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US 8,273,737 B2Granted
Quinolizidinone M1 receptor positive allosteric modulators
AssigneeMerck Sharp & Dohme Corp.
InventorsScott D. Kuduk, Ronald K. Chang
Life of this patent
Estimating the term…
Abstract
The present invention is directed to 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.
Claims19
A compound of formula (I)
- or a pharmaceutically acceptable salt thereof, wherein
- X1 is selected from the group consisting of
- (1) N,
- (2) S,
- (3) SO2, or
- (4) O;
- X2 is CHR7 or CH2CHR7;
- R1 and R2 are each selected from the group consisting of
- (1) hydrogen,
- (2) —C1-6 alkyl,
- (3) —C6-10 aryl,
- (4) —C(═O)—OR6A, or
- (5) OH,
- wherein the alkyl or aryl moiety of R1 and R2 is optionally substituted by one or more
- (b) halogen,
- (b) —C1-6 alkyl, wherein said alkyl is optionally substituted with one or more halogen,
- or R1 and R2 together form the group ═O;
- R7 is hydrogen or R1 and R7 are linked together to form —CH2— or —CH2CH2—;
- R3 is selected from the group consisting of
- (1) hydrogen,
- (2) —C1-6 alkyl,
- (3) —(CH2)n-aryl,
- (4) heteroaryl group having 5 to 12 ring atoms,
- (5) —C4-12 non-aromatic heterocyclic group,
- (6) —C3-12 cycloalkyl,
- (7) —S(O)m—R6A,
- (8) cyano,
- wherein said alkyl, aryl, heteroaryl, heterocyclic or cycloalkyl moiety of R3 is optionally substituted with one or more
- (a) halogen,
- (b) hydroxy,
- (c) cyano,
- (d) —(CH2)q-aryl,
- (e) —C(═O)—OR6A,
- (f) —O—C1-6 alkyl,
- (g) —C1-6 alkyl,
- (h) —C2-6 alkenyl
- (i) —C2-6 alkynyl,
- (j) —NO2,
- (k) —N(R6AR6B),
- and wherein said alkyl, alkenyl, alkynyl or aryl moiety of (d),(f),(g),(h), and (i) is optionally substituted with one or more
- (i) halogen,
- (ii) hydroxy,
- (iii) cyano,
- (iv) —S(O)m—R6A;
- R4 is selected from the group consisting of
- (1) hydrogen,
- (2) —C1-6 alkyl, and
- (3) —CH2-aryl,
- wherein said alkyl or aryl moiety of R4 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;
- R5 is selected from the group consisting of
- (1) hydrogen,
- (2) —C1-6 alkyl,
- (3) —(CH2)n-aryl, or
- (4) heteroaryl group having 5 to 12 ring atoms,
- wherein said alkyl, aryl or heteroaryl moiety of R5 optionally substituted with one or more
- (a) halogen,
- (b) hydroxy,
- (c) cyano,
- (d) —(CH2)q-aryl,
- (e) —O—C1-6 alkyl,
- (f) —C1-6 alkyl,
- (g) —N(R6AR6B),
- and wherein said alkyl or aryl moiety of (d) and (e) is optionally substituted with one or more
- (i) halogen,
- (ii) hydroxy,
- (iii) cyano,
- (iv) —S(O)m—R6A;
- R6A and R6B are independently selected from the group consisting of
- (1) hydrogen,
- (2) —C1-6 alkyl, and
- (3) —(CH2)m-aryl,
- wherein said alkyl or aryl moiety of R6A or R6B 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;
- m, n and q are each selected from 0, 1 or 2;
- provided that if X1 is O, S or SO2 then X2 is —CH2— and R3 is absent.
77 more elements
A compound of formula (I)
- or a pharmaceutically acceptable salt thereof, wherein
- X1 is selected from the group consisting of
- (1) N,
- (2) S,
- (3) SO2, or
- (4) O;
- X2 is CHR7 or CH2CHR7;
- R1 and R2 are each selected from the group consisting of
- (1) hydrogen,
- (2) —C1-6 alkyl,
- (3) —C6-10 aryl,
- (4) —C(═O)—OR6A, or
- (5) OH,
- wherein the alkyl or aryl moiety of R1 and R2 is optionally substituted by one or more
- (b) halogen,
- (b) —C1-6 alkyl, wherein said alkyl is optionally substituted with one or more halogen,
- or R1 and R2 together form the group ═O;
- R7 is hydrogen or R1 and R7 are linked together to form —CH2— or —CH2CH2—;
- R3 is selected from the group consisting of
- (1) hydrogen,
- (2) —C1-6 alkyl,
- (3) —(CH2)n-aryl,
- (4) heteroaryl group having 5 to 12 ring atoms,
- (5) —C4-12 non-aromatic heterocyclic group,
- (6) —C3-12 cycloalkyl,
- (7) —S(O)m—R6A,
- (8) cyano,
- (9) —C(═O)—OC1-6alkyl, more
- wherein said alkyl, aryl, heteroaryl, heterocyclic or cycloalkyl moiety of R3 is optionally substituted with one or more
- (a) halogen,
- (b) hydroxy,
- (c) cyano,
- (d) —(CH2)q-aryl,
- (e) —C(═O)—OR6A,
- (f) —O—C1-6 alkyl,
- (g) —C1-6 alkyl,
- (h) —C2-6 alkenyl
- (i) —C2-6 alkynyl,
- (j) —NO2,
- (k) —N(R6AR6B),
- and wherein said alkyl, alkenyl, alkynyl or aryl moiety of (d),(f),(g),(h), and (i) is optionally substituted with one or more
- (i) halogen,
- (ii) hydroxy,
- (iii) cyano,
- (iv) —S(O)m—R6A;
- R4 is selected from the group consisting of
- (1) hydrogen,
- (2) —C1-6 alkyl, and
- (3) —CH2-aryl,
- wherein said alkyl or aryl moiety of R4 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;
- R5 is selected from the group consisting of
- (1) hydrogen,
- (2) —C1-6 alkyl,
- (3) —(CH2)n-aryl, or
- (4) heteroaryl group having 5 to 12 ring atoms,
- wherein said alkyl, aryl or heteroaryl moiety of R5 optionally substituted with one or more
- (a) halogen,
- (b) hydroxy,
- (c) cyano,
- (d) —(CH2)q-aryl,
- (e) —O—C1-6 alkyl,
- (f) —C1-6 alkyl,
- (g) —N(R6AR6B),
- and wherein said alkyl or aryl moiety of (d) and (e) is optionally substituted with one or more
- (i) halogen,
- (ii) hydroxy,
- (iii) cyano,
- (iv) —S(O)m—R6A;
- R6A and R6B are independently selected from the group consisting of
- (1) hydrogen,
- (2) —C1-6 alkyl, and
- (3) —(CH2)m-aryl,
- wherein alkyl or aryl moiety of R6A or R6B 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;
- m, n and q are each selected from 0, 1 or 2;
- provided that if X1 is O, S or SO2 then X2 is —CH2— and R3 is absent.
78 more elements
Dependencies are inferred from the claim text.