Cyclic ureas
The invention provides amides that inhibit cellular necrosis and/or human receptor interacting protein 1 kinase (RIP1), including corresponding sulfonamides, and pharmaceutically acceptable salts, hydrates and stereoisomers thereof. The compounds are employed in pharmaceutical compositions, and methods of making and use, including treating a person in need thereof with an effective amount of the compound or composition, and detecting a resultant improvement in the person's health or condition.
1 . A compound of structure:
wherein:
R 1 is substituted or unsubstituted phenyl or substituted or unsubstituted 2-, 3- or 4-pyridine;
R 2 is dihydro-pyrazole or isoxazolidine; and
R 3 and R 4 are linked to form a 4-6 membered N-containing, heterocycloalkyl ring, wherein the 4-6 membered N-containing, heterocycloalkyl ring is fused to phenyl or wherein the 4-6 membered N-containing, heterocycloalkyl ring is linked to R 5 through an optional linker selected from —CH 2 —, —O— and ═CH—, wherein R 5 is substituted or unsubstituted C3-C9 cycloalkyl with 0-3 heteroatoms, C3-C9 cycloalkenyl with 0-3 heteroatoms, or C3-C9 cycloalkynyl with 0-3 heteroatoms, or substituted or unsubstituted C5-C14 aryl with 0-3 heteroatoms;
or a pharmaceutically acceptable salt, or a hydrate of the compound.
2 . The compound of claim 1 wherein:
R 1 is fluoro-substituted or unsubstituted phenyl.
3 . The compound of claim 1 wherein:
R 2 is dihydro-pyrazole.
4 . The compound of claim 2 wherein:
R 2 is dihydro-pyrazole.
5 . The compound of claim 1 wherein:
R 3 and R 4 are linked to form an azetidine, pyrrolidine or diazinane.
6 . The compound of claim 1 wherein:
R 3 and R 4 are linked to form an azetidine.
7 . The compound of claim 4 wherein:
R 3 and R 4 are linked to form an azetidine.
8 . The compound of claim 1 wherein the linker is —O—.
9 . The compound of claim 1 wherein:
R 5 is (a) substituted or unsubstituted phenyl;
(b) substituted or unsubstituted 2-, 3- or 4-pyridine;
(c) substituted or unsubstituted naphthyl or 3-azanaphthyl;
(d) substituted or unsubstituted 0-3 heteroatoms cyclohexyl, cyclopentyl; or
(e) substituted or unsubstituted 0-3 heteroatoms cyclopentene or cyclopentadiene.
10 . The compound of claim 1 wherein:
R 5 is substituted or unsubstituted 2-, 3- or 4-pyridine.
11 . The compound of claim 4 wherein:
R 5 is substituted or unsubstituted 2-, 3- or 4-pyridine.
12 . The compound of claim 7 wherein:
R 5 is substituted or unsubstituted 2-, 3- or 4-pyridine.
13 . The compound of claim 1 wherein:
R 5 is substituted or unsubstituted: phenyl, cyclohexyl, furan, thiophene or azole.
14 . The compound of claim 1 wherein:
R 5 is substituted or unsubstituted phenyl.
15 . A compound comprising a structure of any one of the following structures:
or a pharmaceutically acceptable salt, or a hydrate of the compound.
16 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in unit dosage form and one or more pharmaceutically acceptable excipients.
17 . A method inhibiting necrosis, ferroptosis or human RIP1, comprising administering to a person in need thereof a compound of claim 1 .
18 . The compound of claim 1 , wherein: the substituent(s) of R 1 are selected from halogen and CN; and/or the substituent(s) of R 5 are selected from halogen, —R′, —OR′, ═O, —NR′R″, —CO2R′, —CONR′R″, —NR″C(O)R′, and —CN, wherein R′ and R″ are each independently selected from hydrogen, unsubstituted (C1-C4)alkyl, and unsubstituted (C1-C4) heteroalkyl, wherein the (C1-C4) heteroalkyl has at least one heteroatom selected from N, O, and S.
19 . A compound of structure:
or a pharmaceutically acceptable salt, or a hydrate thereof, wherein:
R 1 is substituted or unsubstituted phenyl or substituted or unsubstituted 2-, 3- or 4-pyridyl, wherein the substitute(s) of R 1 are selected from halogen and CN;
R 2 is dihydro-pyrazole or isoxazolidine; and
R 3 and R 4 , together with the nitrogen atom to which they are bound, are linked to form a 4-6 membered N-containing, heterocycloalkyl ring,
wherein the formed 4-6 membered N-containing, heterocycloalkyl ring is fused to phenyl, or wherein the 4-6 membered N-containing, heterocycloalkyl ring is linked through a linker to R 5 ;
wherein the linker is —CH 2 —, —O—, or ═CH—; and
R 5 is
(a) substituted or unsubstituted phenyl;
(b) substituted or unsubstituted 2-, 3- or 4-pyridine;
(c) substituted or unsubstituted naphthyl or 3-azanaphthyl;
(d) substituted or unsubstituted 0-3 heteroatoms cyclohexyl, cyclopentyl, wherein the heteroatoms are selected from N, O, and S; or
(e) substituted or unsubstituted 0-3 heteroatoms cyclopentene or cyclopentadiene,
wherein the heteroatoms are independently selected from N, O, and S; and
wherein the substituent(s) of R 5 are selected from halogen, —R′, —OR′, ═O, —NR′R″, —CO2R′, —CONR′R″, —NR″C(O)R′, and —CN, wherein R′ and R″ are each independently selected from hydrogen, unsubstituted (C1-C8)alkyl, and unsubstituted (C1-C8) heteroalkyl, wherein the (C1-C8) heteroalkyl has at least one heteroatom selected from N, O, and S.
20 . A method inhibiting necrosis, ferroptosis or human RIP1, comprising administering to a person in need thereof a compound of claim 19 .