Pyrrolo[3,2-D] pyrimidines that are selective antagonists of A
View Patent ↗The present invention provides compounds of the following formula and pharmaceutical compositions that are selective antagonists of A 2B adenosine receptors (ARs). These compounds and compositions are useful as pharmaceutical agents.
1. A compound of formula I or a stereoisomer or a pharmaceutically acceptable salt thereof:
wherein:
R is selected from: H, OH, C 1-6 alkyl, halo-C 1-8 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, (C 3-8 cycloalkyl)C 1-8 alkylene, (C 4-10 heterocycle)C 1-8 alkylene, (C 6-10 aryl)C 1-8 alkylene, and (C 5-10 heteroaryl)C 1-8 alkylene, wherein R optionally is substituted with 1 R d ;
R d is independently selected from: F, Cl, Br, I, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, OC 1-6 alkyl, NO 2 , —CN, CF 3 , and OCF 3 ;
R 1 and R 2 are independently selected from: H, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, C 1-8 alkoxy, C 3-8 cycloalkyl, (C 3-8 cycloalkyl)C 1-8 alkylene, C 4-10 heterocycle, (C 4-10 heterocycle)C 1-8 alkylene, C 6-10 aryl, (C 6-10 aryl)C 1-8 alkylene, C 5-10 heteroaryl, and (C 5-10 heteroaryl)C 1-8 alkylene, wherein R 1 and R 2 are independently optionally substituted with 1-2 R 1a ;
R 1a is independently selected from: F, Cl, Br, I, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) a OR a , —(CH 2 ) a NR a R a , —(CH 2 ) a NHOH, —(CH 2 ) a NR a NR a R a , —(CH 2 ) a NO 2 , —(CH 2 ) a CN, —(CH 2 ) a CO 2 R a , —(CH 2 ) a C(O)R a , —(CH 2 ) a OC(O)R a , —(CH 2 ) a CONR a R a , CF 3 , and OCF 3 ;
R a is independently selected from: H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, (C 3-8 cycloalkyl)C 1-8 alkylene, C 4-10 heterocycle, (C 4-10 heterocycle)C 1-8 alkylene, C 6-10 aryl, (C 6-10 aryl)C 1-8 alkylene, C 5-10 heteroaryl, and (C 5-10 heteroaryl)C 1-8 alkylene, wherein the alkyl is optionally interrupted with 1-2 heteroatoms selected from the group consisting of —O—, —S(O) p — and —NR b —;
R b is independently selected from the group consisting of H, C 1-6 alkyl, and benzyl;
R 3 is selected from: OH, C 1-8 alkoxy, NR 3a R 3b , C 3-8 cycloalkyl, C 4-10 heterocycle, C 6-10 aryl, and C 5-10 heteroaryl, wherein the cycloalkyl, heterocycle, aryl, and heteroaryl are optionally substituted with 1-2 R 3c ;
R 3a and R 3b are independently selected from: C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, phenyl, and benzyl;
R 3c is independently selected from: F, Cl, Br, I, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) a OR a , —(CH 2 ) a NR a R a , —(CH 2 ) a NHOH, —(CH 2 ) a NR a NR a R a , —(CH 2 ) a NO 2 , —(CH 2 ) a CN, —(CH 2 ) a CO 2 R a , —(CH 2 ) a C(O)R a , —(CH 2 ) a OC(O)R a , —(CH 2 ) a CONR a R a , CF 3 , and OCF 3 ;
X is selected from: (CH 2 ) q , (CH 2 ) r C(O), and (CH 2 ) r C(O)NR 4 ;
R 4 is selected from: H, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 haloalkyl;
Y is selected from: 5-10 membered heteroaryl and 6-10 membered aryl, wherein Y is optionally substituted with 1-4 Y 1 ;
Y 1 is independently selected from: F, Cl, Br, I, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) a OR a , —(CH 2 ) a NR a R a , —(CH 2 ) a NHOH, —(CH 2 ) a NR a NR a R a , —(CH 2 ) a NO 2 , —(CH 2 ) a CN, —(CH 2 ) a CO 2 R a , —(CH 2 ) a C(O)R a , —(CH 2 ) a OC(O)R a , —(CH 2 ) a CONR a R a , CF 3 , and OCF 3 ;
a is independently selected from the group consisting of 0, 1, and 2;
n is independently selected from: 1, 2, and 3;
p is independently selected from: 0, 1, and 2;
q is independently selected from 1, 2, 3, and 4; and,
r is independently selected from 0, 1, 2, and 3.
2. The compound according to claim 1 , wherein the compound is of formula II or a stereoisomer or a pharmaceutically acceptable salt thereof:
wherein:
R is selected from: H and C 1-4 alkyl;
R 1 and R 2 are independently selected from: H, C 1-4 alkyl, C 3-4 alkenyl, C 3-4 alkynyl, C 3-6 cycloalkyl, (C 3-6 cycloalkyl)C 1-2 alkylene, C 5-6 heterocycle, (C 5-6 heterocycle)C 1-2 alkylene, C 6-10 aryl, (C 6-10 aryl)C 1-2 alkylene, C 5-10 heteroaryl, and (C 5-10 heteroaryl)C 1-2 alkylene, wherein R 1 and R 2 are independently optionally substituted with 1-2 R 1a ;
R 1a is independently selected from: F, Cl, Br, I, C 1-4 alkyl, OR a , NR a R a , NO 2 , —CN, CO 2 R a , C(O)R a , OC(O)R a , CONR a R a , CF 3 , and OCF 3 ;
R 3 is selected from: OCH 3 , OCH 2 CH 3 , NR 3a R 3b , C 3-6 cycloalkyl, and C 5-6 heterocycle, wherein the cycloalkyl and heterocycle are optionally substituted with 1-2 R 3c ;
R 3a and R 3b are independently selected from: C 1-4 alkyl, phenyl, and benzyl;
R 3c is independently selected from: F, Cl, Br, I, C 1-4 alkyl, OR a , NR a R a , NO 2 , —CN, CO 2 R a , C(O)R a , OC(O)R a , CONR a R a , CF 3 , and OCF 3 ;
Y is selected from: 5-6 membered heteroaryl and phenyl, wherein Y is optionally substituted with 1-2 Y 1 ;
Y 1 is independently selected from: F, Cl, Br, I, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, OR a , NR a R a , NO 2 , —CN, CO 2 R a , C(O)R a , OC(O)R a , CONR a R a , CF 3 , and OCF 3 ; and,
R a is independently selected from: H, C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, and benzyl.
3. The compound according to claim 2 , wherein:
R is H;
R 1 and R 2 are independently selected from: n-propyl, cyclopropylmethyl, and cyclobutyl;
R 3 is selected from: cyclopropyl, cyclobutyl, N-pyrrolidino, N-piperidino, N-piperazino, and N-morpholino;
Y is selected from: pyridyl and pyrimidyl, wherein Y is optionally substituted with 1-2 Y 1 ; and,
Y 1 is independently selected from: F, Cl, CH 3 , OCH 3 , NO 2 , —CN, and CF 3 .
4. The compound according to claim 3 , wherein:
R 1 is selected from: n-propyl and cyclopropylmethyl; and,
R 2 is n-propyl.
5. The compound according to claim 3 , wherein:
R 1 is n-propyl; and,
R 2 is n-propyl.
6. The compound according to claim 1 , wherein the compound is of formula IV or a stereoisomer or a pharmaceutically acceptable salt thereof:
wherein:
R is selected from: H and C 1-4 alkyl;
R 1 and R 2 are independently selected from: H, C 1-4 alkyl, C 3-4 alkenyl, C 3-4 alkynyl, C 3-6 cycloalkyl, (C 3-6 cycloalkyl)C 1-2 alkylene, C 5-6 heterocycle, (C 5-6 heterocycle)C 1-2 alkylene, C 6-10 aryl, (C 6-10 aryl)C 1-2 alkylene, C 5-10 heteroaryl, and (C 5-10 heteroaryl)C 1-2 alkylene, wherein R 1 and R 2 are independently optionally substituted with 1-2 R 1a ;
R 1a is independently selected from: F, Cl, Br, I, C 1-4 alkyl, OR a , NR a R a , NO 2 , —CN, CO 2 R a , C(O)R a , OC(O)R a , CONR a R a , CF 3 , and OCF 3 ;
R 3 is selected from: OCH 3 , OCH 2 CH 3 , NR 3a R 3b , C 3-6 cycloalkyl, and C 5-6 heterocycle, wherein the cycloalkyl and heterocycle are optionally substituted with 1-2 R 3c ;
R 3a and R 3b are independently selected from: C 1-4 alkyl, phenyl, and benzyl;
R 3c is independently selected from: F, Cl, Br, I, C 1-4 alkyl, OR a , NR a R a , NO 2 , —CN, CO 2 R a , C(O)R a , OC(O)R a , CONR a R a , CF 3 , and OCF 3 ;
Y is selected from: 5-6 membered heteroaryl and phenyl, wherein Y is optionally substituted with 1-2 Y 1 ;
Y 1 is independently selected from: F, Cl, Br, I, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, OR a , NR a R a , NO 2 , —CN, CO 2 R a , C(O)R a , OC(O)R a , CONR a R a , CF 3 , and OCF 3 ; and,
R a is independently selected from: H, C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, and benzyl.
7. The compound according to claim 1 , wherein the compound is of formula V or VI or stereoisomer or a pharmaceutically acceptable salt thereof:
8. The compound according to claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 1 , wherein the compound is selected from
Ex. #
R
R 1
R 2
R 3
Y′
1.
H
n-propyl
n-propyl
CH 2 OCH 3
H
2.
H
n-propyl
n-propyl
CH 3
H
3.
H
n-propyl
n-propyl
CH 2 OH
H
4.
H
n-propyl
n-propyl
CH 2 N(CH 3 ) 2
H
5.
H
n-propyl
n-propyl
CH 2 —N-piperdinyl
H
6.
H
n-propyl
n-propyl
CH 2 —N-
H
morpholinyl
7.
H
n-propyl
n-propyl
cyclopropyl
H
8.
H
n-propyl
n-propyl
CH 2 -cyclopropyl
H
9.
H
n-propyl
n-propyl
2-tetrahydrofuranyl
H
10.
H
n-propyl
n-propyl
CH 2 -2-tetra-
H
hydrofuran
11.
H
n-propyl
n-propyl
2-tetrahydrothienyl
H
12.
H
n-propyl
n-propyl
CH 2 OCH 3
CF 3
13.
H
n-propyl
n-propyl
CH 3
CF 3
14.
H
n-propyl
n-propyl
CH 2 OH
CF 3
15.
H
n-propyl
n-propyl
CH 2 N(CH 3 ) 2
CF 3
16.
H
n-propyl
n-propyl
CH 2 —N-piperdinyl
CF 3
17.
H
n-propyl
n-propyl
CH 2 —N-
CF 3
morpholinyl
18.
H
n propyl
n-propyl
cyclopropyl
CF 3
19.
H
n-propyl
n-propyl
CH 2 -cyclopropyl
CF 3
20.
H
n-propyl
n-propyl
2-tetrahydrofuranyl
CF 3
21.
H
n-propyl
n-propyl
CH 2 -2-tetra-
CF 3
hydrofuran
22.
H
n-propyl
n-propyl
2-tetrahydrothienyl
CF 3
23.
H
n-propyl
n-propyl
CH 2 OCH 3
F
24.
H
n-propyl
n-propyl
CH 3
F
25.
H
n-propyl
n-propyl
CH 2 OH
F
26.
H
n-propyl
n-propyl
CH 2 N(CH 3 ) 2
F
27.
H
n-propyl
n-propyl
CH 2 —N-piperdinyl
F
28.
H
n-propyl
n-propyl
CH 2 —N-
F
morpholinyl
29.
H
n-propyl
n-propyl
cyclopropyl
F
30.
H
n-propyl
n-propyl
CH 2 -cyclopropyl
F
31.
H
n-propyl
n-propyl
2-tetrahydrofuranyl
F
32.
H
n-propyl
n-propyl
CH 2 -2-tetra-
F
hydrofuran
33.
H
n-propyl
n-propyl
2-tetrahydrothienyl
F
34.
H
n-propyl
n-propyl
CH 2 OCH 3
Cl
35.
H
n-propyl
n-propyl
CH 3
Cl
36.
H
n-propyl
n-propyl
CH 2 OH
Cl
37.
H
n-propyl
n-propyl
CH 2 N(CH 3 ) 2
Cl
38.
H
n-propyl
n-propyl
CH 2 —N-piperdinyl
Cl
39.
H
n-propyl
n-propyl
CH 2 —N-
Cl
morpholinyl
40.
H
n-propyl
n-propyl
cyclopropyl
Cl
41.
H
n-propyl
n-propyl
CH 2 -cyclopropyl
Cl
42.
H
n-propyl
n-propyl
2-tetrahydrofuranyl
Cl
43.
H
n-propyl
n-propyl
CH 2 -2-tetra-
Cl
hydrofuran
44.
H
n-propyl
n-propyl
2-tetrahydrothienyl
Cl
45.
H
n-propyl
n-propyl
CH 2 OCH 3
Br
46.
H
n-propyl
n-propyl
CH 3
Br
47.
H
n-propyl
n-propyl
CH 2 OH
Br
48.
H
n-propyl
n-propyl
CH 2 N(CH 3 ) 2
Br
49.
H
n-propyl
n-propyl
CH 2 —N-piperdinyl
Br
50.
H
n-propyl
n-propyl
CH 2 —N-
Br
morpholinyl
51.
H
n-propyl
n-propyl
cyclopropyl
Br
52.
H
n-propyl
n-propyl
CH 2 -cyclopropyl
Br
53.
H
n-propyl
n-propyl
2-tetrahydrofuranyl
Br
54.
H
n-propyl
n-propyl
CH 2 -2-tetra-
Br
hydrofuran
55.
H
n-propyl
n-propyl
2-tetrahydrothienyl
Br
56.
H
n-propyl
n-propyl
CH 2 OCH 3
I
57.
H
n-propyl
n-propyl
CH 3
I
58.
H
n-propyl
n-propyl
CH 2 OH
I
59.
H
n-propyl
n-propyl
CH 2 N(CH 3 ) 2
I
60.
H
n-propyl
n-propyl
CH 2 —N-piperdinyl
I
61.
H
n-propyl
n-propyl
CH 2 —N-
I
morpholinyl
62.
H
n-propyl
n-propyl
cyclopropyl
I
63.
H
n-propyl
n-propyl
CH 2 -cyclopropyl
I
64.
H
n-propyl
n-propyl
2-tetrahydrofuranyl
I
65.
H
n-propyl
n-propyl
CH 2 -2-tetra-
I
hydrofuran
66.
H
n-propyl
n-propyl
2-tetrahydrothienyl
I
67.
H
i-propyl
n-propyl
CH 2 OCH 3
H
68.
H
i-propyl
n-propyl
CH 3
H
69.
H
i-propyl
n-propyl
CH 2 OH
H
70.
H
i-propyl
n-propyl
CH 2 N(CH 3 ) 2
H
71.
H
i-propyl
n-propyl
CH 2 —N-piperdinyl
H
72.
H
i-propyl
n-propyl
CH 2 —N-
H
morpholinyl
73.
H
i-propyl
n-propyl
cyclopropyl
H
74.
H
i-propyl
n-propyl
CH 2 -cyclopropyl
H
75.
H
i-propyl
n-propyl
2-tetrahydrofuranyl
H
76.
H
i-propyl
n-propyl
CH 2 -2-tetra-
H
hydrofuran
77.
H
i-propyl
n-propyl
2-tetrahydrothienyl
H
78.
H
i-propyl
n-propyl
CH 2 OCH 3
CF 3
79.
H
i-propyl
n-propyl
CH 3
CF 3
80.
H
i-propyl
n-propyl
CH 2 OH
CF 3
81.
H
i-propyl
n-propyl
CH 2 N(CH 3 ) 2
CF 3
82.
H
i-propyl
n-propyl
CH 2 —N-piperdinyl
CF 3
83.
H
i-propyl
n-propyl
CH 2 —N-
CF 3
morpholinyl
84.
H
i-propyl
n-propyl
cyclopropyl
CF 3
85.
H
i-propyl
n-propyl
CH 2 -cyclopropyl
CF 3
86.
H
i-propyl
n-propyl
2-tetrahydrofuranyl
CF 3
87.
H
i-propyl
n-propyl
CH 2 -2-tetra-
CF 3
hydrofuran
88.
H
i-propyl
n-propyl
2-tetrahydrothienyl
CF 3
89.
H
i-propyl
n-propyl
CH 2 OCH 3
F
90.
H
i-propyl
n-propyl
CH 3
F
91.
H
i-propyl
n-propyl
CH 2 OH
F
92.
H
i-propyl
n-propyl
CH 2 N(CH 3 ) 2
F
93.
H
i-propyl
n-propyl
CH 2 —N-piperdinyl
F
94.
H
i-propyl
n-propyl
CH 2 —N-
F
morpholinyl
95.
H
i-propyl
n-propyl
cyclopropyl
F
96.
H
i-propyl
n-propyl
CH 2 -cyclopropyl
F
97.
H
i-propyl
n-propyl
2-tetrahydrofuranyl
F
98.
H
i-propyl
n-propyl
CH 2 -2-tetra-
F
hydrofuran
99.
H
i-propyl
n-propyl
2-tetrahydrothienyl
F
100.
H
i-propyl
n-propyl
CH 2 OCH 3
Cl
101.
H
i-propyl
n-propyl
CH 3
Cl
102.
H
i-propyl
n-propyl
CH 2 OH
Cl
103.
H
i-propyl
n-propyl
CH 2 N(CH 3 ) 2
Cl
104.
H
i-propyl
n-propyl
CH 2 —N-piperdinyl
Cl
105.
H
i-propyl
n-propyl
CH 2 —N-
Cl
morpholinyl
106.
H
i-propyl
n-propyl
cyclopropyl
Cl
107.
H
i-propyl
n-propyl
CH 2 -cyclopropyl
Cl
108.
H
i-propyl
n-propyl
2-tetrahydrofuranyl
Cl
109.
H
i-propyl
n-propyl
CH 2 -2-tetra-
Cl
hydrofuran
110.
H
i-propyl
n-propyl
2-tetrahydrothienyl
Cl
111.
H
i-propyl
n-propyl
CH 2 OCH 3
Br
112.
H
i-propyl
n-propyl
CH 3
Br
113.
H
i-propyl
n-propyl
CH 2 OH
Br
114.
H
i-propyl
n-propyl
CH 2 N(CH 3 ) 2
Br
115.
H
i-propyl
n-propyl
CH 2 —N-piperdinyl
Br
116.
H
i-propyl
n-propyl
CH 2 —N-
Br
morpholinyl
117.
H
i-propyl
n-propyl
cyclopropyl
Br
118.
H
i-propyl
n-propyl
CH 2 -cyclopropyl
Br
119.
H
i-propyl
n-propyl
2-tetrahydrofuranyl
Br
120.
H
i-propyl
n-propyl
CH 2 -2-tetra-
Br
hydrofuran
121.
H
i-propyl
n-propyl
2-tetrahydrothienyl
Br
122.
H
i-propyl
n-propyl
CH 2 OCH 3
I
123.
H
i-propyl
n-propyl
CH 3
I
124.
H
i-propyl
n-propyl
CH 2 OH
I
125.
H
i-propyl
n-propyl
CH 2 N(CH 3 ) 2
I
126.
H
i-propyl
n-propyl
CH 2 —N-piperdinyl
I
127.
H
i-propyl
n-propyl
CH 2 —N-
I
morpholinyl
128.
H
i-propyl
n-propyl
cyclopropyl
I
129.
H
i-propyl
n-propyl
CH 2 -cyclopropyl
I
130.
H
i-propyl
n-propyl
2-tetrahydrofuranyl
I
131.
H
i-propyl
n-propyl
CH 2 -2-tetra-
I
hydrofuran
132.
H
i-propyl
n-propyl
2-tetrahydrothienyl
I
133.
H
n-butyl
n-propyl
CH 2 OCH 3
H
134.
H
n-butyl
n-propyl
CH 3
H
135.
H
n-butyl
n-propyl
CH 2 OH
H
136.
H
n-butyl
n-propyl
CH 2 N(CH 3 ) 2
H
137.
H
n-butyl
n-propyl
CH 2 —N-piperdinyl
H
138.
H
n-butyl
n-propyl
CH 2 —N-
H
morpholinyl
139.
H
n-butyl
n-propyl
cyclopropyl
H
140.
H
n-butyl
n-propyl
CH 2 -cyclopropyl
H
141.
H
n-butyl
n-propyl
2-tetrahydrofuranyl
H
142.
H
n-butyl
n-propyl
CH 2 -2-tetra-
H
hydrofuran
143.
H
n-butyl
n-propyl
2-tetrahydrothienyl
H
144.
H
n-butyl
n-propyl
CH 2 OCH 3
CF 3
145.
H
n-butyl
n-propyl
CH 3
CF 3
146.
H
n-butyl
n-propyl
CH 2 OH
CF 3
147.
H
n-butyl
n-propyl
CH 2 N(CH 3 ) 2
CF 3
148.
H
n-butyl
n-propyl
CH 2 —N-piperdinyl
CF 3
149.
H
n-butyl
n-propyl
CH 2 —N-
CF 3
morpholinyl
150.
H
n-butyl
n-propyl
cyclopropyl
CF 3
151.
H
n-butyl
n-propyl
CH 2 -cyclopropyl
CF 3
152.
H
n-butyl
n-propyl
2-tetrahydrofuranyl
CF 3
153.
H
n-butyl
n-propyl
CH 2 -2-tetra-
CF 3
hydrofuran
154.
H
n-butyl
n-propyl
2-tetrahydrothienyl
CF 3
155.
H
n-butyl
n-propyl
CH 2 OCH 3
F
156.
H
n-butyl
n-propyl
CH 3
F
157.
H
n-butyl
n-propyl
CH 2 OH
F
158.
H
n-butyl
n-propyl
CH 2 N(CH 3 ) 2
F
159.
H
n-butyl
n-propyl
CH 2 —N-piperdinyl
F
160.
H
n-butyl
n-propyl
CH 2 —N-
F
morpholinyl
161.
H
n-butyl
n-propyl
cyclopropyl
F
162.
H
n-butyl
n-propyl
CH 2 -cyclopropyl
F
163.
H
n-butyl
n-propyl
2-tetrahydrofuranyl
F
164.
H
n-butyl
n-propyl
CH 2 -2-tetra-
F
hydrofuran
165.
H
n-butyl
n-propyl
2-tetrahydrothienyl
F
166.
H
n-butyl
n-propyl
CH 2 OCH 3
Cl
167.
H
n-butyl
n-propyl
CH 3
Cl
168.
H
n-butyl
n-propyl
CH 2 OH
Cl
169.
H
n-butyl
n-propyl
CH 2 N(CH 3 ) 2
Cl
170.
H
n-butyl
n-propyl
CH 2 —N-piperdinyl
Cl
171.
H
n-butyl
n-propyl
CH 2 —N-
Cl
morpholinyl
172.
H
n-butyl
n-propyl
cyclopropyl
Cl
173.
H
n-butyl
n-propyl
CH 2 -cyclopropyl
Cl
174.
H
n-butyl
n-propyl
2-tetrahydrofuranyl
Cl
175.
H
n-butyl
n-propyl
CH 2 -2-tetra-
Cl
hydrofuran
176.
H
n-butyl
n-propyl
2-tetrahydrothienyl
Cl
177.
H
n-butyl
n-propyl
CH 2 OCH 3
Br
178.
H
n-butyl
n-propyl
CH 3
Br
179.
H
n-butyl
n-propyl
CH 2 OH
Br
180.
H
n-butyl
n-propyl
CH 2 N(CH 3 ) 2
Br
181.
H
n-butyl
n-propyl
CH 2 —N-piperdinyl
Br
182.
H
n-butyl
n-propyl
CH 2 —N-
Br
morpholinyl
183.
H
n-butyl
n-propyl
cyclopropyl
Br
184.
H
n-butyl
n-propyl
CH 2 -cyclopropyl
Br
185.
H
n-butyl
n-propyl
2-tetrahydrofuranyl
Br
186.
H
n-butyl
n-propyl
CH 2 -2-tetra-
Br
hydrofuran
187.
H
n-butyl
n-propyl
2-tetrahydrothienyl
Br
188.
H
n-butyl
n-propyl
CH 2 OCH 3
I
189.
H
n-butyl
n-propyl
CH 3
I
190.
H
n-butyl
n-propyl
CH 2 OH
I
191.
H
n-butyl
n-propyl
CH 2 N(CH 3 ) 2
I
192.
H
n-butyl
n-propyl
CH 2 —N-piperdinyl
I
193.
H
n-butyl
n-propyl
CH 2 —N-
I
morpholinyl
194.
H
n-butyl
n-propyl
cyclopropyl
I
195.
H
n-butyl
n-propyl
CH 2 -cyclopropyl
I
196.
H
n-butyl
n-propyl
2-tetrahydrofuranyl
I
197.
H
n-butyl
n-propyl
CH 2 -2-tetra-
I
hydrofuran
198.
H
n-butyl
n-propyl
2-tetrahydrothienyl
I
199.
H
i-butyl
n-propyl
CH 2 OCH 3
H
200.
H
i-butyl
n-propyl
CH 3
H
201.
H
i-butyl
n-propyl
CH 2 OH
H
202.
H
i-butyl
n-propyl
CH 2 N(CH 3 ) 2
H
203.
H
i-butyl
n-propyl
CH 2 —N-piperdinyl
H
204.
H
i-butyl
n-propyl
CH 2 —N-
H
morpholinyl
205.
H
i-butyl
n-propyl
cyclopropyl
H
206.
H
i-butyl
n-propyl
CH 2 -cyclopropyl
H
207.
H
i-butyl
n-propyl
2-tetrahydrofuranyl
H
208.
H
i-butyl
n-propyl
CH 2 -2-tetra-
H
hydrofuran
209.
H
i-butyl
n-propyl
2-tetrahydrothienyl
H
210.
H
i-butyl
n-propyl
CH 2 OCH 3
CF 3
211.
H
i-butyl
n-propyl
CH 3
CF 3
212.
H
i-butyl
n-propyl
CH 2 OH
CF 3
213.
H
i-butyl
n-propyl
CH 2 N(CH 3 ) 2
CF 3
214.
H
i-butyl
n-propyl
CH 2 —N-piperdinyl
CF 3
215.
H
i-butyl
n-propyl
CH 2 —N-
CF 3
morpholinyl
216.
H
i-butyl
n-propyl
cyclopropyl
CF 3
217.
H
i-butyl
n-propyl
CH 2 -cyclopropyl
CF 3
218.
H
i-butyl
n-propyl
2-tetrahydrofuranyl
CF 3
219.
H
i-butyl
n-propyl
CH 2 -2-tetra-
CF 3
hydrofuran
220.
H
i-butyl
n-propyl
2-tetrahydrothienyl
CF 3
221.
H
i-butyl
n-propyl
CH 2 OCH 3
F
222.
H
i-butyl
n-propyl
CH 3
F
223.
H
i-butyl
n-propyl
CH 2 OH
F
224.
H
i-butyl
n-propyl
CH 2 N(CH 3 ) 2
F
225.
H
i-butyl
n-propyl
CH 2 —N-piperdinyl
F
226.
H
i-butyl
n-propyl
CH 2 —N-
F
morpholinyl
227.
H
i-butyl
n-propyl
cyclopropyl
F
228.
H
i-butyl
n-propyl
CH 2 -cyclopropyl
F
229.
H
i-butyl
n-propyl
2-tetrahydrofuranyl
F
230.
H
i-butyl
n-propyl
CH 2 -2-tetra-
F
hydrofuran
231.
H
i-butyl
n-propyl
2-tetrahydrothienyl
F
232.
H
i-butyl
n-propyl
CH 2 OCH 3
Cl
233.
H
i-butyl
n-propyl
CH 3
Cl
234.
H
i-butyl
n-propyl
CH 2 OH
Cl
235.
H
i-butyl
n-propyl
CH 2 N(CH 3 ) 2
Cl
236.
H
i-butyl
n-propyl
CH 2 —N-piperdinyl
Cl
237.
H
i-butyl
n-propyl
CH 2 —N-
Cl
morpholinyl
238.
H
i-butyl
n-propyl
cyclopropyl
Cl
239.
H
i-butyl
n-propyl
CH 2 -cyclopropyl
Cl
240.
H
i-butyl
n-propyl
2-tetrahydrofuranyl
Cl
241.
H
i-butyl
n-propyl
CH 2 -2-tetra-
Cl
hydrofuran
242.
H
i-butyl
n-propyl
2-tetrahydrothienyl
Cl
243.
H
i-butyl
n-propyl
CH 2 OCH 3
Br
244.
H
i-butyl
n-propyl
CH 3
Br
245.
H
i-butyl
n-propyl
CH 2 OH
Br
246.
H
i-butyl
n-propyl
CH 2 N(CH 3 ) 2
Br
247.
H
i-butyl
n-propyl
CH 2 —N-piperdinyl
Br
248.
H
i-butyl
n-propyl
CH 2 —N-
Br
morpholinyl
249.
H
i-butyl
n-propyl
cyclopropyl
Br
250.
H
i-butyl
n-propyl
CH 2 -cyclopropyl
Br
251.
H
i-butyl
n-propyl
2-tetrahydrofuranyl
Br
252.
H
i-butyl
n-propyl
CH 2 -2-tetra-
Br
hydrofuran
253.
H
i-butyl
n-propyl
2-tetrahydrothienyl
Br
254.
H
i-butyl
n-propyl
CH 2 OCH 3
I
255.
H
i-butyl
n-propyl
CH 3
I
256.
H
i-butyl
n-propyl
CH 2 OH
I
257.
H
i-butyl
n-propyl
CH 2 N(CH 3 ) 2
I
258.
H
i-butyl
n-propyl
CH 2 —N-piperdinyl
I
259.
H
i-butyl
n-propyl
CH 2 —N-
I
morpholinyl
260.
H
i-butyl
n-propyl
cyclopropyl
I
261.
H
i-butyl
n-propyl
CH 2 -cyclopropyl
I
262.
H
i-butyl
n-propyl
2-tetrahydrofuranyl
I
263.
H
i-butyl
n-propyl
CH 2 -2-tetra-
I
hydrofuran
264.
H
i-butyl
n-propyl
2-tetrahydrothienyl
I
265.
H
cyclobutyl
n-propyl
CH 2 OCH 3
H
266.
H
cyclobutyl
n-propyl
CH 3
H
267.
H
cyclobutyl
n-propyl
CH 2 OH
H
268.
H
cyclobutyl
n-propyl
CH 2 N(CH 3 ) 2
H
269.
H
cyclobutyl
n-propyl
CH 2 —N-piperdinyl
H
270.
H
cyclobutyl
n-propyl
CH 2 —N-
H
morpholinyl
271.
H
cyclobutyl
n-propyl
cyclopropyl
H
272.
H
cyclobutyl
n-propyl
CH 2 -cyclopropyl
H
273.
H
cyclobutyl
n-propyl
2-tetrahydrofuranyl
H
274.
H
cyclobutyl
n-propyl
CH 2 -2-tetra-
H
hydrofuran
275.
H
cyclobutyl
n-propyl
2-tetrahydrothienyl
H
276.
H
cyclobutyl
n-propyl
CH 2 OCH 3
CF 3
277.
H
cyclobutyl
n-propyl
CH 3
CF 3
278.
H
cyclobutyl
n-propyl
CH 2 OH
CF 3
279.
H
cyclobutyl
n-propyl
CH 2 N(CH 3 ) 2
CF 3
280.
H
cyclobutyl
n-propyl
CH 2 —N-piperdinyl
CF 3
281.
H
cyclobutyl
n-propyl
CH 2 —N-
CF 3
morpholinyl
282.
H
cyclobutyl
n-propyl
cyclopropyl
CF 3
283.
H
cyclobutyl
n-propyl
CH 2 -cyclopropyl
CF 3
284.
H
cyclobutyl
n-propyl
2-tetrahydrofuranyl
CF 3
285.
H
cyclobutyl
n-propyl
CH 2 -2-tetra-
CF 3
hydrofuran
286.
H
cyclobutyl
n-propyl
2-tetrahydrothienyl
CF 3
287.
H
cyclobutyl
n-propyl
CH 2 OCH 3
F
288.
H
cyclobutyl
n-propyl
CH 3
F
289.
H
cyclobutyl
n-propyl
CH 2 OH
F
290.
H
cyclobutyl
n-propyl
CH 2 N(CH 3 ) 2
F
291.
H
cyclobutyl
n-propyl
CH 2 —N-piperdinyl
F
292.
H
cyclobutyl
n-propyl
CH 2 —N-
F
morpholinyl
293.
H
cyclobutyl
n-propyl
cyclopropyl
F
294.
H
cyclobutyl
n-propyl
CH 2 -cyclopropyl
F
295.
H
cyclobutyl
n-propyl
2-tetrahydrofuranyl
F
296.
H
cyclobutyl
n-propyl
CH 2 -2-tetra-
F
hydrofuran
297.
H
cyclobutyl
n-propyl
2-tetrahydrothienyl
F
298.
H
cyclobutyl
n-propyl
CH 2 OCH 3
Cl
299.
H
cyclobutyl
n-propyl
CH 3
Cl
300.
H
cyclobutyl
n-propyl
CH 2 OH
Cl
301.
H
cyclobutyl
n-propyl
CH 2 N(CH 3 ) 2
Cl
302.
H
cyclobutyl
n-propyl
CH 2 —N-piperdinyl
Cl
303.
H
cyclobutyl
n-propyl
CH 2 —N-
Cl
morpholinyl
304.
H
cyclobutyl
n-propyl
cyclopropyl
Cl
305.
H
cyclobutyl
n-propyl
CH 2 -cyclopropyl
Cl
306.
H
cyclobutyl
n-propyl
2-tetrahydrofuranyl
Cl
307.
H
cyclobutyl
n-propyl
CH 2 -2-tetra-
Cl
hydrofuran
308.
H
cyclobutyl
n-propyl
2-tetrahydrothienyl
Cl
309.
H
cyclobutyl
n-propyl
CH 2 OCH 3
Br
310.
H
cyclobutyl
n-propyl
CH 3
Br
311.
H
cyclobutyl
n-propyl
CH 2 OH
Br
312.
H
cyclobutyl
n-propyl
CH 2 N(CH 3 ) 2
Br
313.
H
cyclobutyl
n-propyl
CH 2 —N-piperdinyl
Br
314.
H
cyclobutyl
n-propyl
CH 2 —N-
Br
morpholinyl
315.
H
cyclobutyl
n-propyl
cyclopropyl
Br
316.
H
cyclobutyl
n-propyl
CH 2 -cyclopropyl
Br
317.
H
cyclobutyl
n-propyl
2-tetrahydrofuranyl
Br
318.
H
cyclobutyl
n-propyl
CH 2 -2-tetra-
Br
hydrofuran
319.
H
cyclobutyl
n-propyl
2-tetrahydrothienyl
Br
320.
H
cyclobutyl
n-propyl
CH 2 OCH 3
I
321.
H
cyclobutyl
n-propyl
CH 3
I
322.
H
cyclobutyl
n-propyl
CH 2 OH
I
323.
H
cyclobutyl
n-propyl
CH 2 N(CH 3 ) 2
I
324.
H
cyclobutyl
n-propyl
CH 2 —N-piperdinyl
I
325.
H
cyclobutyl
n-propyl
CH 2 —N-
I
morpholinyl
326.
H
cyclobutyl
n-propyl
cyclopropyl
I
327.
H
cyclobutyl
n-propyl
CH 2 -cyclopropyl
I
328.
H
cyclobutyl
n-propyl
2-tetrahydrofuranyl
I
329.
H
cyclobutyl
n-propyl
CH 2 -2-tetra-
I
hydrofuran
330.
H
cyclobutyl
n-propyl
2-tetrahydrothienyl
I
331.
H
cyclopropylmethyl-
n-propyl
CH 2 OCH 3
H
332.
H
cyclopropylmethyl-
n-propyl
CH 3
H
333.
H
cyclopropylmethyl-
n-propyl
CH 2 OH
H
334.
H
cyclopropylmethyl-
n-propyl
CH 2 N(CH 3 ) 2
H
335.
H
cyclopropylmethyl-
n-propyl
CH 2 —N-piperdinyl
H
336.
H
cyclopropylmethyl-
n-propyl
CH 2 —N-
H
morpholinyl
337.
H
cyclopropylmethyl-
n-propyl
cyclopropyl
H
338.
H
cyclopropylmethyl-
n-propyl
CH 2 -cyclopropyl
H
339.
H
cyclopropylmethyl-
n-propyl
2-tetrahydrofuranyl
H
340.
H
cyclopropylmethyl-
n-propyl
CH 2 -2-tetra-
H
hydrofuran
341.
H
cyclopropylmethyl-
n-propyl
2-tetrahydrothienyl
H
342.
H
cyclopropylmethyl-
n-propyl
CH 2 OCH 3
CF 3
343.
H
cyclopropylmethyl-
n-propyl
CH 3
CF 3
344.
H
cyclopropylmethyl-
n-propyl
CH 2 OH
CF 3
345.
H
cyclopropylmethyl-
n-propyl
CH 2 N(CH 3 ) 2
CF 3
346.
H
cyclopropylmethyl-
n-propyl
CH 2 —N-piperdinyl
CF 3
347.
H
cyclopropylmethyl-
n-propyl
CH 2 —N-
CF 3
morpholinyl
348.
H
cyclopropylmethyl-
n-propyl
cyclopropyl
CF 3
349.
H
cyclopropylmethyl-
n-propyl
CH 2 -cyclopropyl
CF 3
350.
H
cyclopropylmethyl-
n-propyl
2-tetrahydrofuranyl
CF 3
351.
H
cyclopropylmethyl-
n-propyl
CH 2 -2-tetra-
CF 3
hydrofuran
352.
H
cyclopropylmethyl-
n-propyl
2-tetrahydrothienyl
CF 3
353.
H
cyclopropylmethyl-
n-propyl
CH 2 OCH 3
F
354.
H
cyclopropylmethyl-
n-propyl
CH 3
F
355.
H
cyclopropylmethyl-
n-propyl
CH 2 OH
F
356.
H
cyclopropylmethyl-
n-propyl
CH 2 N(CH 3 ) 2
F
357.
H
cyclopropylmethyl-
n-propyl
CH 2 —N-piperdinyl
F
358.
H
cyclopropylmethyl-
n-propyl
CH 2 —N-
F
morpholinyl
359.
H
cyclopropylmethyl-
n-propyl
cyclopropyl
F
360.
H
cyclopropylmethyl-
n-propyl
CH 2 -cyclopropyl
F
361.
H
cyclopropylmethyl-
n-propyl
2-tetrahydrofuranyl
F
362.
H
cyclopropylmethyl-
n-propyl
CH 2 -2-tetra-
F
hydrofuran
363.
H
cyclopropylmethyl-
n-propyl
2-tetrahydrothienyl
F
364.
H
cyclopropylmethyl-
n-propyl
CH 2 OCH 3
Cl
365.
H
cyclopropylmethyl-
n-propyl
CH 3
Cl
366.
H
cyclopropylmethyl-
n-propyl
CH 2 OH
Cl
367.
H
cyclopropylmethyl-
n-propyl
CH 2 N(CH 3 ) 2
Cl
368.
H
cyclopropylmethyl-
n-propyl
CH 2 —N-piperdinyl
Cl
369.
H
cyclopropylmethyl-
n-propyl
CH 2 —N-
Cl
morpholinyl
370.
H
cyclopropylmethyl-
n-propyl
cyclopropyl
Cl
371.
H
cyclopropylmethyl-
n-propyl
CH 2 -cyclopropyl
Cl
372.
H
cyclopropylmethyl-
n-propyl
2-tetrahydrofuranyl
Cl
373.
H
cyclopropylmethyl-
n-propyl
CH 2 -2-tetra-
Cl
hydrofuran
374.
H
cyclopropylmethyl-
n-propyl
2-tetrahydrothienyl
Cl
375.
H
cyclopropylmethyl-
n-propyl
CH 2 OCH 3
Br
376.
H
cyclopropylmethyl-
n-propyl
CH 3
Br
377.
H
cyclopropylmethyl-
n-propyl
CH 2 OH
Br
378.
H
cyclopropylmethyl-
n-propyl
CH 2 N(CH 3 ) 2
Br
379.
H
cyclopropylmethyl-
n-propyl
CH 2 —N-piperdinyl
Br
380.
H
cyclopropylmethyl-
n-propyl
CH 2 —N-
Br
morpholinyl
381.
H
cyclopropylmethyl-
n-propyl
cyclopropyl
Br
382.
H
cyclopropylmethyl-
n-propyl
CH 2 -cyclopropyl
Br
383.
H
cyclopropylmethyl-
n-propyl
2-tetrahydrofuranyl
Br
384.
H
cyclopropylmethyl-
n-propyl
CH 2 -2-tetra-
Br
hydrofuran
385.
H
cyclopropylmethyl-
n-propyl
2-tetrahydrothienyl
Br
386.
H
cyclopropylmethyl-
n-propyl
CH 2 OCH 3
I
387.
H
cyclopropylmethyl-
n-propyl
CH 3
I
388.
H
cyclopropylmethyl-
n-propyl
CH 2 OH
I
389.
H
cyclopropylmethyl-
n-propyl
CH 2 N(CH 3 ) 2
I
390.
H
cyclopropylmethyl-
n-propyl
CH 2 —N-piperdinyl
I
391.
H
cyclopropylmethyl-
n-propyl
CH 2 —N-
I
morpholinyl
392.
H
cyclopropylmethyl-
n-propyl
cyclopropyl
I
393.
H
cyclopropylmethyl-
n-propyl
CH 2 -cyclopropyl
I
394.
H
cyclopropylmethyl-
n-propyl
2-tetrahydrofuranyl
I
395.
H
cyclopropylmethyl-
n-propyl
CH 2 -2-tetra-
I
hydrofuran
396.
H
cyclopropylmethyl-
n-propyl
2-tetrahydrothienyl
I
10. A pharmaceutical composition, comprising:
(a) a of a compound of claim 1 ; and
(b) a pharmaceutically acceptable excipient.