, having from five to twelve ring atoms, said ring atoms selected from C, O, N or S, at least one of which is O, N or S,
(m) a heterocyclic group, which is a non-aromatic cyclic or polycyclic group having from five to twelve ring atoms selected from C, O, N or S, at least one of which is O, N or S
(n) —OC(═O)—R6,
wherein the alkyl, alkenyl, aryl, heteroaryl or heterocyclic moiety is optionally substituted with one or more
(i) halogen,
(ii) —C1-6 alkyl, or
(iii) —OC1-6 alkyl;
R3 is selected from the group consisting of
(1) hydrogen,
(2) —C1-6 alkyl, and
(3) —S(O)n—R4,
wherein said R3 alkyl moiety is optionally substituted with one or more
(a) halogen,
(b) cyano, and
(c) —O—C1-6 alkyl, wherein said alkyl is optionally substituted with one or more halo;
R4, R6 and R8 are independently selected from the group consisting of
(1) hydrogen,
(2) —C1-6 alkyl, and
(3) —(CH2)n-aryl,
wherein said R4, R6 or R8 alkyl or aryl moiety is optionally substituted with one or more
(a) halogen,
(b) cyano, and
(c) —O—C1-6 alkyl, wherein said alkyl is optionally substituted with one or more halogen;
R5A and R5B are selected from the group consisting of
(1) hydrogen,
(2) —C1-6 alkyl,
(3) —C3-6 cycloalkyl,
(4) —C(═O)—O—R6,
(5) —S(O)2—R6,
or R5A and R5B are linked together with the nitrogen to which they are both attached to form a 2-6 membered carbocyclic ring, wherein one or two of the ring carbon atoms is optionally replaced by a nitrogen, oxygen or sulfur;
m is 0 or 1;
and
n is 0, 1 or 2.

77 more elements

Dependencies are inferred from the claim text.

Facts

Application: 13/129,593Filed 19 Nov 2009 · us provisional application
Priority: 20 Nov 2008
Published: US 2011/0224198 A115 Sep 2011
Granted: 15 Oct 2013
Term ends: Not estimatedThe source records don’t support an estimate.

Classification22 codes

C07D 239/70
Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings: condensed with carbocyclic rings or ring systems
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/02
Drugs for disorders of the nervous system: for peripheral neuropathies
A61P 25/04
Drugs for disorders of the nervous system: centrally acting analgesics, e.g. opioids

Family

Application61/199,740Us provisional application · filed 20 Nov 2008
US 2011/0224198 A1Pre-grant publication · published 15 Sep 2011
US 8,557,832 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
X, Y and Z are each CH and Q is C, or one of X, Y, Q and Z is N and the others are CH or C, or X and Y are CH and Q, R1 and Z are linked together to form a naphthyl group;
R1 is selected from the group consisting of
(1) hydrogen,
(2) aryl,
(3) a heteroaryl group which is a cyclic or polycyclic group, having from five to twelve ring atoms, said ring atoms selected from C, O, N or S, at least one of which is O, N or S,
(4) halogen,
(5) —CN,
(6) —O—C1-6 alkyl,
(7) —C1-6 alkyl,
(8) —C2-6 alkenyl
(9) —S(═O)n—R4,
(10) —NR5AR5B,
wherein said aryl, heteroaryl, alkyl and alkenyl moiety is optionally substituted with one or more
(a) halogen,
(b) hydroxy,
(c) —O—C1-6 alkyl,
(d) —C1-6 alkyl,
(e) —C(═O)—(O)m—R6,
(f) —N(R5AR5B),
(g) —S(═O)n—R8, or
(h) oxo,
provided that when Q is N then R1 is absent;
R2 is selected from the group consisting of
(1) hydrogen,
(2) aryl,
(3) a heteroaryl group which is a cyclic or polycyclic group, having from five to twelve ring atoms, said ring atoms selected from C, O, N or S, at least one of which is O, N or S,
(4) a heterocyclic group, which is a non-aromatic cyclic or polycyclic group having from five to twelve ring atoms selected from C, O, N or S, at least one of which is O, N or S,
(5) —O—C1-6 alkyl,
(6) —C1-6 alkyl,
(7) —C2-6 alkenyl,
(8) —S(═O)n—R4,
(9) —C3-8 cycloalkyl,
(10) —C5-8 cycloalkenyl,
(11) —NR5AR5B,
wherein said aryl, heteroaryl, heterocyclyl, alkyl, alkenyl, cycloalkyl and cycloalkenyl moiety is optionally substituted with one or more
(a) halogen,
(b) hydroxy,
(c) —O—C1-6 alkyl,
(d) —C1-6 alkyl,
(e) —S(═O)n—R8,
(f) —C2-6 alkenyl,
(g) —CN,
(h) —C(═O)—(O)m—R6,
(i) —NR5AR5B,
(j) oxo,
(k) aryl,
(l) a heteroaryl group which is a cyclic or polycyclic group, having from five to twelve ring atoms, said ring atoms selected from C, O, N or S, at least one of which is O, N or S,
(m) a heterocyclic group, which is a non-aromatic cyclic or polycyclic group having from five to twelve ring atoms selected from C, O, N or S, at least one of which is O, N or S
(n) —OC(═O)—R6,
wherein the alkyl, alkenyl, aryl, heteroaryl or heterocyclic moiety is optionally substituted with one or more
(i) halogen,
(ii) —C1-6 alkyl, or
(iii) —OC1-6 alkyl;
R3 is selected from the group consisting of
(1) hydrogen,
(2) —C1-6 alkyl, and
(3) —S(O)n—R4,
wherein said R3 alkyl moiety is optionally substituted with one or more
(a) halogen,
(b) cyano, and
(c) —O—C1-6 alkyl, wherein said alkyl is optionally substituted with one or more halo;
R4, R6 and R8 are independently selected from the group consisting of
(1) hydrogen,
(2) —C1-6 alkyl, and
(3) —(CH2)n-aryl,
wherein said R4, R6 or R8 alkyl or aryl moiety is optionally substituted with one or more
(a) halogen,
(b) cyano, and
(c) —O—C1-6 alkyl, wherein said alkyl is optionally substituted with one or more halogen;
R5A and R5B are selected from the group consisting of
(1) hydrogen,
(2) —C1-6 alkyl,
(3) —C3-6 cycloalkyl,
(4) —C(═O)—O—R6,
(5) —S(O)2—R6,
or R5A and R5B are linked together with the nitrogen to which they are both attached to form a 2-6 membered carbocyclic ring, wherein one or two of the ring carbon atoms is optionally replaced by a nitrogen, oxygen or sulfur;
m is 0 or 1;
and
n is 0, 1 or 2.

77 more elements

Facts

Application

13/129,593Filed 19 Nov 2009 · us provisional application

Priority

20 Nov 2008

Published

US 2011/0224198 A115 Sep 2011

Granted

15 Oct 2013

Term ends

Not estimatedThe source records don’t support an estimate.

Classification22 codes

C07D 239/70
Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings: condensed with carbocyclic rings or ring systems
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/02
Drugs for disorders of the nervous system: for peripheral neuropathies
A61P 25/04
Drugs for disorders of the nervous system: centrally acting analgesics, e.g. opioids