WO2022269049A1 - Sulfonamide orexin receptor agonists and uses thereof - Google Patents

Sulfonamide orexin receptor agonists and uses thereof Download PDF

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Publication number
WO2022269049A1
WO2022269049A1 PCT/EP2022/067376 EP2022067376W WO2022269049A1 WO 2022269049 A1 WO2022269049 A1 WO 2022269049A1 EP 2022067376 W EP2022067376 W EP 2022067376W WO 2022269049 A1 WO2022269049 A1 WO 2022269049A1
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Prior art keywords
compound
alkyl
cycloalkyl
heterocyclyl
mmol
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PCT/EP2022/067376
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English (en)
French (fr)
Inventor
Davide MARINELLI
Prafulkumar CHOVATIA
Claudia BEATO
Gilles Ouvry
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Jazz Pharmaceuticals Ireland Ltd
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Jazz Pharmaceuticals Ireland Ltd
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Publication date
Application filed by Jazz Pharmaceuticals Ireland Ltd filed Critical Jazz Pharmaceuticals Ireland Ltd
Priority to CN202280044807.8A priority Critical patent/CN117769542A/zh
Priority to IL309108A priority patent/IL309108A/en
Priority to EP22738602.6A priority patent/EP4359387A1/en
Priority to MX2023015074A priority patent/MX2023015074A/es
Priority to CA3224033A priority patent/CA3224033A1/en
Priority to KR1020247000316A priority patent/KR20240026483A/ko
Priority to US18/571,860 priority patent/US20240360081A1/en
Priority to JP2023579045A priority patent/JP2024523488A/ja
Priority to AU2022299418A priority patent/AU2022299418A1/en
Publication of WO2022269049A1 publication Critical patent/WO2022269049A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/94—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
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    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
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    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D471/04—Ortho-condensed systems

Definitions

  • pharmaceutically acceptable salts includes both acid and base addition salts.
  • a C 2 -C 6 alkenyl includes all moieties described above for C 2 -C 5 alkenyls but also includes C 6 alkenyls.
  • a C 2 -C 10 alkenyl includes all moieties described above for C 2 -C 5 alkenyls and C 2 -C 6 alkenyls, but also includes C 7 , C 8 , C 9 and C 10 alkenyls.
  • a C 2 - C 12 alkenyl includes all the foregoing moieties, but also includes C 11 and C12 alkenyls.
  • the heterocyclyl can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged, or spirocyclic ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl can be optionally oxidized; the nitrogen atom can be optionally quatemized; and the heterocyclyl can be partially or fully saturated.
  • R g and R h are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, iV-heteroaryl and/or heteroarylalkyl.
  • R 2 , R 3 , R 4 are independently hydrogen, alkyl, cycloalkyl, heterocyclyl, or halogen, or R 2 and R 3 together with the atom to which they are attached to form a carbocycle or heterocycle, or R 2 and R 4 together with the atom to which they are attached to form a carbocycle or heterocycle;
  • R 5 and R 6 are each independently hydrogen, alkyl, cycloalkyl, heterocyclyl, alkoxy, -O-cycloalkyl, -O-heterocyclyl, or halogen, or R 5 and R 6 together with the atom to which they are attached to form a carbocycle or heterocycle;
  • A is T Inn s soommee e emmbbooddiimmeennttss.
  • a A i iss .
  • A is In some embodiments of the compounds of Formula (I), (I-A), (I-A-I), and (I-B), A is In some embodiments of the compounds of Formula (I),
  • Rn is alkyl optionally substituted with cyano, haloalkyl, cycloalkyl or heterocyclyl.
  • Rn is alkyl or haloalkyl.
  • R 11 is methyl, -CH 2 CN, cyclopropyl, -CH 2 CF 2 H, or -CF 2 H.
  • n is an integer from 0-6 (i.e. 0, 1, 2, 3, 4, 5, or 6).
  • n is an integer from 0-4, or 1-4.
  • n is an integer from 0-3, or 1-3.
  • n is 0, 1, or 2.
  • n is 1 or 2.
  • n is 0.
  • n is 1.
  • n is 2.
  • n is 3.
  • n is 4.
  • n is 5.
  • n is 6.
  • R 11 is alkyl optionally substituted with cyano, haloalkyl, cycloalkyl or heterocyclyl.
  • L 2 is -CR 5 R 6 .
  • R 1 is an alkyl, haloalkyl, cycloalkyl, alkylene-alkoxy, or -NR 7 R 8 .
  • R 1 is alkyl or -NR 7 R 8 ,
  • R 2 , R 3 , R 4 are hydrogen.
  • Z is optionally substituted with one or more R B substituents as defined herein. In embodiments, Z is optionally substituted with 1, 2, 3, 4, or 5 R B .
  • o is 1 and R B is fluoro.
  • the compounds of the present disclosure are provided as a mixture of diastereomers.
  • a diastereomer of a compound of the present disclosure is provided substantially free of other possible diastereomer(s).
  • the present disclosure includes tautomers of any said compounds.
  • the compound of Formula (I), (I-A), (I-A-I), (I-B), or Table 1 has ( S )- configuration at the carbon labelled with an asterisk (*):
  • a pharmaceutical composition as described herein, comprises one or more compounds selected from Table 1, or a pharmaceutically acceptable salt thereof or stereoisomer thereof. [0148] In some embodiments, a pharmaceutical composition, as described herein, comprises one or more compounds selected from Table 1, or a pharmaceutically acceptable salt thereof.
  • Example 2ak N-[2-(2-oxo-1,2-dihydroquinolin-1-yl)-3- ⁇ [(CIS)-4- phenylcyclohexyl]oxy ⁇ propyl]methanesulfonamide
  • Example 5a was prepared following the procedure described for Example 1, starting from Intermediate 22 (39 mg, 0.11 mmol) to afford the title compound (9 mg, 0.022 mmol, 19% yield).
  • R 1 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or -NR 7 R 8 , or R 1 and R 2 together with the atom to which they are attached form a heterocycle;
  • R 5 and R 6 are each independently hydrogen, alkyl, cycloalkyl, heterocyclyl, alkoxy, -O-cycloalkyl, -O-heterocyclyl, or halogen, or R 5 and R 6 together with the atom to which they are attached to form a carbocycle or heterocycle;

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PCT/EP2022/067376 2021-06-25 2022-06-24 Sulfonamide orexin receptor agonists and uses thereof Ceased WO2022269049A1 (en)

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CN202280044807.8A CN117769542A (zh) 2021-06-25 2022-06-24 磺酰胺食欲素受体激动剂及其用途
IL309108A IL309108A (en) 2021-06-25 2022-06-24 Orexin sulfonamide receptor agonists and uses thereof
EP22738602.6A EP4359387A1 (en) 2021-06-25 2022-06-24 Sulfonamide orexin receptor agonists and uses thereof
MX2023015074A MX2023015074A (es) 2021-06-25 2022-06-24 Agonistas de sulfonamidas del receptor de orexina y sus usos.
CA3224033A CA3224033A1 (en) 2021-06-25 2022-06-24 Sulfonamide orexin receptor agonists and uses thereof
KR1020247000316A KR20240026483A (ko) 2021-06-25 2022-06-24 술폰아미드 오렉신 수용체 효능제 및 그의 용도
US18/571,860 US20240360081A1 (en) 2021-06-25 2022-06-24 Sulfonamide orexin receptor agonists and uses thereof
JP2023579045A JP2024523488A (ja) 2021-06-25 2022-06-24 スルホンアミドオレキシン受容体アゴニスト及びその使用
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US12006330B2 (en) 2020-12-21 2024-06-11 Alkermes, Inc. Substituted macrocyclic compounds and related methods of treatment
WO2025124698A1 (en) 2023-12-12 2025-06-19 Idorsia Pharmaceuticals Ltd Aryl sulfone and sulfanone derivatives as orexin receptor modulators
WO2025132542A1 (en) 2023-12-19 2025-06-26 Idorsia Pharmaceuticals Ltd Macrocyclic orexin agonists

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Cited By (5)

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Publication number Priority date Publication date Assignee Title
US11760747B2 (en) 2020-12-21 2023-09-19 Alkermes, Inc. Substituted piperidino compounds and related methods of treatment
US12006330B2 (en) 2020-12-21 2024-06-11 Alkermes, Inc. Substituted macrocyclic compounds and related methods of treatment
US12441710B2 (en) 2020-12-21 2025-10-14 Alkermes, Inc. Substituted piperidino compounds and related methods of treatment
WO2025124698A1 (en) 2023-12-12 2025-06-19 Idorsia Pharmaceuticals Ltd Aryl sulfone and sulfanone derivatives as orexin receptor modulators
WO2025132542A1 (en) 2023-12-19 2025-06-26 Idorsia Pharmaceuticals Ltd Macrocyclic orexin agonists

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