# US 2016/0355458 A1 · Inhibitors of cognitive decline

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- Number: US 2016/0355458 A1
- Document ID: US20160355458A1
- Status: Published application
- Kind: A1
- Application number: 15/181,211
- Filed: 2016-06-13
- Published: 2016-12-08
- Earliest claimed: 2009-04-09
- Assignees: Cognition Therapeutics, Inc.
- Applicants: Cognition Therapeutics, Inc.
- Inventors: Gilbert M. Rishton; Susan Catalano
- Web page: https://patentgrep.com/patent/US20160355458A1

## CPC

- C07C 217/62: linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
- 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
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 211/27: having amino groups linked to the six-membered aromatic ring by saturated carbon chains
- C07D 207/08: with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D 211/22: by oxygen atoms
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Compounds that are central nervous system drug candidates for the treatment of cognitive decline and, more particularly, Alzheimer's disease are provided. Methods of treating, inhibiting, and/or abatement of cognitive decline and/or Alzheimer's disease with a compound or pharmaceutically acceptable salt of the invention are also provided. Also provided are methods of preparing the compounds/compositions of the invention.

## Claims

### Claim 1

A compound of Formula I:
or pharmaceutically acceptable salt thereof, wherein:
R1 is selected from (A1) and (A2):
R2, R3, R4, R5, and R6 are each, independently, selected from H, OH, C1-6 alkoxy, C1-6 haloalkoxy, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, NH2, NH(C1-4 alkyl), NH(C3-7 cycloalkyl), N(C1-4 alkyl)2, NHC(OX)(C1-4 alkyl), SH, S(C1-6 alkyl), C(O)ORa, C(O)Rb, C(O)NRcRd, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)2Rb, and S(O)2NRcRd;
R7 is H, C1-6 alkyl, C1-6 haloalkyl, or C3-7 cycloalkyl;
R8 is C1-6 alkyl, C1-6 haloalkyl, or C3-7 cycloalkyl;
R9 is H, C1-6 alkyl, C1-6 haloalkyl, or C3-7 cycloalkyl;
R10 is H;
R11 is H;
R12, R13, R14, R15, and R16 are each, independently, selected from H, OH, C1-6 alkoxy, C1-6 haloalkoxy, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, NH2, NH(C1-4 alkyl), NH(C3-7 cycloalkyl), N(C1-4 alkyl)2, NHC(O)(C1-4 alkyl), SH, S(C1-6 alkyl), C(O)ORa1, C(O)Rb1, C(O)NRc1 Rd1, OC(O)Rb1, OC(O)NRc1 Rd1, NRc1 Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, NRc1S(O)2NRc1 Rd1, S(O)Rb1, S(O)2Rb1, and S(O)2NRc1 Rd1;
each Ra is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl, wherein each of the C1-6 alkyl, C1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
each Rb is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein each of the C1-6 alkyl, C1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-4 alkoxy, C1-6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
Rc and Rd are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein each of the C1-6 alkyl, C1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
or Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;
each Ra1 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl, wherein each of the C1-6 alkyl, C1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;
each Rb1 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein each of the C1-6 alkyl, C1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;
Rc1 and Rd2 are independently selected from H, C1-10 alkyl, C1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein each of the C1-10 alkyl, C1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, d-6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;
or Rc1 and Rd1 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; and
m is 0, 1, or 2,
with the proviso that
(a) when R1 is a moiety of (A1), then two of R2, R3, R4, R5, and R6 are independently selected from OH, C1-6 alkoxy, and C1-6 haloalkoxy; and
(b) when R1 is a moiety of (A1), then at least one of R12, R13, R14, R15, and R16 is other than H.

### Claim 2 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein two of R2, R3, R4, R5, and R6 are independently selected from OH, C1-6 alkoxy, and C1-6 haloalkoxy.

### Claim 3 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein R2, R3, R4, R5, and R6 are each, independently, selected from H, OH, C1-6 alkoxy, C1-6 haloalkoxy, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, NH2, NH(C1-4 alkyl), NH(C3-7 cycloalkyl), N(C1-4 alkyl)2, NHC(OX C1-6 alkyl), SH, S(C1-6 alkyl), C(O)OH, C(O)O(C1-4 alkyl), C(O)(C1-4 alkyl), and C(O)NH(C1-4 alkyl).

### Claim 4 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein:
one of R2, R3, R4, R5, and R6 is OH; and
one of R2, R3, R4, R5, and R6 is OH, C1-6 alkoxy, or C1-6haloalkoxy.

### Claim 5 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein:
one of R2, R3, R4, R5, and R6 is OH; and
one of R2, R3, R4, R5, and R6 is C1-3 alkoxy or C1-3 haloalkoxy.

### Claim 6 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein:
one of R2, R3, R4, R5, and R6 is OH; and
one of R2, R3, R4, R5, and R6 is methoxy or trihalomethoxy.

### Claim 7 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein:
one of R2, R3, R4, R5, and R6 is OH; and
one of R2, R3, R4, R5, and R6 is methoxy.

### Claim 8 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein:
R4 is OH; and
R5 is methoxy.

### Claim 9 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein:
R4 is OH;
R5 is methoxy; and
R2, R3, and R6 are each H.

### Claim 10 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein R7 is H or C1-6 alkyl.

### Claim 11 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein R7 is H or C1-3 alkyl.

### Claim 12 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein R7 is C1-3 alkyl.

### Claim 13 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein R7 is H.

### Claim 14 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein R8 is C1-6 alkyl.

### Claim 15 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein R8 is C1-3 alkyl.

### Claim 16 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein R8 is methyl.

### Claim 17 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein R9 is H or C1-6 alkyl.

### Claim 18 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein R9 is H or C1-6 alkyl.

### Claim 19 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein R9 is H.

### Claim 20 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein R9 is C1-3 alkyl.

### Claim 21 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein R10 is H or C1-6 alkyl.

### Claim 22

(canceled)

### Claim 23 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein R10 is H.

### Claim 24

(canceled)

### Claim 25

(canceled)

### Claim 26 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein R11 is H.

### Claim 27 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein at least one of R2, R3, R4, R15, and R16 is other than H.

### Claim 28 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein R12, R13, R14, R15, and R16 are each, independently, selected from H, OH, C1-6 alkoxy, C1-6 haloalkoxy, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, NH2, NH(C1-4 alkyl), NH(C3-7 cycloalkyl), N(C1-4 alkyl)2, NHC(O)(C1-6 alkyl), SH, S(C1-6 alkyl), C(O)OH, C(O)O(C1-6 alkyl), C(O)(C1-4 alkyl), and C(O)NH(C1-4 alkyl).

### Claim 29 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein R12, R13, R14, R15, and R16 are each, independently, selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, C(O)O(C1-4 alkyl), C(O)(C1-4 alkyl), and C(O)NH(C1-4 alkyl).

### Claim 30 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein at least one of R12, R13, R14, R15, and R16 is selected from halo, CN, NO2, C1-6 haloalkyl, C(O)O(C1-6 alkyl), C(O)(C1-4 alkyl), and C(O)NH(C1-4 alkyl).

### Claim 31 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein at least one of R12, R13, R14, R15, and R16 is selected from halo and C1-6 haloalkyl.

### Claim 32 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein R14 is halo.

### Claim 33 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein R14 is C1-6 haloalkyl.

### Claim 34 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein R14 and R15 are independently halo.

### Claim 35

(canceled)

### Claim 36 (depends on 35)

The compound of claim 35 or pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula IIa:

### Claim 37 (depends on 35)

The compound of claim 35 or pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula IIb:

### Claim 38 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula III:

### Claim 39 (depends on 38)

The compound of claim 38 or pharmaceutically acceptable salt thereof, wherein m is 1.

### Claim 40 (depends on 38)

The compound of claim 38 or pharmaceutically acceptable salt thereof, wherein m is 0.

### Claim 41

(canceled)

### Claim 42

(canceled)

### Claim 43 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 44

(canceled)

### Claim 45

(canceled)

### Claim 46

(canceled)

### Claim 47

(canceled)

### Claim 48

(canceled)

### Claim 49

(canceled)

### Claim 50

(canceled)

### Claim 51

(canceled)

### Claim 52

(canceled)

### Claim 53 (depends on 1)

A method of inhibiting, treating, and/or abatement of cognitive decline and/or inhibiting Alzheimer's disease in a patient comprising administrating to the patient a compound of claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 54 (depends on 53)

The method of claim 53 wherein the method comprises inhibiting, treating, or abatement of one or more symptoms of cognitive decline selected from the group consisting of memory loss, confusion, impaired judgment, personality changes, disorientation, and loss of language skills.

### Claim 55 (depends on 53)

The method of claim 53 wherein the method comprises one or more of:
(i) restoration of long term potentiation; and/or
(ii) inhibiting, treating, and/or abatement of neurodegeneration; and/or
(iii) inhibiting, treating, and/or abatement of general amyloidosis; and/or
(iv) inhibiting, treating, and/or abatement of one or more of amyloid production, amyloid assembly, amyloid aggregation, amyloid oligomer binding, and amyloid deposition; and/or
(v) inhibiting, treating, and/or abatement of the activity/effect of one or more of Abeta oligomers on a neuron cell.

### Claim 56 (depends on 53)

The method of claim 53 wherein the method comprises inhibiting, treating, and/or abatement of one or more of amyloid production, amyloid assembly, the activity/effect of one or more of Abeta oligomers on a neuron cell, amyloid aggregation, amyloid binding, and amyloid deposition.

### Claim 57 (depends on 53)

The method of claim 53 wherein the method comprises inhibiting, treating, and/or abatement of one or more of the activity/effect of one or more of Abeta oligomers on a neuron cell, amyloid aggregation, amyloid binding, and amyloid deposition.

### Claim 58 (depends on 1)

A method of inhibiting, treating, and/or abatement of cognitive decline and/or inhibiting Alzheimer's disease in a patient comprising administrating to the patient a compound of claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 59 (depends on 58)

The method of claim 58 wherein the method comprises inhibiting, treating, or abatement of one or more symptoms of cognitive decline selected from the group consisting of memory loss, confusion, impaired judgment, personality changes, disorientation, and loss of language skills.

### Claim 60 (depends on 58)

The method of claim 58 wherein the method one or more of:
(i) restoration of long term potentiation; and/or
(ii) inhibiting, treating, and/or abatement of neurodegeneration; and/or
(iii) inhibiting, treating, and/or abatement of general amyloidosis; and/or
(iv) inhibiting, treating, and/or abatement of one or more of amyloid production, amyloid assembly, amyloid aggregation, amyloid oligomer binding, and amyloid deposition; and/or
(v) inhibiting, treating, and/or abatement of the activity/effect of one or more of Abeta oligomers on a neuron cell.

### Claim 61 (depends on 58)

The method of claim 58 wherein the method comprises inhibiting, treating, and/or abatement of one or more of amyloid production, amyloid assembly, the activity/effect of one or more of Abeta oligomers on a neuron cell, amyloid aggregation, amyloid binding, and amyloid deposition.

### Claim 62 (depends on 58)

The method of claim 58 wherein the method comprises inhibiting, treating, and/or abatement of one or more of the activity/effect of one or more of Abeta oligomers on a neuron cell, amyloid aggregation, amyloid binding, and amyloid deposition.