US2016015685A1PendingUtilityA1
Furo [3, 2-b] pyrr0l-3-0nes as cathespin s inhibitors
Est. expiryMar 13, 2028(~1.7 yrs left)· nominal 20-yr term from priority
A61P 7/12A61P 9/10A61P 37/08A61P 3/10A61P 9/00A61P 37/06A61P 43/00A61P 29/00A61P 3/04A61P 25/00A61K 31/4155A61K 31/428C07D 417/12A61P 19/02A61K 31/4709G01N 33/573G01N 2333/96466A61K 31/55A61P 17/06C07D 491/04A61K 31/41C07D 491/048A61K 31/498A61K 31/4196A61K 31/4439A61K 31/4192A61P 11/06A61P 11/00A61K 31/4178G01N 2500/04A61K 31/538A61P 21/04A61P 11/02A61K 31/4245A61K 31/407A61P 17/00
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Claims
Abstract
A first aspect of the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, complex or pro-drug thereof, wherein: one of R 3 and R 4 is H, and the other is selected from C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -alkoxy, and C 6-12 -aralkyl; or R 3 and R 4 are each independently selected from C 1-6 -alkyl and halo; R 9 is a substituted 5 or 6-membered aryl or heteroaryl group or a 6,5- or 6,6-fused biaryl or heterobiaryl group. Compounds of formula (I) exhibit surprisingly high efficacies for human cathepsin S, excellent selectivity verses other mammalian cathepsins and are useful for treatment of diseases such as rheumatoid arthritis, multiple sclerosis, myasthenia gravis, transplant rejection, diabetes, Sjogrens syndrome, Grave's disease, systemic lupus erythematosis, osteoarthritis, psoriasis, idiopathic thrombocytopenic purpura, allergic rhinitis, asthma, atherosclerosis, obesity, chronic obstructive pulmonary disease and chronic pain.
Claims
exact text as granted — not AI-modified1 . A method of inhibiting a cysteine proteinase in a cell, said method comprising contacting said cell with a pharmaceutical or veterinary composition of formula (I), or a pharmaceutically acceptable salt, hydrate, complex or pro-drug thereof,
wherein:
one of R 3 and R 4 is H, and the other is selected from C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -alkoxy and C 6-12 -aralkyl; or R 3 and R 4 are each independently selected from C 1-6 -alkyl and halo; R 9 is selected from the following:
wherein:
X 1 , X 2 , X 3 , X 4 , X 14 , X 15 , X 16 and X 20 are each independently selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C-halo and N;
such that a maximum of two of X 1 , X 2 , X 3 , X 4 , X 14 , X 15 , X 16 and X 20 are selected from N, C-halo and C—(C 1-6 -alkoxy);
X 5 , X 6 , X 7 and X 8 are each independently selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C-halo, N and C—OH;
such that a maximum of one of X 5 , X 6 , X 7 and X 8 is N, C-halo, C—OH or C—(C 1-6 -alkoxy);
X 9 and X 12 are each independently selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C-halo and N;
X 10 and X 11 are each independently selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C-halo, N and R 10 ;
X 19 is selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C—C(O)NH 2 , C—C(O)NH(C 1-6 -alkyl), C—C(O)N(C 1-6 -alkyl) 2 , C-halo and N;
X 18 is selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C—NH 2 , C—N(C 1-6 -alkyl) 2 , C—NH(C 1-6 -alkyl), C—NHC(O)C 1-6 -alkyl, C-halo and N;
or when X 19 is CH, C—(C 1-6 -alkyl), or C-halo then X 18 may additionally be selected from C—C(O)NH 2 and C—C(O)N(C 1-6 -alkyl) 2 ;
X 13 and X 17 are each independently selected from: O, S, NH and N—(C 1-6 -alkyl);
X 22 and X 24 are each independently selected from:
CH 2 , CH—(C 1-6 -alkyl), O, S, NH, NMe and C═O;
X 23 is selected from:
CH 2 , CH—(C 1-6 -alkyl), C—(C 1-6 -alkyl) 2 , NH and NMe;
or when either X 22 or X 24 are other than C═O then X 23 may additionally be C═O or S(O) 2 ;
X 25 is selected from:
O, S, NH and N(C 1-6 -alkyl);
X 26 , X 27 , X 28 and X 29 are each independently selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C—OH, C-halo and N; such that a maximum of two of X 26 , X 27 , X 28 and X 29 are selected from C—(C 1-6 -alkoxy), C—OH, C-halo and N;
X 30 is selected from:
CH 2 , CH 2 CH 2 , NH, NMe, O, S and C═O;
X 31 is selected from:
CH 2 , NH and NMe; or when X 30 is other than C═O, O or S then X 31 may additionally be C═O or O;
X 32 is selected from:
CH 2 , CH 2 CH 2 , NH, NMe and C═O;
X 33 is selected from:
CH 2 , NH and NMe; or when X 32 is other than C═O then X 33 may additionally be C═O or O;
X 34 is selected from:
NH and NMe;
R 10 is selected from:
wherein:
T 1 , T 2 , T 3 and T 4 are each independently selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C—NH 2 , C—NH(C 1-6 -alkyl), C—N(C 1-6 -alkyl) 2 , C-halo and N;
such that a maximum of one of T 1 , T 2 , T 3 and T 4 is C—(C 1-6 -alkoxy), C—NH 2 , C—NH(C 1-6 -alkyl), C—N(C 1-6 -alkyl) 2 or C-halo;
T 5 is selected from:
O, S, NH and N(C 1-6 -alkyl);
T 6 , T 7 , T 8 , T 9 and T 10 are each independently selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C—NH 2 , C—NH(C 1-6 -alkyl), C—N(C 1-6 -alkyl) 2 , C-halo and N;
such that a maximum of two of T 6 , T 7 , T 8 , T 9 and T 10 are selected from C—(C 1-6 -alkoxy), C—NH 2 , C—NH(C 1-6 -alkyl), C—N(C 1-6 -alkyl) 2 , C-halo and N;
T 11 is selected from:
CH 2 , NH and N(C 1-6 -alkyl);
T 12 is selected from:
CH 2 , NH, N(C 1-6 -alkyl) and C═O;
T 13 and T 14 are each independently selected from:
CH, C—(C 1-6 -alkyl) and C-halo;
T 15 is selected from:
O, NH and N(C 1-6 -alkyl);
T 16 is selected from:
CH 2 and C═O;
or R 10 is selected from:
H, C 1-6 -alkyl, OH, C 1-6 -alkoxy, NO 2 , halo, CN, C(O)NH 2 , C(O)NH(C 1-6 -alkyl), C(O)N(C 1-6 -alkyl) 2 , C(O)NH(C 3-6 -cycloalkyl), S(O) 2 NH 2 , S(O) 2 (C 1-6 -alkyl), S(O) 2 NH(C 1-6 -alkyl), S(O) 2 N(C 1-6 -alkyl) 2 , S(O) 2 NH(C 3-6 -cycloalkyl) and (CH 2 ) n —NR 11 R 12 ; wherein n is 0 or 1;
and R 11 is selected from C 1-6 -alkyl, C(O)C 1-6 -alkyl, C(O)(C 3-6 -cycloalkyl), C(O)(aryl), C(O)NH 2 , C(O)NH(C 1-6 -alkyl), C(O)N(C 1-6 -alkyl) 2 , C(O)NH(C 3-6 -cycloalkyl), C(O)O(C 1-6 -alkyl), C(O)O(C 3-6 -cycloalkyl), C(O)O(aryl), S(O) 2 (C 1-6 -alkyl), S(O) 2 (C 3-6 -cycloalkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-6 -alkyl), S(O) 2 N(C 1-6 -alkyl) 2 , S(O) 2 NH(C 3-6 -cycloalkyl) and S(O) 2 (aryl);
and R 11 is selected from H and C 1-6 -alkyl.
R 13 is selected from:
C(O)NH 2 , C(O)NH(C 1-6 -alkyl), C(O)N(C 1-6 -alkyl) 2 , C(O)NH(C 3-6 -cycloalkyl), S(O) 2 NH 2 , S(O) 2 (C 1-6 -alkyl), S(O) 2 NH(C 1-6 -alkyl), S(O) 2 N(C 1-6 -alkyl) 2 , S(O) 2 NH(C 3-6 -cycloalkyl) and (CH 2 ) n —NR 14 R 15 ; wherein n is 0 or 1;
and R 14 is selected from H, C 1-6 -alkyl, C(O)C 1-6 -alkyl, C(O)(C 3-6 -cycloalkyl), C(O)(aryl), C(O)NH 2 , C(O)NH(C 1-6 -alkyl), C(O)N(C 1-6 -alkyl) 2 , C(O)NH(C 3-6 -cycloalkyl), C(O)O(C 1-6 -alkyl), C(O)O(C 3-6 -cycloalkyl), C(O)O(aryl), S(O) 2 (C 1-6 -alkyl), S(O) 2 (C 3-6 -cycloalkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-6 -alkyl), S(O) 2 N(C 1-6 -alkyl) 2 , S(O) 2 NH(C 3-6 -cycloalkyl) and S(O) 2 (aryl);
and R 15 is selected from H and C 1-6 -alkyl.
2 . A method of inhibiting a cysteine proteinase in a subject, said method comprising administering to the subject a pharmacologically effective amount of a pharmaceutical or veterinary composition of formula (I), or a pharmaceutically acceptable salt, hydrate, complex or pro-drug thereof,
wherein:
one of R 3 and R 4 is H, and the other is selected from C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -alkoxy and C 6-12 -aralkyl;
or R 3 and R 4 are each independently selected from C 1-6 -alkyl and halo;
R 9 is selected from the following:
wherein:
X 1 , X 2 , X 3 , X 4 , X 14 , X 15 , X 16 and X 20 are each independently selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C-halo and N;
such that a maximum of two of X 1 , X 2 , X 3 , X 4 , X 14 , X 15 , X 16 and X 20 are selected from N, C-halo and C—(C 1-6 -alkoxy);
X 5 , X 6 , X 7 and X 8 are each independently selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C-halo, N and C—OH;
such that a maximum of one of X 5 , X 6 , X 7 and X 8 is N, C-halo, C—OH or C—(C 1-6 -alkoxy);
X 9 and X 12 are each independently selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C-halo and N;
X 10 and X 11 are each independently selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C-halo, N and R 10 ;
X 19 is selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C—C(O)NH 2 , C—C(O)NH(C 1-6 -alkyl), C—C(O)N(C 1-6 -alkyl) 2 , C-halo and N;
X 18 is selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C—NH 2 , C—N(C 1-6 -alkyl) 2 , C—NH(C 1-6 -alkyl), C—NHC(O)C 1-6 -alkyl, C-halo and N;
or when X 19 is CH, C—(C 1-6 -alkyl), or C-halo then X 18 may additionally be selected from C—C(O)NH 2 and C—C(O)N(C 1-6 -alkyl) 2 ;
X 13 and X 17 are each independently selected from:
O, S, NH and N—(C 1-6 -alkyl);
X 22 and X 24 are each independently selected from:
CH 2 , CH—(C 1-6 -alkyl), O, S, NH, NMe and C═O;
X 23 is selected from:
CH 2 , CH—(C 1-6 -alkyl), C—(C 1-6 -alkyl) 2 , NH and NMe;
or when either X 22 or X 24 are other than C═O then X 23 may additionally be C═O or S(O) 2 ;
X 25 is selected from: O, S, NH and N(C 1-6 -alkyl);
X 26 , X 27 , X 28 and X 29 are each independently selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C—OH, C-halo and N; such that a maximum of two of X 26 , X 27 , X 28 and X 29 are selected from C—(C 1-6 -alkoxy), C—OH, C-halo and N;
X 30 is selected from: CH 2 , CH 2 CH 2 , NH, NMe, O, S and C═O;
X 31 is selected from: CH 2 , NH and NMe; or when X 30 is other than C═O, O or S then X 31 may additionally be C═O or O;
X 32 is selected from: CH 2 , CH 2 CH 2 , NH, NMe and C═O;
X 33 is selected from: CH 2 , NH and NMe; or when X 32 is other than C═O then X 33 may additionally be C═O or O;
X 34 is selected from: NH and NMe;
R 10 is selected from:
wherein:
T 1 , T 2 , T 3 and T 4 are each independently selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C—NH 2 , C—NH(C 1-6 -alkyl), C—N(C 1-6 -alkyl) 2 , C-halo and N; such that a maximum of one of T 1 , T 2 , T 3 and T 4 is C—(C 1-6 -alkoxy), C—NH 2 , C—NH(C 1-6 -alkyl), C—N(C 1-6 -alkyl) 2 or C-halo;
T 5 is selected from: O, S, NH and N(C 1-6 -alkyl);
T 6 , T 7 , T 8 , T 9 and T 10 are each independently selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C—NH 2 , C—NH(C 1-6 -alkyl), C—N(C 1-6 -alkyl) 2 , C-halo and N; such that a maximum of two of T 6 , T 7 , T 8 , T 9 and T 10 are selected from C—(C 1-6 -alkoxy), C—NH 2 , C—NH(C 1-6 -alkyl), C—N(C 1-6 -alkyl) 2 , C-halo and N;
T 11 is selected from: CH 2 , NH and N(C 1-6 -alkyl);
T 12 is selected from: CH 2 , NH, N(C 1-6 -alkyl) and C═O;
T 13 and T 14 are each independently selected from: CH, C—(C 1-6 -alkyl) and C-halo;
T 15 is selected from: O, NH and N(C 1-6 -alkyl);
T 16 is selected from: CH 2 and C═O;
or R 10 is selected from:
H, C 1-6 -alkyl, OH, C 1-6 -alkoxy, NO 2 , halo, CN, C(O)NH 2 , C(O)NH(C 1-6 -alkyl), C(O)N(C 1-6 -alkyl) 2 , C(O)NH(C 3-6 -cycloalkyl), S(O) 2 NH 2 , S(O) 2 (C 1-6 -alkyl), S(O) 2 NH(C 1-6 -alkyl), S(O) 2 N(C 1-6 -alkyl) 2 , S(O) 2 NH(C 3-6 -cycloalkyl) and (CH 2 ) n —NR 11 R 12 ; wherein n is 0 or 1;
and R 11 is selected from C 1-6 -alkyl, C(O)C 1-6 -alkyl, C(O)(C 3-6 -cycloalkyl), C(O)(aryl), C(O)NH 2 , C(O)NH(C 1-6 -alkyl), C(O)N(C 1-6 -alkyl) 2 , C(O)NH(C 3-6 -cycloalkyl), C(O)O(C 1-6 -alkyl), C(O)O(C 3-6 -cycloalkyl), C(O)O(aryl), S(O) 2 (C 1-6 -alkyl), S(O) 2 (C 3-6 -cycloalkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-6 -alkyl), S(O) 2 N(C 1-6 -alkyl) 2 , S(O) 2 NH(C 3-6 -cycloalkyl) and S(O) 2 (aryl);
and R 12 is selected from H and C 1-6 -alkyl.
R 13 is selected from:
C(O)NH 2 , C(O)NH(C 1-6 -alkyl), C(O)N(C 1-6 -alkyl) 2 , C(O)NH(C 3-6 -cycloalkyl), S(O) 2 NH 2 , S(O) 2 (C 1-6 -alkyl), S(O) 2 NH(C 1-6 -alkyl), S(O) 2 N(C 1-6 -alkyl) 2 , S(O) 2 NH(C 3-6 -cycloalkyl) and (CH 2 ) n —NR 14 R 15 ;
wherein n is 0 or 1;
and R 14 is selected from H, C 1-6 -alkyl, C(O)C 1-6 -alkyl, C(O)(C 3-6 -cycloalkyl), C(O)(aryl), C(O)NH 2 , C(O)NH(C 1-6 -alkyl), C(O)N(C 1-6 -alkyl) 2 , C(O)NH(C 3-6 -cycloalkyl), C(O)O(C 1-6 -alkyl), C(O)O(C 3-6 -cycloalkyl), C(O)O(aryl), S(O) 2 (C 1-6 -alkyl), S(O) 2 (C 3-6 -cycloalkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-6 -alkyl), S(O) 2 N(C 1-6 -alkyl) 2 , S(O) 2 NH(C 3-6 -cycloalkyl) and S(O) 2 (aryl);
and R 15 is selected from H and C 1-6 -alkyl.
3 . The method according to claim 1 , wherein the cysteine proteinase is a CAC1 cysteine proteinase.
4 . The method according to claim 3 , wherein the CAC1 cysteine proteinase is cathepsin S.
5 . A method of treating a disease selected from rheumatoid arthritis, multiple sclerosis, myasthenia gravis, transplant rejection, diabetes, Sjogrens syndrome, Grave's disease, systemic lupus erythematosis, osteoarthritis, psoriasis, idiopathic thrombocytopenic purpura, allergic rhinitis, asthma, atherosclerosis, obesity, chronic obstructive pulmonary disease and chronic pain in a subject, said method comprising administering to a subject with said disease a pharmacologically effective amount of a pharmaceutical or veterinary composition of formula (I), or a pharmaceutically acceptable salt, hydrate, complex or pro-drug thereof,
wherein:
one of R 3 and R 4 is H, and the other is selected from C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -alkoxy and C 6-12 -aralkyl;
or R 3 and R 4 are each independently selected from C 1-6 -alkyl and halo;
R 9 is selected from the following:
wherein:
X 1 , X 2 , X 3 , X 4 , X 14 , X 15 , X 16 and X 20 are each independently selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C-halo and N; such that a maximum of two of X 1 , X 2 , X 3 , X 4 , X 14 , X 15 , X 16 and X 20 are selected from N, C-halo and C—(C 1-6 -alkoxy);
X 5 , X 6 , X 7 and X 8 are each independently selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C-halo, N and C—OH; such that a maximum of one of X 5 , X 6 , X 7 and X 8 is N, C-halo, C—OH or C—(C 1-6 -alkoxy);
X 9 and X 12 are each independently selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C-halo and N;
X 10 and X 11 are each independently selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C-halo, N and R 10 ;
X 19 is selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C—C(O)NH 2 , C—C(O)NH(C 1-6 -alkyl), C—C(O)N(C 1-6 -alkyl) 2 , C-halo and N;
X 18 is selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C—NH 2 , C—N(C 1-6 -alkyl) 2 , C—NH(C 1-6 -alkyl), C—NHC(O)C 1-6 -alkyl, C-halo and N;
or when X 19 is CH, C—(C 1-6 -alkyl), or C-halo then X 18 may additionally be selected from C—C(O)NH 2 and C—C(O)N(C 1-6 -alkyl) 2 ;
X 13 and X 17 are each independently selected from: O, S, NH and N—(C 1-6 -alkyl);
X 22 and X 24 are each independently selected from:
CH 2 , CH—(C 1-6 -alkyl), O, S, NH, NMe and C═O;
X 23 is selected from:
CH 2 , CH—(C 1-6 -alkyl), C—(C 1-6 -alkyl) 2 , NH and NMe;
or when either X 22 or X 24 are other than C═O then X 23 may additionally be C═O or S(O) 2 ;
X 25 is selected from:
O, S, NH and N(C 1-6 -alkyl);
X 26 , X 27 , X 28 and X 29 are each independently selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C—OH, C-halo and N; such that a maximum of two of X 26 , X 27 , X 28 and X 29 are selected from C—(C 1-6 -alkoxy), C—OH, C-halo and N;
X 30 is selected from: CH 2 , CH 2 CH 2 , NH, NMe, O, S and C═O;
X 31 is selected from: CH 2 , NH and NMe; or when X 30 is other than C═O, O or S then X 31 may additionally be C═O or O;
X 32 is selected from: CH 2 , CH 2 CH 2 , NH, NMe and C═O;
X 33 is selected from: CH 2 , NH and NMe; or when X 32 is other than C═O then X 33 may additionally be C═O or O;
X 34 is selected from: NH and NMe;
R 10 is selected from:
wherein:
T 1 , T 2 , T 3 and T 4 are each independently selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C—NH, C—NH(C 1-6 -alkyl), C—N(C 1-6 -alkyl) 2 , C-halo and N; such that a maximum of one of T 1 , T 2 , T 3 and T 4 is C—(C 1-6 -alkoxy), C—NH 2 , C—NH(C 1-6 -alkyl), C—N(C 1-6 -alkyl) 2 or C-halo;
T 5 is selected from: O, S, NH and N(C 1-6 -alkyl);
T 6 , T 7 , T 8 , T 9 and T 10 are each independently selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C—NH, C—NH(C 1-6 -alkyl), C—N(C 1-6 -alkyl) 2 , C-halo and N; such that a maximum of two of T 6 , T 7 , T 8 , T 9 and T 10 are selected from C—(C 1-6 -alkoxy), C—NH, C—NH(C 1-6 -alkyl), C—N(C 1-6 -alkyl) 2 , C—N(C 1-6 alkyl) 2 , C-halo and N;
T 11 is selected from: CH 2 , NH and N(C 1-6 -alkyl);
T 12 is selected from: CH 2 , NH, N(C 1-6 -alkyl) and C═O;
T 13 and T 14 are each independently selected from: CH, C—(C 1-6 -alkyl) and C-halo;
T 15 is selected from: O, NH and N(C 1-6 -alkyl);
T 16 is selected from: CH 2 and C═O;
or R 10 is selected from:
H, C 1-6 -alkyl, OH, C 1-6 -alkoxy, NO 2 , halo, CN, C(O)NH 2 , C(O)NH(C 1-6 -alkyl), C(O)N(C 1-6 -alkyl) 2 , C(O)NH(C 3-6 -cycloalkyl), S(O) 2 NH 2 , S(O) 2 (C 1-6 -alkyl), S(O) 2 NH(C 1-6 -alkyl), S(O) 2 N(C 1-6 -alkyl) 2 , S(O) 2 NH(C 3-6 -cycloalkyl) and (CH 2 ) n —NR 11 R 12 ; wherein n is 0 or 1;
and R 11 is selected from C 1-6 -alkyl, C(O)C 1-6 -alkyl, C(O)(C 3-6 -cycloalkyl), C(O)(aryl), C(O)NH 2 , C(O)NH(C 1-6 -alkyl), C(O)N(C 1-6 -alkyl) 2 , C(O)NH(C 3-6 -cycloalkyl), C(O)O(C 1-6 -alkyl), C(O)O(C 3-6 -cycloalkyl), C(O)O(aryl), S(O) 2 (C 1-6 -alkyl), S(O) 2 (C 3-6 -cycloalkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-6 -alkyl), S(O) 2 N(C 1-6 -alkyl) 2 , S(O) 2 NH(C 3-6 -cycloalkyl) and S(O) 2 (aryl);
and R 12 is selected from H and C 1-6 -alkyl.
R 13 is selected from:
C(O)NH 2 , C(O)NH(C 1-6 -alkyl), C(O)N(C 1-6 -alkyl) 2 , C(O)NH(C 3-6 -cycloalkyl), S(O) 2 NH 2 , S(O) 2 (C 1-6 -alkyl), S(O) 2 NH(C 1-6 -alkyl), S(O) 2 N(C 1-6 -alkyl) 2 , S(O) 2 NH(C 3-6 -cycloalkyl) and (CH 2 ) n —NR 14 R 15 ; wherein n is 0 or 1; and
R 14 is selected from:
H, C 1-6 -alkyl, C(O)C 1-6 -alkyl, C(O)(C 3-6 -cycloalkyl), C(O)(aryl), C(O)NH 2 , C(O)NH(C 1-6 -alkyl), C(O)N(C 1-6 -alkyl) 2 , C(O)NH(C 3-6 -cycloalkyl), C(O)O(C 1-6 -alkyl), C(O)O(C 3-6 -cycloalkyl), C(O)O(aryl), S(O) 2 (C 1-6 -alkyl), S(O) 2 (C 3-6 -cycloalkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-6 -alkyl), S(O) 2 N(C 1-6 -alkyl) 2 , S(O) 2 NH(C 3-6 -cycloalkyl) and S(O) 2 (aryl);
and R 15 is selected from H and C 1-6 -alkyl,
said process comprising admixing said compound with a pharmaceutically acceptable or veterinarily acceptable diluent, excipient and/or carrier.
6 . A method of validating a known or putative cysteine proteinase as a therapeutic target, the method comprising:
(a) assessing the in vitro binding of a composition to an isolated or known putative cysteine proteinase, providing a measure of potency; and optionally, one or more of the steps of: (b) assessing the binding of said composition to closely related homologous proteinases of the target and general housekeeping proteinases (e.g. trypsin) to provide a measure of selectivity; (c) monitoring a cell-based functional marker of a particular cysteine proteinase activity in the presence of said composition; and (d) monitoring an animal model-based functional marker of a particular cysteine proteinase activity in the presence of said composition; wherein said composition comprises formula (I), or a pharmaceutically acceptable salt, hydrate, complex or pro-drug thereof,
wherein:
one of R 3 and R 4 is H, and the other is selected from C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -alkoxy and C 6-12 -aralkyl;
or R 3 and R 4 are each independently selected from C 1-6 -alkyl and halo;
R 9 is selected from the following:
wherein:
X 1 , X 2 , X 3 , X 4 , X 14 , X 15 , X 16 and X 20 are each independently selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C-halo and N; such that a maximum of two of X 1 , X 2 , X 3 , X 4 , X 14 , X 15 , X 16 and X 20 are selected from N, C-halo and C—(C 1-6 -alkoxy);
X 5 , X 6 , X 7 and X 8 are each independently selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C-halo, N and C—OH; such that a maximum of one of X 5 , X 6 , X 7 and X 8 is N, C-halo, C—OH or C—(C 1-6 -alkoxy);
X 9 and X 12 are each independently selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C-halo and N;
X 10 and X 11 are each independently selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C-halo, N and R 10 ;
X 19 is selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C—C(O)NH 2 , C—C(O)NH(C 1-6 -alkyl), C—C(O)N(C 1-6 -alkyl) 2 , C-halo and N;
X 18 is selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C—NH 2 , C—N(C 1-6 -alkyl) 2 , C—NH(C 1-6 -alkyl), C—NHC(O)C 1-6 -alkyl, C-halo and N;
or when X 19 is CH, C—(C 1-6 -alkyl), or C-halo then X 18 may additionally be selected from C—C(O)NH 2 and C—C(O)N(C 1-6 -alkyl) 2 ;
X 13 and X 17 are each independently selected from: O, S, NH and N—(C 1-6 -alkyl);
X 22 and X 24 are each independently selected from:
CH 2 , CH—(C 1-6 -alkyl), O, S, NH, NMe and C═O;
X 23 is selected from:
CH 2 , CH—(C 1-6 -alkyl), C—(C 1-6 -alkyl) 2 , NH and NMe;
or when either X 22 or X 24 are other than C═O then X 23 may additionally be C═O or S(O) 2 ;
X 25 is selected from: O, S, NH and N(C 1-6 -alkyl);
X 26 , X 27 , X 28 and X 29 are each independently selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C—OH, C-halo and N;
such that a maximum of two of X 26 , X 27 , X 28 and X 29 are selected from C—(C 1-6 -alkoxy), C—OH, C-halo and N;
X 30 is selected from: CH 2 , CH 2 CH 2 , NH, NMe, O, S and C═O;
X 31 is selected from: CH 2 , NH and NMe; or when X 30 is other than C═O, O or S then X 31 may additionally be C═O or O;
X 32 is selected from: CH 2 , CH 2 CH 2 , NH, NMe and C═O;
X 33 is selected from: CH 2 , NH and NMe;
or when X 32 is other than C═O then X 33 may additionally be C═O or O;
X 34 is selected from: NH and NMe;
R 10 is selected from:
wherein:
T 1 , T 2 , T 3 and T 4 are each independently selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C—NH 2 , C—NH(C 1-6 -alkyl), C—N(C 1-6 -alkyl) 2 , C-halo and N; such that a maximum of one of T 1 , T 2 , T 3 and T 4 is C—(C 1-6 -alkoxy), C—NH 2 , C—NH(C 1-6 -alkyl), C—N(C 1-6 -alkyl) 2 or C-halo;
T 5 is selected from: O, S, NH and N(C 1-6 -alkyl);
T 6 , T 7 , T 8 , T 9 and T 10 are each independently selected from:
CH, C—(C 1-6 -alkyl), C—(C 1-6 -alkoxy), C—NH 2 , C—NH(C 1-6 -alkyl), C—N(C 1-6 -alkyl) 2 , C-halo and N; such that a maximum of two of T 6 , T 7 , T 8 , T 9 and T 10 are selected from C—(C 1-6 -alkoxy), C—NH 2 , C—NH(C 1-6 -alkyl), C—N(C 1-6 -alkyl) 2 , C-halo and N;
T 11 is selected from:
CH 2 , NH and N(C 1-6 -alkyl);
T 12 is selected from:
CH 2 , NH, N(C 1-6 -alkyl) and C═O;
T 13 and T 14 are each independently selected from:
CH, C—(C 1-6 -alkyl) and C-halo;
T 15 is selected from:
O, NH and N(C 1-6 -alkyl);
T 16 is selected from:
CH 2 and C═O;
or R 10 is selected from:
H, C 1-6 -alkyl, OH, C 1-6 -alkoxy, NO 2 , halo, CN, C(O)NH 2 , C(O)NH(C 1-6 -alkyl), C(O)N(C 1-6 -alkyl) 2 , C(O)NH(C 3-6 -cycloalkyl), S(O) 2 NH 2 , S(O) 2 (C 1-6 -alkyl), S(O) 2 NH(C 1-6 -alkyl), S(O) 2 N(C 1-6 -alkyl) 2 , S(O) 2 NH(C 3-6 -cycloalkyl) and (CH 2 ) n —NR 11 R 12 ;
wherein n is 0 or 1;
and R 11 is selected from C 1-6 -alkyl, C(O)C 1-6 -alkyl, C(O)(C 3-6 -cycloalkyl), C(O)(aryl), C(O)NH 2 , C(O)NH(C 1-6 -alkyl), C(O)N(C 1-6 -alkyl) 2 , C(O)NH(C 3-6 -cycloalkyl), C(O)O(C 1-6 -alkyl), C(O)O(C 3-6 -cycloalkyl), C(O)O(aryl), S(O) 2 (C 1-6 -alkyl), S(O) 2 (C 3-6 -cycloalkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-6 -alkyl), S(O) 2 N(C 1-6 -alkyl) 2 , S(O) 2 NH(C 3-6 -cycloalkyl) and S(O) 2 (aryl);
and R 12 is selected from H and C 1-6 -alkyl.
R 13 is selected from:
C(O)NH 2 , C(O)NH(C 1-6 -alkyl), C(O)N(C 1-6 -alkyl) 2 , C(O)NH(C 3-6 -cycloalkyl), S(O) 2 NH 2 , S(O) 2 (C 1-6 -alkyl), S(O) 2 NH(C 1-6 -alkyl), S(O) 2 N(C 1-6 -alkyl) 2 , S(O) 2 NH(C 3-6 -cycloalkyl) and (CH 2 ) n —NR 14 R 15 ;
wherein n is 0 or 1;
and R 14 is selected from H, C 1-6 -alkyl, C(O)C 1-6 -alkyl, C(O)(C 3-6 -cycloalkyl), C(O)(aryl), C(O)NH 2 , C(O)NH(C 1-6 -alkyl), C(O)N(C 1-6 -alkyl) 2 , C(O)NH(C 3-6 -cycloalkyl), C(O)O(C 1-6 -alkyl), C(O)O(C 3-6 -cycloalkyl), C(O)O(aryl), S(O) 2 (C 1-6 -alkyl), S(O) 2 (C 3-6 -cycloalkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-6 -alkyl), S(O) 2 N(C 1-6 -alkyl) 2 , S(O) 2 NH(C 3-6 -cycloalkyl) and S(O) 2 (aryl);
and R 15 is selected from H and C 1-6 -alkyl.Cited by (0)
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