# US 11,440,884 B2 · Compounds, salts thereof and methods for treatment of diseases

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- Number: US 11,440,884 B2
- Document ID: US11440884B2
- Status: Granted
- Kind: B2
- Application number: 16/640,994
- Filed: 2018-08-20
- Published: 2021-04-29
- Granted: 2022-09-13
- Earliest claimed: 2017-08-21
- Assignees: ACADIA Pharmaceuticals Inc.
- Applicants: Acadia Pharmaceuticals Inc.
- Inventors: Ethan S. Burstein; Roger Olsson; Karl Erik Jansson; Niklas Patrik Sköld; Larisa Yudina Wahlström; Björn Gustav Borgström; Henrik Von Wachenfeldt; Magnus Gustav Wilhelm Bergner
- Web page: https://patentgrep.com/patent/US11440884B2

## CPC

- C07D 211/14: with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
- C07D 211/58: attached in position 4
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 407/04: directly linked by a ring-member-to-ring-member bond
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07B 2200/05: Isotopically modified compounds, e.g. labelled
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The present disclosure relates to compounds according to Formulae (I), (II) and (VIII), useful for treating diseases.

## Claims

### Claim 1

A compound according to Formula (1)
or a pharmaceutically acceptable salt; hydrate, solvate, stereoisomer, or deuterated analogue thereof, wherein:
m and n are independently an integer selected from the group consisting of 0, 1, 2, and 3;
p and q are independently an integer selected from the group consisting of 0, 1, 2, 3, and 4;
R1 and R1d are fluoro;
R1a, R1b, and R1c are hydrogen;
R2, R2a, R2b, R2c and R2d are independently selected from the group consisting of hydrogen, deuterium; amino, hydroxyl, -OD, halogen, cyano, unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted C1-6 haloalkyl, unsubstituted or substituted C1-6 hydroxyalkyl, unsubstituted or substituted C2-6 alkenyl, unsubstituted or substituted C1-6 alkoxy, unsubstituted or substituted C3-6 cycloalkyl, unsubstituted or substituted C3-6 heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein at least one of R2, R2a, R2b, R2c and R2d is not hydrogen, or R2 and R2b or R2c, taken together with the atoms to which they are attached form a ring system;
R3 is selected from the group consisting of hydrogen, deuterium, hydroxyl, -OD, unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted C1-6 haloalkyl, unsubstituted or substituted C1-6 hydroxyalkyl, unsubstituted or substituted C2-6 alkenyl, unsubstituted or substituted C3-6 cycloalkyl, unsubstituted or substituted C3-6 heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or
R3, the nitrogen to which R3 is attached and a carbon atom adjacent to the nitrogen taken together with R6 or R7 form a heteroalicyclic ring system;
R4a, R4b, R5a, and R5b, are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-6 alkyl;
R6 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, cyano, substituted or unsubstituted C1-4 alkyl, and substituted or unsubstituted C1-4 alkoxy, and substituted or unsubstituted aryl;
R7 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, cyano, substituted or unsubstituted C1-4 alkyl, and substituted or unsubstituted C1-4 alkoxy;
R8 is absent, or selected from the group consisting of hydrogen, deuterium, cyano, hydroxyl, -OD, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted C2-4 alkenyl, substituted or unsubstituted C3-6 cycloalkyl, and substituted or unsubstituted C1-4 alkoxy;
A is —O—; and
X is O or S.

### Claim 2 (depends on 1)

The compound, or pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or deuterated analogue thereof of claim 1, wherein R2, R2a, R2b, R2c and R2d independently are selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-4 cycloalkyl, C3-4 cycloalkyl-C1-3 alkyl and deuterated analogues thereof; or
R2 and R2b, taken together with the phenyl ling they attach to and the atoms to which they are attached form a bicyclic fused ring system that has the following general formulae
wherein R12a, R12b, R12c, R13a, R13b, R14a, and R14b independently are absent or selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C1-4 alkyl, and C1-4 alkoxy, and wherein Z1, Z2 and Z3 independently are selected from the group consisting of C, N, O and S; or
R2a, R2c, R2d, and R2b, provided R2b is not forming a ring, system with R2, independently are selected from the group consisting of hydrogen, deuterium, hydroxyl, halogen, methyl, —CD3, methoxy, —OCD3,—OCF3, and —CF3; or
R2a, R2c, and R2b, provided R2b is not forming a ring system with R2, are hydrogen, and R2d is hydrogen, fluoro, or hydroxyl.

### Claim 3 (depends on 1)

The compound, or pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or deuterated analogue thereof of claim 1, wherein
R2, provided R2 is not forming a ring system with R2b, is selected from the group consisting of halogen, cyano, methyl, —CD3, ethyl, —CD2CD3, optionally deuterated n-propyl, optionally deuterated iso-propyl, optionally deuterated n-butyl, optionally deuterated iso-butyl, optionally deuterated n-pentyl, optionally deuterated 2-methyl-butyl, optionally deuterated n-hexyl, optionally deuterated 2-methyl-pentyl, optionally deuterated methoxy, optionally deuterated ethoxy, optionally deuterated n-propoxy, optionally deuterated isopropoxy, optionally deuterated allyloxy, optionally deuterated prop-2-yn-1-yloxy, optionally deuterated n-butoxy, optionally deuterated iso-butoxy, optionally deuterated tert-butoxy, optionally deuterated pentyl-oxy, optionally deuterated 4-methyl-butoxy, optionally deuterated hexyl-oxy, optionally deuterated 4-methylpentoxy, optionally deuterated cyclopropyloxy, optionally deuterated cyclopropylmethoxy, optionally deuterated cyclopropylethoxy, optionally deuterated cyclobutyloxy, optionally deuterated cyclobutyloxy, optionally deuterated cyclobutylmethoxy, optionally deuterated cyclobutylethoxy, optionally deuterated C1-6 haloalkoxy, —OCF3, —OCF2CF3, —OCHF2, —OCDF2, —CF3, —CF2CF3, —CHF2, —CDF2 —CH2CF3, CH2F, —CF2CH3, 2-fluoroethoxy, 3-fluoropropoxy, 4-fluorobutoxy, (1,3-difluoropropan-2-yl)oxy, 2-hydroxyl-2-methyl-propoxy, 1,1,2,2-tetrafluorobutyl, and 1,1,1,2,2-pentafluorobutyl, or
or R2, provided R2 is not forming a ring system with R2b, selected from methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, prop-2-yn-1-yloxy, n-butoxy, iso-butoxy, tert-butoxy, pentyl-oxy, 4-methyl-butoxy, hexyl-oxy 4-methylpentoxy cyclopropyloxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutyloxy, cyclobutylmethoxy, cyclobutylethoxy, —CF2CH3, 2-fluoroethoxy, 3-fluoropropoxy, 4-fluorobutoxy, 2-hydroxyl-, 2-methyl-propoxy, 1,1-difluoroethyl, and (1,3-difluoropropan-2-yl)oxy; or
R2 and R2b, taken together with the phenyl ring they attach to and the atoms to which they are attached form a bicyclic fused ring system that, has the following general formula
wherein R12a and R12b are hydrogen or methyl, and both R13a and R13b are hydrogen or methyl, and R2a, R2c, and R2d are hydrogen.

### Claim 4 (depends on 1)

The compound, or pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or deuterated analogue thereof of claim 1, wherein
R1 and R1d are fluoro, and R1a, R1b and R1c are hydrogen; and
R2 is selected from the group consisting of ethoxy, isopropoxy, allyloxy, tert-butoxy, isobutoxy, n-butoxy, cyclopropyloxy, 2-fluoroethoxy, 3-fluoropropoxy, 2-hydroxyl-2-methyl-propoxy, 1,1-difluoroethyl, and (1,3-difluoropropan-2-yl)oxy, and R2a, R2b, R2c and R2d are hydrogen; or R2 and R2b, taken together with the atoms to which they are attached form a heteroalicyclic ring system wherein the formed ring system, taken together with the phenyl group to which it is fused, has the following formulae
and R2a, R2c and R2d are hydrogen.

### Claim 5 (depends on 1)

The compound, or pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or deuterated analogue thereof of claim 1, wherein
R3 is selected from the group consisting of hydrogen, deuterium, hydroxyl, -OD, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted —(CH2)s—C3-6 cycloalkyl, substituted or unsubstituted —(CH2)s—C2-5 heteroalicyclyl, substituted or unsubstituted —(CH2)s—C2-5 heteroaryl, and substituted or unsubstituted —(CH2)s—C5-6 aryl, wherein each s is selected from the group consisting of 0, 1, 2 and 3; or
R3 is selected from the group consisting of hydrogen, methyl, —CD3, ethyl, —CD2CD3, n-propyl, —CD2CD2CD3, iso-propyl, cyclopropyl, 3-oxetanyl, —CDCD3CD3, —(CR9aR9b)tC(═O)OR9c, —(CR9aR9b)t(CR9cR9d)wC(═O)OR9c, —(CH2)t(CR9cR9d)wC(═O)NR9aR9b and —(CH2)tC(═O)NR9aR9b, wherein R9a, R9b, R9c, R9d, and R9e independently are hydrogen or C1-4-alkyl, wherein each of t and w is selected from 0, 1, and 3.

### Claim 6 (depends on 1)

The compound, or pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or deuterated analogue thereof of claim 1, wherein R3 is hydrogen or methyl.

### Claim 7 (depends on 1)

The compound, or pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or deuterated analogue thereof of claim 1, wherein R3 taken together with R6 or R7 form a heteroalicyclic ring system according to the following formulas:
wherein R6a is selected from the group consisting; of hydrogen, deuterium, halogen, hydroxyl, -OD, substituted or unsubstituted C1-4 alkyl, and substituted or unsubstituted C1-4 alkoxy.

### Claim 8 (depends on 1)

The compound, or pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or deuterated analogue thereof of claim 1, wherein
R4a, R4b, R5a, and R5b are independently selected from the group consisting of hydrogen, methyl, and —CF3; or
R4a, R4b, and R5a are hydrogen and R5b is methyl or hydrogen; or
R4a, R5a, and R5b are hydrogen and R4b is methyl or hydrogen.

### Claim 9 (depends on 1)

The compound, or pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or deuterated analogue thereof of claim 1, wherein R4a, R4b, R5a, and R5b are hydrogen.

### Claim 10 (depends on 1)

The compound, or pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or deuterated analogue thereof of claim 1, wherein R7 is hydrogen or fluoro.

### Claim 11 (depends on 1)

The compound, or pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or deuterated analogue thereof of claim 1, wherein q is 1.

### Claim 12 (depends on 1)

The compound, or pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or deuterated analogue thereof of claim 1, wherein p is 0.

### Claim 13 (depends on 1)

The compound, or pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or deuterated analogue thereof of claim 1, wherein
R8 is selected from the group consisting of hydrogen, halogen, methyl, ethyl, propyl, methoxy, ethoxy, C1-2-haloalkyl, and C1-2-haloalkoxy; or
R8 is selected from the group consisting of hydrogen, —CF3, —CHF2, —CF2CF3, —OCF3, —OCF2CF3 and —OCHF2; or
R8 is hydrogen.

### Claim 14 (depends on 1)

The compound, or pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or deuterated analogue thereof of claim 1, wherein X is O.

### Claim 15 (depends on 1)

The compound, or pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or deuterated analogue thereof of claim 1; wherein m is 1 and n is 0 or 1.

### Claim 16 (depends on 1)

The compound, or pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or deuterated analogue thereof of claim 1, wherein the compound is a compound according to Formula (II)
wherein R6a is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, -OD, substituted or unsubstituted C1-4 alkyl, and substituted or unsubstituted C1-4 alkoxy.

### Claim 17

A compound, pharmaceutically acceptable salt, polymorph, or stereoisomer selected from the group consisting of:
[4-(propan-2-yloxy)phenyl]methyl N-[(2,4-difluorophenyl)methyl]-N-(piperidin-4-yl)carbamate;
[4-(propan-2-yloxy)phenyl]methyl N-[(2,4-difluorophenyl)methyl]-N-(1-methylpiperidin-4-yl)carbamate;
[4-(2-methylpropoxy)phenyl]methyl N-[(2,4-difluorophenyl)methyl]-N-(1-methylpiperidin-4-yl)carbamate;
(4-methoxyphenyl)methyl N-[(2,4-difluorophenyl)methyl]-N-(1-methylpiperidin-4-yl)carbamate;
N-[(2,4-difluorophenyl)methyl]-N-(1-methylpiperidin-4-yl){[(4-methoxyphenyl)methyl]sulfanyl}formamide;
4-(allyloxy)benzyl (2,4-difluorobenzyl)(1-methylpiperidin-4-yl)carbamate,
4-ethoxybenzyl (2,4-difluorobenzyl)(1-methylpiperidin-4-yl)carbamate;
4-(3-fluoropropoxy)benzyl (2,4-difluorobenzyl)(1-methylpiperidin-4-yl)carbamate;
4-((1,3-difluoropropan-2-yl)oxy)benzyl (2,4-difluorobenzyl)(1-methylpiperidin-4-yl)carbamate;
4-(2-hydroxy-2-methylpropoxy)benzyl (2,4-difluorobenzyl)(1-methylpiperidin-4-yl)carbamate;
4-cyclopropoxybenzyl (2,4-difluorobenzyl)(1-methylpiperidin-4-yl)carbamate;
[4-(2-fluoroethoxy)phenyl]methyl N-[(2,4-difluorophenyl)methyl]-N-(1-methylpiperidin-4-yl)carbamate;
(4-butoxyphenyl)methyl N-[(2,4-difluorophenyl)methyl]-N-(1-methylpiperidin-4-yl)carbamate;
methyl 3-(4-}[(2,4-difluorophenyl)methyl](}[4-(propan-2-yloxy)phenyl]methoxy}carbonyl)amino}piperidin-1-yl)-2,2-dimethylpropanoate;
3-(4-{[(2,4-difluorophenyl)methyl]({[4-(propan-2-yloxy)phenyl]-methoxy}carbonyl)amino}piperidin-1-yl)-2,2-dimethylpropanoic acid;
[4-(propan-2-yloxy)phenyl]methyl N-[(2,4-difluorophenyl)methyl]-N-(1-ethylpiperidin-4-yl)carbamate;
[4-(propan-2-yloxy)phenyl]methyl N-(1-cyclopropylpiperidin-4-yl)-N-[(2,4-difluorophenyl)methyl]carbamate;
[4-(propan-2-yloxy)phenyl]methyl N-[(2,4-difluorophenyl)methyl]-N-[1-(oxetan-3-yl)piperidin-4-yl]carbamate;
(2E)-N-[(2,4-difluorophenyl)methyl]-N-(1-methylpiperidin-4-yl)-3-[4-(propan-2-yloxy)phenyl]prop-2-enamide;
N-[(2,4-dichlorophenyl)methyl]-N-(1-methylpiperidin-4-yl)-2[4-(2-methylpropoxy)phenyl]acetamide;
N-[(2,4-dichlorophenyl)methyl]-N-(1-methylpiperidin-4-yl)-2-[4-(propan-2-yloxy)phenyl]acetamide;
4-(tert-butoxy)benzyl (2,4-difluorobenzyl)(1-methylpiperidin-4-yl)carbamate; and
4-(1,1-difluoroethyl)benzyl (2,4-difluorobenzyl)(1-methylpiperidin-4-yl)carbamate.