US2012071653A1PendingUtilityA1
Human Adam-10 Inhibitors
Est. expiryJun 12, 2022(expired)· nominal 20-yr term from priority
Inventors:Lynne Canne BannenErick Wang CoVasu JammalamadakaJohn M. NussMoon Hwan KimDonna Tra LeAmy LewMorrison B. MacShumeye MamoZhaoyang WenWei XuRichard George Khoury
A61P 9/10A61P 35/00A61P 43/00A61P 3/10A61P 9/00A61P 29/00C07D 401/06C07D 403/06A61P 15/12C07C 309/87A61P 15/00A61P 15/08C07D 241/04A61P 17/00C07D 401/12A61P 1/04A61P 13/12A61P 19/02C07D 213/70C07D 413/06
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Claims
Abstract
The present invention provides compounds useful for inhibiting the ADAM-10 protein, with selectivity versus MMP-1. Such compounds are useful in the in vitro study of the role of ADAM-10 (and its inhibition) in biological processes. The present invention also comprises pharmaceutical compositions comprising one or more ADAM-10 inhibitors according to the invention in combination with a pharmaceutically acceptable carrier. Such compositions are useful for the treatment of cancer, arthritis, and diseases related to angiogenesis. Correspondingly, the invention also comprises methods of treating forms of cancer, arthritis, and diseases related to angiogenesis in which ADAM-10 plays a critical role.
Claims
exact text as granted — not AI-modified1 . A compound of structural formula I:
and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof wherein
L 1 is —C(O)—, —S(O) 2 —, or —(CH 2 ) n —;
R 1 is —H, —OR 11 , —(CH 2 ) n R 11 , —C(O)R 11 , or —NR 12 R 13 ;
R 11 , R 12 , and R 13 independently are
a) R 50 ;
b) saturated or mono- or poly-unsaturated C 5 -C 14 -mono- or fused poly-cyclic hydrocarbyl, optionally containing one or two annular heteroatoms per ring and optionally substituted with one or two R 50 substituents;
c) C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, or —C(O)H, each of which is optionally substituted with one, two or three substituents independently selected from R 50 and saturated or mono- or poly-unsaturated C 5 -C 14 -mono- or fused poly-cyclic hydrocarbyl, optionally containing one or two annular heteroatoms per ring and optionally substituted with one, two or three R 50 substituents;
or R 12 and R 13 together with the N to which they are covalently bound, a C 5 -C 6 heterocycle optionally containing a second annular heteroatom and optionally substituted with one or two R 50 substituents;
R 2 is —R 21 -L 2 -R 22 ;
R 21 is saturated or mono- or poly-unsaturated C 5 -C 14 -mono- or fused poly-cyclic hydrocarbyl, optionally containing one or two annular heteroatoms per ring and optionally substituted with one, two, or three R 50 substituents;
L 2 is —O—, —C(O)—, —CH 2 —, —NH—, —S(O 2 )— or a direct bond;
R 22 is saturated or mono- or poly-unsaturated C 5 -C 14 -mono- or fused poly-cyclic hydrocarbyl, optionally containing one or two annular heteroatoms per ring and optionally substituted with one, two, or three R 50 substituents; and
R 50 is R 51 -L 3 -(CH 2 ) n —;
L 3 is —O—, —NH—, —S(O) 0-2 —, —C(O)—, —C(O)O—, —C(O)NH—, —OC(O)—, —NHC(O)—, —C 6 H 4 —, or a direct bond;
R 51 is —H, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, halo, —CF 3 , —OCF 3 , —OH, —NH 2 , mono-C 1 -C 6 alkyl amino, di-C 1 -C 6 alkyl amino, —SH, —CO 2 H, —CN, —NO 2 , —SO 3 H, or a saturated or mono- or poly-unsaturated C 5 -C 14 -mono- or fused poly-cyclic hydrocarbyl, optionally containing one or two annular heteroatoms per ring and optionally substituted with one, two, or three substituents;
wherein n is 0, 1, 2, or 3;
provided that an O or S is not singly bonded to another O or S in a chain of atoms.
2 . The compound according to claim 1 , wherein L 1 is —C(O)— or —S(O) 2 —.
3 . The compound according to claim 2 , wherein L 1 is —C(O)— and R 1 is —OR 11 or —(CH 2 ) n R 11 , —OC 1 -C 6 alkyl-mono-C 1 -C 6 alkyl amino, —OC 1 -C 6 alkyl-di-C 1 -C 6 alkyl amino, —OC 1 -C 6 alkyl-N-heterocyclyl, —C 1 -C 6 alkyl-mono-C 1 -C 6 alkyl amino, —C 1 -C 6 alkyl-di-C 1 -C 6 alkyl amino, or —C 1 -C 6 alkyl-N-heterocyclyl.
4 . The compound according to claim 2 , wherein, R 1 is C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy.
5 . The compound according to claim 2 , wherein R 1 is methoxyethoxy.
6 . The compound according to claim 3 , wherein L 1 is —S(O) 2 —, and R 1 is —NR 12 R 13 , —(CH 2 ) n R 11 , —C 1 -C 6 alkyl-mono-C 1 -C 6 alkyl amino, —C 1 -C 6 alkyl-di-C 1 -C 6 alkyl amino, or —C 1 -C 6 alkyl-N-heterocyclyl.
7 . The compound according to claim 3 , wherein L 2 is —O—.
8 . The compound according to claim 7 , wherein, R 2 is phenoxyphenyl wherein each phenyl is optionally substituted with one or two R 50 substituents. In a more specific example, the R 50 substituents are halo.
9 . The compound according to claim 8 , wherein the saturated or mono- or poly-unsaturated C 5 -C 14 -mono- or fused poly-cyclic hydrocarbyl containing one or two annular heteroatoms per ring is selected from the group consisting of morpholinyl, piperazinyl, homopiperazinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, furyl, thienyl, pyranyl, isobenzofuranyl, chromenyl, pyrrolyl, imidazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, oxadiazolyl, indolyl, quinolinyl, carbazolyl, acrydinyl, and furazanyl, optionally substituted with one or two R 50 substituents.
10 . The compound according to claim 8 , wherein R 12 and R 13 , together with the N to which they are covalently bound, form a heterocycle selected from the group consisting of morpholinyl, piperazinyl, homopiperazinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, pyrrolyl, imidazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, oxadiazolyl, indolyl, quinolinyl, carbazolyl, acrydinyl, and furazanyl, optionally substituted with one or two R 50 substituents.
11 . The compound according to claim 1 , comprising the absolute stereochemistry of structural formula II:
12 . The compound according to claim 1 , comprising the absolute stereochemistry of structural formula III:
13 . The compound according to claim 1 , wherein -L 1 -R 1 is selected from:
—R 14
wherein each R 14 is independently selected from —H, —(CH 2 ) 1-3 CO 2 H, alkyl, alkoxy, alkenyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; and
R 2 is selected from:
14 . The compound according to claim 1 , selected from:
15 . A compound according to formula IV,
and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof wherein,
Z is —C(R 15 )═, —C(H)═, or —N═;
Ar is aryl or heteroaryl, each optionally substituted;
R 15 is fluoro;
p is 0, 1, 2, or 3;
L 1 is —C(O)—, —S(O) 2 —, or —(CH 2 ) n —;
L 4 is nothing or —O—;
R 1 is —H, —OR 11 , —(CH 2 ) n R 11 , —C(O)R 11 , or —NR 12 R 13 ;
R 11 , R 12 , and R 13 independently are
d) R 50 ;
e) saturated or mono- or poly-unsaturated C 5 -C 14 -mono- or fused poly-cyclic hydrocarbyl, optionally containing one or two annular heteroatoms per ring and optionally substituted with one or two R 50 substituents;
f) C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, or —C(O)H, each of which is optionally substituted with one, two or three substituents independently selected from R 50 and saturated or mono- or poly-unsaturated C 5 -C 14 -mono- or fused poly-cyclic hydrocarbyl, optionally containing one or two annular heteroatoms per ring and optionally substituted with one, two or three R 50 substituents;
or R 12 and R 13 together with the N to which they are covalently bound, a C 5 -C 6 heterocycle optionally containing a second annular heteroatom and optionally substituted with one or two R 50 substituents; and
R 50 is R 51 -L 3 -(CH 2 ) n —;
L 3 is —O—, —NH—, —S(O) 0-2 —, —C(O)—, —C(O)O—, —C(O)NH—, —OC(O)—, —NHC(O)—, —C 6 H 4 —, or a direct bond;
R 51 is —H, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, halo, —CF 3 , —OCF 3 , —OH, —NH 2 , mono-C 1 -C 6 alkyl amino, di-C 1 -C 6 alkyl amino, —SH, —CO 2 H, —CN, —NO 2 , —SO 3 H, or a saturated or mono- or poly-unsaturated C 5 -C 14 -mono- or fused poly-cyclic hydrocarbyl, optionally containing one or two annular heteroatoms per ring and optionally substituted with one, two, or three substituents;
wherein n is 0, 1, 2, or 3;
provided that an O or S is not singly bonded to another O or S in a chain of atoms.
16 . The compound according to claim 15 , wherein -L 1 -R 1 is selected from:
—R 14
wherein each R 14 is independently selected from —H, —(CH 2 ) 1-3 CO 2 H, alkyl, alkoxy, alkenyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl.
17 . The compound according to claim 16 , wherein Z is —C(R 15 )═ or —C(H)═; L 4 is —O—; and p is at least one.
18 . The compound according to claim 17 , wherein Ar is selected from the group consisting of phenyl, biphenyl, napthyl, tetrahydronaphthalene, chromen-2-one, dibenzofuran, pyryl, furyl, pyridyl, 1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbazolyl, benzimidazolyl, and isoxazolyl, each optionally substituted.
19 . The compound according to claim 18 , wherein Ar is phenyl, optionally substituted, with at least one halogen.
20 . The compound according to claim 19 , wherein p is at least two.
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