# US 2010/0168091 A1 · Imidazole Amines As Inhibitors Of Beta-secretase

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- Number: US 2010/0168091 A1
- Document ID: US20100168091A1
- Status: Published application
- Kind: A1
- Application number: 12/718,771
- Filed: 2010-03-05
- Published: 2010-07-01
- Earliest claimed: 2006-08-17
- Assignees: Wyeth
- Inventors: Michael Sotirios Malamas; Keith Douglas Barnes; Matthew Robert Johnson
- Web page: https://patentgrep.com/patent/US20100168091A1

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- C07D 498/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides a compound of formula I and the use thereof for the therapeutic treatment, prevention or amelioration of a disease or disorder characterized by elevated 3-amyloid deposits or 3-amyloid levels in a patient.

## Claims

### Claim 1

A compound of formula I
wherein
Q is O, S or CH2;
W is O, S or CH2;
X is N, NO, SOm, O or CH;
Y is N, NO, SOm, O or CR10;
Z is N, NO, SOm, O or CR11 with the proviso that when X is CH, Y is CR10 and Z is CR11 then one of Q or W must be O or S;
m is 0, 1 or 2;
n is 0 or 1;
R1 and R2 are each independently H or an optionally substituted C1-C4alkyl group;
R3 and R4 are each independently H, or an optionally substituted C1-C4 alkyl group or R3 and R4 may be taken together to form a 4- to 7-membered ring optionally containing one or two heteroatoms selected from O, N or S;
R5 and R6 are each independently H, halogen, NO2, CN, OR12, CO2R13, COR14, NR17R18, SOpNR19R20 or a C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl or C3-C8cycloalkyl group each optionally substituted;
R7 and R8 are each independently H, halogen, NO2, CN, OR15, NR17R18 or a C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl or cycloheteroalkyl group each optionally substituted or when attached to adjacent carbon atoms R7 and R8 may be taken together with the atoms to which they are attached to form an optionally substituted 5- to 7-membered ring optionally containing one or two heteroatoms selected from O, N or S;
R9 is H, halogen, NO2, CN, OR15, NR17R18 or a C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R10 and R11 are each independently H or a C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, cycloheteroalkyl or aryl group each optionally substituted;
R12, R13, R14 and R15 are each independently H or a C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R17, R18, R19 and R20 are each independently H, C1-C4alkyl, C3-C8cycloalkyl or R17 and R18 or R19 and R20 may be taken together with the atom to which they are attached to form a 5- to 7-membered ring optionally containing an additional heteroatom selected from O, N or S; and
p is 0, 1 or 2; or
a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound according to claim 1 wherein R1 and R2 are H.

### Claim 3 (depends on 1)

The compound according to claim 1 wherein R9 is an optionally substituted heteroaryl group.

### Claim 4 (depends on 1)

The compound according to claim 1 wherein X is N.

### Claim 5 (depends on 1)

The compound according to claim 1 wherein R3 and R4 are H.

### Claim 6 (depends on 2)

The compound according to claim 2 wherein R9 is an optionally substituted heteroaryl group and R9 is attached to the phenyl ring in the 3-position of the phenyl ring.

### Claim 7 (depends on 6)

The compound according to claim 6 wherein X is N.

### Claim 8 (depends on 7)

The compound according to claim 7 wherein R3 and R4 are H.

### Claim 9 (depends on 1)

The compound according to claim 1 selected from the group consisting essentially of:
8-[3-(2-fluoropyridin-3-yl)-phenyl]-8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine;
8-(2,6-diethylpyridin-4-yl)-8-[3-(2-fluoropyridin-3-yl)-phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine;
8-(1-ethyl-1H-pyrazol-4-yl)-8-[3-(2-fluoropyridin-3-yl)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine;
8-[3-(2-fluoropyridin-3-yl)phenyl]-8-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine;
8-[3-(2-fluoropyridin-3-yl)phenyl]-8-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-8H-imidazo[5,1-c][1,2,4]oxadiazin-6-amine;
8-[3-(5-fluoropyridin-3-yl)phenyl]-8-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-8H-imidazo[5,1-c][1,2,4]oxadiazin-6-amine;
a tautomer thereof;
a stereoisomer thereof; and
a pharmaceutically acceptable salt thereof.

### Claim 10

A method for the treatment, prevention or amelioration of a disease or disorder characterized by elevated [3-amyloid deposits or [3-amyloid levels in a patient which comprises providing said patient with a therapeutically effective amount of a compound of formula I
wherein
Q is O, S or CH2;
W is O, S or CH2;
X is N, NO, SOm, O or CH;
Y is N, NO, SOm, O or CR10;
Z is N, NO, SOm, O or CR11 with the proviso that when X is CH, Y is CR10 and Z is CR11 then one of Q or W must be O or S;
m is 0, 1 or 2;
n is 0 or 1;
R1 and R2 are each independently H or an optionally substituted C1-C4alkyl group;
R3 and R4 are each independently H, or an optionally substituted C1-C4 alkyl group or R3 and R4 may be taken together to form a 4- to 7-membered ring optionally containing one or two heteroatoms selected from O, N or S;
R5 and R6 are each independently H, halogen, NO2, CN, OR12, CO2R13, COR14, NR17R18, SOpNR19R20 or a C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl or C3-C8cycloalkyl group each optionally substituted;
R7 and R8 are each independently H, halogen, NO2, CN, OR15, NR17R18 or a C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl or cycloheteroalkyl group each optionally substituted or when attached to adjacent carbon atoms R7 and R8 may be taken together with the atoms to which they are attached to form an optionally substituted 5- to 7-membered ring optionally containing one or two heteroatoms selected from O, N or S;
R9 is H, halogen, NO2, CN, OR15, NR17R18 or a C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R10 and R11 are each independently H or a C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, cycloheteroalkyl or aryl group each optionally substituted;
R12, R13, R14 and R15 are each independently H or a C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R17, R18, R19 and R20 are each independently H, C1-C4alkyl, C3-C8cycloalkyl or R17 and R18 or R19 and R20 may be taken together with the atom to which they are attached to form a 5- to 7-membered ring optionally containing an additional heteroatom selected from O, N or S; and
p is 0, 1 or 2; or
a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 10)

The method according to claim 10 wherein said disease or disorder is selected from the group consisting of: Alzheimer's disease; cognitive impairment; Down's Syndrome; HCHWA-D; cognitive decline; senile dementia; cerebral amyloid angiopathy; and a neurodegenerative disorder.

### Claim 12 (depends on 10)

The method according to claim 10 wherein said disease or disorder is characterized by the production of [3-amyloid deposits or neurofibrillary tangles.

### Claim 13 (depends on 1)

A method for inhibiting the activity of BACE which comprises contacting a receptor thereof with an effective amount of a compound of claim 1.

### Claim 14 (depends on 1)

A method for the treatment of Alzheimer's disease in a patient in need thereof which comprises providing to said patient an effective amount of a compound of claim 1.

### Claim 15

A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of formula I
wherein
Q is O, S or CH2;
W is O, S or CH2;
X is N, NO, SOm, O or CH;
Y is N, NO, SOm, O or CR10;
Z is N, NO, SOm, O or CR11 with the proviso that when X is CH, Y is CR10 and Z is CR11 then one of Q or W must be O or S;
m is 0, 1 or 2;
n is 0 or 1;
R1 and R2 are each independently H or an optionally substituted C1-C4alkyl group;
R3 and R4 are each independently H, or an optionally substituted C1-C4 alkyl group or R3 and R4 may be taken together to form a 4- to 7-membered ring optionally containing one or two heteroatoms selected from O, N or S;
R5 and R6 are each independently H, halogen, NO2, CN, OR12, CO2R13, COR14, NR17R18, SOpNR19R20 or a C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl or C3-C8cycloalkyl group each optionally substituted;
R7 and R8 are each independently H, halogen, NO2, CN, OR15, NR17R18 or a C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl or cycloheteroalkyl group each optionally substituted or when attached to adjacent carbon atoms R7 and R8 may be taken together with the atoms to which they are attached to form an optionally substituted 5- to 7-membered ring optionally containing one or two heteroatoms selected from O, N or S;
R9 is H, halogen, NO2, CN, OR15, NR17R18 or a C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R10 and R11 are each independently H or a C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, cycloheteroalkyl or aryl group each optionally substituted;
R12, R13, R14 and R15 are each independently H or a C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R17, R18, R19 and R20 are each independently H, C1-C4alkyl, C3-C8cycloalkyl or R17 and R18 or R19 and R20 may be taken together with the atom to which they are attached to form a 5- to 7-membered ring optionally containing an additional heteroatom selected from O, N or S; and
p is 0, 1 or 2; or
a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 15)

The composition according to claim 15 having a formula I compound wherein R1 and R2 are H.

### Claim 17 (depends on 16)

The composition according to claim 16 having a formula I compound wherein X is N and R3 and R4 are H.

### Claim 18 (depends on 17)

The composition according to claim 17 having a formula I compound wherein R9 is an optionally substituted heteroaryl group and is attached to the phenyl ring in the 3-position of the phenyl ring.

### Claim 19 (depends on 15)

The composition according to claim 15 having a formula I compound selected from the group consisting essentially of:
8-[3-(2-fluoropyridin-3-yl)-phenyl]-8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine;
8-(2,6-diethylpyridin-4-yl)-8-[3-(2-fluoropyridin-3-yl)-phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine;
8-(1-ethyl-1H-pyrazol-4-yl)-8-[3-(2-fluoropyridin-3-yl)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine;
8-[3-(2-fluoropyridin-3-yl)phenyl]-8-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine;
8-[3-(2-fluoropyridin-3-yl)phenyl]-8-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-8H-imidazo[5,1-c][1,2,4]oxadiazin-6-amine;
8-[3-(5-fluoropyridin-3-yl)phenyl]-8-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-8H-imidazo[5,1-c][1,2,4]oxadiazin-6-amine;
a tautomer thereof;
a stereoisomer thereof; and
a pharmaceutically acceptable salt thereof.

### Claim 20

A process for the preparation of a compound of formula Ia
wherein
Q is O, S or CH2;
W is O, S or CH2;
X is N, NO, SOm, O or CH;
Y is N, NO, SOm, O or CR10;
Z is N, NO, SOm, O or CR11 with the proviso that when X is CH, Y is CR10 and Z is CR11 then one of Q or W must be O or S;
m is 0, 1 or 2;
n is 0 or 1;
R1 and R2 are each independently H or an optionally substituted C1-C4alkyl group;
R3 and R4 are each independently H, or an optionally substituted C1-C4 alkyl group or R3 and R4 may be taken together to form a 4- to 7-membered ring optionally containing one or two heteroatoms selected from O, N or S;
R5 and R6 are each independently H, halogen, NO2, CN, OR12, CO2R13, COR14, NR17R18, SOpNR19R20 or a C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl or C3-C8cycloalkyl group each optionally substituted;
R7 and R8 are each independently H, halogen, NO2, CN, OR15, NR17R18 or a C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, 02-06alkynyl, C3-C8cycloalkyl or cycloheteroalkyl group each optionally substituted or when attached to adjacent carbon atoms R7 and R8 may be taken together with the atoms to which they are attached to form an optionally substituted 5- to 7-membered ring optionally containing one or two heteroatoms selected from O, N or S;
R9 is an optionally substituted aryl or heteroaryl group;
R10 and R11 are each independently H or a C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, cycloheteroalkyl or aryl group each optionally substituted;
R12, R13, R14 and R15 are each independently H or a C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R17, R18, R19 and R20 are each independently H, C1-C4alkyl, C3-C8cycloalkyl or R17 and R18 or R19 and R20 may be taken together with the atom to which they are attached to form a 5- to 7-membered ring optionally containing an additional heteroatom selected from O, N or S; and
p is 0, 1 or 2
which process comprises reacting a compound of formula II
wherein Hal is Cl or Br and R1, R2, R3, R4, R5, R6, R7, R8, n, O, W, X, Y and Z are as described for formula la hereinabove with an optionally substituted aryl or heteroaryl group having a leaving group selected from B(OH)2, Sn(nBu)3 or Sn(CH3)3 in the presence of a palladium catalyst optionally in the presence of a solvent.