# US 10,865,182 B2 · Difluoroketamide derivatives as HtrA1 inhibitors

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- Number: US 10,865,182 B2
- Document ID: US10865182B2
- Status: Granted
- Kind: B2
- Application number: 16/250,905
- Filed: 2019-01-17
- Published: 2019-05-23
- Granted: 2020-12-15
- Earliest claimed: 2016-07-18
- Assignees: Hoffmann-La Roche Inc.
- Applicants: Hoffmann-La Roche Inc.
- Inventors: Hans P. Maerki; Benoit Hornsperger; Peter Mohr; Michael Reutlinger; Markus Rudolph
- Web page: https://patentgrep.com/patent/US10865182B2

## CPC

- C07C 237/22: having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated (peptides C07K)
- A61P 13/12: of the kidneys
- A61P 27/02: Ophthalmic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 255/54: containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
- C07D 213/65: attached in position 3 or 5
- C07D 295/13: to an acyclic saturated chain
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The invention provides novel compounds having the general formula (I) wherein R1, R2, R3, R4, R5, R6, R7, R3, R8, R9, R10 and R11 are as described herein, compositions including the compounds and methods of using the compounds.

## Claims

### Claim 1

A compound of formula (I)
or a pharmaceutically acceptable salt thereof, wherein
R1 is selected from
i) C1-6-alkyl,
ii) C3-8-cycloalkyl substituted with R24, R25 and R26,
iii) halo-C1-6-alkyl,
iv) heterocycloalkyl-C1-6-alkyl substituted with R24, R25 and R26,
v) aryl-C1-6-alkyl substituted with R24, R25 and R26, and
vi) heteroaryl-C1-6-alkyl substituted with R24, R25 and R26;
R2, R3, R4, R6, R7, R9 and R10 are independently selected from
i) H,
ii) C1-6-alkyl, and
iii) C3-8-cycloalkyl;
R5 is selected from
i) aryl substituted with R12, R13 and R14,
ii) aryl-C1-6-alkyl substituted with R12, R13 and R14,
iii) heteroaryl substituted with R12, R13 and R14, and
iv) heteroaryl-C1-6-alkyl substituted with R12, R13 and R14,
R8 is selected from
i) H,
ii) hydroxy,
iii) amino-C1-6-alkyl substituted on the nitrogen atom by one or two substituents selected from H, C1-6-alkylcarbonyl, C1-6-alkoxycarbonyl, C1-6-alkyl, arylcarbonyl and heteroarylcarbonyl, wherein arylcarbonyl and heteroarylcarbonyl are substituted with R15, R16 and R17,
iv) aminocarbonyl substituted on the nitrogen atom by one or two substituents selected from H, C1-6-alkylcarbonyl, C1-6-alkoxycarbonyl, C1-6-alkyl, arylcarbonyl and heteroarylcarbonyl, wherein arylcarbonyl and heteroarylcarbonyl are substituted with R15, R16 and R17,
v) aminocarbonyl-C1-6-alkyl substituted on the nitrogen atom by one or two substituents selected from H, C1-6-alkylcarbonyl, C1-6-alkoxycarbonyl, C1-6-alkyl, arylcarbonyl and heteroarylcarbonyl, wherein arylcarbonyl and heteroarylcarbonyl are substituted with R15, R16 and R17,
vi) carboxy,
vii) carboxy-C1-6-alkyl,
viii) C1-6-alkoxy,
ix) C1-6-haloalkoxy,
x) C1-6-alkoxycarbonyl,
xi) C1-6-alkoxycarbonyl-C1-6-alkyl,
xii) C3-8-cycloalkyl,
xiii) aryl substituted with R15, R16 and R17,
xiv) aryl-C1-6-alkyl substituted with R15, R16 and R17,
xv) aryl-C1-6-alkoxy substituted with R15, R16 and R17,
xvi) heteroaryl substituted with R15, R16 and R17,
xvii) heteroaryl-C1-6-alkyl substituted with R15, R16 and R17, end
xviii) heteroaryl-C1-6-alkoxy substituted with R15, R16 and R17
xix) heterocycloalkyl substituted with R15, R16 and R17,
xx) heterocycloalkyl —C1-6-alkyl substituted with R15, R16 and R17, and
xxi) heterocycloalkyl —C1-6-alkoxy substituted with R15, R16 and R17;
R11 is selected from
i) amino-C1-6-alkyl substituted on the nitrogen atom by R21 and R22,
ii) C3-8-cycloalkyl substituted with R18, R19 and R20,
iii) C3-8-cycloalkyl-C1-6-alkyl substituted with R18, R19 and R20,
iv) C3-8-cycloalkyl(halo)-C1-6-alkyl substituted with R18, R19 and R20,
v) aryl substituted with R18, R19 and R20,
vi) aryl-C1-6-alkyl substituted with R18, R19 and R20,
vii) aryl-C3-9-cycloalkyl substituted with R18, R19 and R20,
viii) aryl-heterocycloalkyl substituted with R18, R19 and R20,
ix) aryl(halo)-C1-6-alkyl substituted with R18, R19 and R20,
x) aryl(halo)-C3-8-cycloalkyl substituted with R18, R19 and R20,
xi) aryl(halo)-heterocycloalkyl substituted with R18, R19 and R20,
xii) aryloxy-C1-6-alkyl substituted with R18, R19 and R20,
xiii) aryloxy-C3-8-cycloalkyl substituted with R18, R19 and R20,
xiv) aryloxy-heterocycloalkyl substituted with R18, R19 and R20,
xv) aryloxy(halo)-C3-8-cycloalkyl substituted with R18, R19 and R20,
xvi) aryloxy(halo)-heterocycloalkyl substituted with R18, R19 and R20,
xvii) aryloxy(halo)-C1-6-alkyl,
xviii) heterocycloalkyl substituted with R18, R19 and R20,
xix) heterocycloalkyl-C1-6-alkyl substituted with R18, R19 and R20,
xx) heterocycloalkyl-C3-8-cycloalkyl substituted with R18, R19 and R20,
xxi) heterocycloalkyl(halo)-C3-8-cycloalkyl substituted with R18, R19 and R20,
xxii) heterocycloalkyl(halo)-C1-6-alkyl substituted with R18, R19 and R20,
xxiii) heteroaryl substituted with R18, R19 and R20,
xxiv) heteroaryl-C1-6-alkyl substituted with R18, R19 and R20,
xxv) heteroaryl-C3-8-cycloalkyl substituted with R18, R19 and R20,
xxvi) heteroaryl(halo)-C3-8-cycloalkyl substituted with R18, R19 and R20,
xxvii) heteroaryl(halo)-C1-6alkyl substituted with R18, R19 and R20,
xxviii) heteroaryloxy-C1-6-alkyl substituted with R18, R19 and R20,
xxix) heteroaryloxy-C3-8-cycloalkyl substituted with R18, R19 and R20,
xxx) heteroaryloxy(halo)-C3-8-cycloalkyl substituted with R18, R19 and R20, and
xxxi) heteroaryloxy(halo)-C1-6-alkyl substituted with R18, R19 and R20;
R12, R13, R14, R15, R16, R17, R18, R19, R20, R24, R25 and R26 are independently selected from
i) H,
ii) cyano,
iii) halogen,
iv) oxo,
v) C1-6-alkyl,
vi) amino substituted on the nitrogen atom by two substituents independently selected from H, C1-6-alkyl, C1-6-alkoxycarbonyl, arylcarbonyl and heteroarylcarbonyl,
vii) amino-C1-6-alkyl substituted on the nitrogen atom by two substituents independently selected from H, C1-6-alkyl, C1-6-alkoxycarbonyl, arylcarbonyl and heteroarylcarbonyl,
viii) C1-6-alkyl,
ix) halo-C1-6-alkyl,
x) C3-8-cycloalkyl,
xi) C1-6-alkoxycarbonyl-C1-6-alkyl,
xii) carboxy-C1-6-alkyl,
xiii) C1-6-alkoxycarbonyl-C1-6-alkylaminocarbonyl-C1-6alkyl,
xiv) carboxy-C1-6-alkylaminocarbonyl-C1-6alkyl,
xv) C1-6-alkoxy,
xvi) halo-C1-6-alkoxy,
xvii) C1-6-alkoxycarbonyl-C1-6-alkoxy,
xviii) carboxy-C1-6-alkoxy,
xix) C1-6alkoxycarbonyl-C1-6alkylaminocarbonyl-C1-6alkoxy,
xx) carboxy-C1-6alkylaminocarbonyl-C1-6alkoxy,
xxi) heterocycloalkyl,
and
R21 and R22 are independently selected from
i) H,
ii) C1-6-alkoxycarbonyl,
iii) carboxy-C1-6-alkyl,
iv) arylcarbonyl, and
v) heteroarylcarbonyl.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
R1 is selected from
i) halo-C1-6-alkyl, and
ii) heterocycloalkyl-C1-6-alkyl substituted with R24, R25 and R26;
R2 is C1-6-alkyl;
R3, R4, R6, R7, R9 and R10 are each H;
R5 is selected from
i) phenyl substituted with R12, R13 and R14, and
ii) phenyl-C1-6-alkyl substituted with R12, R13 and R14,
R8 is phenyl substituted with R15, R16 and R17;
R11 is selected from
i) phenyl substituted with R18, R19 and R20, and
ii) pyridinyl substituted with R18, R19 and R20;
R12 is selected from
i) H, and
ii) C1-6-alkoxy;
R13, R14, R17, R20, R24, R25 and R26 are each H;
R15 is selected from
i) H,
ii) cyano, and
iii) halogen;
R16 is selected from
i) H, and
ii) halogen;
R18 is selected from
i) halogen, and
ii) cyano;
and
R19 is selected from
i) H,
ii) cyano,
iii) C1-6-alkyl, and
iv) halogen.

### Claim 3 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from
i) halo-C1-6-alkyl, and
ii) heterocycloalkyl-C1-6-alkyl substituted with R24, R25 and R26.

### Claim 4 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is halo-C1-6-alkyl.

### Claim 5 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is trifluoroethyl.

### Claim 6 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is C1-6-alkyl.

### Claim 7 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is isopropyl.

### Claim 8 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3, R4, R6, R7, R9 and R10 are H.

### Claim 9 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R5 is elected from
i) phenyl substituted with R12, R13 and R14, and
ii) phenyl-C1-6-alkyl substituted with R12, R13 and R14.

### Claim 10 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R5 is phenyl substituted with R12, R13 and R14.

### Claim 11 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R5 is phenyl substituted with one C1-6-alkoxy.

### Claim 12 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R8 is phenyl substituted with R15, R16 and R17.

### Claim 13 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R11 is selected from
i) phenyl substituted with R18, R19 and R20, and
ii) pyridinyl substituted with R18, R19 and R20.

### Claim 14 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R11 is phenyl substituted with R18, R19 and R20.

### Claim 15 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R12 is selected from
i) H, and
ii) C1-6-alkoxy.

### Claim 16 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R12 is H.

### Claim 17 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R13, R14, R17, R20, R24, R25 and R26 are each H.

### Claim 18 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R15 is selected from
i) H,
ii) cyano, and
iii) halogen.

### Claim 19 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R15 is halogen.

### Claim 20 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R16 is selected from
i) H, and
ii) halogen.

### Claim 21 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R16 is H.

### Claim 22 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R18 is selected from
i) halogen, and
ii) cyano.

### Claim 23 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R19 is selected from
i) H,
ii) cyano,
iii) C1-6-alkyl, and
iv) halogen.

### Claim 24 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R19 is selected from
i) cyano, and
ii) halogen.

### Claim 25 (depends on 1)

A compound according to claim 1, selected from the group consisting of:
(S)-4-((S)-2-((R)-2-(3,5-dichlorophenoxy)-3-phenylpropanamido)-3-phenyl propanamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide;
(S)-4-((S)-2-((R)-2-(3,5-dichlorophenoxy)-3-phenylpropanamido)-2-phenylacetamido)-2,2-difluoro-5-methyl-N-(2-morpholinoethyl)-3-oxohexanamide;
(S)-4-((S)-2-((R)-2-(3,5-dichlorophenoxy)-3-phenylpropanamido)-2-(4-methoxyphenyl)acetamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide;
(S)-4-((S)-2-((R)-3-(3-chlorophenyl)-2-(3,5-dichlorophenoxy)propanamido)-2-(4-methoxyphenyl)acetamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide;
(S)-4-((S)-2-((R)-2-(3-chloro-5-methylphenoxy)-3-(3-chlorophenyl)propanamido)-2-(4-methoxyphenyl)acetamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide;
(S)-4-((S)-2-((R)-2-(3-chlorophenoxy)-3-(3,4-dichlorophenyl)propanamido)-2-(4-methoxyphenyl)acetamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide;
(S)-4-((S)-2-((R)-3-(3-chlorophenyl)-2-(3,5-di cyanophenoxy)propanamido)-2-(4-methoxyphenyl)acetamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide;
(S)-4-((S)-2-((R)-3-(3-chlorophenyl)-2-((5-chloropyridin-3-yl)oxy)propanamido)-2-(4-methoxyphenyl)acetamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide;
(S)-4-((S)-2-((R)-2-(3-chlorophenoxy)-3-(3,5-dichlorophenyl)propanamido)-2-(4-methoxyphenyl)acetamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide;
(S)-4-((S)-2-((S)-3-(3-chlorophenyl)-2-(3,5-dichlorophenoxy)propanamido)-2-(4-methoxyphenyl)acetamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide;
(S)-4-((S)-2-((S)-3-(3-chlorophenyl)-2-(3,5-dichlorophenoxy)propanamido)-2-phenylacetamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide;
(S)-4-((S)-2-((R)-2-(3-chloro-5-cyanophenoxy)-3-(3-chlorophenyl)propanamido)-2-(4-methoxyphenyl)acetamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide;
(S)-4-((S)-2-((R)-2-(3-chloro-5-cyanophenoxy)-3-(3-chlorophenyl)propanamido)-2-phenylacetamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide;
(4S)-4-((2S)-2-(2-(3-chloro-5-cyanophenoxy)-3-(3-cyanophenyl)propanamido)-2-(4-methoxyphenyl)acetamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide;
(S)-4-((S)-2-((R)-2-(3,5-dicyanophenoxy)-3-(3-fluorophenyl)propanamido)-2-(4-methoxyphenyl)acetamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide;
(S)-4-((S)-2-((R)-2-(3-cyanophenoxy)-3-(3-fluorophenyl)propanamido)-2-(4-methoxyphenyl)acetamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide; and
(S)-4-((S)-2-((R)-2-(3-chlorophenoxy)-3-(3-fluorophenyl)propanamido)-2-(4-methoxyphenyl)acetamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide;
or a pharmaceutically acceptable salt thereof.

### Claim 26 (depends on 1)

A process to prepare a compound according to claim 1 comprising
i) the reaction of a compound of formula (III) with a compound of formula (IV)
and
ii) the reaction of a compound of formula (II) in oxidative conditions

### Claim 27 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

### Claim 28 (depends on 1)

A method for the treatment of HtrA1-mediated ocular conditions selected from wet or dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, retinopathy of prematurity and polypoidal choroidal vasculopathy, which method comprises administering an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.