Amura Therapeutics Limited

Grunenthal Gmbh

Amura Limited

John Paul Watts

Martin Quibell

Nicholas Sean Flinn

Lee Patient

Claudio Dagostin

James Nally

Yikang Wang

A compound of formula (I), or a pharmaceutically acceptable salt, hydrate, complex or pro-drug thereof, wherein one of Rand Ris H, and the other is selected from C-alkyl, C-cycloalkyl and C-alkyl-C-aryl; Ris selected from tert-butylmethyl, iso-propylmethyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl and 1-methylcyclopentyl; Ris selected from the following:wherein: Ris selected from C-alkyl and C-cycloalkyl; G is selected from:CH,CMe and N; E is selected from: O, S,SO,NH,NMe and N-oxide (N&#x2192;O); J and R are independently selected from:CH, N and N-oxide (N&#x2192;O); andRis selected from amino, methylamino, dimethylamino, isopropylamino, isopropyl(methyl)amino, cyclopropylamino, cyclopropyl(methyl)amino, cyclopentylamino, morpholino, piperidin-1-yl, piperidin-1-ylmethyl, morpholinomethyl, 4-methylpiperazin-1-yl, 4-(2-methoxyethyl)piperazin-1-yl, 1-morpholinoethyl, 1-(dimethylamino)ethyl, 1-(methylamino)ethyl, 4-fluoro-1-methylpyrrolidin-2-yl, 4,4-difluoropiperidin-1-yl, piperidin-4-yl, 1-methylpiperidin-4-yl, pyridin-3-ylamino, pyridin-2-ylamino, 1-methylpyrrolidin-3-yl, methyl, isopropyl. The invention further relates to pharmaceutical compositions comprising compounds of formula (I), and the use of such compounds in the treatment of various diseases.

Piperazine compounds

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: 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.

Furo[3, 2-B] pyrrol-3-ones as cathespin S inhibitors

The present invention relates to compounds of formula (I), and pharmaceutically acceptable salts thereof, A compound of formula (I), or a pharmaceutically acceptable salt, hydrate, complex or pro-drug thereof (I), wherein: one of Rand Ris H, and the other is selected from F and Cl, or Rand Rare both F; Ris selected from cyclopentyl and cyclohexyl; Ris an optionally substituted 5- or 6-membered monocyclic or an 8- to 10-membered bicyclic aryl or heteroaryl ring which includes up to four heteroatoms. The invention further relates to pharmaceutical compositions comprising compounds of formula (I), and the use of such compounds in the treatment of a disease selected from osteoporosis, Paget's disease, Chagas's disease, malaria, gingival diseases, hypercalaemia, metabolic bone disease, diseases involving matrix or cartilage degradation, and bone cancer disorders such as bone metastases and associated pain. 

Furo[3,2-B] pyrrol -3-one derivatives and their use as cysteinyl proteinase inhibitors

A compound of formula (I), or a pharmaceutically acceptable salt, hydrate, complex or pro-drug thereof, wherein one of Rand Ris H, and the other is selected from C-alkyl, C-cycloalkyl and C-alkyl-C-aryl; Ris selected from tert-butylmethyl, iso-propylmethyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl and 1-methylcyclopentyl; Ris selected from the following: wherein: The invention further relates to pharmaceutical compositions comprising compounds of formula (I), and the use of such compounds in the treatment of various diseases.

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 Rand Ris H, and the other is selected from C-alkyl, C-haloalkyl, C-alkoxy, and C-aralkyl;or Rand Rare each independently selected from C-alkyl and halo;Ris 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.

The present invention relates to compounds of formula (I), and pharmaceutically acceptable salts thereof, wherein: Ris tert-butylmethyl, sec-butyl or tert-butyl; X is CH or N; and Ris optionally substituted Calkyl or optionally substituted Ccycloalkyl. The invention further relates to pharmaceutical compositions comprising compounds of formula (I), and the use of such compounds in the treatment of a disease selected from osteoporosis, Paget's disease, Chagas's disease, malaria, gingival diseases, hypercalaemia, metabolic bone disease, diseases involving matrix or cartilage degradation, and bone cancer disorders such as bone metastases and associated pain. 

Furo[3. 2-B] pyrrol derivatives

The present invention relates to a process for preparing a compound of formula (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof, said process comprising the steps of: (A) (i) treating a compound of formula (IVa), where Ris alkyl or tosyl, with an oxidizing agent to form a compound of formula (Va); and (ii) converting said compound of formula (Va) to a compound of formula (Ia) or (Ic); or (B) (i) treating a compound of formula (IVb), where Ris alkyl or tosyl, with an oxidizing agent to form a compound of formula (Vb); and (ii) converting said compound of formula (Vb) to a compound of formula (Ib) or (Id). 

Tetrahydrofuro[3,2-b] pyrrol-3-one intermediates

A first aspect of the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, complex or pro-drug thereof,  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.

Compounds

The present invention relates to compounds of formula (I), and pharmaceutically acceptable salts thereof (I), wherein: Ris cyclopentyl or cyclohexyl; X is CH or N; and Ris optionally substituted Calkyl or optionally substituted Ccycloalkyl. The invention further relates to pharmaceutical compositions comprising compounds of formula (I), and the use of such compounds in the treatment of a disease selected from osteoporosis, Paget's disease, Chagas's disease, malaria, gingival diseases, hypercalaemia, metabolic bone disease, diseases involving matrix or cartilage degradation, and bone cancer disorders such as bone metastases and associated pain. 

Furo[3,2-B] pyrrol-3-one derivatives and their use as cysteinyl proteinase inhibitors

The present invention relates to compounds of formula (I), and pharmaceutically acceptable salts thereof, wherein:X is CH or N; andRis optionally substituted Calkyl or optionally substituted Ccycloalkyl. The invention further relates to pharmaceutical compositions comprising compounds of formula (I), and the use of such compounds in the treatment of a disease selected from osteoporosis, Paget's disease, Chagas's disease, malaria, gingival diseases, hypercalaemia, metabolic bone disease, diseases involving matrix or cartilage degradation, and bone cancer disorders such as bone metastases and associated pain.

Furo[3,2-B]pyrrol-3-one derivatives and their use as cysteinyl proteinase inhibitors

The present invention relates to compounds of formula (I), and pharmaceutically acceptable salts thereof, wherein: The invention further relates to pharmaceutical compositions comprising compounds of formula (I), and the use of such compounds in the treatment of a disease selected from osteoporosis, Paget's disease, Chagas's disease, malaria, gingival diseases, hypercalaemia, metabolic bone disease, diseases involving matrix or cartilage degradation, and bone cancer disorders such as bone metastases and associated pain.

Tetrahydrofuro[3,2-B] pyrrol-3-ones as cathepsin K inhibitors

A compound of formula (I), or a pharmaceutically acceptable salt, hydrate, complex or pro-drug thereof, wherein: one of Rand Ris H, and the other is selected from OR, SR, NRR, N, Me, Et, CF, SORand SOR; or The invention further relates to pharmaceutical compositions comprising compounds of formula (I), and the use of such compounds in the treatment of a disease selected from osteoporosis, Paget's disease, Chagas's disease, malaria, gingival diseases, hypercalaemia, metabolic bone disease, diseases involving matrix or cartilage degradation, and bone cancer disorders such as bone metastases and associated pain.

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Cambridge, United Kingdom

John Paul Watts