# US 12,760,032 B2 · Heterocyclic compounds

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- Number: US 12,760,032 B2
- Document ID: US12760032B2
- Status: Granted
- Kind: B2
- Application number: 18/172,506
- Filed: 2023-02-22
- Published: 2023-06-29
- Granted: 2026-10-13
- Earliest claimed: 2020-08-26
- Assignees: Hoffmann-La Roche Inc.
- Applicants: Hoffmann-La Roche Inc.
- Inventors: Joerg Benz; Uwe Grether; Benoit Hornsperger; Carsten Kroll; Bernd Kuhn; Rainer E. Martin; Fionn O'Hara; Hans Richter; Martin Ritter; Philipp Schmid
- Web page: https://patentgrep.com/patent/US12760032B2

## CPC

- C07D 491/147: the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
- C07D 487/04: Ortho-condensed systems
- 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 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention provides new heterocyclic compounds having the general formula (I) wherein X, Y, Z, A, L, B, and R1 to R3 are as described herein, compositions including the compounds, processes of manufacturing the compounds and methods of using the compounds.

## Claims

### Claim 1

A compound of formula (I):
or a pharmaceutically acceptable salt thereof,
wherein:
X is CH or N;
Y and Z are independently CH2 or O, wherein at most one of Y and Z is O;
L is selected from a covalent bond, —CHR4—, —OCH2—, and —CH2O;
A is selected from C6-C10-aryl and 5- to 10-membered heteroaryl;
B is a 4- to 7-membered heterocycle comprising 1-2 nitrogen atoms;
R1 and R2 are independently selected from hydrogen, halogen, SF5, cyano, C1-6-alkyl, C1-6-alkoxy, halo-C1-6-alkyl, halo-C1-6-alkoxy, C6-C14-aryl, C3-C10-cycloalkyl, 5-14-membered heteroaryl, 3- to 14-membered heterocyclyl, C6-C14-aryloxy, C3-C10-cycloalkyloxy, 3- to 14-membered heterocyclyloxy, and 5-14-membered heteroaryloxy, wherein each of said 3- to 14-membered heterocyclyl, C6-C14-aryl, C3-C10-cycloalkyl, 5-14-membered heteroaryl, C6-C14-aryloxy, C3-C10-cycloalkyloxy, and 5-14-membered heteroaryloxy, are optionally substituted with 1-2 substituents selected from halogen, C1-6-alkyl, C1-6-alkoxy, halo-C1-6-alkyl and halo-C1-6-alkoxy; or
R1 and R2, taken together with the atom(s) to which they are attached, form a 3- to 14-membered heterocycle that is optionally substituted with one or more C1-6-alkyl;
R3 is selected from hydrogen and C1-6-alkyl; and
R4 is selected from hydrogen, C6-C14-aryl and halo-C6-C14-aryl.

### Claim 2 (depends on 1)

The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:
X is CH or N;
Y is CH2 or O; and
Z is CH2.

### Claim 3 (depends on 1)

The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:
L is selected from a covalent bond, —CHR4—, and —CH2O—;
A is C6-C10-aryl;
R1 is selected from halogen, halo-C1-6-alkyl, and C3-C10-cycloalkyl substituted with halo-C1-6-alkyl;
R2 is selected from hydrogen and halogen; and
R4 is hydrogen.

### Claim 4 (depends on 3)

The compound of formula (I) according to claim 3, or a pharmaceutically acceptable salt thereof, wherein:
L is selected from a covalent bond and —CH2O—;
A is C6-C10-aryl;
R1 is selected from halo-C1-6-alkyl, and C3-C10-cycloalkyl substituted with halo-C1-6-alkyl; and
R2 is selected from hydrogen and halogen.

### Claim 5 (depends on 4)

The compound of formula (I) according to claim 4, or a pharmaceutically acceptable salt thereof, wherein:
L is selected from a covalent bond and —CH2O—;
A is phenyl;
R1 is selected from CF3 and (trifluoromethyl)cyclopropyl; and
R2 is selected from hydrogen and fluoro.

### Claim 6 (depends on 1)

The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:
B is a 4- to 7-membered heterocycle comprising 1 nitrogen atom; and
R3 is hydrogen.

### Claim 7 (depends on 6)

The compound of formula (I) according to claim 6, or a pharmaceutically acceptable salt thereof, wherein:
B is azetidinyl; and
R3 is hydrogen.

### Claim 8 (depends on 1)

The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:
X is CH or N;
Y and Z are independently CH2 or O, wherein at most one of Y and Z is O;
L is selected from a covalent bond, —CHR4—, and —CH2O—;
A is phenyl;
B is a 4- to 7-membered heterocycle comprising 1 nitrogen atom;
R1 is selected from halogen, halo-C1-6-alkyl, and C3-C10-cycloalkyl substituted with halo-C1-6-alkyl;
R2 is selected from hydrogen and halogen; and
R3 and R4 are both hydrogen.

### Claim 9 (depends on 8)

The compound of formula (I) according to claim 8, or a pharmaceutically acceptable salt thereof, wherein:
X is CH or N;
Y is CH2 or O;
Z is CH2;
L is selected from a covalent bond and —CH2O—;
A is phenyl;
B is a 4- to 7-membered heterocycle comprising 1 nitrogen atom;
R1 is selected from halo-C1-6-alkyl, and C3-C10-cycloalkyl substituted with halo-C1-6-alkyl;
R2 is selected from hydrogen and halogen; and
R3 is hydrogen.

### Claim 10

A compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
X is CH or N;
Y is CH2 or O;
Z is CH2;
L is selected from a covalent bond and —CH2O—;
A is phenyl;
B is azetidinyl;
R is selected from CF3 and (trifluoromethyl)cyclopropyl;
R2 is selected from hydrogen and fluoro; and
R3 is hydrogen.

### Claim 11

A compound or a pharmaceutically acceptable salt thereof, selected from:
[3-[[2-Fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidin-1-yl]-[rac-(5aR,8aS)-4,5,5a,6,8,8a-hexahydro-1H-pyrrolo[3,4-g]indazol-7-yl]methanone;
[3-[[2-Fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidin-1-yl]-[rac-(1S,9R)-7-oxa-3,4,11-triazatricyclo[7.3.0.02,6]dodeca-2 (6),4-dien-11-yl]methanone;
(−)- or (+)-[(1S,9R)-7-Oxa-3,4,11-triazatricyclo[7.3.0.02,6]dodeca-2 (6),4-dien-11-yl]-[3-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]azetidin-1-yl]methanone;
(+)- or (−)-[(1R,9S)-7-Oxa-3,4,11-triazatricyclo[7.3.0.02,6]dodeca-2 (6),4-dien-11-yl]-[3-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]azetidin-1-yl]methanone;
(−)- or (+)-[6-[(2,4-Difluorophenyl)methyl]-2-azaspiro[3.3]heptan-2-yl]-[(1S,9R)-7-oxa-3,4,11-triazatricyclo[7.3.0.02,6]dodeca-2 (6),4-dien-11-yl]methanone;
(+)- or (−)-[6-[(2,4-Difluorophenyl)methyl]-2-azaspiro[3.3]heptan-2-yl]-[(1R,9S)-7-oxa-3,4,11-triazatricyclo[7.3.0.02,6]dodeca-2 (6),4-dien-11-yl]methanone;
(−)- or (+)-[3-[[2-Fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidin-1-yl]-[(5aR,8aS)-4,5,5a,6,8,8a-hexahydro-1H-pyrrolo[3,4-e]benzotriazol-7-yl]methanone;
(+)- or (−)-[3-[[2-Fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidin-1-yl]-[(5aS,8aR)-4,5,5a,6,8,8a-hexahydro-1H-pyrrolo[3,4-e]benzotriazol-7-yl]methanone;
(−)- or (+)-[3-[[2-Fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidin-1-yl]-[(1S,9R)-8-oxa-3,4,5,11-tetrazatricyclo[7.3.0.02,6]dodeca-2 (6),4-dien-11-yl]methanone; and
(+)- or (−)-[3-[[2-Fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidin-1-yl]-[(1R,9S)-8-oxa-3,4,5,11-tetrazatricyclo[7.3.0.02,6]dodeca-2 (6),4-dien-11-yl]methanone.

### Claim 12 (depends on 1)

A process of manufacturing a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, the process comprising:
(a) reacting an amine of formula 2, wherein X, Y, and Z are as described in claim 1,
with a carboxylic acid 3a, wherein L, A, B, and R1 to R3 are as described in claim 1,
in the presence of a coupling reagent to form said compound of formula (IB), wherein X, Y, Z, L, A, B, and R1 to R3 are as defined in claim 1
or
(b) reacting an amine of formula 2, wherein X, Y, and Z are as described in claim 1,
with a carboxylic acid chloride 3b, wherein L, A, B, and R1 to R3 are as described in claim 1
in the presence of a base to form said compound of formula (IB), wherein X, Y, Z, L, A, B, and R1 to R3 are as defined in claim 1;
or
(c) reacting a first amine of formula 1, wherein A, B, L, and R1 and R3 are as described in claim 1,
with a second amine 2, wherein X, Y, and Z are as described in claim 1
in the presence of a base and a urea forming agent,
to form said compound of formula (IA), wherein X, Y, Z, L, A, B, and R1 to R3 are as defined in claim 1

### Claim 13 (depends on 12)

The process of claim 12, wherein:
the coupling reagent in process (a) is CDI, DCC, HATU, HBTU, HOBT, TBTU, T3P or Mukaiyama reagent, and the amine and carboxylic acid are further reacted in the presence of a base, wherein the base is TEA, DIPEA (Huenig's base) or DMAP; or
the base in process (b) is TEA, Huenig's base, pyridine, DMAP or lithium bis(trimethylsilyl)amide; or
the base in process (c) is sodium bicarbonate, and the urea forming reagent is bis(trichloromethyl) carbonate, phosgene, trichloromethyl chloroformate, (4-nitrophenyl) carbonate or 1,1′-carbonyldiimidazole.

### Claim 14 (depends on 1)

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

### Claim 15 (depends on 10)

A pharmaceutical composition, comprising a compound of formula (I) according to claim 10, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

### Claim 16 (depends on 11)

A pharmaceutical composition, comprising a compound of claim 11, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

### Claim 17 (depends on 12)

The process of claim 12, part (a), wherein the coupling reagent is CDI, DCC, HATU, HBTU, HOBT, TBTU, T3P or Mukaiyama reagent.

### Claim 18 (depends on 12)

The process of claim 12, part (a), further comprising the presence of a base selected from TEA, DIPEA (Huenig's base) and DMAP.

### Claim 19 (depends on 12)

The process of claim 12, part (b), wherein the base is TEA, Huenig's base, pyridine, DMAP or lithium bis(trimethylsilyl)amide.

### Claim 20 (depends on 12)

The process of claim 12, part (c), wherein the base is sodium bicarbonate and the urea forming reagent is bis(trichloromethyl) carbonate, phosgene, trichloromethyl chloroformate, (4-nitrophenyl) carbonate or 1,1′-carbonyldiimidazole.