# US 2023/0065809 A1 · Tricyclic compounds with oma1/opa1 modulatory properties

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- Number: US 2023/0065809 A1
- Document ID: US20230065809A1
- Status: Published application
- Kind: A1
- Application number: 17/784,239
- Filed: 2020-12-09
- Published: 2023-03-02
- Earliest claimed: 2019-12-13
- Assignees: 712 North Inc.
- Inventors: Marcel Victor Alavi Khorassani Moghadam
- Web page: https://patentgrep.com/patent/US20230065809A1

## CPC

- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 265/34: condensed with carbocyclic rings
- C07D 267/16: condensed with two six-membered rings
- C07D 279/20: with hydrogen atoms directly attached to the ring nitrogen atom
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 407/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 409/14: containing three or more hetero rings
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 471/10: Spiro-condensed systems
- C07D 471/22: in which the condensed systems contains four or more hetero rings
- C07D 487/04: Ortho-condensed systems
- C07D 498/04: Ortho-condensed systems
- C07D 513/04: Ortho-condensed systems
- C07F 7/0807: {comprising Si as a ring atom}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

Tricyclic compounds, and in particular novel dibenzoxazepin derivates are disclosed herein, which were quite surprisingly found as having OMA1 and/or OPA1 modulatory properties. Compounds of present invention may provide useful for the treatment of certain conditions and diseases, which are amenable to OMA1 and/or OPA1-modulatory therapies. Such conditions may include conditions and diseases prevalent in the elderly, including cancer. Pharmaceutical compositions comprising compounds of present invention may be combined with other treatments or further comprise other pharmaceutically active ingredients.

## Claims

### Claim 1

A compound of formula (I)
or any stereochemically isomeric form thereof, wherein A, B, and R1 to R10 represent an atom or a group, and wherein at least one of R1, R2, R3, R4, R7, R8, R9, or R10 is a group of formula (II)
or any stereochemically isomeric form thereof, wherein A′, R′1 and R′2 represent an atom or a group, and B′ represent an atom, or a pharmaceutically acceptable salt thereof, or an N-oxide thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein
A′ is a single bond, alkyl, alkylene, alkenyl, alkynyl, alkylidene, —N(H)—, —N(R′3)—, —N(OH)—, —S(O)2—, —S(O)—, —O—, or the like;
B′ is C, N, O, P or S; and
R′1, R′2, and R′3 represent an atom or a group;
or any stereochemically isomeric form thereof, or a pharmaceutically acceptable salt thereof, or an N-oxide thereof.

### Claim 3 (depends on 1)

The compound of claim 1, wherein
A is a single bond, alkyl, alkylene, alkenyl, alkynyl, alkylidene, —N(H)—, —N(R11)—, —N(OH)—, —S(O)2—, —S(O)—, —O—, or the like;
B is C, N, O, P, or S provided that when B represents N or O then B may or may not be substituted at R6;
R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, or R12 is hydrogen, halo, hydroxy, carboxy, keto, alkyl, alkylene, haloalkyl, polyhaloalkyl, haloalkoxy, carbocyclic residue, aryl, aryloxy, arylamino, arylalkylamino, arylthio, arylalkanoylamino, arylsulfonyl, arylalkoxy, arylsulfinyl, arylheteroaryl, arylalkylthio, arylcarbonyl, arylalkenyl, or arylalkylsulfonyl, alkynyl, alkenyl, alkyloxy, polyhaloalkyloxy, alkylidene, cycloalkyl, cycloalkanone, heterocyclic group, heteroaryl, — C(O)OR12, —NR13R14, —C(O)NR13R14 or the like, wherein NR13R14 may form a heterocyclic ring, or a chemical group;
A′ is a single bond, alkyl, alkylene, alkenyl, alkynyl, alkylidene, —N(H)—, —N(R′3)—, —N(OH)—, —S(O)2—, —S(O)—, —O—, or the like;
B′ is C, N, O, P or S; and
R′1, R′2, and R′3 represent an atom or a group;
or a pharmaceutically acceptable salt thereof, or an N-oxide thereof.

### Claim 4 (depends on 3)

The compound of claim 3, wherein A′ is S or O; and B′ is sulfur dioxide (SO2); and R′1 and R′2 are both hydrogens, or a pharmaceutically acceptable salt thereof, or an N-oxide thereof.

### Claim 5 (depends on 1)

The compound of claim 1, wherein the group of formula (II) is a group of formula (III)
or any stereochemically isomeric form thereof, or a pharmaceutically acceptable salt thereof, or an N-oxide thereof.

### Claim 6 (depends on 1)

The compound of claim 1, wherein A is O; B is N; R3 and/or R8 is a group of formula (II), wherein A′ is S or O; B′ is sulfur dioxide (SO2); and R′1 and R′2 are both hydrogens, or any stereochemically isomeric form thereof, or a pharmaceutically acceptable salt thereof, or an N-oxide thereof.

### Claim 7

(canceled)

### Claim 8 (depends on 1)

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

### Claim at position 9

-15. (canceled)

### Claim 16 (depends on 8)

The pharmaceutical composition of claim 8, wherein the compound is one or more
1-((thiiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepin-11(10H)-one,
2-((thiiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepin-11(10H)-one,
3-((thiiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepin-11(10H)-one,
4-((thiiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepin-11(10H)-one,
6-((thiiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepin-11(10H)-one,
7-((thiiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepin-11(10H)-one,
8-((thiiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepin-11(10H)-one,
9-((thiiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepin-11(10H)-one,
10-((thiiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepin-11(10H)-one,
1-((oxiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepin-11(10H)-one,
2-((oxiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepin-11(10H)-one,
3-((oxiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepin-11(10H)-one,
4-((oxiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepin-11(10H)-one,
6-((oxiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepin-11(10H)-one,
7-((oxiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepin-11(10H)-one,
8-((oxiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepin-11(10H)-one,
9-((oxiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepin-11(10H)-one,
10-((oxiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepin-11(10H)-one,
1-((thiiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepine,
2-((thiiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepine,
3-((thiiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepine,
4-((thiiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepine,
6-((thiiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepine,
7-((thiiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepine,
8-((thiiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepine,
9-((thiiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepine,
11-((thiiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepine,
1-((oxiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepine,
2-((oxiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepine,
3-((oxiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepine,
4-((oxiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepine,
6-((oxiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepine,
7-((oxiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepine,
8-((oxiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepine,
9-((oxiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepine,
11-((oxiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepine,
or any stereochemically isomeric form thereof or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 8)

The pharmaceutical composition of claim 8, wherein the compound is one or more
N-(2-((thiiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepin-8-yl)acetamide,
2-((thiiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepine,
11-(piperazin-1-yl)-2-((1-(thiiran-2-yl)ethyl)sulfonyl)dibenzo[b,f][1,4]oxazepine,
8-(((3-methylthiiran-2-yl)methyl)sulfonyl)dibenzo[b,f][1,4]oxazepine,
8-((thiiran-2-ylmethyl)sulfonyl)-10,11-dihydrodibenzo[b,f][1,4]oxazepine,
N-(2-((2-methylthiiran-2-yl)sulfonyl)-11-(piperazin-1-yl)dibenzo[b,f][1,4]oxazepin-8-yl)methanesulfonamide,
8-((oxiran-2-ylmethyl)sulfonyl)benzo[f]pyrimido[4,5-b][1,4]oxazepin-6(5H)-one,
3-(butoxycarbonyl)-11-(((2-(thiiran-2-yl)ethyl)sulfonyl)methyl)-7-(trifluoromethyl)-5H-dibenzo[b,f]azepine-4-carboxylic acid,
2-((2,3-dihydro-13bH-spiro[dibenzo[b,f]pyrrolo [1,2-d][1,4]oxazepine-1,4′-piperidin]-12-yl)sulfonyl)-2-(thiiran-2-yl)acetonitrile,
2,3-bis((dibenzo[b,f][1,4]oxazepin-2-ylsulfonyl)methyl)thiirane,
2-((3-morpholinodibenzo[b,f][1,2,4]triazolo[4,3-d][1,4]oxazepin-6-yl)sulfonyl)-2-(thiiran-2-yl)acetonitrile,
6,7-dimethyl-3-(4-(thiiran-2-yl)phenyl)benzo[b]naphtho[2,3-f][1,2,4]triazolo[4,3-d][1,4]oxazepine,
2-((thiiran-2-ylmethyl)sulfonyl)-10,11-dihydrodibenzo[b,f][1,4]oxazepine,
1-(10,11-dihydrodibenzo[b,f][1,4]oxazepin-2-yl)-2-(thiiran-2-yl)ethan-1-one,
N-(thiiran-2-yl)-10,11-dihydrodibenzo[b,f][1,4]oxazepine-2-carboxamide,
2-(1-(thiiran-2-ylmethyl)cyclopropyl)-10,11-dihydrodibenzo[b,f][1,4]oxazepine,
2-(3-(thiiran-2-ylmethyl)-1,314-oxathietan-3-yl)-10,11-dihydrodibenzo[b,f][1,4]oxazepine,
(Z)-2-(1-fluoro-2-(thiiran-2-yl)vinyl)-10,11-dihydrodibenzo[b,f][1,4]oxazepine,
2-(5-(thiiran-2-yl)-2H-imidazol-4-yl)-10,11-dihydrodibenzo[b,f][1,4]oxazepine,
3-(thiiran-2-ylmethyl)-1H-benzo[2,3][1,4]oxazepino[6,7-e]isoindole,
1-(thiiran-2-ylmethyl)-3H-benzo[2,3][1,4]oxazepino[6,7-f]isoindole,
2-(dimethyl(thiiran-2-ylmethyl)silyl)-10,11-dihydrodibenzo[b,f][1,4]oxazepine,
(10,11-dihydrodibenzo[b,f][1,4]oxazepin-2-yl)(thiiran-2-ylmethyl)silanediol,
1-phenyl-3-(thiiran-2-ylmethyl)-1H-benzo[2,3][1,4]oxazepino[6,7-f]indazole,
N-hydroxy-N-(thiiran-2-ylmethyl)-10,11-dihydrodibenzo[b,f][1,4]oxazepine-2-carboxamide,
1-(10,11-dihydrodibenzo[b,f][1,4]oxazepin-2-yl)-3-(thiiran-2-yl)urea,
2-(1,1,1-trifluoro-3-(thiiran-2-yl)propan-2-yl)-10,11-dihydrodibenzo[b,f][1,4]oxazepine,
(10,11-dihydrodibenzo[b,f][1,4]oxazepin-2-yl)(thiiran-2-ylmethyl)phosphinic acid,
(10,11-dihydrodibenzo[b,f][1,4]oxazepin-2-yl)(imino)(thiiran-2-ylmethyl)-16-sulfanone,
1-(10,11-dihydrodibenzo[b,f][1,4]oxazepin-2-yl)-2-(thiiran-2-yl)ethan-1-ol,
2-((10,11-dihydrodibenzo[b,f][1,4]oxazepin-2-yl)sulfonyl)-1-(thiiran-2-yl)ethan-1-one
2-((thiiran-2-ylmethyl)sulfinyl)-10,11-dihydrodibenzo[b,f][1,4]oxazepine,
2-(3-(thiiran-2-ylmethyl)-1,2,314-dioxathiiran-3-yl)-10,11-dihydrodibenzo[b,f][1,4]oxazepine,
2-phenoxy-8-((thiiran-2-ylmethyl)sulfonyl)-10,11-dihydrodibenzo[b,f][1,4]oxazepine,
10-((seleniran-2-ylmethyl)sulfonyl)-7a,8,9,10,11,11a,12,13-octahydro-7H-benzo[e]naphtho[1,2-b]azepin-7-one,
5-amino-4-(2-((8-bromo-9-ethyl-7-methyltetradecahydro-1H-dibenzo[a,d][7]annulen-2-yl)sulfonyl)-1-(thiiran-2-yl)ethyl)-1-(3-chlorophenyl)-1H-pyrazole-3-carbonitrile,
8-((thiiran-2-ylmethyl)sulfonyl)-3-(trifluoromethyl)-10,11-dihydrodibenzo[b,f][1,4]oxazepine,
9-((1-(thiiran-2-yl)cyclopenta-2,4-dien-1-yl)sulfonyl)-11,12-dihydro-1H-benzo[2,3][1,4]oxazepino[7,6-g]indole,
(2E,4E,6E)-7-(8-(tert-butyl)-10,11-dihydrodibenzo[b,f][1,4]oxazepin-3-yl)-1-((thiiran-2-ylmethyl)selenonyl)hepta-2,4,6-trien-1-ol,
N-(10-oxo-8-((thiiran-2-ylmethyl)sulfonyl)-10,11-dihydrobenzo[f]pyrido[4,3-b][1,4]oxazepin-3-yl)acetamide,
11-chloro-2-((thiiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepine,
8-((thiiran-2-ylmethyl)sulfonyl)-5,11-dihydrodibenzo[b,e][1,4]oxazepine,
11-bromo-2-((seleniran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepine,
12-((thiiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,2,4]triazolo[4,3-d][1,4]oxazepine,
2-((thiiran-2-ylmethyl)sulfonyl)-11-(trifluoromethyl)dibenzo[b,f][1,4]oxazepine,
11-methyl-2-((thiiran-2-ylmethyl)sulfonyl)dibenzo[b,f][1,4]oxazepine, and
10-benzyl-5-(6-aza-3-silaspirol2.51octan-6-yl)-7,8,9,10,11,12-hexahydro-6H-imidazol[1′,2′:1,6]pyrido[2,3-b]pyrido[4,3-f]azepine,
or any stereochemically isomeric form thereof or a pharmaceutically acceptable salt thereof.

### Claim at position 12

-20. (canceled)

### Claim 21 (depends on 1)

The compound of claim 1, wherein the compound is a compound of formula (VI)
or any stereochemically isomeric form thereof or a pharmaceutically acceptable salt thereof.

### Claim 22 (depends on 8)

The pharmaceutical composition of claim 8 further comprising a cancer drug.

### Claim 23 (depends on 9)

The pharmaceutical composition of claim 9, wherein the cancer drug is temozolomide or a derivate or a prodrug or a pharmaceutical acceptable salt thereof.

### Claim 24 (depends on 9)

The pharmaceutical composition of claim 9, wherein the cancer drug is sorafenib or a derivate or a prodrug or a pharmaceutical acceptable salt thereof.

### Claim 24 (depends on 1)

A method of treatment comprising administering an effective amount of the compound of claim 1 to a subject in need of such a treatment.

### Claim 25 (depends on 14)

The method of claim 14, wherein the subject is diagnosed with OMA1 alterations.

### Claim 26 (depends on 14)

The method of claim 14, wherein the subject has cancer.

### Claim 27 (depends on 14)

The method of claim 14, wherein the subject has a brain tumor.

### Claim 28 (depends on 14)

The method of claim 14, wherein the subject has glioma.

### Claim 29 (depends on 14)

The method of claim 14, wherein the subject has glioblastoma.

### Claim 30 (depends on 14)

The method of claim 14, wherein the compound is administered orally, sublingually, intravenously, intrasternally, transdermally, subcutaneously, intramuscularly, topically, rectally, vaginally, nasally or via the trigeminal nerve.