Back to results
US 8,008,290 B2Granted
Compounds
AssigneeAmura Therapeutics Limited
InventorsMartin Quibell, John P. Watts, Nicholas S. Flinn
Life of this patent
Estimating the term…
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: R3 is selected from cyclopentyl and cyclohexyl; R9 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 dual efficacies for human cathepsin S and K and are useful for the treatment of rheumatoid arthritis, osteoarthritis, chronic obstructive pulmonary disease (COPD), atherosclerosis, cardiovascular diseases which exhibit significant damage and remodeling of extracellular matrix (ECM) and chronic pain.
Claims39
A compound of formula (I), or a pharmaceutically acceptable salt, or hydrate thereof,
- wherein:
- R3 is selected from cyclopentyl and cyclohexyl;
- R9 is selected from the following:
- wherein:
- X1, X2, X3, X4, X14, X15, X16 and X20 are each independently selected from:
- CH, C—(C1-6-alkyl), C—(C1-6-alkoxy), C-halo and N;
- such that a maximum of two of X1, X2, X3, X4, X14, X15, X16 and X20 are selected from N, C-halo and C—(C1-6-alkoxy);
- X5, X6, X7 and X8 are each independently selected from:
- CH, C—(C1-6-alkyl), C—(C1-6-alkoxy), C-halo, N and C—OH;
- such that a maximum of one of X5, X6, X7 and X8 is N, C-halo, C—OH or C—(C1-6-alkoxy);
- X9 and X12 are each independently selected from:
- CH, C—(C1-6-alkyl), C—(C1-6-alkoxy), C-halo and N;
- X10 and X11 are each independently selected from:
- CH, C—(C1-6-alkyl), C—(C1-6-alkoxy), C-halo, N and R10;
- X19 is selected from:
- CH, C—(C1-6-alkyl), C—(C1-6-alkoxy), C—C(O)NH2, C—C(O)NH(C1-6-alkyl), C—C(O)N(C1-6-alkyl)2, C-halo and N;
- X18 is selected from:
- CH, C—(C1-6-alkyl), C—(C1-6-alkoxy), C—NH2, C—N(C1-6-alkyl)2, C—NH(C1-6-alkyl), C—NHC(O)C1-6-alkyl, C-halo and N;
- or when X19 is CH, C—(C1-6-alkyl), or C-halo then X18 may additionally be selected from C—C(O)NH2 and C—C(O)N(C1-6-alkyl)2;
- X13 and X17 are each independently selected from:
- 0, S, NH and N—(C1-6-alkyl);
- X22 and X24 are each independently selected from:
- CH2, CH—(C1-6-alkyl), O, S, NH, NMe and C═O;
- X23 is selected from:
- CH2, CH—(C1-6-alkyl), C—(C1-6-alkyl)2, NH and NMe;
- or when either X22 or X24 are other than C═O then X23 may additionally be C═O or S(O)2;
- X25 is selected from:
- O, S, NH and N(C1-6-alkyl);
- X26, X27, X28 and X29 are each independently selected from:
- CH, C—(C1-6-alkyl), C—(C1-6-alkoxy), C—OH, C-halo and N;
- such that a maximum of two of X26, X27, X28 and X29 are selected from C—(C1-6-alkoxy), C—OH, C-halo and N;
- X30 is selected from:
- CH2, CH2CH2, NH, NMe, O, S and C═O;
- X31 is selected from:
- CH2, NH and NMe;
- or when X30 is other than C═O, O or S then X31 may additionally be C═O or O;
- X32 is selected from:
- CH2, CH2CH2, NH, NMe and C═O,
- X33 is selected from:
- CH2, NH and NMe;
- or when X32 is other than C═O then X33 may additionally be C═O or O;
- X34 is selected from:
- NH and NMe;
- R10 is selected from:
- wherein:
- T1, T2, T3 and T4 are each independently selected from:
- CH, C—(C1-6-alkyl), C—(C1-6-alkoxy), C—NH2, C—NH(C1-6-alkyl), C—N(C1-6-alkyl)2, C-halo and N;
- such that a maximum of one of T1, T2, T3 and T4 is C—(C1-6-alkoxy), C—NH2, C—NH(C1-6-alkyl), C—N(C1-6-alkyl)2 or C-halo;
- T5 is selected from:
- O, S, NH and N(C1-6-alkyl);
- T6, T7, T8, T9 and T10 are each independently selected from:
- CH, C—(C1-6-alkyl), C—(C1-6-alkoxy), C—NH2, C—NH(C1-6-alkyl), C—N(C1-6-alkyl)2, C-halo and N;
- such that a maximum of two of T6, T7, T8, T9 and T10 are selected from C—(C1-6-alkoxy), C—NH2, C—NH(C1-6-alkyl), C—N(C1-6-alkyl)2, C-halo and N;
- T11 is selected from:
- CH2, NH and N(C1-6-alkyl),
- T12 is selected from:
- CH2, NH, N(C1-6-alkyl) and C═O;
- T13 and T14 are each independently selected from:
- CH, C—(C1-6-alkyl) and C-halo;
- T15 is selected from:
- O, NH and N(C1-6-alkyl);
- T16 is selected from:
- CH2 and C═O;
- or R10 is selected from:
- H, C1-6-alkyl, OH, C1-6-alkoxy, NO2, halo, CN, C(O)NH2, C(O)NH(C1-6-alkyl), C(O)N(C1-6-alkyl)2, C(O)NH(C3-6-cycloalkyl), S(O)2NH2, S(O)2(C1-6-alkyl), S(O)2NH(C1-6-alkyl), S(O)2N(C1-6-alkyl)2, S(O)2NH(C3-6-cycloalkyl) and (CH2)n—NR11R12;
- wherein n is 0 or 1;
- and R11 is selected from C1-6-alkyl, C(O)C1-6-alkyl, C(O)(C3-6-cycloalkyl), C(O)(aryl), C(O)NH2, C(O)NH(C1-6-alkyl), C(O)N(C1-6-alkyl)2, C(O)NH(C3-6-cycloalkyl), C(O)O(C1-6-alkyl), C(O)O(C3-6-cycloalkyl), C(O)O(aryl), S(O)2(C1-6-alkyl), S(O)2(C3-6-cycloalkyl), S(O)2NH2, S(O)2NH(C1-6-alkyl), S(O)2N(C1-6-alkyl)2, S(O)2NH(C3-6-cycloalkyl) and S(O)2(aryl);
- and R12 is selected from H and C1-6-alkyl;
- R13 is selected from:
- C(O)NH2, C(O)NH(C1-6-alkyl), C(O)N(C1-6-alkyl)2, C(O)NH(C3-6-cycloalkyl), S(O)2NH2, S(O)2(C1-6-alkyl), S(O)2NH(C1-6-alkyl), S(O)2N(C1-6-alkyl)2, S(O)2NH(C3-6-cycloalkyl) and (CH2)n—NR14R15;
- wherein n is 0 or 1;
- and R14 is selected from H, C1-6-alkyl, C(O)C1-6-alkyl, C(O)(C3-6-cycloalkyl), C(O)(aryl), C(O)NH2, C(O)NH(C1-6-alkyl), C(O)N(C1-6-alkyl)2, C(O)NH(C3-6-cycloalkyl), C(O)O(C1-6-alkyl), C(O)O(C3-6-cycloalkyl), C(O)O(aryl), S(O)2(C1-6-alkyl), S(O)2(C3-6-cycloalkyl), S(O)2NH2, S(O)2NH(C1-6-alkyl), S(O)2N(C1-6-alkyl)2, S(O)2NH(C3-6-cycloalkyl) and S(O)2(aryl);
- and R15 is selected from H and C1-6-alkyl.
70 more elements
Dependencies are inferred from the claim text.