	US 7,521,445 B2
	Heterocyclic substituted carbonyl derivatives and their use as dopamine D3 receptor ligands
James Hendrix, Hillsborough, N.J. (US); Horst Hemmerle, Noblesville, Ind. (US); Matthias Urmann, Eschborn (Germany); Gregory M Shutske, Pittstown, N.J. (US); Joseph T Strupczewski, Flemington, N.J. (US); Kenneth J Bordeau, Kintnersville, Pa. (US); John G Jurcak, Bethlehem, Pa. (US); Thaddeus Nieduzak, Bridgewater, N.J. (US); Sharon A. Jackson, Whitehouse Station, N.J. (US); Paul Angell, Middletown, Ohio (US); James P Carey, Cincinnati, Ohio (US); George Lee, Somerville, N.J. (US); David Fink, Lebanon, N.J. (US); Jean-Francois Sabuco, Paris (France); Yulin Chiang, Convent Station, N.J. (US); and Nicola Collar, Hoboken, N.J. (US)
Assigned to Aventis Pharmaceuticals Inc., Bridgewater, N.J. (US)
Filed on Mar. 05, 2007, as Appl. No. 11/714,047.
Application 11/714047 is a continuation of application No. 10/819037, filed on Apr. 06, 2004, granted, now 7,186,724.
Application 10/819037 is a continuation of application No. 10/078225, filed on Feb. 19, 2002, abandoned.
Claims priority of provisional application 60/269672, filed on Feb. 16, 2001.
Claims priority of application No. 0117577.7 (GB), filed on Jul. 19, 2001.
Prior Publication US 2007/0161641 A1, Jul. 12, 2007
Int. Cl. A61K 31/5377 (2006.01); A61K 31/454 (2006.01); A61K 31/4535 (2006.01); A61K 31/4525 (2006.01); C07D 498/04 (2006.01); C07D 413/04 (2006.01); C07D 409/04 (2006.01)

U.S. Cl. 514—233.8 [514/234.5; 514/235.2; 514/316; 514/321; 514/322; 514/324; 544/130; 546/187; 546/198; 546/199; 546/202]

19 Claims

1. A compound of the formula (I):

wherein

A is CH;

n is 1;

g is 1 or 2;

each R₃is independently hydrogen, C₁-C₆alkyl, or

wherein w is 1, 2, or 3;

R is selected from the group consisting of (a), h), i), k), n)-q), r), t) and (w):

wherein

each R₄, R₁₁, R₁₂and R₁₈is independently hydrogen, C₁-C₆alkyl, halogen, trifluoromethyl, —CO₂C₁-C₆alkyl or —CH₂OC₁-C₆alkyl;

each R₇₁, R₇₂, R₇₄and R₈₀is independently hydrogen, C₁-C₆alkyl, C₁-C₆alkoxy, halogen, trifluoromethyl, —CO₂C₁-C₆alkyl or —CH₂OC₁-C₆alkyl;

R₇₃is hydrogen, alkyl, pyridyl, benzyl, —CH₂CF₃, —CO₂C₁-C₆alkyl, phenyl optionally substituted with halogen, trifluoromethyl, trifluoromethoxy or R₇₃is

wherein w is 1, 2 or 3;

each R₇₅is hydrogen, halogen, C₁-C₆alkyl or C₁-C₆alkoxy;

each R₇₇is hydrogen, halogen, C₁-C₆alkyl or C₁-C₆alkoxy;

p and s are 0, 1, or 2;

R₁₇is hydrogen, C₁-C₆alkyl, Ar, —COAr, —CONHAr or —SO₂—Ar wherein Ar is a phenyl group which is optionally mono- or di-substituted with substituents independently selected from C₁-C₆alkyl, halogen, trifluoromethyl, C₁-C₆alkoxy, nitro, CN and COC₁-C₆alkyl; and

represents a group selected from (b)-(f):

wherein

each R₁₉and R₂₀is independently hydrogen, hydroxy or C₁-C₆alkyl;

R₂₁, R₂₂, and R₂₃are each independently hydrogen or C₁-C₃linear alkyl; and

d is 3 or 4;

R₁is a) hydrogen;

b) C₁-C₆alkyl optionally mono- or di-substituted with hydroxy; or

wherein

each R₂₄is independently hydrogen or C₁-C₆alkyl;

each R₂₅, and R₂₆is independently hydrogen or C₁-C₆alkyl;

t is 0 or 1; and

q is 0 or 1;

R₂is a group selected from (a)-(jj):

wherein

each R₂₇and R₂₈is independently selected from:

(1) hydrogen;

(2) C₁-C₆alkyl;

(3) C₁-C₆alkoxy;

(4) —CO₂—R₄₃wherein R₄₃is hydrogen or C₁-C₆alkyl;

(5) hydroxy;

(6) —(CH₂)_a—OR₄₄wherein a is 1, 2 or 3 and R₄₄is hydrogen or C₁-C₆alkyl;

(7) —(CO)—NR₄₅R₄₆wherein R₄₅and R₄₆are each independently hydrogen, C₁-C₂alkyl, or R₄₅and R₄₆taken together with the nitrogen to which they are attached form

z is 0 or 1;

e is 2, 3, 4, 5, 6 or 7;

h is 0, 1, 2 or 3;

u is 0, 1, 2, 3 or 4;

o is 0 or 1;

l is 0 or 1;

j is 0, 1, 2 or 3;

v is 0, 1, 2, 3 or 4;

w is 1, 2 or 3;

f is 1, 2, 3 or 4;

t is 0 or 1;

b is 0, 1 or 2;

q is 0 or 1;

aa is 0 or 2;

X is O, S or NR₉₀wherein R₉₀is hydrogen, C₁-C₆alkyl, or

wherein R₁₄₃is hydrogen or alkyl;

each M and V is a group independently selected from hydrogen, halogen, C₁-C₆alkyl, C₁-C₆alkoxy, trifluoromethyl, hydroxy, phenyl, phenoxy, —SO₂NH₂or

—NR₄₈R₄₉wherein R₄₈and R₄₉are each independently hydrogen or C₁-C₂alkyl;

each R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, R₃₆, R₃₇, R₃₈, R₃₉, R₄₀, R₆₈, and R₆₉is independently hydrogen or C₁-C₆alkyl;

each R₂₉, R₃₀is independently hydrogen, phenyl or C₁-C₆alkyl;

each R₈₃, R₈₄, R₈₆, R₈₇, R₈₈, R₈₉, R₉₂, R₉₃, R₉₈, R₉₉, R₉₄, R₉₅, R₁₀₀, R₁₀₁, R₁₀₃, R₁₀₄, R₁₀₅, R₁₀₆, R₁₀₈, R₁₀₉, R₁₁₀, R₁₁₁, R₁₁₃, R₁₁₄, R₁₁₅, R₁₁₆, R₁₁₇, R₁₁₈, R₁₁₉, R₁₂₀, R₁₂₂, R₁₂₃, R₁₂₄, R₁₂₅, R₁₂₇, R₁₂₈, R₁₃₀, R₁₃₁, R₁₃₃, R₁₃₄, R₁₃₅, R₁₃₆, R₁₃₇, R₁₃₈, R₁₃₉and R₁₄₀is independently hydrogen or C₁-C₆alkyl;

each R₆₃, R₆₄and R₆₅is independently hydrogen, halogen, C₁-C₆alkyl or C₁-C₆alkoxy;

each R₆₆is independently hydrogen, hydroxy, C₁-C₆alkyl or C₁-C₆alkoxy;

Q is CH₂, CHOH or C═O;

X₅is O or S;

each R₆₇is independently hydrogen or C₁-C₆alkyl;

R₇₀is hydrogen, C₁-C₆alkyl, halogen, nitro or a phenyl group optionally mono-substituted with C₁-C₆alkyl, halogen or trifluoromethyl;

R₈₁is hydrogen, C₁-C₆alkyl, or —CO₂C₁-C₆alkyl;

R₉₁is hydrogen, halogen, C₁-C₆alkyl or C₁-C₆alkoxy;

R₉₆is hydrogen, C₁-C₆alkyl or

wherein R₁₄₅and R₁₄₆are each independently hydrogen or C₁-C₆alkyl and b is 0, 1 or 2;

R₉₇is hydrogen or C₁-C₆alkyl;

each R₁₀₂is independently hydrogen, halogen, C₁-C₆alkyl or C₁-C₆alkoxy;

R₁₀₇is hydrogen or C₁-C₆alkyl;

each R₁₂₁is independently hydrogen, halogen, C₁-C₆alkyl or C₁-C₆alkoxy;

R₁₂₇is hydrogen or C₁-C₆alkyl;

R₁₂₆is C₁-C₆alkyl or benzyl;

R₁₂₉is hydrogen or C₁-C₆alkyl;

R₁₃₂is hydrogen, C₁-C₆alkyl, halogen or C₁-C₆alkoxy;

X₃is O or —NR₁₂₇wherein R₁₂₇is hydrogen or C₁-C₆alkyl;

X₄is O, S or —NR₁₄₃wherein R₁₄₃is hydrogen or C₁-C₆alkyl;

R₁₄₁is hydrogen, C₁-C₆alkyl or amino;

R₁₄₂is benzyl or phenyl each of which may be optionally substituted with C₁-C₆alkyl, halogen or C₁-C₆alkoxy;

R₁₄₄is hydrogen or C₁-C₆alkyl;

R₈₅is hydrogen, C₁-C₆alkoxy, C₁-C₆alkyl, —CO₂C₁-C₆alkyl, C(O)C₁-C₆alkyl or a group selected from the following:

wherein

j is 0, 1, 2 or 3;

w is 1, 2 or 3;

m is 0, 1 or 2;

e is 2, 3, 4, 5, 6 or 7;

each R₁₄₇, R₁₄₈, R₁₅₀, R₁₅₁, R₁₅₂, R₁₅₃, R₁₅₆, R₁₅₇, R₁₅₉, R₁₆₀R₁₆₂and R₁₆₃is independently hydrogen or C₁-C₆alkyl;

R₁₄₉is hydrogen, halogen, C₁-C₆alkyl, phenoxy, trifluoromethyl or trifluoromethoxy;

R₁₅₅is hydrogen, halogen or C₁-C₆alkyl;

R₁₅₈is hydrogen or C₁-C₆alkyl;

R₁₆₁is hydrogen or C₁-C₆alkyl;

R₁₆₄is hydrogen, halogen, C₁-C₆alkyl or trifluoromethyl;

R₁₆₅is hydrogen, C₁-C₆alkyl or halogen;

X₇is O or S or —NR₁₆₇wherein R₁₆₇is hydrogen or C₁-C₆alkyl;

R₁₆₆is hydrogen or C₁-C₆alkyl;

or R₁and R₂are joined together to form a pyrrolidinyl or piperidinyl ring, and in which the ring is optionally mono- or di-substituted, the substituents independently selected from:

(1) C₁-C₆alkyl;

(2) —CO₂—(C₁-C₆alkyl);

(3) —NR₅₀R₅₁wherein R₅₀and R₅₁are each independently hydrogen, C₁-C₆alkyl, or a phenyl group which is optionally mono- or disubstituted with substituents independently selected from C₁-C₆alkyl, halogen or trifluoromethyl;

(4) —C(O)phenyl wherein the phenyl group is optionally mono- or disubstituted with substituents independently selected from C₁-C₆alkyl, halogen or trifluoromethyl;

(5) —(CH₂)_mOR₅₂wherein R₅₂is hydrogen or C₁-C₂alkyl or a phenyl group which is optionally mono- or disubstituted with substituents independently selected from C₁-C₆alkyl, halogen or trifluoromethyl, and m is 0, 1 or 2;

(6) —NR₅₄—COR₅₃wherein R₅₄is hydrogen or C₁-C₆alkyl and R₅₃is hydrogen or C₁-C₂alkyl;

(7) =O;

(8) —CN;

wherein

b is 0, 1 or 2;

w is 1, 2 or 3;

t is 0 or 1;

i is 0, 1 or 2;

v is 0, 1, 2, 3 or 4;

k is 0 or 1;

c are 0, 1 or 2;

R₁₆₇is hydrogen or C₁-C₆alkyl;

each R₅₅, R₅₆, R₅₈, R₅₉, R₁₆₉and R₁₇₀is independently hydrogen or C₁-C₆alkyl;

each R₅₇is independently hydrogen, halogen or C₁-C₆alkyl;

each R₆₀is independently hydrogen, halogen or C₁-C₆alkyl;

R₆₁and R₆₂are each independently hydrogen or C₁-C₆alkyl;

R₁₆₈is hydrogen, thienyl or furanyl;

R₁₇₁is hydrogen, C₁-C₆alkyl, halogen, trifluoromethyl or trifluoromethoxy;

or R₁and R₂are joined together to form a group of formula X;

or R₁and R₂are joined together to form the group of formula (Y)

or R₁and R₂are joined together to form any of the following groups:

wherein

g is 1 or 2;

p is 0, 1 or 2;

R₁₇₂is hydrogen, C₁-C₆alkyl or C₁-C₆alkoxy;

R₁₇₃is hydrogen, C₁-C₆alkyl or phenyl optionally mono- or disubstituted with C₁-C₆alkyl or halogen; and

R₈₂is a substituent selected from the following groups:

(a) C₁-C₆alkyl optionally substituted with hydroxy;

(b) C₁-C₆alkenyl;

(d) —(CH₂)OC₁-C₆alkyl;

wherein X₈is —(CR₁₇₅R₁₇₆)_h- or —(CR₁₇₇=CR₁₈₈)—

wherein each R₁₇₄is independently hydrogen, C₁-C₆alkyl, halogen, trifluoromethyl, C₁-C₆alkoxy or benzyloxy;

h is 0, 1, 2 or 3; each R₁₇₅, R₁₇₆, R₁₇₇and R₁₇₈is independently hydrogen or C₁-C₆alkyl; and

j is 0, 1, 2 or 3;

wherein X₉is —(CR₁₈₀R₁₈₁)_j- or —(CR₁₈₄R₁₈₅CR₁₈₆═CR₁₈₇)— or —(CR₁₈₂═CR₁₈₃)—

wherein

aa is 0 or 2;

R₁₇₉is hydrogen, C₁-C₆alkyl, halogen, trifluoromethyl, C₁-C₆alkoxy, benzyloxy or phenyl;

each R₁₈₀, R₁₈₁, R₁₈₂, R₁₈₃, R₁₈₄, R₁₈₅, R₁₈₆and R₁₈₇is independently hydrogen or C₁-C₆alkyl;

j is 0, 1, 2, or 3;

wherein w is 1, 2 or 3;

each R₁₈₈and R₁₈₉is independently hydrogen or C₁-C₆alkyl;

wherein

i is 0, 1 or 2;

each R₁₉₀is independently hydrogen, alkyl or halogen;

b is 0, 1, or 2;

each R₁₉₁and R₁₉₂is independently hydrogen or C₁-C₆alkyl;

wherein

a is 1, 2 or 3;

each R₁₉₃and R₁₉₄is independently hydrogen or C₁-C₆alkyl;

R₁₉₅is hydrogen, halogen or C₁-C₆alkyl;

wherein

e is 2, 3, 4, 5 or 6;

b is 0, 1 or 2;

each R₁₉₆and R₁₉₇is independently hydrogen or C₁-C₆alkyl;

each R₁₉₈and R₁₉₉is independently hydrogen or C₁-C₆alkyl;

wherein

each R₂₀₀and R₂₀₁is independently hydrogen or C₁-C₆alkyl;

w is 1, 2 or 3;

wherein

each R₂₀₂, R₂₀₃, R₂₀₄and R₂₀₅is independently hydrogen or C₁-C₆alkyl; and

w is 1, 2 or 3;

(n)

—(CR₂₀₆R₂₀₇)_w—OC₁-C₆alkyl

wherein

C₁-C₆alkyl is optionally substituted with hydroxy;

each R₂₀₆and R₂₀₇is independently hydrogen or C₁-C₆alkyl; and

w is 1, 2 or 3;

(o)

—(CR₂₀₈R₂₀₉)_w—NR₂₁₀R₂₁₁

wherein

each R₂₀₈, R₂₀₉, R₂₁₀and R₂₁₁is independently hydrogen or C₁-C₆alkyl;

w is 1, 2 or 3;