US2012058986A1PendingUtilityA1
Di-azetidinyl diamide as monoacylglycerol lipase inhibitors
Est. expirySep 3, 2030(~4.1 yrs left)· nominal 20-yr term from priority
A61P 43/00A61P 29/00A61P 25/06A61P 31/00A61P 25/04C07D 413/14A61P 21/00A61K 31/397A61P 19/02C07D 409/14A61P 1/04A61P 11/02A61K 31/427A61P 1/16A61K 31/429A61P 1/18A61P 1/02A61P 17/00C07D 205/04A61P 1/06A61P 13/02C07D 403/14A61P 17/04C07D 417/12A61K 31/423C07D 417/14A61K 31/428A61K 31/4035A61P 13/10A61P 11/00A61K 31/454A61P 17/02C07D 513/04A61P 15/00A61P 1/00
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Claims
Abstract
Disclosed are compounds, compositions and methods for treating various diseases, syndromes, conditions and disorders, including pain. Such compounds are represented by Formula (I) as follows: wherein Q and Z are defined herein.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A compound of Formula (I)
wherein
Q is selected from
wherein
Y is C 6-10 aryl or a heteroaryl that is thiazolyl, pyrrolyl, or oxazolyl;
R 1 is hydrogen or C 1-4 alkyl; and
m is an integer from 1 to 3;
Z is C 6-10 aryl or a heteroaryl selected from the group consisting of quinolinyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, indolyl, and indazolyl;
wherein Z is
(i) optionally independently substituted with one to three substituents selected from the group consisting of C 1-4 alkyl, fluoro, chloro, bromo, trifluoromethyl, and piperidin-1-yl; provided that no more than one substituent on Z is piperidin-1-yl or
(ii)
(a) substituted with
and
(b) optionally further substituted with one additional methyl, chloro, fluoro, or phenyl substituent;
wherein
ring A is phenyl, thienyl, or benzothiophenyl; provided that
when ring A is thienyl or benzothiophenyl, G is a bond or —CH 2 — or
when A is phenyl, G is selected from the group consisting of a bond, O, —CH 2 —, SO 2 , and C(O); and
R 2 is trifluoromethyl, fluoro, chloro, or methanesulfonyl;
r is an integer from 0 to 3;
and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.
2 . The compound of claim 1 wherein Q is selected from
wherein
Y is phenyl or thiazolyl;
R 1 is hydrogen or methyl; and
m is 1.
3 . The compound of claim 2 wherein R 1 is hydrogen.
4 . The compound of claim 1 wherein Z is C 6-10 aryl or a heteroaryl selected from the group consisting of benzothiophenyl, benzoxazolyl, benzothiazolyl, indolyl, and indazolyl;
wherein Z is
(i) independently substituted with one to two substituents selected from the group consisting of C 1-4 alkyl, fluoro, chloro, bromo, trifluoromethyl, and piperidin-1-yl; provided that no more than one substituent on Z is piperidin-1-yl or
(ii)
(a) substituted with and
(b) optionally further substituted with one additional methyl, chloro, fluoro, or phenyl substituent;
wherein
ring A is phenyl, thienyl, or benzothiophenyl; provided that
when ring A is thienyl or benzothiophenyl, G is a bond or —CH 2 — or
when ring A is phenyl G is a bond, O, —CH 2 —, SO 2 , or C(O); and
R 2 is trifluoromethyl, fluoro, chloro, or methanesulfonyl; and
r is an integer from 0 to 3.
5 . The compound of claim 4 wherein Z is C 6-10 aryl or a heteroaryl selected from the group consisting of benzothiophenyl, benzoxazolyl, benzothiazolyl, indolyl, and indazolyl;
wherein Z is
(i) optionally independently substituted with one to two substituents selected from the group consisting of C 1-4 alkyl, fluoro, chloro, bromo, and trifluoromethyl or
(ii)
(a) substituted with
and
(b) optionally further substituted with one additional methyl, chloro, fluoro, or phenyl substituent;
wherein
ring A is phenyl or thienyl; provided that
when ring A is phenyl, G is a bond, —CH 2 —, or SO 2 or
when ring A is thienyl, G is a bond or —CH 2 —; and
R 2 is trifluoromethyl, fluoro, chloro, or methanesulfonyl; and
r is an integer from 0 to 2.
6 . A compound of Formula (I)
wherein:
Q is selected from
wherein
Y is phenyl or thiazolyl;
R 1 is hydrogen or methyl; and
m is 1;
Z is C 6-10 aryl or a heteroaryl selected from the group consisting of benzothiophenyl, benzoxazolyl, benzothiazolyl, indolyl, and indazolyl;
wherein Z is
(i) independently substituted with one to two substituents selected from the group consisting of C 1-4 alkyl, fluoro, chloro, bromo, trifluoromethyl, and piperidin-1-yl; provided that no more than one substituent on Z is piperidin-1-yl or
(ii)
(a) substituted with
and
(b) optionally further substituted with one additional methyl, chloro, fluoro, or phenyl substituent;
wherein
ring A is phenyl, thienyl, or benzothiophenyl; provided that
when ring A is thienyl or benzothiophenyl, G is a bond or —CH 2 — or
when ring A is phenyl, G is a bond, O, —CH 2 —, SO 2 , or C(O); and
R 2 is trifluoromethyl, fluoro, chloro, or methanesulfonyl; and
r is an integer from 0 to 3;
and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.
7 . A compound of Formula (I)
wherein:
Q is selected from
wherein
Y is phenyl or thiazolyl;
R 1 is hydrogen; and
m is 1;
Z is C 6-10 aryl or a heteroaryl selected from the group consisting of benzothiophenyl, benzoxazolyl, benzothiazolyl, indolyl, and indazolyl;
wherein Z is
(i) independently substituted with one to two substituents selected from the group consisting of C 1-4 alkyl, fluoro, chloro, bromo, and trifluoromethyl or
(ii)
(a) substituted with
and
(b) optionally further substituted with one additional methyl, chloro, fluoro, or phenyl substituent;
wherein
ring A is phenyl or thienyl; provided that
when ring A is thienyl, G is a bond or —CH 2 — or
when ring A is phenyl G is a bond, —CH 2 —, or SO 2 ;
R 2 is trifluoromethyl, fluoro, chloro, or methanesulfonyl; and
r is an integer from 0 to 2;
and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.
8 . A compound of Formula (Ia)
selected from the group consisting of
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 1-(4-trifluoromethylphenyl)-1H-indol-5-yl;
a compound wherein Y is thiazol-4-yl, R 1 is H, and Z is 4-(3-trifluoromethylphenyl)phenyl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 1-(phenylsulfonyl)-1H-indol-5-yl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 2-phenyl-benzothiazol-6-yl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 4-(3-trifluoromethylphenyl)phenyl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 6-phenyl-benzothiophen-2-yl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 6-trifluoromethyl-benzothiophen-2-yl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 4-trifluoromethyl-benzothiophen-2-yl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 4-(5-trifluoromethyl-thien-2-yl)-phenyl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 4-(phenylmethyl)-phenyl;
a compound wherein Y is thiazol-4-yl, R 1 is H, and Z is 1-(4-fluorophenyl)-1H-indol-5-yl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 4-(4-trifluoromethylphenyl)-phenyl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 1-phenyl-1H-indol-5-yl;
a compound wherein Y is thiazol-4-yl, R 1 is H, and Z is 4-(4-trifluoromethylphenyl)-phenyl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 3-methyl-5-chloro-benzothiophen-2-yl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 4-(4-trifluoromethylphenylmethyl)-phenyl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 2-phenyl-benzoxazol-6-yl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 4-(3-methanesulfonylphenyl)phenyl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 5-bromo-naphth-2-yl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 4-(3-trifluoromethylphenylmethyl)-phenyl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 6-phenyl-naphth-2-yl;
a compound wherein Y is thiazol-4-yl, R 1 is H, and Z is 2-phenyl-benzothiazol-6-yl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 6-bromo-benzothiophen-2-yl;
a compound wherein Y is phenyl, R 1 is H, and Z is 5-bromo-naphth-2-yl;
a compound wherein Y is phenyl, R 1 is H, and Z is 5-phenyl-naphth-2-yl;
a compound wherein Y is phenyl, R 1 is H, and Z is 4-(4-trifluoromethyl phenylmethyl)-phenyl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 1-phenyl-1H-indol-6-yl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 2-(3-trifluoromethylphenyl)-benzoxazol-6-yl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 4-phenyl-phenyl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 2-(4-trifluoromethylphenyl)-benzoxazol-6-yl;
a compound wherein Y is phenyl, R 1 is H, and Z is 4-(phenylmethyl)-phenyl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 4-phenoxy-phenyl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 2-(4-chlorophenyl)-benzoxazol-6-yl;
a compound wherein Y is phenyl, R 1 is H, and Z is 6-phenyl-naphth-2-yl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 2-phenyl-benzoxazol-5-yl;
a compound wherein Y is phenyl, R 1 is H, and Z is 3-methyl-5-chloro-benzothiophen-2-yl;
a compound wherein Y is thiazol-2-yl, R 1 is methyl, and Z is 6-trifluoromethyl-benzothiophen-2-yl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 4-(phenylcarbonyl)-phenyl;
a compound wherein Y is phenyl, R 1 is H, and Z is 4-phenyl-phenyl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 6-bromo-naphth-2-yl;
a compound wherein Y is phenyl, R 1 is H, and Z is 2-phenyl-benzoxazol-6-yl;
a compound wherein Y is phenyl, R 1 is H, and Z is 6-bromo-naphth-2-yl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 4-bromophenyl;
a compound wherein Y is phenyl, R 1 is H, and Z is 5-trifluoromethyl-benzothiophen-2-yl;
a compound wherein Y is phenyl, R 1 is H, and Z is 4-phenoxy-phenyl;
a compound wherein Y is thiazol-4-yl, R 1 is H, and Z is 2-bromo-benzothiazol-6-yl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 5-trifluoromethyl-benzothiazol-2-yl;
a compound wherein Y is thiazol-4-yl, R 1 is methyl, and Z is 6-trifluoromethyl-benzothiophen-2-yl;
a compound wherein Y is thiazol-4-yl, R 1 is H, and Z is 6-trifluoromethyl-benzothiophen-2-yl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 3-chloro-6-trifluoromethyl-benzothiophen-2-yl;
a compound wherein Y is thiazol-4-yl, R 1 is H, and Z is 3-chloro-6-trifluoromethyl-benzothiophen-2-yl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 1-phenyl-1H-indazol-5-yl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 5-phenyl-naphth-2-yl;
a compound wherein Y is thiazol-4-yl, R 1 is H, and Z is 1-(3,4-difluorophenyl)-1H-indol-5-yl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 1-(2,4-difluorophenyl)-1H-indol-5-yl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 3-methyl-6-trifluoromethyl-benzothiophen-2-yl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 1-(3,4-difluorophenyl)-1H-indol-5-yl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 2-methyl-4-(3-trifluoromethylphenyl)-phenyl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 2-fluoro-4-(4-trifluoromethylphenyl)-phenyl;
a compound wherein Y is thiazol-4-yl, R 1 is H, and Z is 1-(2,4-difluorophenyl)-1H-indol-5-yl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 1-(4-fluorophenyl)-1H-indol-5-yl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 1-(4-fluorophenyl)-3-methyl-1H-indol-5-yl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 2-methyl-4-(4-trifluoromethylphenyl)phenyl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 2-fluoro-4-(3-trifluoromethylphenyl)-phenyl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 3-methyl-6-bromo-benzothiophen-2-yl;
a compound wherein Y is thiazol-2-yl, R 1 is H, and Z is 3-methyl-6-phenyl-benzothiophen-2-yl; and
a compound wherein Y is thiazol-4-yl, R 1 is H, and Z is 3-methyl-6-trifluoromethyl-benzothiophen-2-yl;
and pharmaceutically acceptable salt forms thereof.
9 . A compound of Formula (Ib)
selected from the group consisting of
a compound wherein m is 1, and Z is 3-chloro-6-phenyl-benzothiophen-2-yl;
a compound wherein m is 1, and Z is 6-phenyl-naphth-2-yl;
a compound wherein m is 1, and Z is 1-(4-trifluoromethylphenyl)-1H-indol-5-yl;
a compound wherein m is 1, and Z is 1-(phenylsulfonyl)-1H-indol-5-yl;
a compound wherein m is 1, and Z is 6-(3-methanesulfonylphenyl)-benzothiophen-2-yl;
a compound wherein m is 1, and Z is 3-chloro-6-bromo-benzothiophen-2-yl;
a compound wherein m is 1, and Z is 3,6-diphenyl-benzothiophen-2-yl;
a compound wherein m is 1, and Z is 1-(3-trifluoromethylphenyl)-1H-indol-5-yl;
a compound wherein m is 1, and Z is 4-(5-trifluoromethyl-thien-2-yl)-phenyl;
a compound wherein m is 1, and Z is 2-phenyl-benzoxazol-5-yl;
a compound wherein m is 1, and Z is 2-(3-trifluoromethylphenyl)-benzoxazol-6-yl;
a compound wherein m is 1, and Z is 5-phenyl-benzothiophen-2-yl;
a compound wherein m is 1, and Z is 4-(3-methanesulfonylphenyl)phenyl;
a compound wherein m is 1, and Z is 6-trifluoromethyl-benzothiophen-2-yl;
a compound wherein m is 1, and Z is 5-(3-methanesulfonylphenyl)benzothiophen-2-yl;
a compound wherein m is 1, and Z is 5-bromo-naphth-2-yl;
a compound wherein m is 1, and Z is 2-phenyl-benzoxazol-6-yl;
a compound wherein m is 1, and Z is 1-phenyl-1H-indol-5-yl;
a compound wherein m is 1, and Z is 4-(3-trifluoromethylphenylmethyl)phenyl;
a compound wherein m is 1, and Z is 6-bromo-benzothiophen-2-yl;
a compound wherein m is 1, and Z is 2-(4-chlorophenyl)-benzoxazol-6-yl;
a compound wherein m is 1, and Z is 1-(2-trifluoromethylphenyl)-1H-indol-5-yl;
a compound wherein m is 1, and Z is 6-bromo-naphth-2-yl;
a compound wherein m is 1, and Z is 4-piperadin-1-yl-phenyl;
a compound wherein m is 1, and Z is 4-phenyl-phenyl;
a compound wherein m is 1, and Z is 5-bromo-benzothiophen-2-yl;
a compound wherein m is 1, and Z is 4-(phenylmethyl)phenyl;
a compound wherein m is 1, and Z is 4-(benzothiophen-2-yl)phenyl a compound wherein m is 1, and Z is 4-bromophenyl;
a compound wherein m is 1, and Z is 5-phenyl-naphth-2-yl;
a compound wherein m is 1, and Z is 6-phenyl-benzothiophen-2-yl;
a compound wherein m is 1, and Z is 3-chloro-6-trifluoromethyl-benzothiophen-2-yl;
a compound wherein m is 1, and Z is 3-chloro-6-fluoro-benzothiophen-2-yl;
a compound wherein m is 1, and Z is 3-methyl-6-trifluoromethyl-benzothiophen-2-yl; and
a compound wherein m is 1, and Z is 1-(4-fluorophenyl)-1H-indol-5-yl;
and pharmaceutically acceptable salt forms thereof.
10 . A compound of Formula (Ic)
selected from the group consisting of
a compound wherein Z is 3-methyl-6-trifluoromethyl-benzothiophen-2-yl;
a compound wherein Z is 2-methyl-4-(3-trifluoromethylphenyl)phenyl;
a compound wherein Z is 2-methyl-4-(4-trifluoromethylphenyl)phenyl; and
a compound wherein Z is 1-(4-trifluoromethylphenyl)-1H-indol-5-yl;
and pharmaceutically acceptable salt forms thereof.
11 . A pharmaceutical composition comprising a compound of claim 1 and at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and a pharmaceutically acceptable diluent.
12 . A pharmaceutical composition of claim 11 , wherein the composition is a solid oral dosage form.
13 . A pharmaceutical composition of claim 11 , wherein the composition is a syrup, an elixir, or a suspension.
14 . A method for treating inflammatory pain in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .
15 . The method of claim 14 , wherein the inflammatory pain is due to inflammatory bowel disease, visceral pain, migraine, post operative pain, osteoarthritis, rheumatoid arthritis, back pain, lower back pain, joint pain, abdominal pain, chest pain, labor, musculoskeletal diseases, skin diseases, toothache, pyresis, burn, sunburn, snake bite, venomous snake bite, spider bite, insect sting, neurogenic bladder, interstitial cystitis, urinary tract infection, rhinitis, contact dermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis, enteritis, irritable bowel syndrome, cholecystitis, pancreatitis, postmastectomy pain syndrome, menstrual pain, endometriosis pain, pain due to physical trauma, headache, sinus headache, tension headache, or arachnoiditis.Cited by (0)
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