Phosphodiesterase 10 inhibitors

• US 20090099175A1
• Filed: 02/28/2007
• Published: 04/16/2009
• Est. Priority Date: 03/01/2006
• Status: Abandoned Application

• Current Assignee: Amgen Inc., Memory Pharmaceuticals Corp. (Roche Holding AG)
• Original Assignee: Memory Pharmaceuticals Corp. (Roche Holding AG)
• Inventors: Gauss, Carla Maria, Hitchcock, Stephen A., Hopper, Allen T., Conticello, Richard D., Arrington, Mark P., Nguyen, Truc M., Hess, Hans-Jurgen E.
• Application Number:
  US11/713,234
• Publication Number:
  US 20090099175A1
• Time in Patent Office: Days
• US Class Current: 514/234.5
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The present invention if directed to certain cinnoline compounds that are PDE10 inhibitors, pharmaceutical compositions containing such compounds and processes for preparing such compounds. The invention is also directed to methods of treating diseases mediated by PDE10 enzyme, such as obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive-compulsive disorder, and the like.

Claims

1. A compound of Formula (I):

or an individual stereoisomer, mixtures of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein;

Y and Z are nitrogen and X is —

CR═

, wherein R is hydrogen, alkyl, cyano, or halo;

X and Y are nitrogen and Z is ═

CH—

;

or X and Z are nitrogen and Y is ═

CH—

;

R¹, R², and R³ are independently hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, alkylcarbonyl, or cycloalkyl;

provided that at least one of R¹, R², and R³ is not hydrogen, and provided that when X and Y or X and Z are nitrogen, and R¹ is hydrogen, then R² and R³ are not both independently hydroxy, alkoxy, or haloalkoxy; and

R^3a is aryl, heteroaryl, or heterocyclyl ring substituted with;

R⁴, where R⁴ is hydrogen;

alkyl;

halo;

haloalkyl;

haloalkoxy;

cycloalkyl;

cycloalkylalkyl;

aryl;

heteroaryl;

heterocyclyl;

aralkyl;

heteroaralkyl;

heterocyclylalkyl;

or —

X¹R⁷ (where X¹ is —

O—

, —

CO—

, —

C(O)O—

, —

OC(O)—

, —

NR⁸CO—

, —

CONR⁹—

, —

NR¹⁰—

, —

S—

, —

SO—

, —

SO₂—

, —

NR¹¹SO₂—

, or —

SO₂NR¹²—

where R⁸-R¹² are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl and R⁷ is cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, or heterocyclylalkyl); and

R⁵ and R⁶, where R⁵ and R⁶ are independently hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, nitro, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, acyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, disubstituted amino, aryl, heteroaryl, or heterocyclyl;

provided that at least one of R⁴, R⁵ and R⁶ is not hydrogen;

wherein the aromatic or alicyclic ring in R⁴, R⁵, R⁶, and R⁷ is optionally substituted with one to three substitutents independently selected from R^a, R^b, and R^c, which are alkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, nitro, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, disubstituted amino, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; and

additionally substituted with one or two substitutents independently selected from R^d and R^e, where R^d and R^e are chloro or fluoro;

provided that;

(i) when R^3a is pyrrolidin-1-yl, then R⁴ is not —

OR⁷, where R⁷ is substituted or unsubstituted aryl or heteroaryl;

(ii) when X and Y or X and Z are nitrogen, R^3a is piperidin-1-yl, one of R⁵ and R⁶ is hydrogen, and R⁴ is substituted or unsubstituted aryl or heteroaryl, then the other of R⁵ and R⁶ is not hydrogen, alkyl, carboxy, alkoxycarbonyl, cyano, hydroxyl, alkoxy, —

COR, —

CONRR′

, or —

NRR′

, where R and R′

are independently hydrogen, alkyl, or unsubstituted aryl, or —

NHCOR, where R is alkyl or unsubstituted aryl;

(iii) when X and Y or X and Z are nitrogen, R^3a is piperidin-1-yl, both of R⁵ and R⁶ are hydrogen, or one of R⁵ and R⁶ is hydrogen and the other of R⁵ and R⁶ is substituted or unsubstituted aryl or heteroaryl, then R⁴ is not hydrogen, alkyl, —

COR⁷ (where R⁷ is unsubstituted aryl), —

COOR⁷ (where R⁷ is unsubstituted aryl), —

CONR⁷R⁹, —

NR⁷R¹⁰, or —

NHCOR⁷ (where R⁹ and R¹⁰ are is hydrogen, alkyl, or unsubstituted aryl; and

each R⁷ is unsubstituted aryl);

(iv) when X and Y are nitrogen, two of R¹, R², and R³ are hydrogen and the other of R¹, R², and R³ is alkyl or halo, and R^3a is aryl, then (a) when two of R⁴, R⁵ and R⁶ are hydrogen, then the other of R⁴, R⁵ and R⁶ is not alkyl, halo, hydroxy, —

COR′

(where R′

is alkyl), or —

OC(O)R′

or —

SO₂R′

(where R′

is aryl optionally substituted with alkyl); and

(b) when one of R⁴, R⁵ and R⁶ is hydrogen, then the other two of R⁴, R⁵ and R⁶ are not independently selected from alkyl, hydroxy, or —

OCOR′

, where R′

is aryl;

(v) when X and Y are nitrogen, two of R¹, R² and R³ are hydrogen and the other of R¹, R², and R³ is chloro, then R^3a is not indolin-1-yl or indol-1-yl, each substituted with alkyl and alkoxy and a third substituent selected from —

CH₂—

C(O)—

OR, wherein R′

is hydrogen or methyl;

(vi) when X and Z or Y and Z are nitrogen, then R^3a is not;

(a) substituted or unsubstituted 1,2,3,4-tetrahydroquinolinyl;

(b) indolin-1-yl substituted with R⁴, R⁵ and R⁶, where two of R⁴, R⁵ and R⁶ are hydrogen and the other of R⁴, R⁵ and R⁶ is halo;

(c) piperidin-1-yl substituted with R⁴, R⁵ and R⁶, where two of R⁴, R⁵ and R⁶ are hydrogen and the other of R⁴, R⁵ and R⁶ is

quinazoline-2,4(1H,3H)-dione or quinazolin-4(3H)-one each of which is optionally substituted with one or two substituents independently selected from nitro and alkyl;

hydroxy, hydroxyalkyl, hydroxyalkyloxy, alkyl, carboxy, alkoxy, alkoxyalkyl, alkoxyalkyloxy, —

COR [where R is aryl substituted with one halo], -(alkylene)-NRR′

[where R is hydrogen or —

COR^a (where R^a is alkyl), and R′

is hydrogen or alkyl], —

O-(alkylene)-NRR′

[where R is hydrogen or —

COR^a (where R^a is alkyl), and R′

is hydrogen or alkyl], —

NRR′

[where R is hydrogen or alkyl, and R′

is alkyl, —

COR″

(where R″

is alkyl, haloalkyl, or aryl), —

SO₂R″

(where R″

is pyridinyl, aralkyl, alkyl, cycloalkyl, or aryl optionally substituted with two alkoxy groups)], piperidin-4-yl-alkyl, piperidin-4-yl, or piperazin-4-yl-alkyl (wherein the piperidinyl in piperidin-4-yl-alkyl or piperidin-4-yl and piperazinyl in piperazin-4-yl-alkyl is substituted with a quinazoline ring optionally substituted with one to three substituents selected from halo, alkyl, alkoxy, haloalkyl, amino, monoalkylamino, or dialkylamino);

2-oxoimidazolidin-1-yl, pyrrolidine-2,5-dione, or 1H-benzo[d]imidazol-2(3H)-one optionally substituted with one alkyl;

or

furanylalkyloxy, 3,4-dihydroquinazolin-2(1H)-one, 1,6-alkylquinazoline-2,4(1H,3H)-dione, 1H-benzo[d][1,2,3]triazole, 3,4-dihydrobenzo[e][1,3]oxazin-2-one, 2H-pyran-2-ylalkyloxy, or tetrahydropyrimidin-2(1H)-one-1-ylalkyl, each of which is optionally substituted with alkyl;

(d) imidazolidin-2-one optionally substituted with one alkyl;

(e) piperidin-1-yl, where one of R⁴, R⁵, and R⁶ is hydrogen, the other of R⁴, R⁵, and R⁶ is hydroxyl, and the third of R⁴, R⁵, and R⁶ is alkyl, aralkyl, or aryl, optionally substituted with one or two substitutents independently selected from halo, hydroxyl, or alkoxy;

(f) indol-1-yl substituted with alkyl and alkoxy and a third substituent selected from alkoxycarbonyl or hydroxyalkyl;

(g) aryl substituted with one or two substitutents independently selected from alkoxy, hydroxyl, alkyl, haloalkyl, acetyl, or 4-methylphenylsulfonyl;

(h) piperazin-1-yl substituted with R⁴, R⁵ and R⁶, where two of R⁴, R⁵ and R⁶ are hydrogen and the other of R⁴, R⁵ and R⁶ is acyl;

alkyl;

aryl optionally substituted with one halo;

alkoxycarbonyl;

or —

CONHR′

(where R′

is aryl optionally substituted with hydroxyl, cyano, nitro, alkyl, or alkylcarbonyl);

or morpholin-4-ylcarbonyl;

(i) aryl substituted with R⁴, R⁵, and R⁶, where R⁵ is hydrogen and one of R⁴ and R⁶ is alkyl, halo, amino, nitro, hydroxyl, alkoxy, phenyl, haloalkyl, dialkylamino, or —

NHCOR, where R′

is alkyl; and

the other of R⁴ and R⁶ is hydrogen, alkyl, amino, or alkoxy;

or all R⁴, R⁵, R⁶ are alkoxy;

or

(j) 3-halopyridin-4-yl;

(vii) when X and Z or Y and Z are nitrogen, then when two of R¹, R², and R³ are hydrogen, then the other of R¹, R², and R³ is not halo;

(viii) when X and Z are nitrogen, then not all of R¹, R², and R³ are alkoxy; and

(ix) the compound is not a salt of any one (i)-(viii).

2. The compound of claim 1, wherein X and Y are nitrogen and Z is carbon.

3. The compound of claim 1, wherein Y and Z are nitrogen and X is carbon.

4. The compound of claim 1, wherein X and Z are nitrogen and Y is carbon.

5. The compound of any one of claims 2-4, wherein R¹ is hydrogen.

6. The compound of claim 3, wherein R¹ is hydrogen, and R² and R³ are alkoxy.

7. The compound of any one of claims 2-4, wherein R¹ is hydrogen, R² is alkoxy, and R³ is alkyl.

8. The compound of any one of claims 2-4, wherein R¹ is hydrogen, R² is alkyl, and R³ is alkoxy.

9. The compound of claim 1, wherein R^3a is a ring of formula (a)

wherein A is a monocyclic five-, six-, or seven-membered heterocyclyl ring substituted with R⁴, R¹ and R⁶.

10. The compound of claim 1, wherein R^3a is a ring of formula:

wherein R⁴ is aryl;

heteroaryl;

heterocyclyl;

or —

X¹R⁷, where X¹ is —

O—

, —

CO—

, —

C(O)O—

, —

OC(O)—

, —

NR⁸CO—

, —

CONR⁹—

, —

NR¹⁰—

, —

S—

, —

SO—

, —

SO₂—

, —

NR¹¹SO₂—

, or —

SO₂NR¹² where R⁸-R¹² are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl; and

R⁷ is cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, or heterocyclylalkyl and optionally substituted, including the ring —

NH—

group, with R⁵ and R⁶.

11. The compound of claim 1, wherein R^3a is a ring of formula:

where R⁴ is aryl, heteroaryl, heterocyclyl, or —

X¹R⁷ (where X¹ is —

O—

, —

CO—

, —

C(O)O—

, —

OC(O)—

, —

NR⁸CO—

, —

CONR⁹—

, —

NR¹⁰—

, —

S—

, —

SO—

, —

SO₂—

, —

NR¹¹SO₂—

, or —

SO₂NR¹²—

where R⁸-R¹² are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl and R⁷ is cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, or heterocyclylalkyl and optionally substituted, including the ring —

NH—

group, with R⁵ and R⁶ as defined above.

12. The compound of claim 1, wherein R^3a is a ring of formula:

wherein R^3a is substituted, including the ring —

NH—

groups, with R⁴, R⁵ and R⁶.

13. The compound of claim 1, wherein R^3a is a ring of formula:

wherein R^3a is substituted, including the ring —

NH—

groups, with R⁴, R⁵ and R⁶.

14. The compound of claim 1, wherein R^3a is a ring of formula:

wherein R⁴ is aryl, heteroaryl, or six-membered saturated heterocyclyl, optionally substituted with R^a, R^b and R^c; and

wherein the ring is optionally substituted, including the hydrogen atom on the —

NH—

group within the ring, with R¹ and R⁶.

15. The compound of claim 1, wherein R^3a is a ring of formula:

wherein R⁴ is phenyl or heteroaryl, substituted at the para position with R^a, and optionally substituted with R^b and R^c.

16. The compound of claim 1, wherein R^3a is a ring of formula:

wherein R⁴ is heterocyclyl substituted at the para position with R^a, and optionally substituted with R^b and R^c.

17. The compound of claim 1, wherein R^3a is a ring of formula:

wherein R⁴ is aryl, heteroaryl, or six-membered saturated heterocyclyl, optionally substituted with R^a, R^b and R^c.

18. The compound of claim 1, wherein R^3a is a ring of formula:

wherein;

R⁴ is aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, or —

X¹R⁷ (where X¹ is —

O—

, —

CO—

, —

NR⁸CO—

, —

CONR⁹—

, —

NR¹⁰—

, —

S—

, —

SO—

, —

SO₂—

, —

NR¹¹SO₂—

, or —

SO₂NR¹²—

where R⁸-R¹² are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl and R⁷ is cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, or heterocyclylalkyl);

wherein R^3a is optionally substituted with R⁵ and R⁶ each independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, nitro, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, acyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, or disubstituted amino; and

wherein the aromatic or alicyclic ring in R⁴, R⁵, R⁶, and R⁷ is optionally substituted with one to three substitutents independently selected from R^a, R^b, and R^c which are alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, nitro, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, or disubstituted amino.

19. The compound of claim 18, wherein R⁴ is phenyl, heteroaryl or heterocyclyl.

20. The compound of claim 1, wherein R^3a is a ring of formula:

wherein R⁴ is aralkyl, optionally substituted with R^a, R^b and R^c.

21. The compound of claim 1, wherein R^3a is a ring of formula:

wherein;

one of R⁴ and R⁵ is hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, cyano, amino, monsubstituted or disubstituted amino, or —

X¹R⁷ (where X¹ is —

O—

, —

CO—

, —

OC(O)—

, —

C(O)O, —

NR⁸CO—

, —

CONR⁹—

, —

S—

, —

SO—

, —

SO₂—

, —

NR¹¹SO₂—

, or —

SO₂NR¹²—

where R⁸-R¹² are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl and R⁷ is alkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, or heterocyclylalkyl); and

the other of R⁴ and R⁵ is aryl, heteroaryl, or heterocyclyl; and

wherein the aromatic or alicyclic ring in R⁴ and R⁵ is optionally substituted with one to three substitutents independently selected from R^a, R^b, and R^c, which are alkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, acyl, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, aminocarbonyl, aminosulfonyl, monosubstituted amino, disubstituted amino, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.

22. The compound of claim 1, wherein R^3a is a ring of formula:

wherein;

one of R⁴ and R⁵ is hydrogen;

alkyl;

halo;

haloalkyl;

alkoxy;

haloalkoxy;

cyano;

amino;

monsubstituted or disubstituted amino;

or —

X¹R⁷ (where X¹ is —

O—

, —

CO—

, —

OC(O)—

, —

C(O)O, —

NR⁸CO—

, —

CONR⁹—

, —

S—

, —

SO—

, —

SO₂—

, —

NR¹¹SO₂—

, or —

SO₂NR¹²—

where R⁸-R¹² are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl and R⁷ is alkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, or heterocyclylalkyl); and

the other of R⁴ and R⁵ is aryl, heteroaryl, or heterocyclyl; and

wherein the aromatic or alicyclic ring in R⁴ and R⁵ is optionally substituted with one to three substitutents independently selected from R^a, R^b, and R^c, which are alkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, acyl, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, aminocarbonyl, aminosulfonyl, monosubstituted amino, disubstituted amino, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.

23. The compound of claim 1, wherein R^3a is a ring of formula:

wherein R⁵ is hydrogen or alkyl and R⁴ is aryl, heteroaryl, aralkyl, heteroaralkyl, or heterocyclyl, optionally substituted with one to three substituents independently selected from R^a, R^b, and R^e, which are alkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, acyl, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, aminocarbonyl, aminosulfonyl, monosubstituted amino, disubstituted amino, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.

24. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

25. A method of treating a disorder treatable by inhibiting a PDE10 enzyme in a patient, wherein the method comprises administering to the patient a pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

26. The method of claim 25, wherein the disorder is schizophrenia, bipolar disorder, or obsessive-compulsive disorder.