US2009192129A1PendingUtilityA1
Bicyclic pyrrole derivatives
Assignee: DAINIPPON SUMITOMO PHARMA COPriority: Dec 12, 2004Filed: Jun 23, 2008Published: Jul 30, 2009
Est. expiryDec 12, 2024(expired)· nominal 20-yr term from priority
A61P 37/00A61P 9/00A61P 43/00A61P 29/00A61P 3/00C07D 487/04A61P 3/10A61K 31/519
56
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Claims
Abstract
Compounds represented by the general formula (I), prodrugs thereof, or pharmaceutically acceptable salts of both are provided as compounds which have high DPP-IV inhibiting activity and are improved in safety, toxicity and so on: (I) wherein the solid line and dotted line between A 1 and A 2 represents a double bond (A 1 =A 2 ) or the like; A 1 is C(R 4 ) or the like; A 2 is nitrogen atom or the like; R 1 is hydrogen atom, optionally substituted alkly group, or the like; R 2 is hydrogen atom, optionally substituted alkyl group, or the like; R 3 is hydrogen atom, halogen atom, or the like; R 4 is hydrogen atom, hydroxyl, halogen atom, or the like; and Y is a group represented by the general formula (A) or the like; (A) [wherein m1 is 0, 1, 2 or 3; and the group (A) may be freed from R 6 or substituted with one or two R 6 's which are each independently halogen atom or the like.]
Claims
exact text as granted — not AI-modified1 - 21 . (canceled)
22 . A compound of formula (I):
wherein A 1 is —CH═ and A 2 is ═N—; or A 1 is —C(O)— and A 2 is —N(R 5 )—;
R 1 , R 2 and R 5 are independently each hydrogen, —W-hydrocarbyl or —W-heterocyclyl, any of which is optionally substituted, particularly on the hydrocarbyl or heterocyclyl part, with 1, 2, 3, 4 or 5 R 12 ; wherein the or each W is independently a bond or a linker having from 1 to 8 in-chain atoms and selected from, for example, —CH 2 —, —O—, —C(O)—, —S(O) m —, NR a —, cyclopropylene; C 1 , C 2 , C 3 , C 4 , C 5 or C 6 alkyl; and chemically appropriate combinations thereof; and wherein the or each Ra is independently hydrogen, hydroxy or hydrocarbyl optionally interrupted by an —O— or —NH— linkage;
R 3 is hydrogen or an electron withdrawing group, for example CF 3 , CN, C(O)OR 8′ , C(O)NR 8′ R 9′ , —S(O) m R 8′ or —CH 2 OR 10′ ;
wherein Y is a group represented by formula (i):
wherein Q is a bond or alkylene comprising 1, 2 or 3 in-chain carbon atoms optionally substituted with 1, 2, 3, 4 or 5 R 12 ; and R w , R x , R y and R z are each independently hydrogen or C 1-6 alkyl optionally substituted with 1, 2, 3, 4 or 5 R 12 ; or two of R w , R x , R y and R z taken together form an alkylene bridge comprising 1, 2, 3, 4, 5 or 6 in-chain carbon atoms, the bridge optionally substituted with 1, 2, 3, 4 or 5 R 12 ; and the other two are each hydrogen or C 1-6 alkyl optionally substituted with 1, 2, 3, 4 or 5 R 12 ; R 8′ and R 9′ are independently each hydrogen or C 1-6 alkyl optionally substituted with 1, 2, 3, 4 or 5 R 12 ; or R 8′ and R 9′ taken together with the nitrogen atom to which they are attached form heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 R 12 ; R 10′ is C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from R 11′ and R 12 ; R 11′ is aryl or heteroaryl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 ; each R 12 is independently selected from:
(i) functional moieties selected from hydroxy, halogen, amino and —CN;
(ii) alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms and optionally substituted with 1, 2, 3, 4 or 5 halogens;
(iii) alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms and optionally substituted with one or two of said functional moieties (i);
(iv) alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms and optionally substituted with 1, 2, 3, 4 or 5 halogens; and
(v) alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms and optionally substituted with one or two of said functional moieties (i); or two R 12 attached to the same carbon atom form oxo; and m is 0, 1 or 2;
or a pharmaceutically acceptable salt or prodrug thereof.
23 . A compound according to claim 22 , wherein Q is a bond, i.e. Y is a group of formula (ii):
24 . A compound according to claim 22 , wherein Q is methylene optionally substituted with 1 or 2 R 12 ; or ethylene optionally substituted with 1, 2, 3 or 4 R 12 .
25 . A compound according to any preceding claim, wherein:
R w and R x form —CH 2 —, —(CH 2 ) 2 — or —(CH 2 ) 3 —; and R y and R z are each hydrogen; R x and R z form —CH 2 —, —(CH 2 ) 2 — or —(CH 2 ) 3 —; and R w and R z are each hydrogen; or R y and R z form —(CH 2 ) 3 —, —(CH 2 ) 4 — or —(CH 2 ) 5 —; and R x and R w are each hydrogen.
26 . A compound according to claim 22 , wherein Y is a group selected from:
wherein the symbol * signifies a chiral centre of (S)- or (R)-configuration.
27 . A compound according to claim 22 , which is of formula (II) or formula (III):
or a pharmaceutically acceptable salt of prodrug thereof.
28 . A compound according to claim 22 , which is of formula (IV) or formula (V):
or a pharmaceutically acceptable salt or prodrug thereof.
29 . A compound according to claim 22 , wherein Y is homopiperazinyl optionally substituted with 1, 2, 3, 4 or 5 R 12 .
30 . A compound according to claim 29 , which is of the formula (VI) or (VII):
or a pharmaceutically acceptable salt or prodrug thereof.
31 . A compound according to any preceding claim,
wherein R 2 is C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 .
32 . A compound according to claim 31 ,
wherein R 2 is selected from C 1 , C 2 , C 3 or C 4 alkyl (e.g. methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or tert-butyl); C 2 , C 3 , C 4 , C 5 or C 6 alkenyl (e.g. ethenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-but-2-enyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1-hexenyl, 2-hexenyl or 3-hexenyl); and C 2 , C 3 , C 4 , C 5 or C 6 alkynyl (e.g. ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl or 3-hexynyl); any of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 , wherein the or each R 12 is, for example, C 1-6 alkoxy, hydroxy or halogen (e.g. chlorine or fluorine).
33 . A compound according to claim 32 , wherein R 2 is methyl, butyl, 2-methoxyethyl, 3-methyl-buten-2-yl or but-2-ynyl.
34 . A compound according to any of claims 22 to 30 ,
wherein R 2 is —(CH 2 ) n —R 6′ , wherein n is 0, 1, 2, 3, 4, 5 or 6, and R 6′ is carbocyclyl (e.g. cycloalkyl or aryl) or heterocyclyl (e.g. heterocycloalkyl or heteroaryl), either of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 ; and wherein the or each R 12 is selected from, for example, cyano, trifluoromethyl, hydroxy; halogen (e.g. chlorine or fluorine); C 1 , C 2 , C 3 or C 4 alkyl (e.g. methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or tert-butyl) optionally substituted with 1, 2 or 3 hydroxy or with 1, 2, 3 or more halogen (e.g. chlorine or fluorine); and C 1 , C 2 , C 3 or C 4 alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy), optionally substituted with 1, 2, 3 or more halogen (e.g. fluorine or chlorine) atoms.
35 . A compound according to claim 34 , wherein R 6′ is aryl optionally substituted with 1, 2, 3, 4 or 5 R 12 .
36 . A compound according to claim 35 ,
wherein R 6′ is phenyl optionally substituted with 1, 2 or 3 substituents selected from halogen (e.g. fluorine or chlorine), hydroxy, cyano, methoxy, ethoxy, trifluoromethyl, methyl and ethyl; and n is 0, 1 or 2.
37 . A compound according to claim 36 , wherein R 2 is 2-fluorobenzyl or unsubstituted benzyl.
38 . A compound according to claim 34 , wherein R 6′ is cycloalkyl optionally substituted with 1, 2, 3, 4 or 5 R 12 .
39 . A compound according to claim 38 ,
wherein R 6′ is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, any of which is optionally substituted with 1, 2 or 3 substituents selected from halogen (e.g. fluorine or chlorine), hydroxy, cyano, methoxy, ethoxy, trifluoromethyl, methyl and ethyl, and n is 0, 1 or 2.
40 . A compound according to claim 39 ,
wherein R 2 is cyclopropylmethyl, 2-methylcyclopropylmethyl, cyclopropylethyl, or cyclobutylmethyl.
41 . A compound according to claim 34 , wherein R 6′ is heterocycloalkyl optionally substituted with 1, 2, 3, 4 or 5 R 12 .
42 . A compound according to claim 41 , wherein R 6′ is tetrahydrofuranyl; and n is 0, 1 or 2.
43 . A compound according to claim 42 , wherein R 2 is tetrahydrofuranylmethyl, for example tetrahydrofuran-2-ylmethyl.
44 . A compound according to claim 34 , wherein R 6′ is heteroaryl optionally substituted with 1, 2, 3, 4 or 5 R 12 .
45 . A compound according to claim 44 ,
wherein R 6′ is thiazolyl, furanyl or oxazolyl, any of which is optionally substituted with 1, 2 or 3 substituents selected from halogen (e.g. fluorine or chlorine), hydroxy, cyano, methoxy, ethoxy, trifluoromethyl, methyl and ethyl; and n is 0, 1 or 2.
46 . A compound according to claim 45 , wherein R 2 is thiazolylmethyl, furanylmethyl or oxazolylmethyl.
47 . A compound according to any preceding claim,
wherein R 1 is —(CH 2 ) n —R 7′ , —(CH 2 ) n —OR 7′ , —(CH 2 ) n —C(O)R 7′ , or —(CH 2 ) n —S(O) m R 7′ wherein n is 0, 1, 2, 3, 4, 5 or 6; and R 7′ is aryl or heteroaryl; either of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 ; wherein the or each R 12 is selected from, for example, cyano, trifluoromethyl, hydroxy; halogen (e.g. chlorine or fluorine); C 1 , C 2 , C 3 or C 4 alkyl (e.g. methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or tert-butyl) optionally substituted with 1, 2 or 3 hydroxy or with 1 or more halogen (e.g. chlorine or fluorine); and C 1 , C 2 , C 3 or C 4 alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy), optionally substituted with 1, 2 or 3 or more halogen (e.g. fluorine or chlorine) atoms.
48 . A compound according to claim 47 ,
wherein n is 1 or 2, and R 7′ is phenyl, naphthyl, thiophen-1-yl, thiophen-2-yl, benzo[b]thiophenyl, pyridin-1-yl, pyridin-2-yl, pyridin-3-yl, pyrazin-2-yl or quinolin-4-yl, any of which is optionally substituted with 1, 2 or 3 substituents selected from halogen (e.g. fluorine or chlorine), hydroxy, cyano, methoxy, ethoxy, trifluoromethyl, methyl and ethyl.
49 . A compound according to claim 46 ,
wherein R 1 is 2-oxo-2-phenyl-ethyl, 2-oxo-2-(3-methoxyphenyl)-ethyl or R 1 is isoquinolin-1-ylmethyl.
50 . A compound according to any preceding claim, wherein R 5 is hydrogen or C 1-6 alkyl (e.g. methyl).
51 . A compound according to any preceding claim, wherein R 3 is —CN, —C(O)OR 7′ or —C(O)NR 8′ R 9′ .
52 . A compound according to claim 51 ,
wherein R 7′ , R 8′ and R 9′ are each independently hydrogen or C 1 , C 2 , C 3 or C 4 alkyl (e.g. methyl).
53 . A compound according to claim 22 , wherein:
R 2 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or —(CH 2 ) n —R 6′ , any of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 ; R 1 is —(CH 2 ) n —R 7′ , —(CH 2 ) n —OR 7′ , —(CH 2 ) n —C(O)R 7′ or —(CH 2 ) n —S(O) m R 7′ , any of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 ; R 5 is hydrogen or C 1-6 alkyl; and R 3 is hydrogen, —CF 3 , —CN, —C(O)OR 8′ , —C(O)NR 8 R 9′ , —S(O) m R 8′ or —CH 2 OR 10′ ; Y is a group of formula (i) or formula (ii):
and k is 0, 1 or 2; R 6′ and R 7′ are independently each carbocyclyl (e.g. cycloalkyl or aryl) or heterocyclyl (e.g. heterocycloalkyl or heteroaryl), either of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 ; R 8′ and R 9′ are independently each hydrogen or C 1-6 alkyl optionally substituted with 1, 2, 3, 4 or 5 R 12 ; or R 8′ and R 9′ taken together with the nitrogen atom to which they are attached form heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 R 12 ; R 10′ is C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from R 11 and R 12 ; R 11 is aryl or heteroaryl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 ; each R 12 is independently selected from:
(i) functional moieties selected from hydroxy, halogen, amino and —CN;
(ii) alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms and optionally substituted with 1, 2, 3, 4 or 5 halogens;
(iii) alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms and optionally substituted with one or two of said functional moieties (i);
(iv) alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms and optionally substituted with 1, 2, 3, 4 or 5 halogens; and
(v) alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms and optionally substituted with one or two of said functional moieties (i); and
m is 0, 1 or 2; and wherein the or each n is 0, 1, 2, 3, 4, 5 or 6;
or a pharmaceutically acceptable salt or prodrug thereof.
54 . A compound according to claim 22 , which is of formula (VIII) or formula (IX):
wherein * signifies a chiral center of (S)- or (R)-configuration, in particular (R)-configuration;
R 2 is as defined in claim 1 ; R 13 is aryl or heteroaryl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 ; and j is 0 or 1;
or a pharmaceutically acceptable salt, or prodrug thereof.
55 . A compound according to any preceding claim,
wherein R 2 is C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 .
56 . A compound according to claim 55 ,
wherein R 2 is selected from C 1 , C 2 , C 3 or C 4 alkyl (e.g. methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or tert-butyl); C 2 , C 3 , C 4 , C 6 or C 6 alkenyl (e.g. ethenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-but-2-enyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1-hexenyl, 2-hexenyl or 3-hexenyl); and C 2 , C 3 , C 4 , C 5 or C 6 alkynyl (e.g. ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl or 3-hexynyl); any of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 , wherein the or each R 12 is, for example, C 1-6 alkoxy, hydroxy or halogen (e.g. chlorine or fluorine).
57 . A compound according to claim 55 , wherein R 2 is methyl, butyl, 2-methoxyethyl, 3-methyl-buten-2-yl or but-2-ynyl.
58 . A compound according to claim 54 ,
wherein R 2 is —(CH 2 ) n —R 6′ , wherein n is 0, 1, 2, 3, 4, 5 or 6 and R 6′ is carbocyclyl (e.g. cycloalkyl or aryl) or heterocyclyl (e.g. heterocycloalkyl or heteroaryl), either of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 ; and wherein the or each R 12 is selected from, for example, cyano, trifluoromethyl, hydroxy; halogen (e.g. chlorine or fluorine); C 1 , C 2 , C 3 or C 4 alkyl (e.g. methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or tert-butyl) optionally substituted with 1, 2, 3 or more halogen (e.g. chlorine or fluorine); and C 1 , C 2 , C 3 or C 4 alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy), optionally substituted with 1, 2 or 3 hydroxy or with 1, 2, 3 or more halogen (e.g. fluorine or chlorine) atoms.
59 . A compound according to claim 58 , wherein R 6′ is aryl optionally substituted with 1, 2, 3, 4 or 5 R 12 .
60 . A compound according to claim 59 ,
wherein R 6′ is phenyl optionally substituted with 1, 2 or 3 substituents selected from halogen (e.g. fluorine or chlorine), hydroxy, cyano, methoxy, ethoxy, trifluoromethyl, methyl and ethyl; and n is 0, 1 or 2.
61 . A compound according to claim 59 , wherein R 2 is 2-fluorobenzyl or unsubstituted benzyl.
62 . A compound according to claim 58 , wherein R 6′ is cycloalkyl optionally substituted with 1, 2, 3, 4 or 5 R 12 .
63 . A compound according to claim 62 ,
wherein R 6′ is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, any of which is optionally substituted with 1, 2 or 3 substituents selected from halogen (e.g. fluorine or chlorine), hydroxy, cyano, methoxy, ethoxy, trifluoromethyl, methyl and ethyl; and n is 0, 1 or 2.
64 . A compound according to claim 62 ,
wherein R 2 is cyclopropylmethyl, 2-methylcyclopropylmethyl, cyclopropylethyl, or cyclobutylmethyl.
65 . A compound according to claim 58 , wherein R 6′ is heterocycloalkyl optionally substituted with 1, 2, 3, 4 or 5 R 12 .
66 . A compound according to claim 65 , wherein R 6′ is tetrahydrofuranyl; and n is 0, 1 or 2.
67 . A compound according to claim 66 , wherein R 2 is tetrahydrofuranylmethyl, for example tetrahydrofuran-2-ylmethyl.
68 . A compound according to claim 57 , wherein R 6′ is heteroaryl optionally substituted with 1, 2, 3, 4 or 5 R 12 .
69 . A compound according to claim 68 ,
wherein R 6′ is thiazolyl, furanyl or oxazolyl, any of which is optionally substituted with 1, 2 or 3 substituents selected from halogen (e.g. fluorine or chlorine), hydroxy, cyano, methoxy, ethoxy, trifluoromethy, methyl and ethyl; and n is 0, 1 or 2.
70 . A compound according to claim 69 , wherein R 2 is thiazolylmethyl, furanylmethyl or oxazolylmethyl.
71 . A compound according to any of claims 54 to 70 ,
wherein R 13 is aryl, in particular phenyl, optionally substituted with 1, 2, 3, 4 or 5 R 12 , wherein the or each R 12 is, for example, independently selected from halogen (e.g., fluorine or chlorine), hydroxy, cyano, methoxy, ethoxy, methyl, trifluoromethyl and ethyl.
72 . A compound according to any of claims 54 to 70 ,
wherein R 13 is heteroaryl, in particular quinolinyl, e.g. quinolin-4-yl, optionally substituted with 1, 2, 3, 4 or 5 R 12 , wherein the or each R 12 is, for example, independently selected from halogen (e.g. fluorine or chlorine), hydroxy, cyano, methoxy, ethoxy, methyl, trifluoromethyl and ethyl.
73 . A compound according to any of claims 54 to 72 , wherein j is 0.
74 . A compound according to any of claims 54 to 72 , wherein j is 1.
75 . A compound according to any of claims 22 to 28 or 31 to 74 ,
wherein Y is other than homopiperazinyl optionally substituted with 1, 2, 3, 4 or 5 R 12 , and, wherein at least two of the following provisos apply: (i) R 2 is selected from C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from R 12 , carbocyclyl and heterocyclyl; or R 2 is carbocyclyl or heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 ; (ii) R 1 is —W-hydrocarbyl or —W-heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 , wherein W is a linker; and (iii) R 3 is cyano.
76 . A compound according to any preceding claim,
wherein at least two of the following provisos apply: (i) R 2 is selected from C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from R 12 , carbocyclyl and heterocyclyl; or R 2 is carbocyclyl or heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 ; (ii) R 1 is —W-hydrocarbyl or —W-heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 , wherein W is a linker; and (iii) R 3 is cyano.
77 . A compound according to claim 75 or claim 76 , wherein provisos (i) and (ii) apply.
78 . A compound according to claim 75 or claim 76 , wherein provisos (i) and (iii) apply.
79 . A compound according to claim 75 or claim 76 , wherein provisos (ii) and (iii) apply.
80 . A compound according to claim 75 or claim 76 , wherein provisos (i), (ii) and (iii) apply.
81 . A compound according to any of claims 75 to 78 or claim 79 ,
wherein R 2 is a group of formula (iii), (iv) or (v):
and, wherein R u and R v are each independently selected from hydrogen and R 12 , or taken together with the carbon atom to which they are attached form cyclopropyl.
82 . A compound according to claim 81 , wherein R u and R v are each independently hydrogen, fluorine, chlorine or methyl.
83 . A compound according to any of claims 75 to 77 , claim 79 or claim 80 ,
wherein R 1 is a group of formula (vi):
and wherein R 13 is hydrocarbyl or heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 ; and, j is 0 or 1.
84 . A compound according to claim 75 , claim 76 or claim 80 , wherein R 2 is a group of formula (vi), (vii) or (viii):
wherein R u and R v are each independently selected from hydrogen and R 12 ; and R 2 is a group of formula (ix):
wherein R 13 is hydrocarbyl or heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 ; and j is 0 or 1.
85 . A compound according to any of claims 75 to 84 ,
wherein Y is a group of formula (x) or formula (xi):
and k is 0, 1 or 2.
86 . A compound according to any of claims 76 to 84 , wherein Y is a group of formula (xii):
87 . A compound according to any of claims 75 to 86 , wherein A 1 is —CH═ and A 2 is ═N—.
88 . A compound according to any of claims 75 to 86 , wherein A 1 is —C(O)— and A 2 is —N(R3)-.
89 . A compound according to claim 83 , wherein R 5 is hydrogen or methyl.
90 . A compound according to claim 22 , selected from:
or, in each case, a pharmaceutically acceptable salt or prodrug thereof.
91 . A compound according to claim 22 , selected from:
or, in each case, a pharmaceutically acceptable salt or prodrug thereof.
92 . A compound according to any preceding claim for use in therapy.
93 . A pharmaceutical formulation comprising a compound of any of claims 22 to 91 .
94 . A formulation according to claim 93 , which further comprises a pharmaceutically acceptable excipient or carrier.
95 . A formulation according to claim 93 or claim 94 , which further comprises a therapeutic agent selected from anti-diabetic agents, hypolipidemic agents, anti-obesity or appetite-regulating agents, anti-hypertensive agents, HDL-increasing agents, cholesterol absorption modulators, Apo-A1 analogues and mimetics, thrombin inhibitors, ldosterone inhibitors, inhibitors of platelet aggregation, estrogen, testosterone, selective estrogen receptor modulators, selective androgen receptor modulators, chemotherapeutic agents, and 5-HT3 or 5-HT4 receptor modulators; or pharmaceutically acceptable salts or prodrugs thereof.
96 . A formulation according to claim 95 , wherein the agent is tegaserod, imatinib, vildagliptin, metformin, thiazolidone derivative, a sulfonylurea receptor ligand, aliskiren, valsartan, orlistat or a statin, or pharmaceutically acceptable salts or prodrugs.
97 . A product comprising a compound of any of claims 22 to 91 and an agent as defined in claim 77 ; as a combined preparation for simultaneous, separate or sequential use in therapy.
98 . A product according to claim 97 , wherein the agent is as defined in claim 96 .
99 . Use of a compound of any of claims 22 to 91 for the manufacture of a medicament for the treatment or prevention of a disease or condition selected from non-insulin-dependent diabetes mellitus, arthritis, obesity, allograft transplantation, calcitonin-osteoporosis, heart failure, impaired glucose metabolism or impaired glucose tolerance, neurodegenerative diseases, cardiovascular or renal diseases, and neurodegenerative or cognitive disorders, hyperglycemia, insulin resistance, lipid disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis, vascular restenosis, irritable bowel syndrome, inflammatory bowel disease, pancreatitis, retinopathy, nephropathy, neuropathy, syndrome X, ovarian hyperandrogenism (polycystic ovarian syndrome), type 2 diabetes, growth hormone deficiency, neutropenia, neuronal disorders, tumor metastasis, benign prostatic hypertrophy, gingivitis, hypertension and osteoporosis.
100 . Use according to claim 99 , wherein the disease or condition is Alzheimer's disease, Parkinson's disease, Crohn's disease or ulcerative colitis.
101 . Use according to claim 99 , wherein the disease is diabetic cardiomyopathy, left or right ventricular hypertrophy, hypertrophic medial thickening in arteries and/or in large vessels, mesenteric vasculature hypertrophy or mesanglial hypertrophy.
102 . Use of a compound of any of claims 22 to 91 for the manufacture of a medicament for producing a sedative or anxiolytic effect, attenuating post-surgical catabolic changes or hormonal responses to stress, reducing mortality and morbidity after myocardial infarction, modulating hyperlipidemia or associated conditions, or lowering VLDL, LDL or Lp(a) levels.
103 . A method of treating or preventing a disease or condition in a patient, which comprises administering a therapeutically effective amount of a compound of any of claims 22 to 91 .
104 . A method according to claim 103 , wherein the disease or condition is as defined in any of claims 99 to 102 .
105 . A compound of formula (I):
wherein the solid line and dotted line between A 1 and A 2 indicate a double bond (A 1 =A 2 ) or a single bond (A 1 -A 2 ); A 1 is a group represented by the formula C(R 4 ) and A 2 is a nitrogen atom, in the case of the solid line and dotted line between A 1 and A 2 being a double bond (A 1 =A 2 ); A 1 is a group represented by the formula C═O and A 2 is a group represented by the formula N(R 5 ), in the case of the solid line and dotted line between A 1 and A 2 being a single bond (A 1 -A 2 );
wherein R 1 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group,
wherein R 2 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group, an optionally substituted heteroarylalkyl group, an optionally substituted alkenyl group or an optionally substituted alkynyl group
wherein R 3 is a hydrogen atom, a halogen atom, a cyano group, a formyl group, a carboxyl group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group, an optionally substituted heteroarylalkyl group, an optionally substituted alkylcarbonyl group, an optionally substituted cycloalkylcarbonyl group, an optionally substituted aroyl group, an optionally substituted heteroarylcarbonyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted aryloxycarbonyl group, an optionally substituted carbamoyl group, a hydroxyl group, an optionally substituted alkoxy group, or the formula: —Rd-C(O)O—Re wherein Rd is a single bond, an alkylene group or an alkenylene group and Re is tetrahydrofuranyl, cinnamyl, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl, 5-(tert-butyl)-2-oxo-1,3-dioxolen-4-ylmethyl or the formula: —CH(R4a)OC(O)R4b wherein R4a is a hydrogen atom, an alkyl group, an alkenyl group, a cycloalkyl group or an alkoxy group and R4b is an optionally substituted alkyl group, an optionally substituted alkenyl group, a cycloalkyl group, a cycloalkyloxy group, an optionally substituted alkoxy group, an optionally substituted alkenyloxy group, a 2-indanyloxy group, a 5-indanyloxy group or an optionally substituted aryloxy group;
wherein R 4 is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a formyl group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkyloxy group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, a carboxyl group, an optionally substituted alkoxy group, an optionally substituted aryl group, an optionally substituted aryloxy group, an optionally substituted aralkyl group, an optionally substituted aralkyloxy group, an optionally substituted aroyl group, an optionally substituted arylthio group, an optionally substituted arylsulfinyl group, an optionally substituted arylsulfonyl group, an optionally substituted alkylthio group, an optionally substituted alkylsulfinyl group, an optionally substituted alkylsulfonyl group, an optionally substituted heteroaryl group, an optionally substituted heteroarylalkyl group, an optionally substituted heteroarylcarbonyl group, an optionally substituted heteroaryloxy group, an optionally substituted alkylcarbonyl group, an optionally substituted nitrogen-containing saturated heterocyclic group, an optionally substituted alkoxycarbonyl group, an optionally substituted aryloxycarbonyl group, an optionally substituted aralkyloxycarbonyl group, an optionally substituted cycloalkyloxycarbonyl group, or the formula: —Rd-C(O)O—Re wherein Rd and Re are as defined above;
wherein R 5 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted vinyl group, an optionally substituted nitrogen-containing saturated heterocyclic group, or an optionally substituted heteroaryl group;
wherein Y is a group represented by any of the formula (A), formula (B), formula (C) and formula (D) shown below:
wherein m1 is 0, 1, 2 or 3, and R 6 is absent or one or two R 6 s are present and are independently a halogen atom, a hydroxyl group, an oxo group, an optionally substituted alkoxy group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, a carboxyl group, an optionally substituted alkoxycarbonyl group or an optionally substituted carbamoyl group, or two R6s, when taken together, represent methylene or ethylene and may bind to two carbon atoms constituting the ring, to form a new ring;
wherein m2 is 0, 1, 2 or 3, and R 7 is absent or one or two R 7 s are present and are independently a halogen atom, a hydroxyl group, an oxo group, an optionally substituted alkoxy group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, a carboxyl group, an optionally substituted alkoxycarbonyl group or an optionally substituted carbamoyl group, or two R 7 s, when taken together, represent methylene or ethylene and may bind to two carbon atoms constituting the ring, to form a new ring;
wherein m3 and m4 are independently 0 or 1, and R 8 is absent or one or two R 8 s are present and are independently a halogen atom, a hydroxyl group, an oxo group, an optionally substituted alkoxy group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, a carboxyl group, an optionally substituted alkoxycarbonyl group or an optionally substituted carbamoyl group, or two R 8 s, when taken together, represent methylene or ethylene and may bind to two carbon atoms constituting the ring, to form a new ring; and
wherein m5 is 1, 2 or 3, R 9 is absent or one or two R 9 s are present and are independently a halogen atom, a hydroxyl group, an oxo group, an optionally substituted alkoxy group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, a carboxyl group, an optionally substituted alkoxycarbonyl group or an optionally substituted carbamoyl group, or two R 9 s, when taken together, represent methylene or ethylene and may bind to two carbon atoms constituting the ring, to form a new ring, and R 10 and R 11 are independently a hydrogen atom, methyl, ethyl, propyl or isopropyl, or R 10 and R 11 , when taken together, represent cyclopropyl, cyclobutyl or cyclopentyl,
a prodrug of said compound, or a pharmaceutically acceptable salt of said compound or prodrug.
106 . A compound according to claim 105 , wherein Y is a group represented by formula (A), formula (B), formula (C) and formula (D):
107 . A compound according to claim 105 , wherein Y is a group represented by formula (A):
108 . A compound according to claim 105 , wherein Y is a group represented by formula (A), formula (B), formula (C) and formula (D):
109 . A compound according to claim 105 , which is of formula (II) or formula (III):
or a pharmaceutically acceptable salt of prodrug thereof.
110 . A compound according to claim 105 , which is of formula (IV) or formula (V):
or a pharmaceutically acceptable salt or prodrug thereof.
111 . A compound according to any preceding claim,
wherein R 2 is C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 ; wherein R 12 is a halogen atom, a hydroxyl group, a cyano group, a carboxyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aroyl group, an optionally substituted heteroarylcarbonyl group, an optionally substituted arylaminocarbonyl group, an optionally substituted heteroarylaminocarbonyl group, an optionally substituted aryloxy group, an optionally substituted arylsulfonyl group, an optionally substituted aralkylsulfonyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkyloxy groups, an optionally substituted alkoxycarbonyl groups, an optionally substituted aryloxycarbonyl groups, an optionally substituted amino groups, an optionally substituted carbamoyl groups, an alkylsulfonyl groups, an optionally substituted alkylcarbonyl groups, a cycloalkyloxycarbonyl group, a tetrahydrofuranyloxycarbonyl group, and a tetrahydrofuranyl group.
112 . A compound according to claim 111 ,
wherein R 2 is selected from C 1 , C 2 , C 3 or C 4 alkyl (e.g. methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or tert-butyl); C 2 , C 3 , C 4 , C 5 or C 6 alkenyl (e.g. ethenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-but-2-enyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1-hexenyl, 2-hexenyl or 3-hexenyl); and C 2 , C 3 , C 4 , C 5 or C 6 alkynyl (e.g. ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl or 3-hexynyl); any of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 , wherein the or each R 12 is, for example, C 1-6 alkoxy, hydroxy or halogen (e.g. chlorine or fluorine).
113 . A compound according to claim 112 ,
wherein R 2 is methyl, butyl, 2-methoxyethyl, 3-methyl-buten-2-yl or but-2-ynyl.
114 . A compound according to any of claims 105 to 110 ,
wherein R 2 is —(CH 2 ) n —R 6 , wherein n is 0, 1, 2, 3, 4, 5 or 6, and R 6 is carbocyclyl (e.g. cycloalkyl or aryl) or heterocyclyl (e.g. or heteroaryl), either of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 ; and wherein the or each R 12 is selected from, for example, cyano, trifluoromethyl, hydroxy; halogen (e.g. chlorine or fluorine); C 1 , C 2 , C 3 or C 4 alkyl (e.g. methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or tert-butyl) optionally substituted with 1, 2 or 3 hydroxy or with 1, 2, 3 or more halogen (e.g. chlorine or fluorine); and C 1 , C 2 , C 3 or C 4 alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy), optionally substituted with 1, 2, 3 or more halogen (e.g. fluorine or chlorine) atoms.
115 . A compound according to claim 114 , wherein R 6 is aryl optionally substituted with 1, 2, 3, 4 or 5 R 12 .
116 . A compound according to claim 115 ,
wherein R 6 is phenyl optionally substituted with 1, 2 or 3 substituents selected from halogen (e.g. fluorine or chlorine), hydroxy, cyano, methoxy, ethoxy, trifluoromethyl, methyl and ethyl; and n is 0, 1 or 2.
117 . A compound according to claim 116 , wherein R 1 is 2-fluorobenzyl or unsubstituted benzyl.
118 . A compound according to claim 114 , wherein R 6 is cycloalkyl optionally substituted with 1, 2, 3, 4 or 5 R 12 .
119 . A compound according to claim 118 ,
wherein R 6 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, any of which is optionally substituted with 1, 2 or 3 substituents selected from halogen (e.g. fluorine or chlorine), hydroxy, cyano, methoxy, ethoxy, methyl, ethyl, and n is 1 or 2.
120 . A compound according to claim 119 ,
wherein R 1 is cyclopropylmethyl, 2-methylcyclopropylmethyl, cyclopropylethyl, or cyclobutylmethyl.
121 . A compound according to claim 114 , wherein R 6 is tetrahydrofuranyl; and n is 0, 1 or 2.
122 . A compound according to claim 121 , wherein R 2 is tetrahydrofuranylmethyl, for example tetrahydrofuran-2-ylmethyl.
123 . A compound according to claim 114 , wherein R 6 is heteroaryl optionally substituted with 1, 2, 3, 4 or 5 R 12 .
124 . A compound according to claim 123 ,
wherein R 6 is thiazolyl, furanyl or oxazolyl, any of which is optionally substituted with 1, 2 or 3 substituents selected from halogen (e.g. fluorine or chlorine), hydroxy, cyano, methoxy, ethoxy, trifluoromethyl, methyl and ethyl; and n is 0, 1 or 2.
125 . A compound according to claim 124 , wherein R 2 is thiazolylmethyl, furanylmethyl or oxazolylmethyl.
126 . A compound according to any preceding claim,
wherein R 1 is —(CH 2 ) n —R 7 , —(CH 2 ) n —OR 7 , —(CH 2 ) n —C(O)R 7 , or —(CH 2 ) n —S(O) 2 R 7 wherein n is 0, 1, 2, 3, 4, 5 or 6; and R 7 is aryl or heteroaryl; either of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 ; wherein the or each R 12 is selected from, for example, cyano, trifluoromethyl, hydroxy; halogen (e.g. chlorine or fluorine); C 1 , C 2 , C 3 or C 4 alkyl (e.g. methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or tert-butyl) optionally substituted with 1, 2 or 3 hydroxy or with 1 or more halogen (e.g. chlorine or fluorine); and C 1 , C 2 , C 3 or C 4 alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy), optionally substituted with 1, 2 or 3 or more halogen (e.g. fluorine or chlorine) atoms.
127 . A compound according to claim 126 ,
wherein n is 1 or 2, and R 7 is phenyl, naphthyl, thiophen-1-yl, thiophen-2-yl, benzo[b]thiophenyl, pyridin-1-yl, pyridin-2-yl, pyridin-3-yl, pyrazin-2-yl or quinolin-4-yl, any of which is optionally substituted with 1, 2 or 3 substituents selected from halogen (e.g. fluorine or chlorine), hydroxy, cyano, methoxy, ethoxy, trifluoromethyl, methyl and ethyl.
128 . A compound according to claim 125 ,
wherein R 1 is 2-oxo-2-phenyl-ethyl, 2-oxo-2-(3-methoxyphenyl)-ethyl or R 2 is isoquinolin-1-ylmethyl.
129 . A compound according to any preceding claim, wherein R 5 is hydrogen or C 1-6 alkyl (e.g. methyl).
130 . A compound according to any preceding claim,
wherein R 3 is —CN, —C(O)OR 7 or —C(O)NR 8 R 9 ; wherein —C(O)OR 7 is a carboxyl group, an optionally substituted aryloxycarbonyl group, or the formula: —Rd-C(O)O—Re wherein Rd is a single bond, Re is tetrahydrofuranyl, cinnamyl, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl, 5-(tert-butyl)-2-oxo-1,3-dioxolen-4-ylmethyl; and wherein R 8 and R 9 are each independently a hydrogen atom, optionally substituted alkyl, cycloalkyl groups which may be substituted by a halogen atom(s), aryl groups, which may be substituted by a halogen atom(s), an alkoxy group(s) which may be substituted by a halogen atom(s), an alkyl group(s) which may be substituted by a halogen atom(s) or a C 1-3 alkylenedioxy group(s), alkylsulfonyl groups, cycloalkylsulfonyl groups, optionally substituted arylsulfonyl groups, alkylcarbonyl groups, alkoxycarbonyl groups, optionally substituted aroyl groups, cycloalkylalkyl groups, isoxazolyl group, optionally substituted adamantly; and, wherein R 8 and R 9 may bind to each other to form a 4- to 6-membered aliphatic heterocyclic ring which may contain carbon, nitrogen, oxygen or sulfur.
131 . A compound according to claim 130 ,
wherein R 7 , R 8 and R 9 are each independently hydrogen or C 1 , C 2 , C 3 or C 4 alkyl (e.g. methyl).
132 . A compound according to claim 105 ,
wherein R 2 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or —(CH 2 ) n —R 6 , any of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 ; wherein R 1 is —(CH 2 ) n —R 7 , —(CH 2 ) n —OR 7 , —(CH 2 ) n —C(O)R 7 or any of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 ; wherein R 5 is hydrogen or C 1-6 alkyl; and wherein R 3 is hydrogen, —CF 3 , —CN, —C(O)OR 8 , —C(O)NR 8 R 9 , or —CH 2 OR 10 ; wherein Y is a group of formula (i) or formula (ii):
and k is 0, 1 or 2;
wherein R 6 and R 7 are independently each carbocyclyl (e.g. cycloalkyl or aryl) or heterocyclyl (e.g. heteroaryl), either of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 ;
wherein R 8 and R 9 are independently each hydrogen or C 1-6 alkyl optionally substituted with 1, 2, 3, 4 or 5 R 12 ; or
wherein R 8 and R 9 taken together with the nitrogen atom to which they are attached form heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 R 12 ;
wherein the or each n is 0, 1, 2, 3, 4, 5 or 6;
wherein R 12 is halogen atoms, hydroxyl group, cyano group, carboxyl group, alkyl groups, alkyl groups substituted by a halogen atom(s) or an alkoxy group, optionally substituted cycloalkyl groups, optionally substituted aryl groups, optionally substituted heteroaryl groups, optionally substituted aroyl groups, optionally substituted heteroarylcarbonyl groups, optionally substituted arylaminocarbonyl groups, optionally substituted heteroarylaminocarbonyl groups, optionally substituted aryloxy groups, optionally substituted arylsulfonyl groups, optionally substituted aralkylsulfonyl groups, optionally substituted alkoxy groups, optionally substituted cycloalkyloxy groups, optionally substituted alkoxycarbonyl groups, optionally substituted aryloxycarbonyl groups, optionally substituted amino groups, optionally substituted carbamoyl groups, alkylsulfonyl groups, optionally substituted alkylcarbonyl groups, cycloalkyloxycarbonyl groups, tetrahydrofuranyloxycarbonyl group, and tetrahydrofuranyl group;
or a pharmaceutically acceptable salt or prodrug thereof.
133 . A compound according to claim 105 , which is of formula (VIII) or formula (IX):
wherein R 2 is as defined in claim 1 ; R 13 is aryl or heteroaryl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 ; and j is 0 or 1; or a pharmaceutically acceptable salt,
wherein R 12 is independently selected from: hydroxy, halogen, amino, —CN, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms and optionally substituted with halogens, hydroxy, amino, —CN; alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms and optionally substituted with halogens, hydroxy, amino, —CN; or two R 12 attached to the same carbon atom form oxo;
or prodrug thereof.
134 . A compound according to any preceding claim,
wherein R 2 is C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 ; wherein R 12 is a halogen atom, a hydroxyl group, a cyano group, a carboxyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aroyl group, an optionally substituted heteroarylcarbonyl group, an optionally substituted arylaminocarbonyl group, an optionally substituted heteroarylaminocarbonyl group, an optionally substituted aryloxy group, an optionally substituted arylsulfonyl group, an optionally substituted aralkylsulfonyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkyloxy groups, an optionally substituted alkoxycarbonyl groups, an optionally substituted aryloxycarbonyl groups, an optionally substituted amino groups, an optionally substituted carbamoyl groups, an alkylsulfonyl groups, an optionally substituted alkylcarbonyl groups, a cycloalkyloxycarbonyl group, a tetrahydrofuranyloxycarbonyl group, and a tetrahydrofuranyl group.
135 . A compound according to claim 134 ,
wherein R 2 is selected from C 1 , C 2 , C 3 or C 4 alkyl (e.g. methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or tert-butyl); C 2 , C 3 , C 4 , C 6 or C 6 alkenyl (e.g. ethenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-but-2-enyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1-hexenyl, 2-hexenyl or 3-hexenyl); and C 2 , C 3 , C 4 , C 5 or C 6 alkynyl (e.g. ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl(1-pentynyl, 2-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl or 3-hexynyl); any of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 , wherein the or each R 12 is, for example, C 1-6 alkoxy, hydroxy or halogen (e.g. chlorine or fluorine).
136 . A compound according to claim 134 , wherein R 12 is methyl, butyl, 2-methoxyethyl, 3-methyl-buten-2-yl or but-2-ynyl.
137 . A compound according to claim 133 ,
wherein R 2 is —(CH 2 ) n —R 6 , wherein n is 0, 1, 2, 3, 4, 5 or 6, and R 6 is carbocyclyl (e.g. cycloalkyl or aryl) or heterocyclyl (e.g. heteroaryl), either of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 ; and wherein the or each R 12 is selected from, for example, cyano, trifluoromethyl, hydroxy; halogen (e.g. chlorine or fluorine); C 1 , C 2 , C 3 or C 4 alkyl (e.g. methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or tert-butyl) optionally substituted with 1, 2, 3 or more halogen (e.g. chlorine or fluorine); and C 1 , C 2 , C 3 or C 4 alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy), optionally substituted with 1, 2, 3 or more halogen (e.g. fluorine or chlorine) atoms.
138 . A compound according to claim 137 , wherein R 6 is aryl optionally substituted with 1, 2, 3, 4 or 5 R 12 .
139 . A compound according to claim 138 ,
wherein R 6 is phenyl optionally substituted with 1, 2 or 3 substituents selected from halogen (e.g. fluorine or chlorine), hydroxy, cyano, methoxy, ethoxy, trifluoromethyl, methyl and ethyl; and n is 0, 1 or 2.
140 . A compound according to claim 138 , wherein R 2 is 2-fluorobenzyl or unsubstituted benzyl.
141 . A compound according to claim 138 , wherein R 6 is cycloalkyl optionally substituted with 1, 2, 3, 4 or 5 R 12 .
142 . A compound according to claim 137 ,
wherein R 6 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, any of which is optionally substituted with 1, 2 or 3 substituents selected from halogen (e.g. fluorine or chlorine), hydroxy, cyano, methoxy, ethoxy, methyl, ethyl, and n is 1 or 2.
143 . A compound according to claim 138 ,
wherein R 2 is cyclopropylmethyl, 2-methylcyclopropylmethyl, cyclopropylethyl, or cyclobutylmethyl.
144 . A compound according to claim 143 , wherein R 6 is tetrahydrofuranyl; and n is 1 or 2.
145 . A compound according to claim 137 , wherein R 2 is tetrahydrofuranylmethyl, for example tetrahydrofuran-2-ylmethyl.
146 . A compound according to claim 136 , wherein R 6 is heteroaryl optionally substituted with 1, 2, 3, 4 or 5 R 12 .
147 . A compound according to claim 146 ,
wherein R 6 is thiazolyl, furanyl or oxazolyl, any of which is optionally substituted with 1, 2 or 3 substituents selected from halogen (e.g. fluorine or chlorine), hydroxy, cyano, methoxy, ethoxy, trifluoromethy), methyl and ethyl; and n is 0, 1 or 2.
148 . A compound according to claim 136 , wherein R 2 is thiazolylmethyl, furanylmethyl or oxazolylmethyl.
149 . A compound according to any of claims 133 to 148 ,
wherein R 13 is aryl, in particular phenyl, optionally substituted with 1, 2, 3, 4 or 5 R 12 , wherein the or each R 12 is, for example, independently selected from halogen (e.g., fluorine or chlorine), hydroxy, cyano, methoxy, ethoxy, methyl, trifluoromethyl and ethyl.
150 . A compound according to any of claims 133 to 148 ,
wherein R 13 is heteroaryl, in particular quinolinyl, e.g. quinolin-4-yl, optionally substituted with 1, 2, 3, 4 or 5 R 12 , wherein the or each R 12 is, for example, independently selected from halogen (e.g. fluorine or chlorine), hydroxy, cyano, methoxy, ethoxy, methyl, trifluoromethyl and ethyl.
151 . A compound according to any of claims 134 to 150 , wherein j is 0.
152 . A compound according to any of claims 134 to 150 , wherein j is 1.
153 . A compound according to any of claims 105 to 152 ,
wherein —Y is other than homopiperazinyl optionally substituted with 1, 2, 3, 4 or 5 R 12 , wherein R 12 is a halogen atom, an alkyl group, an alkyl group substituted by a halogen atom(s) or an alkoxy group, an alkoxy group, an alkoxy groups substituted by a halogen atom(s) or an alkoxy group, a cyano group, and an oxo group; and, wherein at least two of the following provisos apply: (i) R 2 is selected from C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from R 12 , carbocyclyl and heterocyclyl; or R 1 is carbocyclyl or heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 ; (ii) R 1 is —W-hydrocarbyl or —W-heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 , wherein W is a linker; and (iii) R 3 is cyano.
154 . A compound according to any preceding claim,
wherein at least two of the following provisos apply: (i) R 2 is selected from C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from R 12 , carbocyclyl and heterocyclyl; or R 1 is carbocyclyl or heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 ; (ii) R 1 is —W-hydrocarbyl or —W-heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 , wherein W is a linker; and (iii) R 3 is cyano.
155 . A compound according to claim 153 or claim 154 , wherein provisos (i) and (ii) apply.
156 . A compound according to claim 153 or claim 154 , wherein provisos (i) and (iii) apply.
157 . A compound according to claim 153 or claim 154 , wherein provisos (ii) and (iii) apply.
158 . A compound according to claim 153 or claim 154 , wherein provisos (i), (ii) and (iii) apply.
159 . A compound according to any of claims 153 to 157 or claim 158 ,
wherein R 2 is a group of formula (iii), (iv) or (v):
and, wherein R u and R v are each independently selected from hydrogen and R 12
160 . A compound according to claim 159 , wherein R u and R v are each independently hydrogen, fluorine, chlorine or methyl.
161 . A compound according to any of claims 153 to 155 , claim 157 or claim 158 ,
wherein R 1 is a group of formula (vi):
and wherein R 13 is hydrocarbyl or heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 ;
wherein R 12 is halogen, hydroxyl, cyano, a carboxyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aroyl group, an optionally substituted heteroarylcarbonyl group, an optionally substituted arylaminocarbonyl group, an optionally substituted heteroarylaminocarbonyl group, an optionally substituted aryloxy group, an optionally substituted arylsulfonyl group, an optionally substituted aralkylsulfonyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkyloxy group, an optionally substituted alkoxycarbonyl group, an optionally substituted aryloxycarbonyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an alkylsulfonyl group, an optionally substituted alkylcarbonyl group, a cycloalkyloxycarbonyl group, a tetrahydrofuranyloxycarbonyl group, and a tetrahydrofuranyl group; and,
j is 0 or 1.
162 . A compound according to any of claims 153 to 161 ,
wherein —Y is a group of formula (i) or formula (ii):
and k is 0, 1 or 2.
163 . A compound according to any of claims 153 to 162 ,
wherein A 1 of formula (1) is a group represented by the formula C(R 4 ) and A 2 of formula (1) is a nitrogen atom, in the case of the solid line and dotted line between A 1 and A 2 being a double bond (A 1 =A 2 ).
164 . A compound according to any of claims 153 to 162 ,
wherein A 1 of formula (1) is a group represented by the formula C═O and A 2 of formula (1) is a group represented by the formula N(R 5 ), in the case of the solid line and dotted line between A 1 and A 2 being a single bond (A 1 -A 2 ).
165 . A compound according to claim 164 , wherein R 5 is hydrogen or methyl.
166 . A compound according to any preceding claim for use in therapy.
167 . A pharmaceutical formulation comprising a compound of any of claims 105 to 165 .
168 . A formulation according to claim 167 , which further comprises a pharmaceutically acceptable excipient or carrier.
169 . A formulation according to claim 167 or claim 168 , which further comprises a therapeutic-agent selected from anti-diabetic agents, hypolipidemic agents, or anti-obesity.
170 . A formulation according to claim 169 , wherein the agent is metformin, a sulfonylurea receptor ligand, orlistat or a statin, or pharmaceutically acceptable salts or prodrugs.
171 . A product comprising a compound of any of claims 105 to 165 and an agent as defined in claim 75 ; as a combined preparation for simultaneous, separate or sequential use in therapy.
172 . Use of a compound of any of claims 105 to 165 for the manufacture of a medicament for the treatment or prevention of a disease or condition selected from non-insulin-dependent diabetes mellitus, arthritis, obesity, allograft transplantation, calcitonin-osteoporosis, tumor metastasis, osteoporosis.
173 . A method of treating or preventing a disease or condition in a patient, which comprises administering a therapeutically effective amount of a compound of any of claims 105 to 165 .Join the waitlist — get patent alerts
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