Heterocyclic substituted carbonyl derivatives and their use as dopamine D

1. A compound of the formula (I):

wherein

A is CH;

n is 1;

g is 1 or 2;

each R 3 is independently hydrogen, C 1 -C 6 alkyl, or

wherein w is 1, 2, or 3;

R is selected from the group consisting of (a) and (k):

wherein

each R 4 , R 12 is independently hydrogen, C 1 -C 6 alkyl, halogen, trifluoromethyl, —CO 2 C 1 -C 6 alkyl or —CH 2 OC 1 -C 6 alkyl;

p and s are 0, 1, or 2;

 represents a group (a):

wherein

each R 19 and R 20 is independently hydrogen, hydroxy or C 1 -C 6 alkyl;

and

d is 3 or 4;

R 1 is

a) hydrogen;

b) C 1 -C 6 alkyl optionally mono- or di-substituted with hydroxy; or

wherein

each R 24 is independently hydrogen or C 1 -C 6 alkyl;

each R 25 , and R 26 is independently hydrogen or C 1 -C 6 alkyl;

t is 0 or 1; and

q is 0 or 1;

R 2 is a group selected from (a)-(jj):

wherein

each R 27 and R 28 is independently selected from:

(1) hydrogen;

(2) C 1 -C 6 alkyl;

(3) C 1 -C 6 alkoxy;

(4) —CO 2 —R 43 wherein R 43 is hydrogen or C 1 -C 6 alkyl;

(5) hydroxy;

(6) —(CH 2 ) a —OR 44 wherein a is 1, 2 or 3 and R 44 is hydrogen or C 1 -C 6 alkyl;

(7) —(CO)—NR 45 R 46

 wherein R 45 and R 46 are each independently hydrogen, C 1 -C 2 alkyl, or R 45 and R 46 taken together with the nitrogen atom to which they are attached from

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 NR 90 wherein R 90 is hydrogen, C 1 -C 6 alkyl, or

wherein R 143 is hydrogen or alkyl;

each M and V is a group independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, hydroxy, phenyl, phenoxy, —SO 2 NH 2 or

 or

—NR 48 R 49 wherein R 48 , and R 49 are each independently hydrogen or C 1 -C 2 alkyl;

each R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 68 , and R 69 is independently hydrogen or C 1 -C 6 alkyl;

each R 29 , R 30 is independently hydrogen, phenyl or C 1 -C 6 alkyl;

each R 83 , R 84 , R 86 , R 87 , R 88 , R 89 , R 92 , R 93 , R 98 , R 99 , R 94 , R 95 , R 100 , R 101 , R 103 , R 104 , R 105 , R 106 , R 108 , R 109 , R 110 , R 111 , R 113 , R 114 , R 115 , R 116 , R 117 , R 118 , R 119 , R 120 , R 122 , R 123 , R 124 , R 125 , R 127 , R 128 , R 130 , R 131 , R 133 , R 134 , R 135 , R 136 , R 137 , R 138 , R 139 and R 140 is independently hydrogen or C 1 -C 6 alkyl;

each R 63 , R 64 and R 65 is independently hydrogen, halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;

each R 66 is independently hydrogen, hydroxy, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;

Q is CH 2 , CHOH or C═O;

X 5 is O or S;

each R 67 is independently hydrogen or C 1 -C 6 alkyl;

R 70 is hydrogen, C 1 -C 6 alkyl, halogen, nitro or a phenyl group optionally mono-substituted with C 1 -C 6 alkyl, halogen or trifluoromethyl;

R 81 is hydrogen, C 1 -C 6 alkyl, or —CO 2 C 1 -C 6 alkyl;

R 91 is hydrogen, halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;

R 96 is hydrogen, C 1 -C 6 alkyl or

wherein R 145 and R 146 are each independently hydrogen or C 1 -C 6 alkyl and b is 0, 1 or 2;

R 97 is hydrogen or C 1 -C 6 alkyl;

each R 102 is independently hydrogen, halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;

R 107 is hydrogen or C 1 -C 6 alkyl;

each R 121 is independently hydrogen, halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;

R 127 is hydrogen or C 1 -C 6 alkyl;

R 126 is C 1 -C 6 alkyl or benzyl;

R 129 is hydrogen or C 1 -C 6 alkyl;

R 132 is hydrogen, C 1 -C 6 alkyl, halogen or C 1 -C 6 alkoxy;

X 3 is O or —NR 127 wherein R 127 is hydrogen or C 1 -C 6 alkyl;

X 4 is O, S or —NR 143 wherein R 143 is hydrogen or C 1 -C 6 alkyl;

R 141 is hydrogen, C 1 -C 6 alkyl or amino;

R 142 is benzyl or phenyl each of which may be optionally substituted with C 1 -C 6 alkyl, halogen or C 1 -C 6 alkoxy;

R 144 is hydrogen or C 1 -C 6 alkyl;

R 85 is hydrogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, —CO 2 C 1 -C 6 alkyl, C(O)C 1 -C 6 alkyl 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 R 147 , R 148 , R 150 , R 151 , R 152 , R 153 , R 156 , R 157 , R 159 , R 160 R 162 and R 163 is independently hydrogen or C 1 -C 6 alkyl;

R 149 is hydrogen, halogen, C 1 -C 6 alkyl, phenoxy, trifluoromethyl or trifluoromethoxy;

R 155 is hydrogen, halogen or C 1 -C 6 alkyl;

R 158 is hydrogen or C 1 -C 6 alkyl;

R 161 is hydrogen or C 1 -C 6 alkyl;

R 164 is hydrogen, halogen, C 1 -C 6 alkyl or trifluoromethyl;

R 165 is hydrogen, C 1 -C 6 alkyl or halogen;

X 7 is O or S or —NR 167 wherein R 167 is hydrogen or C 1 -C 6 alkyl;

R 166 is hydrogen or C 1 -C 6 alkyl;

or R 1 and R 2 are 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) C 1 -C 6 alkyl;

(2) —CO 2 —(C 1 -C 6 alkyl);

(3) —NR 50 R 51 wherein R 50 and R 51 are each independently hydrogen, C 1 -C 6 alkyl, or a phenyl group which is optionally mono- or disubstituted with substituents independently selected from C 1 -C 6 alkyl, halogen or trifluoromethyl;

(4) —C(O)phenyl wherein the phenyl group is optionally mono- or disubstituted with substituents independently selected from C 1 -C 6 alkyl, halogen or trifluoromethyl;

(5) —(CH 2 ) m OR 52 wherein R 52 is hydrogen or C 1 -C 2 alkyl or a phenyl group which is optionally mono- or disubstituted with substituents independently selected from C 1 -C 6 alkyl, halogen or trifluoromethyl, and m is 0, 1 or 2;

(6) —NR 54 —COR 53 wherein R 54 is hydrogen or C 1 -C 6 alkyl and R 53 is hydrogen or C 1 -C 2 alkyl;

(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;

R 167 is hydrogen or C 1 -C 6 alkyl;

each R 55 , R 56 , R 58 , R 59 , R 169 and R 170 is independently hydrogen or C 1 -C 6 alkyl;

each R 57 is independently hydrogen, halogen or C 1 -C 6 alkyl;

each R 60 is independently hydrogen, halogen or C 1 -C 6 alkyl;

R 61 and R 62 are each independently hydrogen or C 1 -C 6 alkyl;

R 168 is hydrogen, thienyl or furanyl;

R 171 is hydrogen, C 1 -C 6 alkyl, halogen, trifluoromethyl or trifluoromethoxy;

or R 1 and R 2 are joined together to form a group of formula X;

or R 1 and R 2 are joined together to form the group of formula (Y)

or R 1 and R 2 are joined together to form any of the following groups:

wherein

g is 1 or 2;

p is 0, 1 or 2;

R 172 is hydrogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;

R 173 is hydrogen, C 1 -C 6 alkyl or phenyl optionally mono- or disubstituted with C 1 -C 6 alkyl or halogen; and

R 82 is a substituent selected from the following groups:

(a) C 1 -C 6 alkyl optionally substituted with hydroxy;

(b) C 1 -C 6 alkenyl;

(c) C 1 -C 6 alkoxy;

(d) —(CH 2 )OC 1 -C 6 alkyl;

(e)

wherein X 8 is —(CR 175 R 176 ) h — or —(CR 177 ═CR 188 )—

 wherein each R 174 is independently hydrogen, C 1 -C 6 alkyl, halogen, trifluoromethyl, C 1 -C 6 alkoxy or benzyloxy;

 h is 0, 1, 2 or 3; each R 175 , R 176 , R 177 and R 178 is independently hydrogen or C 1 -C 6 alkyl; and

 j is 0, 1, 2 or 3;

wherein X 9 is —(CR 180 R 181 ) j — or —(CR 184 R 185 CR 186 ═CR 187 )— or —(CR 182 ═CR 183 )—

 wherein

 aa is 0 or 2;

 R 179 is hydrogen, C 1 -C 6 alkyl, halogen, trifluoromethyl,

 C 1 -C 6 alkoxy, benzyloxy or phenyl;

 each R 180 , R 181 , R 182 , R 183 , R 184 , R 185 , R 186 and R 187 is independently hydrogen or C 1 -C 6 alkyl;

 j is 0, 1, 2, or 3;

wherein w is 1, 2 or 3;

 each R 188 and R 189 is independently hydrogen or C 1 -C 6 alkyl;

wherein

 i is 0, 1 or 2;

 each R 190 is independently hydrogen, alkyl or halogen;

 b is 0, 1, or 2 as;

 each R 191 and R 192 is independently hydrogen or C 1 -C 6 alkyl;

wherein

 a is 1, 2 or 3;

 each R 193 and R 194 is independently hydrogen or C 1 -C 6 alkyl;

 R 195 is hydrogen, halogen or C 1 -C 6 alkyl;

wherein

 e is 2, 3, 4, 5 or 6 as hereinbefore defined;

 b is 0, 1 or 2;

 each R 196 and R 197 is independently hydrogen or C 1 -C 6 alkyl;

 each R 198 and R 199 is independently hydrogen or C 1 -C 6 alkyl;

wherein

 each R 200 and R 201 is independently hydrogen or C 1 -C 6 alkyl;

 w is 1, 2 or 3;

wherein

each R 202 , R 203 , R 204 and R 205 is independently hydrogen or C 1 -C 6 alkyl; and

w is 1, 2 or 3;

—(CR 206 R 207 ) w —OC 1 -C 6 alkyl  (n)

wherein

C 1 -C 6 alkyl is optionally substituted with hydroxy;

each R 206 and R 207 is independently hydrogen or C 1 -C 6 alkyl; and

w is 1, 2 or 3;

—(CR 208 R 209 ) w —NR 210 R 211   (o)

wherein

each R 208 , R 209 , R 210 and R 211 is independently hydrogen or C 1 -C 6 alkyl;

w is 1, 2 or 3;

with the proviso that when n is 1; and R 3 is hydrogen or C 1 -C 6 alkyl; and

is group (a);

and R is group:

(a) wherein R 4 is hydrogen, halogen or C 1 -C 6 alkyl, and R 1 is hydrogen or unsubstituted C 1 -C 6 alkyl,

then R 2 cannot be a group of the following formula:

group (a) wherein z is 0,

group (b) wherein u is 0 and M is hydrogen, halogen, C 1 -C 6 alkyl, or trifluoromethyl,

group (c) wherein o is 0,

group (d) wherein l is 0,

group (e) wherein j is 0,

group (g) wherein v is 0, or

the group formula (i);

and also when R is the group of formula (a), R 1 and R 2 cannot be joined together to form the group of formula Y or a pyrrolidinyl or piperidinyl ring wherein said ring is unsubstituted or mono- or di-substituted with C 1 -C 6 alkyl.

2. The compound of claim 1 wherein R is group (a).

3. The compound of claim 2 wherein R 4 is halogen or CF 3 .

4. The compound of claim 3 wherein R 2 is group (a).

5. The compound of claim 4 wherein z is 0 or 1;

e is 5 and each R 27 and R 28 is independently selected from hydrogen or C 1 -C 6 alkyl.

6. The compound of claim 3 wherein R 2 is group (b).

7. The compound of claim 6 wherein M is hydrogen, C 1 -C 6 alkoxy or C 1 -C 6 alkyl and u is 0 or 1.

8. The compound of claim 3 wherein R 2 is group (n).

9. The compound of claim 8 wherein R 70 is hydrogen and f is 3.

10. The compound of claim 1 wherein R is group (k).

11. The compound of claim 10 wherein R 12 is hydrogen, C 1 -C 6 alkyl, or —CH 2 OC 1 -C 6 alkyl.

12. The compound of claim 11 wherein R 2 is group (a).

13. The compound of claim 12 wherein z is 0 or 1;

e is 5 and each R 27 and R 28 is independently selected from hydrogen or C1-C6alkyl.

14. The compound of claim 11 wherein R 2 is group (b).

15. The compound of claim 14 wherein M is hydrogen, C 1 -C 6 alkoxy or C 1 -C 6 alkyl and u is 0 or 1.

16. The compound of claim 11 wherein R 2 is group (n).

17. The compound of claim 16 wherein R 70 is hydrogen and f is 3.

18. A pharmaceutical composition comprising an effective amount of a compound of claim 1 with a pharmaceutically-acceptable carrier or diluent.

19. A process for preparing a compound of formula I of claim 1 which comprises:

(a) reacting a compound of formula (II):

wherein R 3 , g, y, R, A and n are as defined in formula I of claim 1 ; with a compound of formula (III)

wherein “LG” is a suitable leaving group selected from chlorine, bromine, iodine and mesyl; and

 is as defined in formula I of claim 1 ;

to provide a compound of formula (IV)

(b) hydrolyzing a compound of formula (IV) to provide a compound of formula (V)

and (c) reacting a compound of formula (V) with a compound of formula (VI)

wherein R 1 and R 2 are as defined in formula (I) of claim 1 ;

to provide the compound of formula (I).

20. A process for preparing compounds of formula I of claim 1 which comprises:

(a) reacting a compound of formula (VII)

wherein “LG” is a suitable leaving group selected from chlorine, bromine, iodine and mesyl; and

 R 1 and R 2 are as defined in formula I of claim 1 ;

with a compound of formula (II)

wherein R 3 , g, y, R, A and n are as defined in formula I of claim 1 ;

to provide the compound of formula (I).