US 2010/0076004 A1Published application

Bicyclic spiropiperidine beta-secretase inhibitors for the treatment of alzheimer's disease

AssigneeMerck Sharp & Dohme Corp.

InventorsShaun R. Stauffer, Samuel L. Graham

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Abstract

The present invention is directed to bicyclic spiropiperidine compounds of formula (I) which are inhibitors of the beta-secretase enzyme and that are useful in the treatment of diseases in which the beta-secretase enzyme is involved, such as Alzheimer's disease. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the treatment of such diseases in which the beta-secretase enzyme is involved.

Claims19

Dependent claims

A compound of formula (I)

wherein:
W represents a 5 or 6 membered aromatic or non-aromatic ring cyclic ring fused to the spirocyclic group at the X and X′ atoms, wherein one or two of the W carbon ring atoms is optionally replaced by a nitrogen ring atom, and wherein one or two W ring carbon atoms is optionally substituted with a —C1-10 alkyl group;
X is selected from the group consisting of
(1) N,
(2) C, or
(3) CH;
X′ is selected from the group consisting of
(1) C, or
(2) CH;
R2 is selected from the group consisting of
(1) hydrogen,
(2) —C1-10 alkyl,
(3) —C2-10 alkenyl,
(4) —C2-10 alkynyl,
(5) —C3-12 cycloalkyl,
(6) a nonaromatic heterocyclic group having 4 to 8 ring atoms, wherein one ring atom is a heteroatom selected from the group consisting of nitrogen and oxygen,
(7) aryl, and
(8) heteroaryl,
wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl R2 moiety is optionally substituted with one or more
(a) halo,
(b) —OH,
(c) —CN,
(d) —C1-10 alkyl,
(e) —C3-12 cycloalkyl,
(f) —O—C1-10 alkyl,
(g) —C0-6 alkyl-aryl,
(h) —C0-6 alkyl-heteroaryl,
(i) —NC(═O)—NR6AR6B,
(j) —NC(═O)—C1-3 alkyl-NR6AR6B,
(k) —NC(═O)R6A,
(l) —NR6AR6B, and
(m) a nonaromatic heterocyclic group having 4 to 8 ring atoms, wherein one ring atom is a heteroatom selected from the group consisting of nitrogen and oxygen, and said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic moiety is optionally substituted with one or more
(i) halo,
(ii) —OH,
(iii) —CN,
(iv) —C1-6 alkyl, wherein said alkyl is optionally substituted with one or more halo,
(v) —OC1-6 alkyl,
(vi) —C2-6 alkenyl,
(vii) —SO2C1-3 alkyl,
(viii) —SO2 NR6CR6D,
(ix) —NR6CSO2C1-3alkyl,
(x) —CO2R6C, and
(xi) —CONR6CR6D;
Q is a bond or —C1-6 alkyl, wherein said alkyl is optionally substituted with one or more
(a) halo,
(b) —OH,
(c) —CN,
(d) —C1-10 alkyl,
(e) —C3-12 cycloalkyl,
(f) —O—C1-10 alkyl,
(g) aryl, and
(h) heteroaryl;
R3 is selected from the group consisting of
(1) hydrogen,
(2) —C1-10 alkyl,
(3) —C2-10 alkenyl,
(4) —C2-10 alkynyl,
(5) —C3-12 cycloalkyl,
(6) —C3-12 cycloalkenyl,
(7) aryl, and
(8) heteroaryl,
wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heteroaryl R3 moiety is optionally substituted with one or more
(a) halo,
(b) —OH,
(c) —CN,
(d) —C1-10 alkyl,
(e) —C2-10 alkenyl,
(f) —C3-12 cycloalkyl,
(g) —O—C3-12 cycloalkyl,
(h) —O—C1-10 alkyl,
(i) —O—C3-12 nonaromatic heterocyclic, wherein said heterocyclic group has from 4 to 8 ring atoms, wherein one ring atom is a heteroatom selected from the group consisting of nitrogen and oxygen,
(j) aryl,
(k) heteroaryl,
(l) —NR6AR6B,
and said alkyl, alkenyl, cycloalkyl, aryl and heteroaryl moiety is optionally substituted with one or more
(i) halo,
(ii) —OH,
(iii) —CN,
(iv) —C1-6 alkyl, wherein said alkyl is optionally substituted with one or more halo,
(v) —OC1-6 alkyl,
(vi) —NR6CR6D,
(vii) —C2-6 alkenyl,
(viii) —SO2C1-3 alkyl,
(ix) —SO2 NR6CR6D, or
(x) —CONR6CR6D,
provided that when Q is a bond then R3 must be hydrogen;
R4 is selected from the group consisting of
(1) hydrogen,
(2) —C1-10 alkyl,
(3) —C3-4 alkenyl, and
(4) aryl,
wherein said alkyl, alkenyl or aryl R4 group is optionally substituted with one or more
(a) halo,
(b) —OH
(c) —C1-6 alkyl,
(d) —CN,
(e) —O—C1-10 alkyl,
(f) —NR8R9, wherein R8 and R9 are selected from the group consisting of
(i) hydrogen, and
(ii) —C1-6 alkyl,
(g) —S(O)m—C1-6 alkyl, wherein m is 0, 1 or 2,
(h) —C(═O)—R7, wherein R7 is selected from the group consisting of (i) hydrogen,
(ii) OH,
(iii) —C1-6 alkyl, and
(iv) —OC1-6 alkyl, and
(v) aryl;
R6A, R6B, R6C and R6D are selected from the group consisting of
(1) hydrogen,
(2) —C1-6 alkyl,
(3) —C3-7 cycloalkyl,
(4) —C0-6 alkyl-aryl,
(5) —C0-6alkyl-heteroaryl,
(6) halo, and
(7) a nonaromatic heterocyclic group having 4 to 8 ring atoms, wherein one ring atom is a heteroatom selected from the group consisting of nitrogen and oxygen,
wherein said alkyl, cycloalkyl, aryl or heteroaryl R6A or R6B moiety is optionally substituted with one or more
(a) halo,
(b) —C1-6 alkyl,
(c) —O—C1-6 alkyl, and
(d) —NO2;
and pharmaceutically acceptable salts thereof.

117 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/522,056Filed 28 Dec 2007
Priority: 4 Jan 2007
Published: 25 Mar 2010
Term ends: Not estimatedThe source records don’t support an estimate.

Classification11 codes

C07D 471/20
In which the condensed system contains three hetero rings: spiro-condensed systems
A61P 1/18
Drugs for disorders of the alimentary tract or the digestive system: for pancreatic disorders, e.g. pancreatic enzymes
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
A61P 9/00
Drugs for disorders of the cardiovascular system

Family

Application60/878,518Us provisional application · filed 4 Jan 2007
US 8,377,954 B2Related patent
US 2010/0076004 A1This patent

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

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Abstract

A compound of formula (I)

wherein:
W represents a 5 or 6 membered aromatic or non-aromatic ring cyclic ring fused to the spirocyclic group at the X and X′ atoms, wherein one or two of the W carbon ring atoms is optionally replaced by a nitrogen ring atom, and wherein one or two W ring carbon atoms is optionally substituted with a —C1-10 alkyl group;
X is selected from the group consisting of
(1) N,
(2) C, or
(3) CH;
X′ is selected from the group consisting of
(1) C, or
(2) CH;
R2 is selected from the group consisting of
(1) hydrogen,
(2) —C1-10 alkyl,
(3) —C2-10 alkenyl,
(4) —C2-10 alkynyl,
(5) —C3-12 cycloalkyl,
(6) a nonaromatic heterocyclic group having 4 to 8 ring atoms, wherein one ring atom is a heteroatom selected from the group consisting of nitrogen and oxygen,
(7) aryl, and
(8) heteroaryl,
wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl R2 moiety is optionally substituted with one or more
(a) halo,
(b) —OH,
(c) —CN,
(d) —C1-10 alkyl,
(e) —C3-12 cycloalkyl,
(f) —O—C1-10 alkyl,
(g) —C0-6 alkyl-aryl,
(h) —C0-6 alkyl-heteroaryl,
(i) —NC(═O)—NR6AR6B,
(j) —NC(═O)—C1-3 alkyl-NR6AR6B,
(k) —NC(═O)R6A,
(l) —NR6AR6B, and
(m) a nonaromatic heterocyclic group having 4 to 8 ring atoms, wherein one ring atom is a heteroatom selected from the group consisting of nitrogen and oxygen, and said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic moiety is optionally substituted with one or more
(i) halo,
(ii) —OH,
(iii) —CN,
(iv) —C1-6 alkyl, wherein said alkyl is optionally substituted with one or more halo,
(v) —OC1-6 alkyl,
(vi) —C2-6 alkenyl,
(vii) —SO2C1-3 alkyl,
(viii) —SO2 NR6CR6D,
(ix) —NR6CSO2C1-3alkyl,
(x) —CO2R6C, and
(xi) —CONR6CR6D;
Q is a bond or —C1-6 alkyl, wherein said alkyl is optionally substituted with one or more
(a) halo,
(b) —OH,
(c) —CN,
(d) —C1-10 alkyl,
(e) —C3-12 cycloalkyl,
(f) —O—C1-10 alkyl,
(g) aryl, and
(h) heteroaryl;
R3 is selected from the group consisting of
(1) hydrogen,
(2) —C1-10 alkyl,
(3) —C2-10 alkenyl,
(4) —C2-10 alkynyl,
(5) —C3-12 cycloalkyl,
(6) —C3-12 cycloalkenyl,
(7) aryl, and
(8) heteroaryl,
wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heteroaryl R3 moiety is optionally substituted with one or more
(a) halo,
(b) —OH,
(c) —CN,
(d) —C1-10 alkyl,
(e) —C2-10 alkenyl,
(f) —C3-12 cycloalkyl,
(g) —O—C3-12 cycloalkyl,
(h) —O—C1-10 alkyl,
(i) —O—C3-12 nonaromatic heterocyclic, wherein said heterocyclic group has from 4 to 8 ring atoms, wherein one ring atom is a heteroatom selected from the group consisting of nitrogen and oxygen,
(j) aryl,
(k) heteroaryl,
(l) —NR6AR6B,
and said alkyl, alkenyl, cycloalkyl, aryl and heteroaryl moiety is optionally substituted with one or more
(i) halo,
(ii) —OH,
(iii) —CN,
(iv) —C1-6 alkyl, wherein said alkyl is optionally substituted with one or more halo,
(v) —OC1-6 alkyl,
(vi) —NR6CR6D,
(vii) —C2-6 alkenyl,
(viii) —SO2C1-3 alkyl,
(ix) —SO2 NR6CR6D, or
(x) —CONR6CR6D,
provided that when Q is a bond then R3 must be hydrogen;
R4 is selected from the group consisting of
(1) hydrogen,
(2) —C1-10 alkyl,
(3) —C3-4 alkenyl, and
(4) aryl,
wherein said alkyl, alkenyl or aryl R4 group is optionally substituted with one or more
(a) halo,
(b) —OH
(c) —C1-6 alkyl,
(d) —CN,
(e) —O—C1-10 alkyl,
(f) —NR8R9, wherein R8 and R9 are selected from the group consisting of
(i) hydrogen, and
(ii) —C1-6 alkyl,
(g) —S(O)m—C1-6 alkyl, wherein m is 0, 1 or 2,
(h) —C(═O)—R7, wherein R7 is selected from the group consisting of (i) hydrogen,
(ii) OH,
(iii) —C1-6 alkyl, and
(iv) —OC1-6 alkyl, and
(v) aryl;
R6A, R6B, R6C and R6D are selected from the group consisting of
(1) hydrogen,
(2) —C1-6 alkyl,
(3) —C3-7 cycloalkyl,
(4) —C0-6 alkyl-aryl,
(5) —C0-6alkyl-heteroaryl,
(6) halo, and
(7) a nonaromatic heterocyclic group having 4 to 8 ring atoms, wherein one ring atom is a heteroatom selected from the group consisting of nitrogen and oxygen,
wherein said alkyl, cycloalkyl, aryl or heteroaryl R6A or R6B moiety is optionally substituted with one or more
(a) halo,
(b) —C1-6 alkyl,
(c) —O—C1-6 alkyl, and
(d) —NO2;
and pharmaceutically acceptable salts thereof.

117 more elements

Facts

Application

12/522,056Filed 28 Dec 2007

Priority

4 Jan 2007

Published

25 Mar 2010

Term ends

Not estimatedThe source records don’t support an estimate.

Classification11 codes

C07D 471/20
In which the condensed system contains three hetero rings: spiro-condensed systems
A61P 1/18
Drugs for disorders of the alimentary tract or the digestive system: for pancreatic disorders, e.g. pancreatic enzymes
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
A61P 9/00
Drugs for disorders of the cardiovascular system