# US 9,434,727 B2 · Substituted 4-phenylpiperidines, their preparation and use

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- Number: US 9,434,727 B2
- Document ID: US9434727B2
- Status: Granted
- Kind: B2
- Application number: 14/699,672
- Filed: 2015-04-29
- Published: 2015-11-05
- Granted: 2016-09-06
- Earliest claimed: 2014-04-30
- Assignees: The Trustees of Columbia University in the City of New York
- Applicants: Konstantin Petrukhin; Christopher Cioffi; Graham Johnson; Rando Allikmets; Emily Freeman; Ping Chen; Michael Conlon; Lei Zhu
- Inventors: Konstantin Petrukhin; Christopher Cioffi; Graham Johnson; Rando Allikmets; Emily Freeman; Ping Chen; Michael Conlon; Lei Zhu
- Web page: https://patentgrep.com/patent/US9434727B2

## CPC

- A61P 27/02: Ophthalmic agents
- C07D 487/04: Ortho-condensed systems
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- C07D 471/04: Ortho-condensed systems
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

The present invention provides a compound having the structure: wherein R1, R2, R3, R4, and R5 are each independently H, halogen, CF3 or C1-C4 alkyl, wherein two or more of R1, R2, R3, R4, or R5 are other than H; R6 is H, OH, or halogen; and B is a substituted or unsubstituted heterobicycle, wherein when R1 is CF3, R2 is H, R3 is F, R4 is H, and R5 is H, or R1 is H, R2 is CF3, R3 is H, R4 is CF3, and R5 is H, or R1 is Cl, R2 is H, R3 is H, R4 is F, and R5 is H, or R1 is CF3, R2 is H, R3 is F, R4 is H, and R5 is H, or R1 is CF3, R2 is F, R3 is H, R4 is H, and R5 is H, or R1 is Cl, R2 is F, R3 is H, R4 is H, and R5 is H, then B is other than or a pharmaceutically acceptable salt thereof.

## Claims

### Claim 1

A compound having the structure:
wherein
R1, R2, R3, R4, and R5 are each independently H, halogen, CF3 or C1-C4 alkyl,
wherein two or more of R1, R2, R3, R4, or R5 are other than H;
R6 is H, OH, or halogen; and
B has the structure:
wherein
α, β, χ, and δ are each independently absent or present, and when present each is a bond;
X is C or N;
Z1 is N;
Z2 is N or NR7,
wherein R7 is H, C1-C4 alkyl, or oxetane; and
Q is a substituted or unsubstituted 5, 6, or 7 membered ring structure,
wherein
when R1 is CF3, R2 is H, R3 is F, R4 is H, and R5 is H, or
R1 is H, R2 is CF3, R3 is H, R4 is CF3, and R5 is H, or
R1 is Cl, R2 is H, R3 is H, R4 is F, and R5 is H, or
R1 is CF3, R2 is H, R3 is F, R4 is H, and R5 is H, or
R1 is CF3, R2 is F, R3 is H, R4 is H, and R5 is H, or
R1 is Cl, R2 is F, R3 is H, R4 is H, and R5 is H, then B is other than
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1,
wherein when R1 is CF3, R2 is H, R3 is F, R4 is H, and R5 is H, or
R1 is H, R2 is CF3, R3 is H, R4 is CF3, and R5 is H, or
R1 is Cl, R2 is H, R3 is H, R4 is F, and R5 is H, or
R1 is CF3, R2 is H, R3 is F, R4 is H, and R5 is H, or
R1 is CF3, R2 is F, R3 is H, R4 is H, and R5 is H, or
R1 is Cl, R2 is F, R3 is H, R4 is H, and R5 is H,
then B is other than
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound of claim 1,
wherein
R1 is CF3, R2 is F, R3 is F, R4 is H, and R5 is H, or
R1 is CF3, R2 is F, R3 is H, R4 is H, and R5 is H, or
R1 is CF3, R2 is F, R3 is H, R4 is F, and R5 is H, or
R1 is CF3, R2 is H, R3 is F, R4 is F, and R5 is H, or
R1 is CF3, R2 is H, R3 is H, R4 is H, and R5 is F, or
R1 is CF3, R2 is H, R3 is F, R4 is H, and R5 is H, or
R1 is CF3, R2 is H, R3 is H, R4 is Cl, and R5 is H, or
R1 is CF3, R2 is Cl, R3 is H, R4 is H, and R5 is H, or
R1 is H, R2 is CF3, R3 is H, R4 is CF3, and R5 is H, or
R1 is Cl, R2 is H, R3 is H, R4 is F, and R5 is H, or
R1 is Cl, R2 is F, R3 is H, R4 is H, and R5 is H.

### Claim 4 (depends on 1)

The compound of claim 1, wherein B has the structure:
wherein
when α is present, then Z1 and Z2 are N, X is N, β is present, and χ and δ are absent; and
when α is absent, then Z1 is N, Z2 is N—R7, X is C, β and δ are present, and χ is absent.

### Claim 5 (depends on 4)

The compound of claim 4, wherein B has the structure:
wherein
n is an integer from 0-2;
α, ρ, χ, δ, ε, and φ are each independently absent or present, and when present each is a bond;
Z1 is N;
Z2 is N or N—R7,
wherein R7 is H, C1-C10 alkyl, or oxetane;
X is C or N; and
Y1, Y2, Y3, and each occurrence of Y4 are each independently CR8, CH2, or N—R9,
wherein
R8 is H, halogen, OCH3, CN, or CF3; and
R9 is H, CN, oxetane, C1-C6 alkyl, C3-C6 cycloalkyl, (C1-C4 alkyl) (C3-C6 cycloalkyl), (C1-C5 alkyl)-OCH3, (C1-C6 alkyl)-CF3, C(O)—(C1-C6 alkyl), C(O)2—(C1-C6 alkyl), C(O)—NH2C(O)NH—(C1-C6 alkyl), C(O)—(C6 aryl), C(O)—(C6 heteroaryl), C(O)-pyrrolidine, C(O)-piperidine, C(O)-piperazine, (C1-C6 alkyl)-CO2H, (C1-C6 alkyl)-CO2(C1-C6 alkyl) or SO2—(C1-C6 alkyl).

### Claim 6 (depends on 5)

The compound of claim 5, wherein B has the structure:
wherein
n is 0;
R7 is H, C1-C4 alkyl, or oxetane;
Y1 and Y3 are each CH2; and
Y2 is N—R9,
wherein
R9 is H, CN, oxetane, C1-C6 alkyl, C3-C6 cycloalkyl, (C1-C4 alkyl) (C3-C6 cycloalkyl), (C1-C6 alkyl)-OCH3, (C1-C6 alkyl)-CF3, C(O)—(C1-C6 alkyl), C(O)2—(C1-C6 alkyl), C(O)—NH2C(O)NH—(C1-C6 alkyl), C(O)—(C6 aryl), C(O)—(C6 heteroaryl), C(O)-pyrrolidine, C(O)-piperidine, C(O)-piperazine, (C1-C6 alkyl)-CO2H, (C1-C6 alkyl)-CO2(C1-C6 alkyl) or SO2—(C1-C6 alkyl); or
B has the structure:
wherein
n is 1;
R7 is H, C1-C4 alkyl, or oxetane;
Y1, Y2 and Y4 are each CH2; and
Y3 is N—R9,
wherein
R9 is H, CN, oxetane, C1-C6 alkyl, C3-C6 cycloalkyl, (C1-C4 alkyl) (C3-C6 cycloalkyl), (C1-C6 alkyl)-OCH9, (C1-C6 alkyl)-CF3, C(O)—(C1-C6 alkyl), C(O)2—(C1-C6 alkyl), C(O)—NH2C(O)NH—(C1-C6 alkyl), C(O)—(C6 aryl), C(O)—(C6 heteroaryl), C(O)-pyrrolidine, C(O)-piperidine, C(O)-piperazine, (C1-C5 alkyl)-CO2H, (C1-C6 alkyl)-CO2(C1-C6 alkyl) or SO2—(C1-C6 alkyl); or
B has the structure:
wherein
n is 1;
R7 is H, C1-C4 alkyl, or oxetane;
Y1, Y3 and Y4 are each CH2; and
Y2 is N—R9,
wherein
R9 is H, CN, oxetane, C1-C6 alkyl, C3-C6 cycloalkyl, (C1-C4 alkyl) (C3-C6 cycloalkyl), (C1-C6 alkyl)-OCH3, (C1-C6 alkyl)-CF3, C(O)—(C1-C6 alkyl), C(O)2—(C1-C6 alkyl), C(O)—NH2C(O)NH—(C1-C6 alkyl), C(O)—(C6 aryl), C(O)—(C6 heteroaryl), C(O)-pyrrolidine, C(O)-piperidine, C(O)-piperazine, (C1-C6 alkyl)-CO2H, (C1-C6 alkyl)-CO2(C1-C6 alkyl) or SO2—(C1-C6 alkyl).

### Claim 7 (depends on 6)

The compound of claim 6, wherein B has the structure:

### Claim 8 (depends on 7)

The compound of claim 7,
wherein R9 is H, CN, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, t-Bu, CH2CH(CH3)2, CH2C(CH3)3, CH2CF3, CH2CH2CF3, CH2OCH3, CH2CH2OCH3,
SO2, CH3, C(O)—CH3, C(O)—CH2CH3, C(O)—CH2CH2CH3, C(O)—CH(CH3)2, C(O)—CH2CH(CH3)2, C(O)-t-Bu, C(O)—OCH3, C(O)—NHCH3,

### Claim 9 (depends on 6)

The compound of claim 6,
wherein
R7 is H, CH3, CH2CH3, CH(CH3)2, or

### Claim 10 (depends on 5)

The compound of claim 5, wherein B has the structure:
wherein
Y1, Y2, Y3 and Y4 are each independently CR8 or N,
wherein each R8 is independently H, halogen, OCH3, CN, or CF3.

### Claim 11 (depends on 10)

The compound of claim 10, wherein B has the structure:
wherein each R8 is CN or OCH3.

### Claim 12 (depends on 8)

The compound of claim 8 having the structure:
or a pharmaceutically acceptable salt of the compound.

### Claim 13 (depends on 11)

The compound of claim 11 having the structure:
or a pharmaceutically acceptable salt of the compound.

### Claim 14 (depends on 1)

The compound of claim 1 having the structure:
or a pharmaceutically acceptable salt of the compound.

### Claim 15 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.