1H-pyrrolo[3,4-D]pyrimidin-2(6H)-one compounds

Patent metadata

Field	Value
Publication number	US-8927556-B2
Application number	US-200913133147-A
Country	US
Kind code	B2
Filing date	Dec 7, 2009
Priority date	Dec 6, 2008
Publication date	Jan 6, 2015
Grant date	Jan 6, 2015

Abstract

Optionally substituted (5- or 7-amino)-3,4-dihydro-(optionally 4-oxo, 4-thioxo or 4-imino)-1H-pyrrolo[3,4-d]pyrimidin-2(6H)-ones, Compounds of Formula I, processes for their production, their use as pharmaceuticals and pharmaceutical compositions comprising them.

First claim

What is claimed is:

1. The Compound of formula II-A:

wherein
(i) Q is —C(═S)—, —C(═O)—, —C(═N(R 7 ))— or —C(R 14 )(R 15 )—;
(ii) R 1 is H or C 1-6 alkyl:
(iii) R 2 is
H,
C 1-6 alkyl wherein said alkyl group is optionally substituted with halo or hydroxy,
N(R 14 )(R 15 )—C 1-6 alkyl,
arylC 0-6 alkyl,
heteroarylC 0-6 alkyl,
C 1-6 alkoxyarylC 1-6 alkyl;
-G-J wherein:
G is a single bond or C 1-6 alkylene;
J is C 3-8 cycloalkyl or heteroC 3-8 cycloalkyl optionally substituted with one or more C 1-6 alkyl, or amino;

(iv) R 3 is
1) -D-E-F wherein:
D is methylene;
E is
phenylene, wherein the phenylene group is optionally substituted with halo;
F is
H,
halo,
C 1-6 alkyl,
aryl, or
C 3-8 cycloalkyl optionally containing at least one atom selected from a group consisting of N or O, and said cycloalkyl is optionally substituted with C 1-6 alkyl,
heteroaryl optionally substituted with C 1-6 alkyl, wherein said heteroaryl is optionally substituted with halo or haloC 1-6 alkyl;
amino,
C 1-6 alkoxy,
O-halo C 1-6 alkyl,
C 1-6 alkylsulfonyl,
C(O)—R 13 ,
—N(R 14 )(R 15 ); or

2) attached to the nitrogen on the pyrrolo portion of Formula II and is a moiety of Formula A

wherein X, Y and Z are C, and R 8 , R 9 , R 11 and R 12 are independently H or halogen; and R 10 is halogen,
C 1-6 alkyl,
C 1-6 alkoxy,
C 3-8 cycloalkyl,
heteroC 3-8 cycloalkyl
haloC 1-6 alkyl,
aryl,
heteroaryl,
C 1-6 alkyl sulfonyl,
arylcarbonyl,
heteroarylcarbonyl,
alkoxycarbonyl,
aminocarbonyl;
wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more C 1-6 alkyl haloC 1-6 alkyl, hydroxy, carboxy, —SH, or an additional aryl or heteroaryl;

(v) R 4 and R 5 are independently
H,
C 1-6 alkyl,
C 3-8 cycloalkyl,
C 3-8 heterocycloalkyl,
aryl or
heteroaryl
wherein said aryl or heteroaryl is optionally substituted with halo, hydroxy, C 1-6 alkyl, C 1-6 alkoxy or another aryl group;

(vi) R 6 is H, C 1-6 alkyl, hydroxy, C 1-6 alkoxy, aryloxy, —N(R 16 )(R 17 ), oxo, or C 3-8 cycloalkyl;
(vii) R 7 is H, C 1-6 alkyl C 3-8 cycloalkyl wherein said cycloalkyl is optionally substituted with one or more oxo;
(viii) R 13 is —N(R 14 )(R 15 ), C 1-6 alkyl, —OC 1-6 alkyl, haloC 1-6 alkyl, aryl, or heteroaryl; and
(ix) R 14 and R 15 are independently H or C 1-6 alkyl;
(x) R 16 and R 17 are independently H, C 1-6 alkyl, aryl, heteroaryl, wherein said aryl or heteroaryl is optionally substituted with, C 1-6 alkoxy;

in free or salt form.

2. The compound according to claim 1 , which is the compound:

in free or salt form.

3. The compound according to claim 1 , selected from any of the following:

in free or salt form.

4. The compound according to claim 1 , selected from any of the following:

in free or salt form.

5. The compound according to claim 1 , wherein Q is —(C═O)—, in free or salt form.

6. The compound according to claim 5 , wherein R 2 is C 1-6 alkyl, in free or salt form.

7. The compound according to claim 5 , wherein R 2 is isobutyl or 2,2-dimethylpropyl, in free or salt form.

8. The compound according to claim 6 , wherein R 4 or R 5 is H or C 1-6 alkyl, in free or salt form.

9. The compound according to claim 6 , wherein R 4 or R 5 is phenyl, free or salt form.

10. The compound according to claim 6 , wherein R 4 is H and R 5 is phenyl optionally substituted with halo, hydroxy, C 1-6 alkyl, C 1-6 alkoxy or another aryl, in free or salt form.

11. The compound according to claim 10 , wherein R 3 is attached to the nitrogen on the pyrrolo portion of Formula II-A and is a moiety of Formula A

wherein X, Y and Z are C, and R 8 , R 9 , R 11 and R 12 are independently H or halogen; and R 10 is phenyl, pyridyl, piperidinyl or pyrrolidinyl optionally substituted with halo or C 1-6 alkyl,
in free or salt form.

12. The compound according to claim 11 , wherein R 7 is H or C 1-6 alkyl, in free or salt form.

13. The compound according to claim 1 selected from any of the following:

in free or salt form.

14. The compound according to claim 1 , wherein said compound is a compound of Formula P-A:

wherein:
(i) X═O;
(ii) R 1 is C 1-6 alkyl;
(iii) R 2 is C 1-6 alkyl;
(iv) R 3 is a moiety of Formula A:

wherein X, Y, Z are C, R 8 , R 9 , R 11 and R 12 are independently H or halogen and R 10 is
C 1-6 alkoxy,
aryl or heteroaryl wherein said aryl and heteroaryl are independently and optionally substituted with one or more halo;
heteroC 3-8 cycloalkyl-C 0-6 alkyl wherein said heterocycloalkyl is optionally substituted with one or more C 1-6 alkyl;

(v) R 4 is aryl optionally substituted with one or more halo, hydroxy and/or another aryl;
(vi) R 5 is H;
(vii) R 6 is H,

in free or salt form.

15. The compound according to claim 1 , wherein said compound is a compound of Formula P-A:

wherein:
(i) X═O;
(ii) R 1 is methyl;
(iii) R 2 is C 1-6 alkyl;
(iv) R 3 is a moiety of Formula A:

wherein X, Y, Z are C, R 8 , R 9 , R 11 and R 12 are independently H or halogen and R 10 is
aryl or heteroaryl wherein said aryl and heteroaryl are independently and optionally substituted with one or more halo; or
heteroC 3-8 cycloalkyl-C 0-6 alkyl wherein said heterocycloalkyl is optionally substituted with one or more C 1-6 alkyl;

(v) R 4 is pheny

Assignees

• Li Peng
• Zhao Jun
• Zheng Hailin
• Wennogle Lawrence P
• Intra Cellular Therapies Inc

Inventors

• Li Peng
• Zhao Jun
• Zheng Hailin
• Wennogle Lawrence P

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/12

  Antihypertensives · CPC title