WO2016027285A2 - Bicyclic heteroaryl amides as cathepsin cysteine protease inhibitors - Google Patents

Bicyclic heteroaryl amides as cathepsin cysteine protease inhibitors Download PDF

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WO2016027285A2
WO2016027285A2 PCT/IN2015/050097 IN2015050097W WO2016027285A2 WO 2016027285 A2 WO2016027285 A2 WO 2016027285A2 IN 2015050097 W IN2015050097 W IN 2015050097W WO 2016027285 A2 WO2016027285 A2 WO 2016027285A2
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group
optionally substituted
alkyl
hydrogen
compound according
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PCT/IN2015/050097
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French (fr)
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WO2016027285A3 (en
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Harish Kumar Mysore Nagaraj
Balachandra S BANDODKAR
Lokesh RAVILLA
Sudhakar YELLAPU
Ashok Seegebagi RUDRESHA
Jitendra Kumar Singh
Vaidyanathan. G
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Alkem Laboratories Ltd.
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Publication of WO2016027285A2 publication Critical patent/WO2016027285A2/en
Publication of WO2016027285A3 publication Critical patent/WO2016027285A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to substituted bicyclic heteroaryl amide derivatives that are inhibitors of cathepsin K proteases and which are therefore useful in the treatment of certain disorders that can be prevented or treated by inhibition of these enzymes.
  • the invention relates to the compounds, methods for their preparation, pharmaceutical compositions containing the compounds and the uses of these compounds in the treatment of certain disorders. It is expected that the compounds of the invention will find application in the treatment of bone diseases such as osteoporosis and osteoarthritis as well as other diseases and conditions.
  • Cathepsins belong to the papain superfamily of cysteine proteases, which share a common papain-like structural fold and a conserved catalytic Cys-His-Asn triad. These proteases function in the normal physiological as well as pathological degradation of connective tissue. Cathepsins play a major role in intracellular protein degradation and turnover and remodelling. To date, a number of cathepsins have been identified and sequenced from a number of sources. These cathepsins are naturally found in a wide variety of tissues. There are currently 1 1 of these cathepsins known in human, that is, cathepsin (Cat) B, H, L, S, C, K, O, F, V, X and W.
  • Cat cathepsin
  • Cathepsin K (which is also known by the abbreviation cat K) is also known as cathepsin O and cathepsin 02. See PCT Application WO 96/13523, Khepri Pharmaceuticals, Inc., and published May 9, 1996, which is hereby incorporated by reference in its entirety. Cathepsin L is implicated in normal lysosomal proteolysis as well as several diseases states, including, but not limited to, metastasis of melanomas.
  • Cathepsin S is implicated in Alzheimer's disease and certain autoimmune disorders, including, but not limited to juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves' disease, myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis and Hashimoto's thyroiditis; allergic disorders, including but not limited to asthma; and allogenic immune responses, including but not limited to, rejection of organ transplants or tissue grafts. Increased cathepsin B levels and redistribution of the enzyme are found in tumours, suggesting a role in tumour invasion and metastasis.
  • aberrant cathepsin B activity is implicated in such disease states as rheumatoid arthritis, osteoarthritis, pneumocystosis carinii, acute pancreatitis, inflammatory airway disease and bone and joint disorders.
  • disorders in humans and other mammals involve are associated with abnormal bone resorption.
  • Such disorders include but are not limited to, osteoporosis, glucocorticoid induced osteoporosis, Paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, bone fractures, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignancy, and multiple myeloma.
  • osteoporosis which in its most frequent manifestation occurs in postmenopausal women. Osteoporotic fractures are a major cause of morbidity and mortality in the elderly population.
  • osteoporotic fracture As many as 50% of women and a third of men will experience an osteoporotic fracture. A large segment of the older population already has low bone density and a high risk of fractures. There is a significant need to both prevent and treat osteoporosis and other conditions associated with bone resorption. Because osteoporosis, as well as other disorders associated with bone loss, is generally a chronic condition, it is believed that appropriate therapy will typically require chronic treatment.
  • Osteoporosis is characterized by progressive loss of bone architecture and mineralization leading to the loss in bone strength and an increased fracture rate.
  • the skeleton is constantly being remodelled by a balance between osteoblasts that lay down new bone and osteoclasts that breakdown, or resorb, bone.
  • the balance between bone formation and resorption is disrupted; bone is removed at a faster rate.
  • Such a prolonged imbalance of resorption over formation leads to weaker bone structure and a higher risk of fractures.
  • Bone resorption is primarily performed by osteoclasts, which are multinuclear giant cells. Osteoclasts resorb bone by forming an initial cellular attachment to bone tissue, followed by the formation of an extracellular compartment or lacunae. The lacunae are maintained at a low pH by a proton-ATP pump. Acid secretion subsequently dissolves the inorganic content of bone, mainly calcium phosphate. The exposed organic bone matrix composed primarily of type I collagen is then degraded by proteases. The osteoclast-specific localization and high expression level of Cat K suggest that this cysteine protease plays a critical role in bone matrix degradation. See Delaisse, J. M.
  • Collagen constitutes 95% of the organic matrix of bone. Therefore, proteases involved in collagen degradation are an essential component of bone turnover, and as a consequence, the development and progression of osteoporosis. Cysteine protease inhibitors such as E-64 (trans-epoxysuccinyl-L- leucylamide-(4- guanidino) butane) are known to be effective in inhibiting bone resorption.
  • Cathepsin K is synthesized as a 37 kDa pre-pro enzyme, which is localized to the lysosomal compartment and where it is presumably autoactivated to the mature 27 kDa enzyme at low pH. See McQueney, M. S. et al., 1997, J Biol Chem 272:13955-13960; Littlewood- Evans, A. et al, 1997, Bone 20:81 -86, which are hereby incorporated by reference in their entirety. Cathepsin K is most closely related to cathepsin S having 56 % sequence identity at the amino acid level.
  • the S 2 P 2 substrate specificity of cathepsin K is similar to that of cathepsin S with a preference in the P1 and P2 positions for a positively charged residue such as arginine, and a hydrophobic residue such as phenylalanine or leucine, respectively. See Bromme, D. et al. , 1996, J Biol Chem 271 : 2126-2132; Bossard, M. J. et al, 1996, J Biol Chem 271 :12517- 12524, which are hereby incorporated by reference in their entirety.
  • Cathepsin K is active at a broad pH range with significant activity between pH 4-8, thus allowing for good catalytic activity in the resorption lacunae of osteoclasts where the pH is about 4-5.
  • Human type I collagen, the major collagen in bone is a good substrate for cathepsin K.
  • the present invention provides compounds that are inhibitors of cathepsin K. These compounds would be expected to be useful in the treatment of conditions that can be treated by inhibition of these proteases.
  • the present invention provides a pharmaceutical composition containing a compound that is an inhibitor of cathepsin K and a pharmaceutically acceptable excipient, diluent or carrier.
  • the present invention provides a method of prevention or treatment of a condition that can be treated by inhibition of cathepsin K in a mammal.
  • the applicants have discovered a class of compounds which have activity as inhibitors of cathepsin K. This activity may be by way of one or more of selectivity over CatL, CatS, and CatV; potency; solubility; metabolic stability; or dosage profile.
  • the present invention provides a compound of formula (I)
  • each R 1 is independently selected from the group consisting of hydrogen, C ⁇ .C 6 alkyl and C ⁇ C haloalkyl
  • each R 2 is independently is selected from the group consisting of hydrogen, C ⁇ .C 6 alkyl and C 6 haloalkyl, or
  • R 1 and R 2 when taken together with the carbon atoms to which they are attached form a C 3 .C
  • R 3 is selected from the group consisting of hydrogen, optionally substituted d-C 6 alkyl and C 6 haloalkyl,
  • R 4 is selected from the group consisting of hydrogen and optionally substituted d-C 6 alkyl, or
  • each R 5 is independently selected from the group consisting of hydrogen, halogen, OH, N0 2 , CN, SH, NH 2 , Ci-C 6 alkyl, d_C 6 haloalkyl, d_C 6 alkyloxy and d_C 6 haloalkyloxy;
  • V 1 is C or N
  • V 2 and V 3 are independently selected from the group consisting of CR 6 , N and NR 6 , and wherein if V 1 is C then at least one of V 2 and V 3 is N or NR 6 ; each R 6 is independently selected from the group consisting of H, optionally substituted C r C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted d-C ⁇ haloalkyl, optionally substituted C 2 -C 12 heteroalkyl, optionally substituted C 3 - Ci 2 cycloalkyl, optionally substituted C 3 -Ci 2 cycloalkenyl, optionally substituted C 2 - C 12 heterocycloalkyl, optionally substituted C 2 -C 12 heterocycloalkenyl, optionally substituted C 6 - C 18 aryl, optionally substituted CrC 18 heteroaryl, optionally substituted C 6 -C 18 aryld-C 12
  • the invention relates to a pharmaceutical composition containing a compound of the invention and a pharmaceutically acceptable diluent, excipient or carrier.
  • the invention relates to a method of treating a cathepsin dependent condition in a patient which comprises administering to a patient in need thereof an effective amount of a compound of the invention.
  • the condition is a condition that can be prevented or treated by the inhibition of cathepsin K.
  • the invention relates to a method of selectively inhibiting cathepsin K activity in a patient which comprises administering to a patient in need thereof an effective amount of a compound of the invention.
  • the invention relates to the use of a compound of the invention in the preparation of a medicament for the treatment of a cathepsin dependent condition.
  • the condition is a condition that can be prevented or treated by the inhibition of cathepsin K.
  • unsubstituted means that there is no substituent or that the only substituents are hydrogen.
  • optionally substituted denotes that the group may or may not be further substituted or fused (so as to form a condensed polycyclic system), with one or more non-hydrogen substituent groups.
  • the group may be a terminal group or a bridging group. This is intended to signify that the use of the term is intended to encompass the situation where the group is a linker between two other portions of the molecule as well as where it is a terminal moiety.
  • alkyl alkyl
  • alkylene alkylene
  • examples of acyl include acetyl and benzoyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the carbonyl carbon.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
  • Alkenyl as a group or part of a group denotes an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched preferably having 2-12 carbon atoms, more preferably 2-10 carbon atoms, most preferably 2-6 carbon atoms, in the normal chain.
  • the group may contain a plurality of double bonds in the normal chain and the orientation about each is independently E or Z
  • the alkenyl group is preferably a 1 -alkenyl group.
  • Exemplary alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and nonenyl.
  • the group may be a terminal group or a bridging group.
  • alkenyloxy refers to an alkenyl-O- group in which alkenyl is as defined herein. Preferred alkenyloxy groups are d-C 6 alkenyloxy groups. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Alkyl as a group or part of a group refers to a straight or branched aliphatic hydrocarbon group, preferably a C 1 -C 12 alkyl, more preferably a Ci-Ci 0 alkyl, most preferably C C 6 unless otherwise noted.
  • suitable straight and branched C Cealkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl, hexyl, and the like.
  • the group may be a terminal group or a bridging group.
  • Alkylamino includes both mono-alkylamino and dialkylamino, unless specified.
  • Mono- alkylamino means an Alkyl-NH- group, in which alkyl is as defined herein.
  • Dialkylamino means a (alkyl) 2 N- group, in which each alkyl may be the same or different and are each as defined herein for alkyl.
  • the alkyl group is preferably a C Cealkyl group.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the carbonyl carbon.
  • Alkyloxy refers to an alkyl-O- group in which alkyl is as defined herein.
  • the alkyloxy is a Ci-C 6 alkyloxy. Examples include, but are not limited to, methoxy and ethoxy.
  • the group may be a terminal group or a bridging group.
  • Alkyloxyalkyl refers to an alkyloxy-alkyl- group in which the alkyloxy and alkyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
  • Alkyloxyaryl refers to an alkyloxy-aryl- group in which the alkyloxy and aryl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the aryl group.
  • the alkyl group is preferably a C Cealkyl group. Examples include, but are not limited to, methoxycarbonyl and ethoxycarbonyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the carbonyl carbon.
  • Alkyloxycycloalkyl refers to an alkyloxy-cycloalkyl- group in which the alkyloxy and cycloalkyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the cycloalkyl group.
  • Alkyloxyheteroaryl refers to an alkyloxy-heteroaryl- group in which the alkyloxy and heteroaryl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroaryl group.
  • Alkyloxyheterocycloalkyl refers to an alkyloxy-heterocycloalkyl- group in which the alkyloxy and heterocycloalkyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heterocycloalkyl group.
  • the alkyl group is preferably a C Cealkyl group.
  • Exemplary alkylsulfinyl groups include, but not limited to, methylsulfinyl and ethylsulfinyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
  • the alkyl group is preferably a C Cealkyl group. Examples include, but not limited to methylsulfonyl and ethylsulfonyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
  • Alkynyl as a group or part of a group means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched preferably having from 2-12 carbon atoms, more preferably 2-10 carbon atoms, more preferably 2-6 carbon atoms in the normal chain. Exemplary structures include, but are not limited to, ethynyl and propynyl. The group may be a terminal group or a bridging group. "Alkynyloxy” refers to an alkynyl-O- group in which alkynyl is as defined herein.
  • alkynyloxy groups are CVCealkynyloxy groups.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Aminoalkyl means an NH 2 -alkyl- group in which the alkyl group is as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
  • Aryl as a group or part of a group denotes (i) an optionally substituted monocyclic, or fused polycyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) preferably having from 5 to 12 atoms per ring.
  • aryl groups include phenyl, naphthyl, and the like; (ii) an optionally substituted partially saturated bicyclic aromatic carbocyclic moiety in which a phenyl and a C 5 . 7 cycloalkyl or C 5 . 7 cycloalkenyl group are fused together to form a cyclic structure, such as tetrahydronaphthyl, indenyl or indanyl.
  • the group may be a terminal group or a bridging group.
  • an aryl group is a C 6 -Ci 8 aryl group.
  • Arylalkenyl means an aryl-alkenyl- group in which the aryl and alkenyl are as defined herein.
  • exemplary arylalkenyl groups include phenylallyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.
  • Arylalkyl means an aryl-alkyl- group in which the aryl and alkyl moieties are as defined herein. Preferred arylalkyl groups contain a d- 5 alkyl moiety. Exemplary arylalkyl groups include benzyl, phenethyl, 1 -naphthalenemethyl and 2-naphthalenemethyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
  • Arylalkyloxy refers to an aryl-alkyl-O- group in which the alkyl and aryl are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Arylamino includes both mono-arylamino and di-arylamino unless specified.
  • Mono-arylamino means a group of formula arylNH-, in which aryl is as defined herein.
  • Di-arylamino means a group of formula (aryl) 2 N- where each aryl may be the same or different and are each as defined herein for aryl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
  • Arylheteroalkyl means an aryl-heteroalkyl- group in which the aryl and heteroalkyi moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyi group.
  • Aryloxy refers to an aryl-O- group in which the aryl is as defined herein. Preferably the aryloxy is a C 6 -Ci 8 aryloxy, more preferably a C 6 -Ci 0 aryloxy.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
  • a “bond” is a linkage between atoms in a compound or molecule.
  • the bond may be a single bond, a double bond, or a triple bond.
  • Cycloalkenyl means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and preferably having from 5-10 carbon atoms per ring.
  • Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.
  • the cycloalkenyl group may be substituted by one or more substituent groups.
  • a cycloalkenyl group typically is a C 3 -C 12 alkenyl group. The group may be a terminal group or a bridging group.
  • Cycloalkyl refers to a saturated monocyclic or fused or spiro polycyclic, carbocycle preferably containing from 3 to 9 carbons per ring, such as cydopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified. It includes monocyclic systems such as cydopropyl and cyclohexyl, bicyclic systems such as decalin, and polycyclic systems such as adamantane.
  • a cycloalkyl group typically is a C 3 -Ci 2 alkyl group. The group may be a terminal group or a bridging group.
  • Cycloalkylalkyl means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are as defined herein.
  • Exemplary monocycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
  • Cycloalkylalkenyl means a cycloalkyl-alkenyl- group in which the cycloalkyl and alkenyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.
  • Cycloalkylheteroalkyl means a cycloalkyl-heteroalkyl- group in which the cycloalkyl and heteroalkyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.
  • Cycloalkyloxy refers to a cycloalkyl-O- group in which cycloalkyl is as defined herein.
  • the cycloalkyloxy is a CVCeCycloalkyloxy. Examples include, but are not limited to, cyclopropanoxy and cyclobutanoxy.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Cycloalkenyloxy refers to a cycloalkenyl-O- group in which the cycloalkenyl is as defined herein.
  • the cycloalkenyloxy is a CVCeCycloalkenyloxy.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • "Haloalkyl” refers to an alkyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom selected from the group consisting of fluorine, chlorine, bromine and iodine.
  • a haloalkyl group typically has the formula C n H (2 n + i-m ) Xm whereineach X is independently selected from the group consisting of F, CI, Br and I.
  • n is typically from 1 to 10, more preferably from 1 to 6, most preferably 1 to 3.
  • m is typically 1 to 6, more preferably 1 to 3.
  • haloalkyl include fluoromethyl, difluoromethyl and trifluoromethyl.
  • Haloalkenyl refers to an alkenyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom independently selected from the group consisting of F, CI, Br and I.
  • Haloalkynyl refers to an alkynyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom independently selected from the group consisting of F, CI, Br and I.
  • Halogen represents chlorine, fluorine, bromine or iodine.
  • Heteroalkyl refers to a straight- or branched-chain alkyl group preferably having from 2 to 12 carbons, more preferably 2 to 6 carbons in the chain, in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced by a heteroatomic group selected from S, O, P and NR' where R' is selected from the group consisting of H, optionally substituted CrC ⁇ alkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 6 -C 18 aryl, and optionally substituted CrC 18 heteroaryl.
  • heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, and the like.
  • heteroalkyl also include hydroxyCrCealkyl, d-CealkyloxyC Cealkyl, aminoCrCealkyl, d-CealkylaminoC Cealkyl, and d C Cealky aminoCrCealkyl.
  • the group may be a terminal group or a bridging group.
  • Heteroalkyloxy refers to a heteroalkyl-O- group in which heteroalkyl is as defined herein. Preferably the heteroalkyloxy is a C 2 -C 6 heteroalkyloxy.
  • the group may be a terminal group or a bridging group.
  • Heteroaryl either alone or part of a group refers to groups containing an aromatic ring
  • the group may be a monocyclic or bicyclic heteroaryl group.
  • heteroaryl examples include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, tetrazole, indole, isoindole, 1 H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isooxazole, furazane, pheno
  • Heteroarylalkyl means a heteroaryl-alkyl group in which the heteroaryl and alkyl moieties are as defined herein. Preferred heteroarylalkyl groups contain a lower alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
  • Heteroarylalkenyl means a heteroaryl-alkenyl- group in which the heteroaryl and alkenyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.
  • Heteroarylheteroalkyl means a heteroaryl-heteroalkyl- group in which the heteroaryl and heteroalkyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.
  • Heteroaryloxy refers to a heteroaryl-O- group in which the heteroaryl is as defined herein.
  • the heteroaryloxy is a CVC ⁇ heteroaryloxy.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Heterocyclic refers to saturated, partially unsaturated or fully unsaturated monocyclic, bicyclic or polycyclic ring system containing at least one heteroatom selected from the group consisting of nitrogen, sulfur and oxygen as a ring atom.
  • heterocyclic moieties include heterocycloalkyl, heterocycloalkenyl and heteroaryl.
  • Heterocycloalkenyl refers to a heterocycloalkyl group as defined herein but containing at least one double bond.
  • a heterocycloalkenyl group typically is a C 2 -C 12 heterocycloalkenyl group.
  • the group may be a terminal group or a bridging group.
  • Heterocycloalkyl refers to a saturated monocyclic, bicyclic, or polycyclic ring containing at least one heteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms in at least one ring. Each ring is preferably from 3 to 10 membered, more preferably 4 to 7 membered.
  • heterocycloalkyi substituents examples include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1 ,3-diazapane, 1 ,4-diazapane, 1 ,4-oxazepane, and 1 ,4-oxathiapane.
  • a heterocycloalkyi group typically is a C 2 -C 12 heterocycloalkyl group. The group may be a terminal group or a bridging group.
  • Heterocycloalkylalkyl refers to a heterocycloalkyl-alkyl- group in which the heterocycloalkyi and alkyl moieties are as defined herein.
  • exemplary heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl) methyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
  • Heterocycloalkylalkenyl refers to a heterocycloalkyl-alkenyl- group in which the heterocycloalkyi and alkenyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.
  • Heterocycloalkylheteroalkyl means a heterocycloalkyl-heteroalkyl- group in which the heterocycloalkyi and heteroalkyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.
  • Heterocycloalkyloxy refers to a heterocycloalkyl-O- group in which the heterocycloalkyi is as defined herein.
  • the heterocycloalkyloxy is a CrCeheterocycloalkyloxy.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Heterocycloalkenyloxy refers to a heterocycloalkenyl-O- group in which heterocycloalkenyl is as defined herein.
  • the Heterocycloalkenyloxy is a Ci-C 6 Heterocycloalkenyloxy.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • HydroalkyI refers to an alkyl group as defined herein in which one or more of the hydrogen atoms has been replaced with an OH group.
  • a hydroxyalkyl group typically has the formula C n H (2 Trouble + i. X) (OH) x .
  • n is typically from 1 to 10, more preferably from 1 to 6, most preferably 1 to 3.
  • x is typically 1 to 6, more preferably 1 to 3.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
  • isomeric forms including diastereoisomers, enantiomers, tautomers, and geometrical isomers in "P or "Z configurational isomer or a mixture of E and Z isomers. It is also understood that some isomeric forms such as diastereomers, enantiomers, and geometrical isomers can be separated by physical and/or chemical methods and by those skilled in the art. For those compounds where there is the possibility of geometric isomerism the applicant has drawn the isomer that the compound is thought to be although it will be appreciated that the other isomer may be the correct structural assignment.
  • Some of the compounds of the disclosed embodiments may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and /or diastereomers. All such single stereoisomers, racemates and mixtures thereof, are intended to be within the scope of the subject matter described and claimed.
  • Formula (I) is intended to cover, where applicable, solvated as well as unsolvated forms of the compounds.
  • each formula includes compounds having the indicated structure, including the hydrated as well as the non-hydrated forms.
  • pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the above-identified compounds, and include pharmaceutically acceptable acid addition salts and base addition salts.
  • Suitable pharmaceutically acceptable acid addition salts of compounds of Formula (I) may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, sulfuric, and phosphoric acid.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propanoic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, fumaric, maleic, alkyl sulfonic, arylsulfonic.
  • base addition salts may be prepared by ways well known in the art using organic or inorganic bases.
  • suitable organic bases include simple amines such as methylamine, ethylamine, triethylamine and the like.
  • suitable inorganic bases include NaOH, KOH, and the like.
  • nitrogen protecting group means a group that can prevent the nitrogen moiety reacting during further derivatisation of the protected compound and which can be readily removed when desired.
  • the protecting group is removable in the physiological state by natural metabolic processes.
  • suitable nitrogen protecting groups include formyl, trityl, phthalimido, acetyl, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl ; urethane-type blocking groups such as benzyloxycarbonyl ( ⁇ '), 4- phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4- fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2- chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbony
  • the actual nitrogen protecting group employed is not critical so long as the derivatised nitrogen group is stable to the condition of subsequent reaction(s) and can be selectively removed as required without substantially disrupting the remainder of the molecule including any other nitrogen protecting group(s).
  • Further examples of these groups are found in: Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis, Second edition; Wiley-lnterscience: 1991 ; Chapter 7; McOmie, J. F. W. (ed.), Protective Groups in Organic Chemistry, Plenum Press, 1973; and Kocienski, P. J., Protecting Groups, Second Edition, Thieme Medical Pub. , 2000.
  • terapéuticaally effective amount or “effective amount” is an amount sufficient to effect beneficial or desired clinical results.
  • An effective amount can be administered in one or more administrations.
  • An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state.
  • V 1 , V , V 3 , R , R , R , R s , n and m are as described above.
  • V 1 may be either C or N; and V 2 and V 3 are independently selected from the group consisting of CR 6 , N and NR 6 ; wherein if V 1 is C then at least one of V 2 and V 3 is N or NR 6 ,wherein R 6 is as described above.
  • V 1 is C; and V 2 is NR 6 ; and V 3 is CR 6 . In some embodiments, V 1 is C; and V 2 is NR 6 ; and V 3 is N. In some embodiments, V 1 is C; and V 2 is N; and V 3 is NR 6 . In some embodiments, V 1 is N; and V 2 is CR 6 , and V 3 is N. In some embodiments, V 1 is N; and V 2 is N, and V 3 is CR 6 . In some embodiments, V 1 is C; and V 2 is CR 6 ; and V 3 is NR 6 . In some embodiments, V 1 is N; and V 2 is NR 6 , and V 3 is CR 6 .
  • V 1 is N; and V 2 is NR 6 ; and V 3 is N. In some embodiments, V 1 is N; and V 2 is N; and V 3 is N. In some embodiments, V 1 is C; and V 2 is NR 6 ; and V 3 is CR 6 wherein R 6 is H.
  • V 1 is C; and V 2 is NR 6 ; and V 3 is N.
  • V 1 is N; and V 2 is CR 6 , and V 3 is N.
  • the point of attachment to the indole ring may be at any of the attachment points on the 6 membered ring.
  • the point of attachment is at the 4 position.
  • the point of attachment is at the 5 position.
  • the point of attachment is at the 6 position.
  • the point of attachment is at the 7 position.
  • the point of attachment is at the 5 position.
  • n is an integer selected from the group consisting of 1 , 2, and 3. In some embodiments n is 1 . In some embodiments n is 2. In some embodiments n
  • n 1 which provides compounds of formula (2a):
  • n 2 which provides compounds of formula (2b):
  • each R 1 and R 2 are independently selected from the group consisting of hydrogen, Ci.CealkyI and C ⁇ Cehaloalkyl, or R 1 and R 2 when taken together with the carbon atom to which they are attached form a C 3 .C 8 cycloalkyl group;
  • R 1 is H. In certain embodiments R 1 is Ci_C 6 alkyl. In certain embodiments R 1 is C ⁇ Cehaloalkyl. In certain embodiments R 2 is H. In certain embodiments R 2 is Ci_C 6 alkyl. In certain embodiments R 2 is C ⁇ .C 6 haloalkyl.
  • R 1 and R 2 examples of suitable values for R 1 and R 2 are H, methyl, fluoromethyl, difluoromethyl and trifluoromethyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl, pentyl, and hexyl.
  • R 1 and R 2 are both H.
  • R 1 and R 2 are both methyl.
  • R 1 and R 2 when taken together with the carbon atom to which they are attached form a C 3 .C 8 cycloalkyl group.
  • C 3 .C 8 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • R 1 and R 2 when taken together with the carbon atom to which they are attached form a cyclopropyl group.
  • R 1 and R 2 when taken together with the carbon atom to which they are attached form a cyclobutyl group.
  • R 1 and R 2 when taken together with the carbon atom to which they are attached form a cyclopentyl group.
  • R 1 and R 2 when taken together with the carbon atom to which they are attached form a cyclohexyl group. In certain embodiments R 1 and R 2 when taken together with the carbon atom to which they are attached form a cycloheptyl group. In certain embodiments R 1 and R 2 when taken together with the carbon atom to which they are attached form a cyclooctyl group.
  • n 1 and R 1 and R 2 are both H which provides compounds of formula (3a):
  • n 2 and each R 1 and R 2 are H which provides compounds of formula (3b):
  • R 3 is selected from the group consisting of hydrogen, optionally substituted Ci.Cealkyl and C ⁇ Cehaloalkyl. In certain embodiments R 3 is H. In certain embodiments R 3 is optionally substituted Ci.C 6 alkyl. In certain embodiments R 3 is Ci_ C 6 haloalkyl.
  • R 4 is selected from the group consisting of hydrogen and optionally substituted Ci.C 6 alkyl. In certain embodiments R 4 is H. In certain embodiments R 4 is optionally substituted Chalky!
  • R 3 and R 4 examples of suitable values for R 3 and R 4 are H, methyl, fluoromethyl, difluoromethyl and trifluoromethyl, ethyl, isopropyl, 2-fluoro-2-methyl propyl, propyl, 2-ethyl-propyl, 3,3- dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl, pentyl, and hexyl.
  • R 3 is H and R 4 is optionally substituted Ci.C 6 alkyl.
  • R 3 and R 4 when taken together with the carbon atom to which they are attached form a C 3 .C 8 cycloalkyl group.
  • suitable C 3 .C 8 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cydohexyl, cycloheptyl and cyclooctyl.
  • R 3 and R 4 when taken together with the carbon atom to which they are attached form a cyclopropyl group.
  • R 3 and R 4 when taken together with the carbon atom to which they are attached form a cyclobutyl group.
  • R 3 and R 4 when taken together with the carbon atom to which they are attached form a cyclopentyl group. In certain embodiments R 3 and R 4 when taken together with the carbon atom to which they are attached form a cydohexyl group. In certain embodiments R 3 and R 4 when taken together with the carbon atom to which they are attached form a cycloheptyl group. In certain embodiments R 3 and R 4 when taken together with the carbon atom to which they are attached form a cyclooctyl group.
  • n 1 , R 1 , R 2 and R 3 are H which provides compounds of formula (4a):
  • n is 2 and each R 1 , R 2 and R 3 are H which provid
  • R 5 is selected from the group consisting of hydrogen, halogen, OH, N0 2 , CN, S0 2 H, S0 2 Ci.C 6 alkyl, SH, NH 2 , Ci.C 6 alkyl, d.Cghaloalkyl, Ci.C 6 alkyloxy and C ⁇ Cehaloalkyloxy.
  • R 5 is hydrogen. In certain embodiments R 5 is Halogen. In certain embodiments R 5 is OH. In certain embodiments R 5 is N0 2 . In certain embodiments R 5 is CN. In certain embodiments R 5 is S0 2 H. In certain embodiments R 5 is S0 2 Ci-C 6 alkyl. In certain embodiments R 5 is SH. In certain embodiments R 5 is NH 2 . In certain embodiments R 5 is Ci_ C 6 alkyl. In certain embodiments R 5 is Ci_C 6 haloalkyl. In certain embodiments R 5 is Ci_ C 6 alkyloxy. In certain embodiments R 5 is C ⁇ Cehaloalkyloxy.
  • R 5 examples include H, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2- ethyl-butyl, pentyl, 2-methyl, pentyl, and hexyl.
  • m is an integer selected from the group consisting of 0, 1 , 2, and 3. In certain embodiments m is 0. In certain embodiments m is 1 . In certain embodiments m is 2. In certain embodiments m is 3.
  • n 1 , R 1 , R 2 , and R 3 are H and m is 0 which provides compounds of formula (5a):
  • R 6 is optionally substituted d-d 2 alkyl.
  • suitable values for R 6 of this type are methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl, pentyl, and hexyl.
  • R 6 is optionally substituted C 2 -C 12 heteroalkyl.
  • the C 2 -C 12 heteroalkyl group is selected from the group consisting of hydroxy, C C 6 alkyl, d-CealkyloxyC Cealkyl, aminoCrCealkyl, d-CealkylaminoC Cealkyl, and di(Cr Cealky aminoCrCealkyl.
  • R 6 as C 2 -C 12 heteroalkyl examples include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, methoxymethyl, 2- methoxyethyl, 3-methoxypropyl, 2-ethoxyethyl, 3-ethoxypropyl, aminomethyl, 2-aminoethyl, 3- aminopropyl, 4-aminobutyl, 5 aminopentyl, methylaminomethyl, 2-methylaminoethyl, 3- methylaminopropyl, 4-methylaminobutyl, 5-methylaminopentyl, ethylaminomethyl, 2- ethylaminoethyl, 3-ethylaminopropyl, 4-ethylaminobutyl, 5-ethylaminopentyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethyl
  • R 6 is S0 2 R 7 , wherein R 7 is as defined above. In some embodiments R 6 is S0 2 R 7 , and R 7 is optionally substituted C Cealkyl. Examples of groups of this type are S0 2 CH 3 and S0 2 CH 2 CH 3 . In some embodiments R 6 is S0 2 R 7 , and R 7 is optionally substituted C Cearyl. Examples of groups of this type are S0 2 Ph and S0 2 PhMe.
  • R 7 is H.
  • R 7 is optionally substituted Ci -Ci 2 alkyl.
  • suitable values for R 7 of this type are methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl, pentyl, and hexyl.
  • R 7 is optionally substituted C 3 -C 12 cycloalkyl. Examples of suitable values for R 7 of this type arecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • R 7 is optionally substituted C 6 -Ci 8 aryl.
  • suitable values for R 7 of this type are benzyl, phenyl, p-tolyl and naphthyl.
  • R 7 is optionally substituted CVC ⁇ heteroaryl.
  • suitable values for R 7 of this type are thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, tetrazole, indole, isoindole, 1 H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazole,
  • each optional substituent is independently selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3, CI, Br, F, I, OH, N0 2 , NH 2 , CN, OCH 3 , OCH 2 CH 2 CH 3 , CF 3 , and OCF 3 .
  • two optional substituents on the same moiety when taken together may be joined to form a fused cyclic substituent attached to the moiety that is optionally substituted.
  • optionally substituted includes a fused ring such as a cycloalkyi ring, a heterocycloalkyl ring, an aryl ring or a heteroaryl ring.
  • the embodiments disclosed are also directed to pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of such compounds, and pharmaceutically acceptable salts of such metabolites.
  • the invention also relates to pharmaceutical compositions including a compound of the invention and a pharmaceutically acceptable carrier, diluent or excipient.
  • the compounds of the invention are inhibitors of cathepsin K and therefore have the ability to inhibit these enzymes.
  • the ability to inhibit the enzymes may be a result of the compounds acting directly and solely on the enzyme to modulate/potentiate biological activity. However, it is understood that the compounds may also act at least partially on other factors associated with the activity of the enzyme.
  • the inhibition of cathepsin K may be carried out in any of a number of ways known in the art. For example if inhibition in vitro is desired an appropriate amount of the compound may be added to a solution containing the cathepsin K. In circumstances where it is desired to inhibit cathepsin K in a mammal, the inhibition of the cathepsin K typically involves administering the compound to a mammal containing the cathepsin K.
  • the present invention provides a method of prevention or treatment of a condition in a mammal, the method comprising administering an effective amount of a compound of the invention.
  • the condition is a condition that can be treated by inhibition of cathepsin K.
  • the invention provides the use of a compound of the invention in the preparation of a medicament for the treatment of a condition in a mammal. In one embodiment the condition is a condition that can be treated by inhibition of cathepsin K.
  • the invention provides the use of a compound of the invention in the treatment of a condition in a mammal.
  • the condition is a condition that can be treated by inhibition of cathepsin K.
  • the condition is selected from the group consisting of osteoporosis, glucocorticoid induced osteoporosis, Paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, bone fractures, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignancy, and multiple myeloma.
  • condition is bone disease. In some embodiments the condition is osteoporosis.
  • Administration of compounds within Formula (I) to humans can be by any of the accepted modes for enteral administration such as oral or rectal, or by parenteral administration such as subcutaneous, intramuscular, intravenous and intradermal routes. Injection can be bolus or via constant or intermittent infusion.
  • the active compound is typically included in a pharmaceutically acceptable carrier or diluent and in an amount sufficient to deliver to the patient a therapeutically effective dose.
  • the compounds of the invention they can be administered in any form or mode which makes the compound bioavailable.
  • One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular characteristics of the compound selected, the condition to be treated, the stage of the condition to be treated and other relevant circumstances. We refer the reader to Remingtons Pharmaceutical Sciences, 19 th edition, Mack Publishing Co. (1995) for further information.
  • the compounds of the present invention can be administered alone or in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, diluent or excipient.
  • a pharmaceutically acceptable carrier diluent or excipient.
  • the compounds of the invention while effective themselves, are typically formulated and administered in the form of their pharmaceutically acceptable salts as these forms are typically more stable, more easily crystallised and have increased solubility.
  • the present invention provides a pharmaceutical composition including a compound of Formula (I) and a pharmaceutically acceptable carrier, diluent or excipient.
  • the compositions are prepared in manners well known in the art.
  • the invention in other embodiments provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. In such a pack or kit can be found a container having a unit dosage of the agent(s).
  • kits can include a composition comprising an effective agent either as concentrates (including lyophilized compositions), which can be diluted further prior to use or they can be provided at the concentration of use, where the vials may include one or more dosages.
  • an effective agent either as concentrates (including lyophilized compositions), which can be diluted further prior to use or they can be provided at the concentration of use, where the vials may include one or more dosages.
  • single dosages can be provided in sterile vials so that the physician can employ the vials directly, where the vials will have the desired amount and concentration of agent(s).
  • Associated with such container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
  • the compounds of the invention may be used or administered in combination with one or more additional drug(s) for the treatment of the disorder/diseases mentioned.
  • the components can be administered in the same formulation or in separate formulations. If administered in separate formulations the compounds of the invention may be administered sequentially or simultaneously with the other drug(s).
  • the compounds of the invention may be used in a combination therapy. When this is done the compounds are typically administered in combination with each other. Thus one or more of the compounds of the invention may be administered either simultaneously (as a combined preparation) or sequentially in order to achieve a desired effect. This is especially desirable where the therapeutic profile of each compound is different such that the combined effect of the two drugs provides an improved therapeutic result.
  • compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of micro-organisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminium monostearate and gelatin.
  • the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and gly
  • compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
  • the active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3- butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifier
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Dosage forms for topical administration of a compound of this invention include powders, patches, sprays, ointments and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants which may be required.
  • the amount of compound administered will preferably treat and reduce or alleviate the condition.
  • a therapeutically effective amount can be readily determined by an attending diagnostician by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining the therapeutically effective amount a number of factors are to be considered including but not limited to, the species of animal, its size, age and general health, the specific condition involved, the severity of the condition, the response of the patient to treatment, the particular compound administered, the mode of administration, the bioavailability of the preparation administered, the dose regime selected, the use of other medications and other relevant circumstances.
  • a preferred dosage will be a range from about 0.01 to 300 mg per kilogram of body weight per day.
  • a more preferred dosage will be in the range from 0.1 to 100 mg per kilogram of body weight per day, more preferably from 0.2 to 80 mg per kilogram of body weight per day, even more preferably 0.2 to 50 mg per kilogram of body weight per day.
  • a suitable dose can be administered in multiple sub-doses per day.
  • the agents of the various embodiments may be prepared using the reaction routes and synthesis schemes as described below, employing the techniques available in the art using starting materials that are readily available.
  • the preparation of particular compounds of the embodiments is described in detail in the following examples, but the artisan will recognize that the chemical reactions described may be readily adapted to prepare a number of other agents of the various embodiments.
  • the synthesis of non-exemplified compounds may be successfully performed by modifications apparent to those skilled in the art, e.g. by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions.
  • a list of suitable protecting groups in organic synthesis can be found in T.W.
  • Mass spectra were obtained on single quadruple 6120 LCMS from Agilent technologies, using either atmospheric chemical ionization (APCI) or Electrospray ionization (ESI) or in the combination of these two sources. All samples were run on SHIMADZU system with an LC-20 AD pump, SPD-M20A diode array detector, SIL-20A auto sampler.
  • APCI atmospheric chemical ionization
  • ESI Electrospray ionization
  • the aqueous was extracted with ethyl acetate (3x25 mL), washed the extracted organics with water (1 x25 mL).
  • the organic layer was separated and dried over anhydrous Na 2 S0 4 , concentrated the organics under vacuum to get 80% of the N-alkylated-5-bromo Indole. This material was pure enough to take it to the next stage.
  • Step 2 Synthesis of N-alkyl lndole-5-carboxylic acid
  • N-alkylated- 5-bromo Indole (2.5 g, 9.83 mmol) in 25 mL of anhydrous THF, which was cooled to -70 to -75 S C (dry ice/acetone) under nitrogen atmosphere, was added 15 mL of 2.5M n-butyl lithium in over a period of 15-20 mins.
  • the reaction mixture was stirred at the same temperature for 30-45 mins. Dry carbon dioxide gas passed to reaction mass at -70 to -75 S C for about 15 mins to ensure the reaction completion. LCMS of the aliquot was checked to monitor the progress of the reaction. The reaction was complete and hence worked-up.
  • the pH of the reaction mixture was adjusted to 2-3 using 3N HCI (aqueous) at-70 to -75 S C. Allowed to attain room temperature and extracted the reaction mixture with ethyl acetate (2x40 mL). The ethyl acetate layer was separated and washed with water (40 mL). The organics were separated, dried over anhydrous sodium sulfate and the volatiles were distilled off under vacuum to get slurry. The slurry was washed a twice with 10 mL portions of petroleum ether to get solid which was filtered off to get the pure labelled compounds in 30% yield as solid. This was characterised by 1 H NMR, LCMS and HPLC before using for the next steps.
  • the aqueous layer was extracted with (3x 25 mL) ethyl acetate.
  • the organic layer was separated, washed with (1 x 10 mL) water.
  • the separated organic layer was dried over anhydrous sodium sulfate; evaporation of the volatiles gave the desired product in 60-80% yields. This product was consumed for the next reactions without further purifications.
  • the aqueous layer was acidified with 1 N HCI and the aqueous layer was extracted with ethyl acetate (2 x 10 mL).
  • the pooled organic layers were washed with water (2 x 5 mL) and brine (1 x 5 mL), dried and filtered to get 0.05 g (yield: 90.07%) of 4-methyl-2-(1-(methylsulfonyl)-1 H-indole-5- carboxamido)pentanoic acid as pale yellow solid.
  • Step 1 To a 100 mL RB Flask containing anhydrous t-butyl methyl ether (MTBE) under nitrogen, pyridine. HF (3.6 mL, 138.67 mmol) was added cooled at -10 to -20 S C (ice/salt mixture) then isobutylene oxide (6.15 ml_,69.3 mmol) added drop wise over 20 min. The resulting solution was warmed to RT and stirred for 18 h. The reaction was followed by TLC. The reaction mixture was quenched slowly with 16 g of aq. K 2 C0 3 (pH 8). The organic layer was separated, aqueous layer again washed with MTBE.
  • HF 3.6 mL, 138.67 mmol
  • Step 2 To a solution of 2-fluoro-2-methylpropan-1 -ol (4.5 g, 48.85 mmol) and Et 3 N (10.30 ml_,73.28 mmol) in dry dichloromethane (45 mL), at -20 °C was added trifluoromethane sulfonic anhydride (9.08 mL, 53.74 mmol) drop wise. The resulting brown solution was stirred at -20 s C(dry ice/acetone) for 2 h. The reaction was followed by TLC, after completion, reaction mix was diluted with dichloromethane and quenched with 25 mL of 1 N HCI solution.
  • Step 3 To a 500 mL three neck RB flask equipped with a distillation and a Dean-Stark separator, benzophenone (20 g, 109.8 mmol), glycine ethyl ester Hydrochloride (15.32 g, 109.8 mmol), p-toluenesulfonic acid (0.522 g, 2.745 mmol) and 400 mL of toluene were added. The mixture was heated at 1 15 S C with stirring to get a good reflux in toluene. Finally N, N- diisopropyl ethyl amine (14.4 mL, 82.35 mmole) was added using a dropping funnel over 45 min.
  • Step 4 To a 100 mL 2-neck Flask with nitrogen balloon, was taken Ethyl-2- (diphenylmethyleneamino) acetate (9.0 g, 33.67 mmol) and dry DMF (30 mL) then solution was cooled to 0 S C. To this was added solid KOtBu (4.15 g, 37.03 mmol) in small portions. The resulting red-orange solution was stirred for 15 min, and then treated with 2-fluoro-2- methylpropyl trifluoromethane sulfonate (8.3 g, 37.03 mmol) in dry DMF (15 mL) drop wise at the same temperature. The contents were allowed to stir at room temperature for 20 h.
  • reaction mixture was monitored by TLC. Once the reaction was complete, the reaction mixture was poured into a separating funnel containing ethyl acetate (200 mL) and saturated aqueous NH 4 CI solution (50 mL). The organic layer was separated, washed once with water (100 mL) and brine, dried over Na 2 S0 4 filtered and concentrated under vacuum. The crude material was purified by flash chromatography. Ethyl-2-(diphenylmethyleneamino) -4-fluoro-4- methylpentanoate was analysed by LCMS it showed only 48% of required product. This material was used for the next step without further purification.
  • Step 5 To a solution of Ethyl-2-(diphenylmethyleneamino) -4-fluoro-4-methylpentanoate (5 g, 14.64 mmol) in MTBE (30 mL) at 0 S C wasadded 1 N aqueous HCI (29.28 mL, 29.2 mmol)drop wise. The resulting solution was then warmedto room temperature and stirred for 20 h. The reaction wasmonitored by LCMS showed complete consumption of starting material.
  • Step 1 N-methylated-5 Methyl 1 H-indazole-5-carboxylic acid
  • the product was extracted with ethyl acetate (2x20 mL).
  • the ethyl acetate extracts were separated washed with (1x20 mL) water, separated the organics, dried over anhydrous sodium sulphate and distilled off the volatiles under reduced pressure to get the crude product.
  • This crude material was subjected to purification using combiflash at 40% ethyl acetate: 60%Hexane as a mobile phase to yield Leucine coupled N- methylated-5 Methyl 1 H-indazole-5-carboxamide. Isomers were separated but not characterized. The pure materials thus obtained yielded 80%, as such taken it to the next stage.
  • Step-4 Coupling To a 50 mL single neck RB flask material from step 3 (0.3 g, 0.85 mmol), was added 2- Aminoacetonitrile hydrochloride (57 mg, 0.85 mmol), HATU (0.323 g, 0.85 mmol) and DMF (8 mL). The contents were stirred for 5mins. After clear solution formation DI PEA (0.16 mL, 1 .70 mmol) was added and the reaction mass stirred for 16 h at 20-30 °C. After 16 h, the completion of the reaction was confirmed by TLC/LCMS, and worked-up. Ice-cold water (20 mL) was added slowly to the reaction mixture with stirring.
  • the product was extracted with ethyl acetate (2x20 mL).
  • the ethyl acetate extracts were separated washed with (1 x20 mL) water, separated the organics, dried over anhydrous sodium sulphate and distilled off the volatiles under reduced pressure to get the crude product.
  • This crude material was subjected to purification using preparative RP HPLC. The pure material thus obtained yielded 30-40% yield of the product of desired purity.
  • Step 1 Ethyl 2-(H-imidazo[1 ,5-a]pyridine-7-carboxamido)-4-methylpentanoate synthesis To a 50 mL single neck RB flask starting 1 H-lmidazol (1 ,5-a)pyridine-7-carboxylic acid
  • Step 2 2-lmidazole (1 ,5-a)Pyridine-7-carboxamido)-4-methylpentanoic acid
  • Step3 N-(Cyanomethyl)-2-( ⁇ imidazo[1 ,5-a]pyridin-7-yl ⁇ formamido)-4-methylpentanamide
  • Step 1 Ethyl 4-methyl-2-[(quinolin-6-yl)formamido]pentanoate
  • the product was extracted with ethyl acetate (2x20 ml_).
  • the ethyl acetate extracts were separated washed with (1 x20 ml_) water, separated the organics, dried over anhydrous sodium sulphate and distilled off the volatiles under reduced pressure to get the crude product.
  • This crude material was subjected to purification using preparative RP HPLC.
  • the pure material thus obtained yielded 50-60% yield of the product of desired purity.
  • the compounds outlined in Table 1 were synthesized following the procedures outlined above or variations thereof typically by variation of the starting materials used.
  • Standard assay conditions for the determination of kinetic constants used a fluorogenic peptide substrate, typically (5S,8S)-13- amino-5-benzyl-13-imino-3-methylene-N-(4-methyl-2-oxo-2H-chromen-7-yl)-6-oxo-1 -phenyl-2- oxa-4,7, 12-triazatridecane-8-carboxamide (Cbz-Phe-Arg-AMC) for Cat K and were determined in 50 mM sodium acetate at pH 5.5 containing 1 m M dithiothreitol, 2.5 mM EDTA and 0.01 % TritinX-1 00.
  • a fluorogenic peptide substrate typically (5S,8S)-13- amino-5-benzyl-13-imino-3-methylene-N-(4-methyl-2-oxo-2H-chromen-7-yl)-6-oxo-1 -phenyl-2- oxa-4,7, 12-triazatridecane
  • the substrate used was benzyl N-[1 -[[5- (diam inomethylideneamino)-1 -[(4-methyl-2-oxochromen-7-yl)amino]-1 -oxopentan-2-yl]amino]-4- methyl-1 -oxopentan-2-yl]carbamate (Cbz-Leu-Arg-AMC).
  • a stock substrate solution of Cbz- Phe-Arg-AMC or Cbz-Leu-Arg-AMC was prepared at a concentration of 50 mM in dimethyl sulfoxide. This substrate was diluted into the assay for a final substrate concentration of 10 ⁇ in all the assays.
  • the Km value for Cbz-Phe-Arg-AMC on human Cat K is 12 ⁇ .
  • the Km value for Cbz-Leu-Arg-AMC on human Cat S is 32 ⁇ , on human Cat L is 4 ⁇ and on human cathepsin V is 7 ⁇ .
  • the total reaction time was 60 min for human Cat K, L and V (final protein concentrations were 0.3 nM, 0.1 nM and 5 nM respectively) ; for human Cat S it was 30 min (final protein concentration was 1 .25 nM).
  • Prior to the addition of substrate different concentrations of the inhibitor ranging from
  • a stock substrate solution of Cbz-Phe-Arg-AMC was prepared at a concentration of 50 mM in dimethyl sulfoxide. This substrate was diluted into the assay for a final substrate concentration of 30 ⁇ in the rat cathepsin K assay.
  • the Km value for Cbz-Phe-Arg-AMC on rat cathepsin K is 27 ⁇ .
  • the total reaction time was 120 min for rat Cat K (final protein concentrations was 50 nM).
  • Osteoclast precursor basal medium (OPBM) was supplemented by adding the FBS, L-glutamine, penicillin and streptomycin to final concentrations of 10%, 2 mM, 100 units/ml and 100 mg/ml respectively.
  • Media were refreshed after 7 days with and without drug (inhibitor), and the culture was terminated on day 10. Aliquots from media were collected for measuring CTx (CrossLaps®, IDS, Fountain Hills, AZ, USA) and Ca+2 release (Biovision, USA).
  • a stock of 1 mM of the test compound is prepared in 100% DMSO from a 50mM stock (in 100% DMSO). This 1 mM solution is used for spectrum scan from 200 nm to 400 nm with increment of 1 nm to identify wavelength maxima of test compound. A standard curve was plotted by using serial dilution of 1 mM stock in a 96-well plate and measuring absorbance at the A max of the test compound. To 1 ml of PBS, 0ul of 50mM stock of test compound was added and kept under mixing condition at 50rpm overnight at 25°C.
  • test solution was filtered using 0.45 ⁇ PVDF injector filters, and 150 ⁇ of the flow through was used for quantification using UV-Vis spectrophotometer at respective A max value.
  • the aqueous solubility is calculated based on observed absorbance from the standard plot.
  • the compounds of the invention have been demonstrated to be superior to known inhibitors of cathepsin K.
  • a representative compound has a selectivity of >1000 fold over CatL and CatS, whereas its selectivity is >100 fold with respect to CatV.
  • Known inhibitors lack >1000 fold selectivity wrt CatS compared with a known inhibitor.
  • CatS inhibition could be a safety concern since CatS is also responsible for antigen presentation. CatS inhibition is expected to result in immunosupression, and therefore the representative compound is superior in this regard.
  • the representative compound and a known inhibitor were dosed in healthy rats.
  • C max levels in Rats at the same dose(10 mg/kg) is 3 fold higher for the representative compound, yielding a C max /CatK (rat IC 50 ) that is ⁇ 2 fold higher for the representative compound compared to a known inhibitor.
  • This may be significant to the pharmacodynamic translation in an animal model.
  • the solubility of the representative compound is far superior to a known inhibitor; a 20- fold improvement, resulting in 5-fold better bioavailability in rats (52% vs. 10%).
  • the improved solubility and bio-availability may help in developing a simpler oral formulation for the representative compound leading to cost advantage.
  • LogD 74 of the representative compound is ⁇ 2, so it is less lipophilic and has better absorption profile.
  • the representative compound is also metabolically more stable in human microsomes as compared to a known inhibitor.
  • the known inhibitor has a Cyp2D6 liability whereas the representative compound does not have the same liability, thus has a lower potential for any DDIs.
  • the plasma protein binding which relates to the free fraction also differs and is favourable for the representative compound.
  • the representative compound has about 50% free fraction while the known inhibitor has only 8% free fraction and the rest seems to be plasma protein bound.
  • the representative compound could be dosed as once a day regimen, while the known inhibitor has a longer half-life compound and is being dosed once a week. With the cost advantage, superior PK profile, stability and selectivity, the representative compound demonstrates a clear advantage over known inhibitors.
  • CTx-1 C-terminal telopeptide (or more formally, carboxy-terminal collagen crosslinks), is a telopeptide generated from Collagen type 1 by the action of CatK, used as a biomarker in the serum to measure the rate of bone turnover/CatK activity.
  • Osteocalcin is secreted solely by osteoblasts & is often used as a marker for the bone formation process.
  • P1 NP amino-terminal propeptide (PINP), sensitive marker of bone formation.
  • Body weight gain Ovariectomy is manifested by increase in body weight.
  • Toxicity evaluation Necropsy after treatment & visual observation during treatment. Study Design:
  • Age, Weight 12-13 weeks of age at study, 220-260g
  • Compound#1 showed dose dependant reduction in CTx-1 levels after 3 weeks when compared to untreated OVX animals.

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Abstract

The present invention relates to substituted bicyclic heteroaryl amide derivatives that are inhibitors of cathepsin K proteases and which are therefore useful in the treatment of certain disorders that can be prevented or treated by inhibition of these enzymes. In addition, the invention relates to the compounds, methods for their preparation, pharmaceutical compositions containing the compounds and the uses of these compounds in the treatment of certain disorders. It is expected that the compounds of the invention will find application in the treatment of bone diseases such as osteoporosis and osteoarthritis as well as other diseases and conditions. The compounds have the general formula: [Formula should be inserted here]

Description

BICYCLIC HETEROARYL AMIDES AS
CATHEPSIN CYSTEINE PROTEASE INHIBITORS
FIELD OF THE INVENTION
The present invention relates to substituted bicyclic heteroaryl amide derivatives that are inhibitors of cathepsin K proteases and which are therefore useful in the treatment of certain disorders that can be prevented or treated by inhibition of these enzymes. In addition, the invention relates to the compounds, methods for their preparation, pharmaceutical compositions containing the compounds and the uses of these compounds in the treatment of certain disorders. It is expected that the compounds of the invention will find application in the treatment of bone diseases such as osteoporosis and osteoarthritis as well as other diseases and conditions.
BACKGROUND OF THE INVENTION
Cathepsins belong to the papain superfamily of cysteine proteases, which share a common papain-like structural fold and a conserved catalytic Cys-His-Asn triad. These proteases function in the normal physiological as well as pathological degradation of connective tissue. Cathepsins play a major role in intracellular protein degradation and turnover and remodelling. To date, a number of cathepsins have been identified and sequenced from a number of sources. These cathepsins are naturally found in a wide variety of tissues. There are currently 1 1 of these cathepsins known in human, that is, cathepsin (Cat) B, H, L, S, C, K, O, F, V, X and W. Cathepsin K (which is also known by the abbreviation cat K) is also known as cathepsin O and cathepsin 02. See PCT Application WO 96/13523, Khepri Pharmaceuticals, Inc., and published May 9, 1996, which is hereby incorporated by reference in its entirety. Cathepsin L is implicated in normal lysosomal proteolysis as well as several diseases states, including, but not limited to, metastasis of melanomas. Cathepsin S is implicated in Alzheimer's disease and certain autoimmune disorders, including, but not limited to juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves' disease, myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis and Hashimoto's thyroiditis; allergic disorders, including but not limited to asthma; and allogenic immune responses, including but not limited to, rejection of organ transplants or tissue grafts. Increased cathepsin B levels and redistribution of the enzyme are found in tumours, suggesting a role in tumour invasion and metastasis. In addition, aberrant cathepsin B activity is implicated in such disease states as rheumatoid arthritis, osteoarthritis, pneumocystosis carinii, acute pancreatitis, inflammatory airway disease and bone and joint disorders.
A variety of disorders in humans and other mammals involve are associated with abnormal bone resorption. Such disorders include but are not limited to, osteoporosis, glucocorticoid induced osteoporosis, Paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, bone fractures, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignancy, and multiple myeloma. One of the most common of these disorders is osteoporosis, which in its most frequent manifestation occurs in postmenopausal women. Osteoporotic fractures are a major cause of morbidity and mortality in the elderly population. As many as 50% of women and a third of men will experience an osteoporotic fracture. A large segment of the older population already has low bone density and a high risk of fractures. There is a significant need to both prevent and treat osteoporosis and other conditions associated with bone resorption. Because osteoporosis, as well as other disorders associated with bone loss, is generally a chronic condition, it is believed that appropriate therapy will typically require chronic treatment.
Osteoporosis is characterized by progressive loss of bone architecture and mineralization leading to the loss in bone strength and an increased fracture rate. The skeleton is constantly being remodelled by a balance between osteoblasts that lay down new bone and osteoclasts that breakdown, or resorb, bone. In some disease conditions and advancing age the balance between bone formation and resorption is disrupted; bone is removed at a faster rate. Such a prolonged imbalance of resorption over formation leads to weaker bone structure and a higher risk of fractures.
Bone resorption is primarily performed by osteoclasts, which are multinuclear giant cells. Osteoclasts resorb bone by forming an initial cellular attachment to bone tissue, followed by the formation of an extracellular compartment or lacunae. The lacunae are maintained at a low pH by a proton-ATP pump. Acid secretion subsequently dissolves the inorganic content of bone, mainly calcium phosphate. The exposed organic bone matrix composed primarily of type I collagen is then degraded by proteases. The osteoclast-specific localization and high expression level of Cat K suggest that this cysteine protease plays a critical role in bone matrix degradation. See Delaisse, J. M. et al, 1980, Biochem J 192:365-368; Delaisse, J. et al, 1984, Biochem Biophys Res Commun:441 -447; Delaisse, J. M. et al. , 1987, Bone 8:305-313, which are hereby incorporated by reference in their entirety. Collagen constitutes 95% of the organic matrix of bone. Therefore, proteases involved in collagen degradation are an essential component of bone turnover, and as a consequence, the development and progression of osteoporosis. Cysteine protease inhibitors such as E-64 (trans-epoxysuccinyl-L- leucylamide-(4- guanidino) butane) are known to be effective in inhibiting bone resorption. See Delaisse, J. M. et al., 1987, Bone 8:305-313, which is hereby incorporated by reference in its entirety. Recently, cathepsin K was cloned and found specifically expressed in osteoclasts See Tezuka, K. et al., 1994, J Biol Chem 269:1 106-1 109; Shi, G. P. et al.,1995, EEES Lett 357: 129-134; Bromme, D. and Okamoto, K., 1995, Biol Chem Hoppe Seyler 376:379-384; Bromme, D. et al, 1996, J Biol Chem 271 :2126-2132: Drake, F. H. et al, 1996, J Biol Chem 271 :1251 1 - 12516, which are hereby incorporated by reference in their entirety. Concurrent to the cloning, the autosomal recessive disorder, pycnodysostosis, characterized by an osteoporotic phenotype with a decrease in bone resorption, was mapped to mutations present in the cathepsin K gene. To date, all mutations identified in the cathepsin K gene are known to result in inactive protein. See Gelb, B. D. et al., 1996, Science 273:1236-1238; Johnson, M. R. et al., 1996, Genome Res 6:1050-1055, which are hereby incorporated by reference in their entirety. Therefore, it appears that cathepsin K is involved in osteoclast mediated bone resorption.
Cathepsin K is synthesized as a 37 kDa pre-pro enzyme, which is localized to the lysosomal compartment and where it is presumably autoactivated to the mature 27 kDa enzyme at low pH. See McQueney, M. S. et al., 1997, J Biol Chem 272:13955-13960; Littlewood- Evans, A. et al, 1997, Bone 20:81 -86, which are hereby incorporated by reference in their entirety. Cathepsin K is most closely related to cathepsin S having 56 % sequence identity at the amino acid level. The S2P2 substrate specificity of cathepsin K is similar to that of cathepsin S with a preference in the P1 and P2 positions for a positively charged residue such as arginine, and a hydrophobic residue such as phenylalanine or leucine, respectively. See Bromme, D. et al. , 1996, J Biol Chem 271 : 2126-2132; Bossard, M. J. et al, 1996, J Biol Chem 271 :12517- 12524, which are hereby incorporated by reference in their entirety. Cathepsin K is active at a broad pH range with significant activity between pH 4-8, thus allowing for good catalytic activity in the resorption lacunae of osteoclasts where the pH is about 4-5. Human type I collagen, the major collagen in bone is a good substrate for cathepsin K.
See Kafienah, W., et al, 1998, Biochem J 331 :727-732, which is hereby incorporated by reference in its entirety. In vitro experiments using antisense oligonucleotides to cathepsin K, have shown diminished bone resorption in vitro, which is probably due to a reduction in translation of cathepsin K mRNA. See Inui, T., et al, 1997, Biol Chem 272:8109-81 12, which is hereby incorporated by reference in its entirety. The crystal structure of cathepsin K has been resolved. See McGrath, M. E., et al, 1997, Nat Struct Biol 4:105-109; Zhao, B., et al, 1997, Nat Struct Biol 4: 109-1 1 , which are hereby incorporated by reference in their entirety. Also, selective peptide based inhibitors of cathepsin K have been developed See Bromme, D., et al, 1996, Biochem 315:85-89; Thompson, S. K., et al, 1997, Proc Natl Acad Sci U S A 94: 14249- 14254, which are hereby incorporated by reference in their entirety. Accordingly, inhibitors of cathepsin K can reduce bone resorption. Such inhibitors would be useful in treating disorders involving bone resorption, such as osteoporosis. SUMMARY OF INVENTION
In one aspect, the present invention provides compounds that are inhibitors of cathepsin K. These compounds would be expected to be useful in the treatment of conditions that can be treated by inhibition of these proteases.
In a further aspect, the present invention provides a pharmaceutical composition containing a compound that is an inhibitor of cathepsin K and a pharmaceutically acceptable excipient, diluent or carrier. In further aspect, the present invention provides a method of prevention or treatment of a condition that can be treated by inhibition of cathepsin K in a mammal.
The applicants have discovered a class of compounds which have activity as inhibitors of cathepsin K. This activity may be by way of one or more of selectivity over CatL, CatS, and CatV; potency; solubility; metabolic stability; or dosage profile.
The present invention provides a compound of formula (I)
Figure imgf000005_0001
(I)
wherein each R1 is independently selected from the group consisting of hydrogen, C^.C6 alkyl and C^C haloalkyl, each R2 is independently is selected from the group consisting of hydrogen, C^.C6 alkyl and C6 haloalkyl, or
R1 and R2 when taken together with the carbon atoms to which they are attached form a C3.C| cycloalkyl group; R3 is selected from the group consisting of hydrogen, optionally substituted d-C6 alkyl and C6 haloalkyl,
R4 is selected from the group consisting of hydrogen and optionally substituted d-C6 alkyl, or
R3 and R4 when taken together with the carbon atoms to which they are attached form a C3-C8 cycloalkyl group; each R5 is independently selected from the group consisting of hydrogen, halogen, OH, N02, CN, SH, NH2, Ci-C6 alkyl, d_C6 haloalkyl, d_C6 alkyloxy and d_C6 haloalkyloxy;
V1 is C or N, and
V2 and V3 are independently selected from the group consisting of CR6, N and NR6, and wherein if V1 is C then at least one of V2 and V3 is N or NR6; each R6 is independently selected from the group consisting of H, optionally substituted Cr C12alkyl, optionally substituted C2-C12alkenyl, optionally substituted C2-C12alkynyl, optionally substituted d-C^haloalkyl, optionally substituted C2-C12heteroalkyl, optionally substituted C3- Ci2cycloalkyl, optionally substituted C3-Ci2cycloalkenyl, optionally substituted C2- C12heterocycloalkyl, optionally substituted C2-C12heterocycloalkenyl, optionally substituted C6- C18aryl, optionally substituted CrC18heteroaryl, optionally substituted C6-C18aryld-C12alkyl, optionally substituted d-d8heteroaryld -d2alkyl, S03H, S02NR7R7, S02R7, SONR7R7, SOR7, COR7, COOH, COOR7, CONR7R7, acyl, and a nitrogen protecting group; each R7 is independently selected from the group consisting of H, optionally substituted d_C6 alkyl, optionally substituted C3-C12cycloalkyl, optionally substituted C6-C18aryl and optionally substituted d-d8heteroaryl; m is an integer selected from the group consisting of 0, 1 , 2 and 3; n is an integer selected from the group consisting of 1 and 2; or a pharmaceutically acceptable salt thereof.
In a further aspect the invention relates to a pharmaceutical composition containing a compound of the invention and a pharmaceutically acceptable diluent, excipient or carrier. In yet an even further aspect the invention relates to a method of treating a cathepsin dependent condition in a patient which comprises administering to a patient in need thereof an effective amount of a compound of the invention. In one embodiment the condition is a condition that can be prevented or treated by the inhibition of cathepsin K.
In yet an even further aspect the invention relates to a method of selectively inhibiting cathepsin K activity in a patient which comprises administering to a patient in need thereof an effective amount of a compound of the invention.
In yet an even further aspect the invention relates to the use of a compound of the invention in the preparation of a medicament for the treatment of a cathepsin dependent condition. In one embodiment the condition is a condition that can be prevented or treated by the inhibition of cathepsin K.
These and other teachings of the invention are set forth herein.
DETAILED DESCRIPTION OF THE INVENTION
In this specification a number of terms are used which are well known to a skilled addressee. Nevertheless for the purposes of clarity a number of terms will be defined.
As used herein, the term "unsubstituted" means that there is no substituent or that the only substituents are hydrogen. The term "optionally substituted" as used throughout the specification denotes that the group may or may not be further substituted or fused (so as to form a condensed polycyclic system), with one or more non-hydrogen substituent groups. In certain embodiments the substituent groups are one or more groups independently selected from the group consisting of halogen, =0, =S, -CN, -N02, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkenyl, heterocycloalkylalkenyl, arylalkenyl, heteroarylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, arylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkyloxy, alkyloxyalkyl, alkyloxycycloalkyl, alkyloxyheterocycloalkyl, alkyloxyaryl, alkyloxyheteroaryl, alkyloxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl, arylsulfinyl, aminosulfinylaminoalkyl, -C(=0)OH, -C(=0)Re, -C(=0)ORe, C(=0)NReRf, C(=NOH)Re, C(=NRe)NRfR9, NReRf, NReC(=0)Rf, NReC(=0)ORf, NReC(=0)NRfR9, NReC(=NRf)NR9Rh, NReS02Rf, -SRe, S02NReRf, -ORe OC(=0)NReRf, OC(=0)Re and acyl, wherein Re, Rf, R9 and Rh are each independently selected from the group consisting of
H, Ci-Ci2alkyl, Ci-Ci2 aloalkyl, C2-Ci2alkenyl, C2-Ci2alkynyl, C1-C10 heteroalkyl, C3- C12cycloalkyl, C3-C12cycloalkenyl, d-C12heterocycloalkyl, d-C12heterocycloalkenyl, C6-C18aryl, Ci -Ci8heteroaryl, and acyl, or any two or more of Ra, Rb, Rc and Rd, when taken together with the atoms to which they are attached form a heterocyclic ring system with 3 to 12 ring atoms.
In some embodiments each optional substituent is independently selected from the group consisting of: halogen, =0, =S, -CN, -N02, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkyloxy, alkyloxyalkyl, alkyloxyaryl, alkyloxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, -COOH, -SH, and acyl. Examples of particularly suitable optional substituents include F, CI, Br, I, CH3, CH2CH3,
OH, OCH3, C02H, C02CH3, S02H, S02CH3, CF3, OCF3, N02, NH2, and CN.
In the definitions of a number of substituents below it is stated that "the group may be a terminal group or a bridging group". This is intended to signify that the use of the term is intended to encompass the situation where the group is a linker between two other portions of the molecule as well as where it is a terminal moiety. Using the term alkyl as an example, some publications would use the term "alkylene" for a bridging group and hence in these other publications there is a distinction between the terms "alkyl" (terminal group) and "alkylene" (bridging group). In the present application no such distinction is made and most groups may be either a bridging group or a terminal group.
"Acyl" means an R-C(=0)- group in which the R group may be an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group as defined herein. Examples of acyl include acetyl and benzoyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the carbonyl carbon.
"Acylamino" means an R-C(=0)-NH- group in which the R group may be an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
"Alkenyl" as a group or part of a group denotes an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched preferably having 2-12 carbon atoms, more preferably 2-10 carbon atoms, most preferably 2-6 carbon atoms, in the normal chain. The group may contain a plurality of double bonds in the normal chain and the orientation about each is independently E or Z The alkenyl group is preferably a 1 -alkenyl group. Exemplary alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and nonenyl. The group may be a terminal group or a bridging group.
"Alkenyloxy" refers to an alkenyl-O- group in which alkenyl is as defined herein. Preferred alkenyloxy groups are d-C6alkenyloxy groups. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
"Alkyl" as a group or part of a group refers to a straight or branched aliphatic hydrocarbon group, preferably a C1-C12 alkyl, more preferably a Ci-Ci0 alkyl, most preferably C C6 unless otherwise noted. Examples of suitable straight and branched C Cealkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl, hexyl, and the like. The group may be a terminal group or a bridging group.
"Alkylamino" includes both mono-alkylamino and dialkylamino, unless specified. "Mono- alkylamino" means an Alkyl-NH- group, in which alkyl is as defined herein. "Dialkylamino" means a (alkyl)2N- group, in which each alkyl may be the same or different and are each as defined herein for alkyl. The alkyl group is preferably a C Cealkyl group. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
"Alkylaminocarbonyl" refers to a group of the formula (Alkyl)x(H)yNC(=0)- in which alkyl is as defined herein, x is 1 or 2, and the sum of X+Y =2. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the carbonyl carbon.
"Alkyloxy" refers to an alkyl-O- group in which alkyl is as defined herein. Preferably the alkyloxy is a Ci-C6alkyloxy. Examples include, but are not limited to, methoxy and ethoxy. The group may be a terminal group or a bridging group. "Alkyloxyalkyl" refers to an alkyloxy-alkyl- group in which the alkyloxy and alkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
"Alkyloxyaryl" refers to an alkyloxy-aryl- group in which the alkyloxy and aryl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the aryl group. "Alkyloxycarbonyl" refers to an alkyl-0-C(=0)- group in which alkyl is as defined herein.
The alkyl group is preferably a C Cealkyl group. Examples include, but are not limited to, methoxycarbonyl and ethoxycarbonyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the carbonyl carbon.
"Alkyloxycycloalkyl" refers to an alkyloxy-cycloalkyl- group in which the alkyloxy and cycloalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the cycloalkyl group.
"Alkyloxyheteroaryl" refers to an alkyloxy-heteroaryl- group in which the alkyloxy and heteroaryl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroaryl group.
"Alkyloxyheterocycloalkyl" refers to an alkyloxy-heterocycloalkyl- group in which the alkyloxy and heterocycloalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heterocycloalkyl group.
"Alkylsulfinyl" means an alkyl-S-(=0)- group in which alkyl is as defined herein. The alkyl group is preferably a C Cealkyl group. Exemplary alkylsulfinyl groups include, but not limited to, methylsulfinyl and ethylsulfinyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
"Alkylsulfonyl" refers to an alkyl-S(=0)2- group in which alkyl is as defined above. The alkyl group is preferably a C Cealkyl group. Examples include, but not limited to methylsulfonyl and ethylsulfonyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
"Alkynyl" as a group or part of a group means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched preferably having from 2-12 carbon atoms, more preferably 2-10 carbon atoms, more preferably 2-6 carbon atoms in the normal chain. Exemplary structures include, but are not limited to, ethynyl and propynyl. The group may be a terminal group or a bridging group. "Alkynyloxy" refers to an alkynyl-O- group in which alkynyl is as defined herein.
Preferred alkynyloxy groups are CVCealkynyloxy groups. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom. "Aminoalkyl" means an NH2-alkyl- group in which the alkyl group is as defined herein.
The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
"Aminosulfonyl" means an NH2-S(=0)2- group. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
"Aryl" as a group or part of a group denotes (i) an optionally substituted monocyclic, or fused polycyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) preferably having from 5 to 12 atoms per ring. Examples of aryl groups include phenyl, naphthyl, and the like; (ii) an optionally substituted partially saturated bicyclic aromatic carbocyclic moiety in which a phenyl and a C5.7cycloalkyl or C5.7cycloalkenyl group are fused together to form a cyclic structure, such as tetrahydronaphthyl, indenyl or indanyl. The group may be a terminal group or a bridging group. Typically an aryl group is a C6-Ci8aryl group.
"Arylalkenyl" means an aryl-alkenyl- group in which the aryl and alkenyl are as defined herein. Exemplary arylalkenyl groups include phenylallyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.
"Arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl moieties are as defined herein. Preferred arylalkyl groups contain a d-5alkyl moiety. Exemplary arylalkyl groups include benzyl, phenethyl, 1 -naphthalenemethyl and 2-naphthalenemethyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
"Arylalkyloxy" refers to an aryl-alkyl-O- group in which the alkyl and aryl are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
"Arylamino" includes both mono-arylamino and di-arylamino unless specified. Mono-arylamino means a group of formula arylNH-, in which aryl is as defined herein. Di-arylamino means a group of formula (aryl)2N- where each aryl may be the same or different and are each as defined herein for aryl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom. "Arylheteroalkyl" means an aryl-heteroalkyl- group in which the aryl and heteroalkyi moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyi group. "Aryloxy" refers to an aryl-O- group in which the aryl is as defined herein. Preferably the aryloxy is a C6-Ci8aryloxy, more preferably a C6-Ci0aryloxy. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom. "Arylsulfonyl" means an aryl-S(=0)2- group in which the aryl group is as defined herein.
The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
A "bond" is a linkage between atoms in a compound or molecule. The bond may be a single bond, a double bond, or a triple bond.
"Cycloalkenyl" means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and preferably having from 5-10 carbon atoms per ring. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl. The cycloalkenyl group may be substituted by one or more substituent groups. A cycloalkenyl group typically is a C3-C12alkenyl group. The group may be a terminal group or a bridging group. "Cycloalkyl" refers to a saturated monocyclic or fused or spiro polycyclic, carbocycle preferably containing from 3 to 9 carbons per ring, such as cydopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified. It includes monocyclic systems such as cydopropyl and cyclohexyl, bicyclic systems such as decalin, and polycyclic systems such as adamantane. A cycloalkyl group typically is a C3-Ci2alkyl group. The group may be a terminal group or a bridging group.
"Cycloalkylalkyl" means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are as defined herein. Exemplary monocycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
"Cycloalkylalkenyl" means a cycloalkyl-alkenyl- group in which the cycloalkyl and alkenyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.
"Cycloalkylheteroalkyl" means a cycloalkyl-heteroalkyl- group in which the cycloalkyl and heteroalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.
"Cycloalkyloxy" refers to a cycloalkyl-O- group in which cycloalkyl is as defined herein. Preferably the cycloalkyloxy is a CVCeCycloalkyloxy. Examples include, but are not limited to, cyclopropanoxy and cyclobutanoxy. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom. "Cycloalkenyloxy" refers to a cycloalkenyl-O- group in which the cycloalkenyl is as defined herein. Preferably the cycloalkenyloxy is a CVCeCycloalkenyloxy. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom. "Haloalkyl" refers to an alkyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom selected from the group consisting of fluorine, chlorine, bromine and iodine. A haloalkyl group typically has the formula CnH(2n+i-m)Xm whereineach X is independently selected from the group consisting of F, CI, Br and I. In groups of this type n is typically from 1 to 10, more preferably from 1 to 6, most preferably 1 to 3. m is typically 1 to 6, more preferably 1 to 3. Examples of haloalkyl include fluoromethyl, difluoromethyl and trifluoromethyl. "Haloalkenyl" refers to an alkenyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom independently selected from the group consisting of F, CI, Br and I.
"Haloalkynyl" refers to an alkynyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom independently selected from the group consisting of F, CI, Br and I.
"Halogen" represents chlorine, fluorine, bromine or iodine. "Heteroalkyl" refers to a straight- or branched-chain alkyl group preferably having from 2 to 12 carbons, more preferably 2 to 6 carbons in the chain, in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced by a heteroatomic group selected from S, O, P and NR' where R' is selected from the group consisting of H, optionally substituted CrC^alkyl, optionally substituted C3-C12cycloalkyl, optionally substituted C6-C18aryl, and optionally substituted CrC18 heteroaryl. Exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, and the like. Examples of heteroalkyl also include hydroxyCrCealkyl, d-CealkyloxyC Cealkyl, aminoCrCealkyl, d-CealkylaminoC Cealkyl, and d C Cealky aminoCrCealkyl. The group may be a terminal group or a bridging group.
"Heteroalkyloxy" refers to a heteroalkyl-O- group in which heteroalkyl is as defined herein. Preferably the heteroalkyloxy is a C2-C6heteroalkyloxy. The group may be a terminal group or a bridging group. "Heteroaryl" either alone or part of a group refers to groups containing an aromatic ring
(preferably a 5 or 6 membered aromatic ring) having one or more heteroatoms as ring atoms in the aromatic ring with the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include nitrogen, oxygen and sulfur. The group may be a monocyclic or bicyclic heteroaryl group. Examples of heteroaryl include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, tetrazole, indole, isoindole, 1 H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isooxazole, furazane, phenoxazine, 2-, 3- or 4- pyridyl, 2-, 3-, 4-, 5-, or 8- quinolyl, 1 -, 3-, 4-, or 5- isoquinolinyl 1 -, 2-, or 3- indolyl, and 2-, or 3-thienyl. A heteroaryl group is typically a CVC^heteroaryl group. The group may be a terminal group or a bridging group.
"Heteroarylalkyl" means a heteroaryl-alkyl group in which the heteroaryl and alkyl moieties are as defined herein. Preferred heteroarylalkyl groups contain a lower alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
"Heteroarylalkenyl" means a heteroaryl-alkenyl- group in which the heteroaryl and alkenyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.
"Heteroarylheteroalkyl" means a heteroaryl-heteroalkyl- group in which the heteroaryl and heteroalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.
"Heteroaryloxy" refers to a heteroaryl-O- group in which the heteroaryl is as defined herein. Preferably the heteroaryloxy is a CVC^heteroaryloxy. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
"Heterocyclic" refers to saturated, partially unsaturated or fully unsaturated monocyclic, bicyclic or polycyclic ring system containing at least one heteroatom selected from the group consisting of nitrogen, sulfur and oxygen as a ring atom. Examples of heterocyclic moieties include heterocycloalkyl, heterocycloalkenyl and heteroaryl.
"Heterocycloalkenyl" refers to a heterocycloalkyl group as defined herein but containing at least one double bond. A heterocycloalkenyl group typically is a C2-C12heterocycloalkenyl group. The group may be a terminal group or a bridging group.
"Heterocycloalkyl" refers to a saturated monocyclic, bicyclic, or polycyclic ring containing at least one heteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms in at least one ring. Each ring is preferably from 3 to 10 membered, more preferably 4 to 7 membered. Examples of suitable heterocycloalkyi substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1 ,3-diazapane, 1 ,4-diazapane, 1 ,4-oxazepane, and 1 ,4-oxathiapane. A heterocycloalkyi group typically is a C2-C12heterocycloalkyl group. The group may be a terminal group or a bridging group.
"Heterocycloalkylalkyl" refers to a heterocycloalkyl-alkyl- group in which the heterocycloalkyi and alkyl moieties are as defined herein. Exemplary heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl) methyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
"Heterocycloalkylalkenyl" refers to a heterocycloalkyl-alkenyl- group in which the heterocycloalkyi and alkenyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.
"Heterocycloalkylheteroalkyl" means a heterocycloalkyl-heteroalkyl- group in which the heterocycloalkyi and heteroalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.
"Heterocycloalkyloxy" refers to a heterocycloalkyl-O- group in which the heterocycloalkyi is as defined herein. Preferably the heterocycloalkyloxy is a CrCeheterocycloalkyloxy. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
"Heterocycloalkenyloxy" refers to a heterocycloalkenyl-O- group in which heterocycloalkenyl is as defined herein. Preferably the Heterocycloalkenyloxy is a Ci-C6 Heterocycloalkenyloxy. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
"HydroxyalkyI" refers to an alkyl group as defined herein in which one or more of the hydrogen atoms has been replaced with an OH group. A hydroxyalkyl group typically has the formula CnH(2„+i.X)(OH)x. In groups of this type n is typically from 1 to 10, more preferably from 1 to 6, most preferably 1 to 3. x is typically 1 to 6, more preferably 1 to 3. "Sulfinyl" means an R-S(=0)- group in which the R group may be OH, alkyl, cycloalkyl, heterocycloalkyl; aryl or heteroaryl group as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
"Sulfinylamino" means an R-S(=0)-NH- group in which the R group may be OH, alkyl, cycloalkyl, heterocycloalkyl; aryl or heteroaryl group as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
"Sulfonyl" means an R-S(=0)2- group in which the R group may be OH, alkyl, cycloalkyl, heterocycloalkyl; aryl or heteroaryl group as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
"Sulfonylamino" means an R-S(=0)2-NH- group. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom. It is understood that included in the family of compounds of Formula (I) are isomeric forms including diastereoisomers, enantiomers, tautomers, and geometrical isomers in "P or "Z configurational isomer or a mixture of E and Z isomers. It is also understood that some isomeric forms such as diastereomers, enantiomers, and geometrical isomers can be separated by physical and/or chemical methods and by those skilled in the art. For those compounds where there is the possibility of geometric isomerism the applicant has drawn the isomer that the compound is thought to be although it will be appreciated that the other isomer may be the correct structural assignment.
Some of the compounds of the disclosed embodiments may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and /or diastereomers. All such single stereoisomers, racemates and mixtures thereof, are intended to be within the scope of the subject matter described and claimed.
Additionally, Formula (I) is intended to cover, where applicable, solvated as well as unsolvated forms of the compounds. Thus, each formula includes compounds having the indicated structure, including the hydrated as well as the non-hydrated forms. The term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the above-identified compounds, and include pharmaceutically acceptable acid addition salts and base addition salts. Suitable pharmaceutically acceptable acid addition salts of compounds of Formula (I) may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, sulfuric, and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propanoic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, fumaric, maleic, alkyl sulfonic, arylsulfonic. In a similar vein base addition salts may be prepared by ways well known in the art using organic or inorganic bases. Examples of suitable organic bases include simple amines such as methylamine, ethylamine, triethylamine and the like. Examples of suitable inorganic bases include NaOH, KOH, and the like. Additional information on pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995. In the case of agents that are solids, it is understood by those skilled in the art that the inventive compounds, agents and salts may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulae.
The term "nitrogen protecting group" means a group that can prevent the nitrogen moiety reacting during further derivatisation of the protected compound and which can be readily removed when desired. In one embodiment the protecting group is removable in the physiological state by natural metabolic processes. Examples of suitable nitrogen protecting groups that may be used include formyl, trityl, phthalimido, acetyl, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl ; urethane-type blocking groups such as benzyloxycarbonyl (ΌΒζ'), 4- phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4- fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2- chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3- bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, t- butoxycarbonyl ('t-Boc'), 2-(4-xenyl)-isopropoxycarbonyl, 1 ,1 -diphenyleth-1 -yloxycarbonyl, 1 ,1 - diphenylprop-1 -yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)-prop-2-yloxycarbonyl, cyclopentanyloxy-carbonyl, 1 -methylcyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1 - methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfono)- ethoxycarbonyl, 2-(methylsulfono)ethoxycarbonyl, 2-(triphenylphosphino)-ethoxycarbonyl, fluorenylmethoxycarbonyl ("Fmoc"), 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1 - (trimethylsilylmethyl)prop-l -enyloxycarbonyl, 5-benzisoxalylmethoxycarbonyl, 4- acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4-(decycloxy)benzyloxycarbonyl, isobornyloxycarbonyl, 1 - piperidyloxycarbonlyl, and the like; benzoylmethylsulfono group, 2-nitrophenylsulfenyl, diphenylphosphine oxide, and the like. The actual nitrogen protecting group employed is not critical so long as the derivatised nitrogen group is stable to the condition of subsequent reaction(s) and can be selectively removed as required without substantially disrupting the remainder of the molecule including any other nitrogen protecting group(s). Further examples of these groups are found in: Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis, Second edition; Wiley-lnterscience: 1991 ; Chapter 7; McOmie, J. F. W. (ed.), Protective Groups in Organic Chemistry, Plenum Press, 1973; and Kocienski, P. J., Protecting Groups, Second Edition, Thieme Medical Pub. , 2000. The term "therapeutically effective amount" or "effective amount" is an amount sufficient to effect beneficial or desired clinical results. An effective amount can be administered in one or more administrations. An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state.
As stated
Figure imgf000019_0001
(I)
or a pharmaceutically acceptable salt thereof; wherein V1 , V , V3, R , R , R , R , Rs, n and m are as described above.
As with any group of structurally related compounds which possess a particular utility, certain embodiments of variables of the compounds of the Formula (I), are particularly useful in their end use application.
In the compounds of the invention, V1 may be either C or N; and V2 and V3 are independently selected from the group consisting of CR6, N and NR6; wherein if V1 is C then at least one of V2 and V3 is N or NR6,wherein R6 is as described above.
In some embodiments, V1 is C; and V2 is NR6; and V3 is CR6. In some embodiments, V1 is C; and V2 is NR6; and V3 is N. In some embodiments, V1 is C; and V2 is N; and V3 is NR6. In some embodiments, V1 is N; and V2 is CR6, and V3 is N. In some embodiments, V1 is N; and V2is N, and V3 is CR6. In some embodiments, V1 is C; and V2 is CR6; and V3 is NR6. In some embodiments, V1 is N; and V2 is NR6, and V3 is CR6. In some embodiments, V1 is N; and V2 is NR6; and V3 is N. In some embodiments, V1 is N; and V2 is N; and V3 is N. In some embodiments, V1 is C; and V2 is NR6; and V3 is CR6 wherein R6 is H.This provides compounds of formula (la)
Figure imgf000020_0001
(la) or a pharmaceutically acceptable salt thereof; wherein R , R , R , R , R , R , n and m are as described above.
In some embodiments, V1 is C; and V2 is NR6; and V3 is N. This provides compounds of formula (lb)
Figure imgf000020_0002
(lb) or a pharmaceutically acceptable salt thereof; wherein R1 , R2, R3, R4, R5, R6, n and m are as described above. In some embodiments, V1 is C; and V2 is N; and V3 is NR6. This provides compounds of formula (lc)
Figure imgf000021_0001
(lc) or a pharmaceutically acceptable salt thereof; wherein R , R , R , R , R , R , n and m are as described above.
In some embodiments, V1 is N; and V2 is CR6, and V3 is N. This provides compounds of formula (Id)
Figure imgf000021_0002
(Id) or a pharmaceutically acceptable salt thereof; wherein R1 , R2, R3, R4, R5, R6, n and m are as described above. In the compounds of the invention the point of attachment to the indole ring may be at any of the attachment points on the 6 membered ring. In some embodiments the point of attachment is at the 4 position. In some embodiments the point of attachment is at the 5 position. In some embodiments the point of attachment is at the 6 position. In some embodiments the point of attachment is at the 7 position. In some embodiments of the compound of formula (la) the point of attachment is at the 5 position. This pro
Figure imgf000022_0001
(la" or a pharmaceutically acceptable salt thereof; wherein R1 , R2, R3, R4, R5, R6, n and m are as described above.
In some embodiments of the compound of formula (la) the point of attachment is at the 6 position. This provides compounds of formula (la"):
Figure imgf000022_0002
(la" or a pharmaceutically acceptable salt thereof; wherein R , R , R , R , R , R , n and m are as described above.
In the compounds of the invention n is an integer selected from the group consisting of 1 , 2, and 3. In some embodiments n is 1 . In some embodiments n is 2. In some embodiments n
In some embodiments of the compound of formula (la) n is 1 which provides compounds of formula (2a):
Figure imgf000023_0001
(2a) or a pharmaceutically acceptable salt thereof; wherein R1 , R2, R3, R4, R5, R6 and m are as described above, and the point of attachment is at the 4, 5, 6, or 7 position of the indole ring.
In some embodiments of the compound of formula (la) n is 2 which provides compounds of formula (2b):
Figure imgf000023_0002
(2b) or a pharmaceutically acceptable salt thereof; wherein R1 , R2, R3, R4, R5, R6 and m are as described above, and the point of attachment is at the 4, 5, 6, or 7 position of the indole ring.
In the compounds of the invention each R1 and R2 are independently selected from the group consisting of hydrogen, Ci.CealkyI and C^Cehaloalkyl, or R1 and R2 when taken together with the carbon atom to which they are attached form a C3.C8cycloalkyl group;
In certain embodiments R1 is H. In certain embodiments R1 is Ci_C6alkyl. In certain embodiments R1 is C^Cehaloalkyl. In certain embodiments R2 is H. In certain embodiments R2 is Ci_C6 alkyl. In certain embodiments R2 is C^.C6 haloalkyl. Examples of suitable values for R1 and R2 are H, methyl, fluoromethyl, difluoromethyl and trifluoromethyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl, pentyl, and hexyl. In some embodiments R1 and R2 are both H. In some embodiments R1 and R2 are both methyl. In certain embodiments R1 and R2 when taken together with the carbon atom to which they are attached form a C3.C8cycloalkyl group. Examples of suitable C3.C8cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. In certain embodiments R1 and R2 when taken together with the carbon atom to which they are attached form a cyclopropyl group. In certain embodiments R1 and R2 when taken together with the carbon atom to which they are attached form a cyclobutyl group. In certain embodiments R1 and R2 when taken together with the carbon atom to which they are attached form a cyclopentyl group. In certain embodiments R1 and R2 when taken together with the carbon atom to which they are attached form a cyclohexyl group. In certain embodiments R1 and R2 when taken together with the carbon atom to which they are attached form a cycloheptyl group. In certain embodiments R1 and R2 when taken together with the carbon atom to which they are attached form a cyclooctyl group.
In some embodiments of the compound of formula (la) n is 1 and R1 and R2 are both H which provides compounds of formula (3a):
Figure imgf000024_0001
or a pharmaceutically acceptable salt thereof; wherein R3, R4, R5, R6 and m are as described above, and the point of attachment is at the 4, 5, 6, or 7 position of the indole ring. In some embodiments of the compound of formula (la) n is 2 and each R1 and R2 are H which provides compounds of formula (3b):
Figure imgf000025_0001
(3b) or a pharmaceutically acceptable salt thereof; wherein R3, R4, R5, R6 and m are as described above, and the point of attachment is at the 4, 5, 6, or 7 position of the indole ring.
In the compounds of the invention R3 is selected from the group consisting of hydrogen, optionally substituted Ci.Cealkyl and C^Cehaloalkyl. In certain embodiments R3 is H. In certain embodiments R3 is optionally substituted Ci.C6alkyl. In certain embodiments R3 is Ci_ C6haloalkyl.
In the compounds of the invention R4 is selected from the group consisting of hydrogen and optionally substituted Ci.C6alkyl. In certain embodiments R4 is H. In certain embodiments R4 is optionally substituted Chalky!
Examples of suitable values for R3 and R4 are H, methyl, fluoromethyl, difluoromethyl and trifluoromethyl, ethyl, isopropyl, 2-fluoro-2-methyl propyl, propyl, 2-ethyl-propyl, 3,3- dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl, pentyl, and hexyl.
In certain embodiments R3 is H and R4 is optionally substituted Ci.C6alkyl.
In certain embodiments of the compounds of the invention R3 and R4 when taken together with the carbon atom to which they are attached form a C3.C8cycloalkyl group. Examples of suitable C3.C8cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cydohexyl, cycloheptyl and cyclooctyl. In certain embodiments R3 and R4 when taken together with the carbon atom to which they are attached form a cyclopropyl group. In certain embodiments R3 and R4 when taken together with the carbon atom to which they are attached form a cyclobutyl group. In certain embodiments R3 and R4 when taken together with the carbon atom to which they are attached form a cyclopentyl group. In certain embodiments R3 and R4 when taken together with the carbon atom to which they are attached form a cydohexyl group. In certain embodiments R3 and R4 when taken together with the carbon atom to which they are attached form a cycloheptyl group. In certain embodiments R3 and R4 when taken together with the carbon atom to which they are attached form a cyclooctyl group.
In some embodiments of the compound of formula (la) n is 1 , R1 , R2 and R3 are H which provides compounds of formula (4a):
Figure imgf000026_0001
(4a) or a pharmaceutically acceptable salt thereof; wherein R4, R5, R6 and m are as described above, and the point of attachment is at the 4, 5, 6, or 7 position of the indole ring.
In some embodiments of the compound of formula (la) n is 2 and each R1 , R2 and R3 are H which provid
Figure imgf000026_0002
(4b) or a pharmaceutically acceptable salt thereof; wherein R4, R5, R6 and m are as described above and the point of attachment is at the 4, 5, 6, or 7 position of the indole ring.
In the compounds of the invention R5 is selected from the group consisting of hydrogen, halogen, OH, N02, CN, S02H, S02Ci.C6alkyl, SH, NH2, Ci.C6alkyl, d.Cghaloalkyl, Ci.C6alkyloxy and C^Cehaloalkyloxy.
In certain embodiments R5 is hydrogen. In certain embodiments R5 is Halogen. In certain embodiments R5 is OH. In certain embodiments R5 is N02. In certain embodiments R5 is CN. In certain embodiments R5 is S02H. In certain embodiments R5 is S02Ci-C6alkyl. In certain embodiments R5 is SH. In certain embodiments R5 is NH2. In certain embodiments R5 is Ci_ C6alkyl. In certain embodiments R5 is Ci_C6haloalkyl. In certain embodiments R5 is Ci_ C6alkyloxy. In certain embodiments R5 is C^Cehaloalkyloxy.
Suitable examples of R5 include H, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2- ethyl-butyl, pentyl, 2-methyl, pentyl, and hexyl.
In the compounds of the invention m is an integer selected from the group consisting of 0, 1 , 2, and 3. In certain embodiments m is 0. In certain embodiments m is 1 . In certain embodiments m is 2. In certain embodiments m is 3.
In some embodiments of the compound of formula (la) n is 1 , R1 , R2, and R3 are H and m is 0 which provides compounds of formula (5a):
Figure imgf000027_0001
(5a) or a pharmaceutically acceptable salt thereof; wherein R4 and R6 are as described above and the point of attachment is at the 4, 5, 6, or 7 position of the indole ring.
In some embodiments of the compound of formula (la) n is 2, each R1 , R2, and R3 are H and m is 0 which provides compounds of formula (5b):
Figure imgf000028_0001
(5b) or a pharmaceutically acceptable salt thereof; wherein R4 and R6 are as described above and the point of attachment is at the 4, 5, 6, or 7 position of the indole ring.
In the compounds of the invention Reelected from the group consisting of H, optionally substituted CVC^alkyl, optionally substituted C2-C12alkenyl, optionally substituted C2-C12alkynyl, optionally substituted CVC^haloalkyl, optionally substituted C2-C12heteroalkyl, optionally substituted C3-C12cycloalkyl, optionally substituted C3-C12cycloalkenyl, optionally substituted C2- C12heterocycloalkyl, optionally substituted C2-C12heterocycloalkenyl, optionally substituted C6- C18aryl, optionally substituted CrC18heteroaryl, optionally substituted C6-C18aryld-C12alkyl, optionally substituted d-C18heteroaryld-C12alkyl S03H, S02NR7R7, S02R7, SONR7R7, SOR7, COR7, COOH, COOR7, CONR7R7,acyl,and a nitrogen protecting group; wherein each R7 is selected from the group consisting of H, optionally substituted d-dalkyl, optionally substituted C3-C12cycloalkyl, optionally substituted C6-C18aryl and optionally substituted d-d8heteroaryl.
In some embodiments R6 is optionally substituted d-d2alkyl. Examples of suitable values for R6 of this type are methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl, pentyl, and hexyl. In some embodiments R6 is optionally substituted C2-C12heteroalkyl. In some embodiments the C2-C12heteroalkyl group is selected from the group consisting of hydroxy, C C6alkyl, d-CealkyloxyC Cealkyl, aminoCrCealkyl, d-CealkylaminoC Cealkyl, and di(Cr Cealky aminoCrCealkyl. Examples of possible values of R6 as C2-C12heteroalkyl include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, methoxymethyl, 2- methoxyethyl, 3-methoxypropyl, 2-ethoxyethyl, 3-ethoxypropyl, aminomethyl, 2-aminoethyl, 3- aminopropyl, 4-aminobutyl, 5 aminopentyl, methylaminomethyl, 2-methylaminoethyl, 3- methylaminopropyl, 4-methylaminobutyl, 5-methylaminopentyl, ethylaminomethyl, 2- ethylaminoethyl, 3-ethylaminopropyl, 4-ethylaminobutyl, 5-ethylaminopentyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl, 5- dimethylaminopentyl, diethylaminomethyl, 2-diethylaminoethyl, 3-diethylaminopropyl, 4- diethylaminobutyl and 5-diethylaminopentyl.
In some embodiments R6 is S02R7, wherein R7 is as defined above. In some embodiments R6 is S02R7, and R7 is optionally substituted C Cealkyl. Examples of groups of this type are S02CH3 and S02CH2CH3. In some embodiments R6 is S02R7, and R7 is optionally substituted C Cearyl. Examples of groups of this type are S02Ph and S02PhMe.
In some embodiments R7 is H.
In some embodiments R7 is optionally substituted Ci -Ci2alkyl. Examples of suitable values for R7of this type are methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl, pentyl, and hexyl. In some embodiments R7 is optionally substituted C3-C12cycloalkyl. Examples of suitable values for R7 of this type arecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
In some embodiments R7 is optionally substituted C6-Ci8aryl. Examples of suitable values for R7 of this type are benzyl, phenyl, p-tolyl and naphthyl.
In some embodiments R7 is optionally substituted CVC^heteroaryl. Examples of suitable values for R7 of this type are thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, tetrazole, indole, isoindole, 1 H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isooxazole, furazane, phenoxazine, 2-, 3- or 4- pyridyl, 2-, 3-, 4-, 5-, or 8- quinolyl, 1 -, 3-, 4-, or 5- isoquinolinyl 1 -, 2-, or 3- indolyl, and 2-, or 3-thienyl.
Many if not all of the variables discussed above may be optionally substituted. If the variable is optionally substituted then in some embodiments each optional substituent is independently selected from the group consisting of halogen, =0, =S, -CN, -N02, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkenyl, heterocycloalkylalkenyl, arylalkenyl, heteroarylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, arylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkyloxy, alkyloxyalkyl, alkyloxycycloalkyl, alkyloxyheterocycloalkyi, alkyloxyaryl, alkyloxyheteroaryl, alkyloxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl, arylsulfinyl, aminosulfinylaminoalkyl, -C(=0)OH, -C(=0)Re, -C(=0)ORe, C(=0)NReRf, C(=NOH)Re, C(=NRe)NRfR9, NReRf, NReC(=0)Rf, NReC(=0)ORf, NReC(=0)NRfR9, NReC(=NRf)NR9Rh, NReS02Rf, -SRe, S02NReRf, -ORe OC(=0)NReRf, OC(=0)Re and acyl, wherein Re, Rf, R9 and Rh are each independently selected from the group consisting of H, d-C12alkyl, d-C12haloalkyl, C2-C12alkenyl, C2-C12alkynyl, d-C10 heteroalkyl, C3- C12cycloalkyl, C3-C12cycloalkenyl, d-C12heterocycloalkyl, d-C12 heterocycloalkenyl, C6-C18aryl, Ci -Ci8heteroaryl, and acyl, or any two or more of Ra, Rb, Rc and Rd, when taken together with the atoms to which they are attached form a heterocyclic ring system with 3 to 12 ring atoms.
In some embodiments each optional substituent is independently selected from the group consisting of: F, CI, Br, =0, =S, -CN, -N02, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkylamino, aminoalkyl, acylamino, phenoxy, alkoxyalkyl, benzyloxy, alkylsulfonyl, arylsulfonyl, aminosulfonyl, -C(0)ORa, COOH, SH, and acyl.
In some embodiments each optional substituent is independently selected from the group consisting of: F, Br, CI, =0, =S, -CN methyl, trifluoro-methyl, ethyl, 2,2,2-trifluoroethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl- butyl, pentyl, 2-methyl-pentyl, pent-4-enyl, hexyl, heptyl, octyl, phenyl, NH2, -N02, phenoxy, hydroxy, methoxy, trifluoro-methoxy, ethoxy, and methylenedioxy. In some embodiments each optional substituent is independently selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, (CH2)3CH3, CI, Br, F, I, OH, N02, NH2, CN, OCH3, OCH2CH2CH3, CF3, and OCF3. Alternatively, two optional substituents on the same moiety when taken together may be joined to form a fused cyclic substituent attached to the moiety that is optionally substituted. Accordingly the term optionally substituted includes a fused ring such as a cycloalkyi ring, a heterocycloalkyl ring, an aryl ring or a heteroaryl ring. In addition to compounds of formula (I), the embodiments disclosed are also directed to pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of such compounds, and pharmaceutically acceptable salts of such metabolites. The invention also relates to pharmaceutical compositions including a compound of the invention and a pharmaceutically acceptable carrier, diluent or excipient.
Specific compounds of the invention include the following:
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
or a pharmaceutically acceptable salt thereof.
The compounds of the invention are inhibitors of cathepsin K and therefore have the ability to inhibit these enzymes. The ability to inhibit the enzymes may be a result of the compounds acting directly and solely on the enzyme to modulate/potentiate biological activity. However, it is understood that the compounds may also act at least partially on other factors associated with the activity of the enzyme.
The inhibition of cathepsin K may be carried out in any of a number of ways known in the art. For example if inhibition in vitro is desired an appropriate amount of the compound may be added to a solution containing the cathepsin K. In circumstances where it is desired to inhibit cathepsin K in a mammal, the inhibition of the cathepsin K typically involves administering the compound to a mammal containing the cathepsin K. In a further aspect the present invention provides a method of prevention or treatment of a condition in a mammal, the method comprising administering an effective amount of a compound of the invention. In one embodiment the condition is a condition that can be treated by inhibition of cathepsin K. In yet an even further aspect the invention provides the use of a compound of the invention in the preparation of a medicament for the treatment of a condition in a mammal. In one embodiment the condition is a condition that can be treated by inhibition of cathepsin K.
In yet an even further aspect the invention provides the use of a compound of the invention in the treatment of a condition in a mammal. In one embodiment the condition is a condition that can be treated by inhibition of cathepsin K.
In some embodiments the condition is selected from the group consisting of osteoporosis, glucocorticoid induced osteoporosis, Paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, bone fractures, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignancy, and multiple myeloma.
In some embodiments the condition is bone disease. In some embodiments the condition is osteoporosis.
Administration of compounds within Formula (I) to humans can be by any of the accepted modes for enteral administration such as oral or rectal, or by parenteral administration such as subcutaneous, intramuscular, intravenous and intradermal routes. Injection can be bolus or via constant or intermittent infusion. The active compound is typically included in a pharmaceutically acceptable carrier or diluent and in an amount sufficient to deliver to the patient a therapeutically effective dose. In using the compounds of the invention they can be administered in any form or mode which makes the compound bioavailable. One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular characteristics of the compound selected, the condition to be treated, the stage of the condition to be treated and other relevant circumstances. We refer the reader to Remingtons Pharmaceutical Sciences, 19th edition, Mack Publishing Co. (1995) for further information.
The compounds of the present invention can be administered alone or in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, diluent or excipient. The compounds of the invention, while effective themselves, are typically formulated and administered in the form of their pharmaceutically acceptable salts as these forms are typically more stable, more easily crystallised and have increased solubility.
The compounds are, however, typically used in the form of pharmaceutical compositions which are formulated depending on the desired mode of administration. As such in some embodiments the present invention provides a pharmaceutical composition including a compound of Formula (I) and a pharmaceutically acceptable carrier, diluent or excipient. The compositions are prepared in manners well known in the art. The invention in other embodiments provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. In such a pack or kit can be found a container having a unit dosage of the agent(s). The kits can include a composition comprising an effective agent either as concentrates (including lyophilized compositions), which can be diluted further prior to use or they can be provided at the concentration of use, where the vials may include one or more dosages. Conveniently, in the kits, single dosages can be provided in sterile vials so that the physician can employ the vials directly, where the vials will have the desired amount and concentration of agent(s). Associated with such container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
The compounds of the invention may be used or administered in combination with one or more additional drug(s) for the treatment of the disorder/diseases mentioned. The components can be administered in the same formulation or in separate formulations. If administered in separate formulations the compounds of the invention may be administered sequentially or simultaneously with the other drug(s). In addition to being able to be administered in combination with one or more additional drugs, the compounds of the invention may be used in a combination therapy. When this is done the compounds are typically administered in combination with each other. Thus one or more of the compounds of the invention may be administered either simultaneously (as a combined preparation) or sequentially in order to achieve a desired effect. This is especially desirable where the therapeutic profile of each compound is different such that the combined effect of the two drugs provides an improved therapeutic result.
Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of micro-organisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminium monostearate and gelatin.
If desired, and for more effective distribution, the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3- butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Dosage forms for topical administration of a compound of this invention include powders, patches, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants which may be required.
The amount of compound administered will preferably treat and reduce or alleviate the condition. A therapeutically effective amount can be readily determined by an attending diagnostician by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining the therapeutically effective amount a number of factors are to be considered including but not limited to, the species of animal, its size, age and general health, the specific condition involved, the severity of the condition, the response of the patient to treatment, the particular compound administered, the mode of administration, the bioavailability of the preparation administered, the dose regime selected, the use of other medications and other relevant circumstances.
A preferred dosage will be a range from about 0.01 to 300 mg per kilogram of body weight per day. A more preferred dosage will be in the range from 0.1 to 100 mg per kilogram of body weight per day, more preferably from 0.2 to 80 mg per kilogram of body weight per day, even more preferably 0.2 to 50 mg per kilogram of body weight per day. A suitable dose can be administered in multiple sub-doses per day.
SYNTHESIS OF COMPOUNDS OF THE INVENTION
The agents of the various embodiments may be prepared using the reaction routes and synthesis schemes as described below, employing the techniques available in the art using starting materials that are readily available. The preparation of particular compounds of the embodiments is described in detail in the following examples, but the artisan will recognize that the chemical reactions described may be readily adapted to prepare a number of other agents of the various embodiments. For example, the synthesis of non-exemplified compounds may be successfully performed by modifications apparent to those skilled in the art, e.g. by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions. A list of suitable protecting groups in organic synthesis can be found in T.W. Greene's Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, 1991. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the various embodiments. Reagents useful for synthesizing compounds may be obtained or prepared according to techniques known in the art.
The symbols, abbreviations and conventions in the processes, schemes, and examples are consistent with those used in the contemporary scientific literature. Specifically but not meant as limiting, the following abbreviations may be used in the examples and throughout the specification. g (grams)
L (litres)
Hz (Hertz)
mol (moles)
RT (room temperature)
min (minutes)
MeOH (methanol)
CHCI3 (chloroform)
DCM (dichloromethane)
DMSO (dimethylsulfoxide)
EtOAc (ethyl acetate)
mg (milligrams)
ml_ (millilitres)
psi ( pounds per square inch)
mM (millimolar)
MHz (megahertz)
h (hours)
TLC (thin layer chromatography)
EtOH (ethanol)
CDCI 3 (deuterated chloroform) • HCI (hydrochloric acid)
• DMF (N, N-dimethylformamide)
• THF (tetrahydro furan)
• K2C03 (potassium carbonate)
· Na2S04 (sodium sulfate)
• RM (Reaction Mixture)
• HATU (0-(7-Aza-1 H-benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate)
• DMF (dimethylformamide)
· DIPEA(diisopropyl ethyl amine)
• PyBOP((Benzotriazo!-1 -yloxy)tripyrroiidinophosphonium hexafluorophosphate)
• TEA(trieihyiamine)
Unless otherwise indicated, all temperatures are expressed in °C (degree centigrade). All reactions conducted at room temperature unless otherwise mentioned.
All the solvents and reagents used are commercially available and purchased from Sigma Aldrich, Fluka, Acros, Spectrochem, Alfa Aesar, Avra, Qualigens, Merck, Rankem and Leonid Chemicals.
1 H NMR spectra were recorded on a Bruker AV 300. Chemical shifts are expressed in parts per million (ppm, δ units). Coupling constants are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), or br (broad).
Mass spectra were obtained on single quadruple 6120 LCMS from Agilent technologies, using either atmospheric chemical ionization (APCI) or Electrospray ionization (ESI) or in the combination of these two sources. All samples were run on SHIMADZU system with an LC-20 AD pump, SPD-M20A diode array detector, SIL-20A auto sampler.
SYNTHETIC SCHEMES
As stated above there are a number of ways in which the compounds of the invention can be synthesized as would be appreciated by a person skilled in the art. Nevertheless we provide a reaction scheme for making certain compounds of the invention in Scheme 1 . The general reaction scheme shown in Scheme 1 produces an indole where the point of substitution is at the 5 position. A skilled addressee would readily appreciate that by variation of the point of substitution on the starting material indole the scheme could be readily modified to produce 4, 6 or 7 substituted indoles. In effect the reaction scheme starts with a 5-bromo indole (A) which is N alkylated to produce the corresponding 5-bromo-N-alkyl indole (B). Compound (B) is then subjected to halogen metal exchange with Lithium followed by reaction with C02 to form the N- alkylindole-5-carboxylic acid (C). The acid is then reacted with a suitable amino acid ester to form the amide (D) which is then de-protected to form the free acid (E). Finally compound (E) is reacted with a suitable cyanomethylamine to form the final product (F). As will be appreciated by a skilled worker in the art, by modification of the reaction scheme (such as by modification of some of the reagents such as the alkyl halide, the amino acid ester or the cyanomethyl amine a wide variety of compounds within the scope of the invention can be synthesized.
SCHEME 1 - Alkyl Indoles
Figure imgf000045_0001
xylic acid (A) (B) (C)
Figure imgf000045_0002
(D)
Figure imgf000045_0003
Example 1.Synthesis of a compound following the general procedure in scheme 1.
Step 1 : Synthesis of 5-bromo-N-alkyl Indole
To a 100 ml_ RB flask 5-Bromo-1 H-indole (2.5 g, 12.75 mmol), powder potassium hydroxide (1 .43 g, 25.55 mmol) and 25 ml_ DMF were added and stirred under nitrogen atmosphere. Corresponding alkyl halide (2.0 eq, 25.55 mmol) was added slowly and stirred the reaction mass for 4 hours at 20-30 5C. The reaction was followed by LCMS/TLC. After complete consumption of the starting indole, the reaction mixture was concentrated under vacuum, diluted the residual material in 25 ml_ of water. The aqueous was extracted with ethyl acetate (3x25 mL), washed the extracted organics with water (1 x25 mL). The organic layer was separated and dried over anhydrous Na2S04, concentrated the organics under vacuum to get 80% of the N-alkylated-5-bromo Indole. This material was pure enough to take it to the next stage.
Step 2: Synthesis of N-alkyl lndole-5-carboxylic acid
To a 100 mL two neck round bottom flask N-alkylated- 5-bromo Indole (2.5 g, 9.83 mmol) in 25 mL of anhydrous THF, which was cooled to -70 to -75SC (dry ice/acetone) under nitrogen atmosphere, was added 15 mL of 2.5M n-butyl lithium in over a period of 15-20 mins. The reaction mixture was stirred at the same temperature for 30-45 mins. Dry carbon dioxide gas passed to reaction mass at -70 to -75 SC for about 15 mins to ensure the reaction completion. LCMS of the aliquot was checked to monitor the progress of the reaction. The reaction was complete and hence worked-up. The pH of the reaction mixture was adjusted to 2-3 using 3N HCI (aqueous) at-70 to -75SC. Allowed to attain room temperature and extracted the reaction mixture with ethyl acetate (2x40 mL). The ethyl acetate layer was separated and washed with water (40 mL). The organics were separated, dried over anhydrous sodium sulfate and the volatiles were distilled off under vacuum to get slurry. The slurry was washed a twice with 10 mL portions of petroleum ether to get solid which was filtered off to get the pure labelled compounds in 30% yield as solid. This was characterised by 1 H NMR, LCMS and HPLC before using for the next steps.
Step-3:
To a 50 mL single neck RB flask containing material from step-2, (400 mg, 1 .82 mmol), Leucine ethyl ester hydrochloride (0.53 g, 2.73 mmol), HATU (0.76 g, 2.0 mmol) and DMF (8 mL) were added. The contents were stirred for 5 mins. After clear solution formation diisopropyl ethyl amine (0.6 mL, 3.5 mmol) was added and the reaction mass stirred for 6 hours at 20-30sC. The completion of the reaction was confirmed by LCMS analysis. Work up:-25mL of cold water added slowly to the reaction mass with stirring. The contents were stirred for 30 mins. The aqueous layer was extracted with (3x 25 mL) ethyl acetate. The organic layer was separated, washed with (1 x 10 mL) water. The separated organic layer was dried over anhydrous sodium sulfate; evaporation of the volatiles gave the desired product in 60-80% yields. This product was consumed for the next reactions without further purifications.
Step-4:
To a 50 mL single neck RB flask containing the material obtained from step 3 (0.55 g,
1 .52 mmol) in THF: MeOH:H20 (10 mL)(1 :1 :0.5) was added lithium hydroxide (128 mg, 5.34 mmol). The reaction mixture was stirred for 4 hours at 20-30sC.TLC and LCMS confirmed the absence of the reactant and presence of a new product of desired mass. After reaction completion, the contents of the round bottom flask were concentrated under vacuum and the residual material was diluted with 25 ml_ of water. The pH adjusted to 3-4 using 3N HCI and extracted product using ethyl acetate(2 x 25 ml_). The ethyl acetate layer was separated, washed once with water (25 ml_). Ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under vacuum. This material was thoroughly dried under vacuum. 80-90% yield of the desired acid was obtained. The acid in this step was directly used for the next step without further purification.
Step-5:
To a 50 mL single neck RB flask material from step 4 (0.3 g, 0.85 mmol), was added 2-
Aminoacetonitrile hydrochloride (120 mg, 1 .28 mmol), HATU (0.356 g, 0.93 mmol) and DMF (6 mL). The contents were stirred for 5 mins. After clear solution formation DIPEA (0.22 mL, 1 .70 mmol) was added and the reaction mass stirred for 16 h at 20-30sC. After 16 h, the completion of the reaction was confirmed by TLC/LCMS, and worked-up. Ice-cold water (20 mL) was added slowly to the reaction mixture with stirring. The product was extracted with ethyl acetate (2 x 20 mL). The ethyl acetate extracts were separated washed with (1 x 20 mL) water, separated the organics, dried over anhydrous sodium sulfate and distilled off the volatiles under reduced pressure to get the crude product. This crude material was subjected to purification using preparative RP HPLC. The pure material thus obtained yielded 35-45% yield of the product of desired purity.
Example 2
Synthesis of N-(1-(cyanomethylamino)-4-methyl-1-oxopentan-2-yl)-1-(methylsulfonyl)-1 H- indole-5-carboxamide
Figure imgf000047_0001
N-(1-(cyanomethylamino)-4-methyl- 1 -oxopentan-2-yl)-1 -(methylsulf onyl) -1 H-indole-5-carboxamide ynthesis of benzyl 1 H-indole-5-carboxylate
Figure imgf000048_0001
To a suspension of 1 H-indole-5-carboxylic acid (0.2 g, 1 .0 eq) and sodium bicarbonate (0.623 g, 6.0 eq) in DMF (8ml) was added Benzyl bromide (0.88 ml_) drop wise under nitrogen gas atmosphere at room temperature with stirring. The resultant brown colour suspension was left for stirring at room temperature for 18 h. TLC showed the complete consumption of starting material lndole-5-carboxylic acid. The reaction mix was quenched into a beaker containing ice- cold water. The aqueous was extracted with (3 x 25 ml_) ethyl acetate. Combined organics were washed with ice cold water, saturated NaCI solution. Organics were separated, dried over anhydrous Na2S04, concentrated under vacuum to get 0.352 g of pale oil. The crude material was purified on an automated purification system (Si02 stationery phase) using gradient mixtures of ethyl acetate, hexane as mobile phase, to get the desired product in 97% yield. Synthesis of benzyl 1 -(methylsulfonyl)-l H-indole-5-carboxylate
Figure imgf000048_0002
To a colourless oily suspension of benzyl 1 H-indole-5-carboxylate(0.18 g, 1 .0 eq) , Sodium hydroxide (0.1033 g, 3.6 eq) and Tetra butyl ammonium hydrogen sulfate (0.0037 g, 0.015 eq) in DCM (5 ml_) was added methane sulfonyl chloride (0.061 1 ml, 1 .1 eq) in DCM (2 ml_) drop wise at 0SC under nitrogen atmosphere. The resultant brown suspension was stirred for one hour while maintaining the temperature between 0 SC to 5 SC. TLC showed complete consumption of starting material and formation of new spot.
Reaction mass was taken quenched into ice water, extracted with ethyl acetate (3 x 10 mL) and the combined organic layers were washed with cold water and saturated NaCI solution, dried over anhydrous sodium sulfate, filtered and concentrated to get 250 mg crude material. Purification of the crude material was done on an automated purification system (Si02 stationery phase) using gradient mixtures of ethyl acetate, hexane as mobile phase, to get the desired product in 51 % yield as an off-white solid. Synthesis of 1-(methylsulfonyl)-1 H-indole-5-carboxylic acid
Figure imgf000049_0001
To a solution of benzyl 1 -(methyl sulfonyl)-1 H-indole-5-carboxylate(0.062 g, 1 .0 eq) and
Ν,Ν-Dimethyl aniline (0.1 19 mL, 5 eq) in DCM (8 mL) was added Aluminium Chloride (0.0754 g, 3 eq) in one portion at room temperature under nitrogen atmosphere. The reaction mixture was stirred under nitrogen for two hours. TLC showed complete consumption of starting material and formation of new spots. Reaction mass poured on ice-water mixture and then extracted with DCM (3 x 15 mL). The combined organics were washed with 1 N HCI, water and saturated NaCI solution, separated, dried over anhydrous Na2S04 and concentrated to get 0.080 g of oil. Purification of the crude material was done on an automated purification system (Si02 stationery phase) using gradient mixtures of ethyl acetate, hexane as mobile phase, to get the desired product in 97% yield as an off-white solid (0.044 g).
Synthesis of ethyl 4-methyl-2-(1-(methylsulfonyl)-1 H-indole-5-carboxamidopentanoate)
Figure imgf000049_0002
To a pale yellow solution of 1 -(methyl sulfonyl)-1 Hindole-5-carboxylic acid (0.044 g, 1 eq) , leucine ethyl ester HCI (0.054 g, 1 .5 eq) and PyBOP (0.1054 g, 1 .1 eq) in DMF (3 mL) was added Ν,Ν-diisopropyl ethylamine (0.0641 mL, 2.0 eq). The resultant yellow solution was stirred for 18 hours at room temperature under nitrogen atmosphere. TLC showed the complete consumption of starting materials and formation of new spot. Reaction mass diluted with cold water (10 mL) and then ethyl acetate (15 mL) was added. The biphasic layer was stirred for l Ominutes and the ethyl acetate layer was separated. The aqueous phase was extracted with ethyl acetate (2 x 10 mL). The organics were combined and washed with cold water (2 x 15 mL), saturated NaCI solution (5 mL). Organic layer was separated and dried over anhydrous sodium sulfate, filtered and concentrated to get 0.06 g (yield: 85.66%) of ethyl 4-methyl-2-(1- (methylsulfonyl)-l H-indole-5-carboxamidopentanoate) as pale yellow oil. ido)pentanoic acid
Figure imgf000050_0001
To a pale yellow solution of ethyl 4-methyl-2-(1 - (methyl sulfonyl)-1 H-indole-5- carboxamido)pentanoate (0.06 g, 1 eq) in a mixture of THF (2 mL) and methanol (2 mL) was added lithium hydroxide monohydrate (0.32 mL, 2M). The resultant yellow solution was stirred for one hour at room temperature. The reaction progress was followed by LCMS. Since the reaction was complete, volatiles were removed from the reaction mass and then diluted with water (3 mL) and washed with ethyl acetate (2 x 5 mL) and these washings are discarded. The aqueous layer was acidified with 1 N HCI and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The pooled organic layers were washed with water (2 x 5 mL) and brine (1 x 5 mL), dried and filtered to get 0.05 g (yield: 90.07%) of 4-methyl-2-(1-(methylsulfonyl)-1 H-indole-5- carboxamido)pentanoic acid as pale yellow solid.
Synthesis of N-(1-(cyanomethylamino)-4-methyl-1-oxopentan-2-yl)-1-(methylsulfonyl)-1 H- indole-5-carboxamide
Figure imgf000050_0002
To a pale yellow solution of 4-methyl-2-(1 -(methylsulfonyl)-1 H-indole-5- carboxamido)pentanoic acid(0.05 g, 1 eq), Amino acetonitrile Hydrochloride (0.0197 g, 1 .5 eq) and PyBOP (0.0183 g,1 .1 eq) in DMF (1 .5 mL) was added Ν,Ν-diisopropyl ethylamine(0.0495 mL, 2.0 eq). The resultant yellow solution was stirred for 48 h at room temperature. TLC had shown that complete consumption of starting materials and formation of new spot.
Reaction mass diluted with cold water (10 mL) and then ethyl acetate (5 mL) was added. The biphasic layer was stirred for 10 minutes and the ethyl acetate layer was separated. The aqueous phase was extracted with ethyl acetate (2 x 10 mL) and the pooled organics. The combined organics was washed with cold water (2 x 15 ml_), brine (5 ml_). The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated to get 0.046 g of pale yellow oil. This crude product was subjected to preparative HPLC (RP) using mobile phase as acetonitrile/water (0.1 %formic acid) gradients to get the desired product in >95% purity with (0.013 g) 25% yield, as a white solid.
Example 3 Scheme for the synthesis of DL- Fluoroleucine ethyl ester
STAGE 1
Figure imgf000051_0001
Synthetic procedures:
Step 1 : To a 100 mL RB Flask containing anhydrous t-butyl methyl ether (MTBE) under nitrogen, pyridine. HF (3.6 mL, 138.67 mmol) was added cooled at -10 to -20SC (ice/salt mixture) then isobutylene oxide (6.15 ml_,69.3 mmol) added drop wise over 20 min. The resulting solution was warmed to RT and stirred for 18 h. The reaction was followed by TLC. The reaction mixture was quenched slowly with 16 g of aq. K2C03 (pH 8). The organic layer was separated, aqueous layer again washed with MTBE. The organic layer dried over Na2S04, concentrated under vacuum at below 30sCto get 4.5 g (yield: 70%) of 2-fluoro-2- methylpropan-1 -ol as colourless oil and product was confirmed by H1and F19NMR.
Step 2: To a solution of 2-fluoro-2-methylpropan-1 -ol (4.5 g, 48.85 mmol) and Et3N (10.30 ml_,73.28 mmol) in dry dichloromethane (45 mL), at -20 °C was added trifluoromethane sulfonic anhydride (9.08 mL, 53.74 mmol) drop wise. The resulting brown solution was stirred at -20 sC(dry ice/acetone) for 2 h. The reaction was followed by TLC, after completion, reaction mix was diluted with dichloromethane and quenched with 25 mL of 1 N HCI solution. The organic layer was separated, washed with 25 mL saturated NaHC03andNaCI solution, dried over Na2S04 filtered and concentrated to get crude 8.3 g of 2-fluoro-2-methylpropyl trifluoromethane sulfonate as brown colour liquid. This product was characterised by H1 NMR.
Step 3: To a 500 mL three neck RB flask equipped with a distillation and a Dean-Stark separator, benzophenone (20 g, 109.8 mmol), glycine ethyl ester Hydrochloride (15.32 g, 109.8 mmol), p-toluenesulfonic acid (0.522 g, 2.745 mmol) and 400 mL of toluene were added. The mixture was heated at 1 15 SC with stirring to get a good reflux in toluene. Finally N, N- diisopropyl ethyl amine (14.4 mL, 82.35 mmole) was added using a dropping funnel over 45 min. During the reaction, water was formed which was decanted from the Dean-Stark separator and toluene were returned to the reactor. The reaction was monitored by TLC, and it took about 18 h for 50% completion. The reaction mixture was cooled down to room temperature, and extracted (3 x 100 mL) with ethyl acetate, collected organic layer and washed organic layer once with saturated NaCI solution. The organic layer separated, dried over Na2S04, and distilled off the volatiles to get crude material, which was flash chromatographed to get 9.0 g (30% isolated) ofEthyl-2-(diphenylmethyleneamino) acetate as a white solid, which was confirmed by H1 NMR.
Step 4:To a 100 mL 2-neck Flask with nitrogen balloon, was taken Ethyl-2- (diphenylmethyleneamino) acetate (9.0 g, 33.67 mmol) and dry DMF (30 mL) then solution was cooled to 0SC. To this was added solid KOtBu (4.15 g, 37.03 mmol) in small portions. The resulting red-orange solution was stirred for 15 min, and then treated with 2-fluoro-2- methylpropyl trifluoromethane sulfonate (8.3 g, 37.03 mmol) in dry DMF (15 mL) drop wise at the same temperature. The contents were allowed to stir at room temperature for 20 h. The reaction mixture was monitored by TLC. Once the reaction was complete, the reaction mixture was poured into a separating funnel containing ethyl acetate (200 mL) and saturated aqueous NH4CI solution (50 mL). The organic layer was separated, washed once with water (100 mL) and brine, dried over Na2S04 filtered and concentrated under vacuum. The crude material was purified by flash chromatography. Ethyl-2-(diphenylmethyleneamino) -4-fluoro-4- methylpentanoate was analysed by LCMS it showed only 48% of required product. This material was used for the next step without further purification.
Step 5: To a solution of Ethyl-2-(diphenylmethyleneamino) -4-fluoro-4-methylpentanoate (5 g, 14.64 mmol) in MTBE (30 mL) at 0SC wasadded 1 N aqueous HCI (29.28 mL, 29.2 mmol)drop wise. The resulting solution was then warmedto room temperature and stirred for 20 h. The reaction wasmonitored by LCMS showed complete consumption of starting material. The aqueous layer containing HCI, was separated, washed once with MTBE and aqueous layer azeotroped with toluene (2 x 50 mL) to get crude 3.5 g of Fluoroleucine ethyl ester as a brown thick liquid. The presence of the product was confirmed by H1 NMR, LCMS. This material was used immediately after preparation without further purification.
Example 4
Synth les:
methyl
Figure imgf000053_0001
1 /-/-indazole-5-carboxyl
o nex step.
Figure imgf000053_0002
Isomers were separed but not characterized,
Figure imgf000053_0003
Isomers were separed and characterized by TOSCY -NMR exclusively.
Synthetic procedures
Step 1 : N-methylated-5 Methyl 1 H-indazole-5-carboxylic acid
To a 100 mL RB flask Methyl 1 H-indazole-5-carboxylate (1 .0 g, 5.68 mmol), powder sodium hydride (0.2 g, 8.52 mmol) and 10 mL DMF were added and stirred under nitrogen atmosphere. Methyl halide (0.80 g, 5.68 mmol) was added slowly and stirred the reaction mass for 1 h at 0 °C. The reaction was followed by LCMS/TLC. After complete consumption of the starting indazole, the reaction mixture was concentrated under vacuum, diluted the residual material in 25 mL of water and quenched with saturated ammonium chloride solution. The aqueous was extracted with ethyl acetate (3x25 mL), washed the extracted organics with water (1 x25 mL). The organic layer was separated and dried over anhydrous Na2S04. Concentrated the organics under vacuum to get 80% of the N-methylated-1 H-indazole-5-carboxylic acid. This material was mixture of two positional isomers, and isomers were not separated at this stage. This was taken directly to the next stage. Step-2: Synthesis of Leucine coupled N-methylated-5 Methyl 1 H-indazole-5-carboxamide
To a 50 mL single neck RB flask material from step 1 (0.8 g, 4.545mmol), was added L- Leucine hydrochloride (0.79 g, 4.545 mmol), HATU (1 .69 g, 4.4545 mmol) and DMF (10 mL). The contents were stirred for 5mins. After clear solution formation DIPEA (1 .6 mL, 8.909 mmol) was added and the reaction mass stirred for 16 h at 20-30 °C. After 16 h, the completion of the reaction was confirmed by TLC/LCMS, and worked-up. Ice-cold water (20 mL) was added slowly to the reaction mixture with stirring. The product was extracted with ethyl acetate (2x20 mL). The ethyl acetate extracts were separated washed with (1x20 mL) water, separated the organics, dried over anhydrous sodium sulphate and distilled off the volatiles under reduced pressure to get the crude product. This crude material was subjected to purification using combiflash at 40% ethyl acetate: 60%Hexane as a mobile phase to yield Leucine coupled N- methylated-5 Methyl 1 H-indazole-5-carboxamide. Isomers were separated but not characterized. The pure materials thus obtained yielded 80%, as such taken it to the next stage.
Step-3: Hydrolysis
To a 50 mL single neck RB flask containing the material obtained from step 2 (0.4 g,
1 .52 mmol) in THF: MeOH: H20 (10 mL)(1 :1 :0.5) was added lithium hydroxide (61 mg, 15.2 mmol). The reaction mixture was stirred for 4 hours at 20-30°C.TLC and LCMS confirmed the absence of the reactant and presence of a new product of desired mass.
After reaction completion, the contents of the round bottom flask were concentrated under vacuum and the residual material was diluted with 25 mL of water. pH adjusted to 3-4 using 3N HCI and extracted product using ethyl acetate(2x25 mL). The ethyl acetate layer was separated, washed once with water (25 mL). Ethyl acetate layer was dried over anhydrous sodium sulphate and concentrated under vacuum. This material was thoroughly dried under vacuum. 80-90% yield of the desired acid was obtained. The acid in this step was directly used for the next step without further purification
Step-4: Coupling To a 50 mL single neck RB flask material from step 3 (0.3 g, 0.85 mmol), was added 2- Aminoacetonitrile hydrochloride (57 mg, 0.85 mmol), HATU (0.323 g, 0.85 mmol) and DMF (8 mL). The contents were stirred for 5mins. After clear solution formation DI PEA (0.16 mL, 1 .70 mmol) was added and the reaction mass stirred for 16 h at 20-30 °C. After 16 h, the completion of the reaction was confirmed by TLC/LCMS, and worked-up. Ice-cold water (20 mL) was added slowly to the reaction mixture with stirring. The product was extracted with ethyl acetate (2x20 mL). The ethyl acetate extracts were separated washed with (1 x20 mL) water, separated the organics, dried over anhydrous sodium sulphate and distilled off the volatiles under reduced pressure to get the crude product. This crude material was subjected to purification using preparative RP HPLC. The pure material thus obtained yielded 30-40% yield of the product of desired purity.
Isomers were characterized by TOSCY-NMR. Example 5
Synthesis of N-(cyanomethyl)-2-({imidazo[1 ,5-a]pyridin-7-yl}formamido)-4-
Figure imgf000055_0001
Step 1 : Ethyl 2-(H-imidazo[1 ,5-a]pyridine-7-carboxamido)-4-methylpentanoate synthesis To a 50 mL single neck RB flask starting 1 H-lmidazol (1 ,5-a)pyridine-7-carboxylic acid
(0.5 g, 3.086 mmol) was added, followed by ethyl ester of L-Leucine Hydrochloride (0.5 g, 3.086 mmol), HATU (0.323 g, 0.85 mmol) and DMF (8 mL). The contents were stirred for 5 mins. After clear solution formation DIPEA (1 .1 mL, 6.172 mmol) was added and the reaction mass stirred for 16h at 20-30°C. After 16h, the completion of the reaction was confirmed by TLC/LCMS, and worked-up. Ice-cold water (20mL) was added slowly to the reaction mixture with stirring. The product was extracted with ethyl acetate (2x20mL). The ethyl acetate extracts were separated washed with (1 x20 mL) water, separated the organics, dried over anhydrous sodium sulphate and distilled off the volatiles under reduced pressure to get the crude product. This crude material was subjected to purification using preparative RP HPLC. The pure material thus obtained yielded 60-70% yield of the product of desired purity.
Step 2: 2-lmidazole (1 ,5-a)Pyridine-7-carboxamido)-4-methylpentanoic acid
To a 50 mL single neck RB flask containing the material obtained from step 1 (0.3 g,
0.990 mmol) in THF: MeOH: H20 (10 ml_)(1 :1 :0.5) was added lithium hydroxide (0.22 mg, 9.99 mmol). The reaction mixture was stirred for 4 hours at 20-30 °C.TLC and LCMS confirmed the absence of the reactant and presence of a new product of desired mass.
After reaction completion, the contents of the round bottom flask were concentrated under vacuum and the residual material was diluted with 25 mL of water. pH adjusted to 3-4 using 3N HCI and extracted product using ethyl acetate(2x25 mL). The ethyl acetate layer was separated, washed once with water (25 mL). Ethyl acetate layer was dried over anhydrous sodium sulphate and concentrated under vacuum. This material was thoroughly dried under vacuum. 80-90% yield of the desired acid was obtained. The acid in this step was directly used for the next step without further purification.
Step3: N-(Cyanomethyl)-2-({imidazo[1 ,5-a]pyridin-7-yl}formamido)-4-methylpentanamide
To a 50 mL single neck RB flask material from step 2 (0.2 g, 0.727 mmol), was added 2- Aminoacetonitrile hydrochloride (41 mg, 0.727 mmol), HATU (0.323 g, 0.85 mmol) and DMF (8 mL). The contents were stirred for 5 mins. After clear solution formation DIPEA (0.26 mL, 1 .454 mmol) was added and the reaction mass stirred for 16 h at 20-30 °C. After 16 h, the completion of the reaction was confirmed by TLC/LCMS, and worked-up. Ice-cold water (20 mL) was added slowly to the reaction mixture with stirring. The product was extracted with ethyl acetate (2x20 mL). The ethyl acetate extracts were separated washed with (1 x20 mL) water, separated the organics, dried over anhydrous sodium sulphate and distilled off the volatiles under reduced pressure to get the crude product. This crude material was subjected to purification using preparative RP HPLC. The pure material thus obtained yielded 50-60% yield of the product of desired purity. Example 6
Synthesis of N-(1-(cyanomethylcarbamoyl)-3-methylbutyl)quinoline-6-carboxamide
Figure imgf000057_0001
Figure imgf000057_0002
Step 1 : Ethyl 4-methyl-2-[(quinolin-6-yl)formamido]pentanoate
To a 50 ml_ single neck RB flask quinoline-6-carboxylic acid (0.5 g, 2.896 mmol), was added ethyl ester of L-Leucine Hydrochloride (0.45 g, 2.869 mmol), HATU (1 .10 g, 2.896 mmol) and DMF (10 ml_). The contents were stirred for 5 mins. After clear solution formation DIPEA (1 .106 ml_, 5.792 mmol) was added and the reaction mass stirred for 16 h at 20-30 °C. After 16 h, the completion of the reaction was confirmed by TLC/LCMS, and worked-up. Ice-cold water (20 ml_) was added slowly to the reaction mixture with stirring. The product was extracted with ethyl acetate (2x20 ml_). The ethyl acetate extracts were separated washed with (1 x20 ml_) water, separated the organics, dried over anhydrous sodium sulphate and distilled off the volatiles under reduced pressure to get the crude product. This crude material was subjected to purification using preparative RP HPLC. The pure material thus obtained yielded 70-80% yield of the product of desired purity. Step 2: 4-Methyl-2-[(quinoline-6-carbonyl)-amino]-pentanoic acid
To a 50 ml_ single neck RB flask containing the material obtained from step 1 (0.35 g,
I .1 14 mmol) in THF: MeOH: H20 (10 ml_)(1 :1 :0.5) was added lithium hydroxide (0.256 mg,
I I .14 mmol). The reaction mixture was stirred for 4 hours at 20-30 °C. TLC and LCMS confirmed the absence of the reactant and presence of a new product of desired mass.
After reaction completion, the contents of the round bottom flask were concentrated under vacuum and the residual material was diluted with 25 ml_ of water. pH adjusted to 3-4 using 3N HCI and extracted product using ethyl acetate(2x25 ml_). The ethyl acetate layer was separated, washed once with water (25 ml_). Ethyl acetate layer was dried over anhydrous sodium sulphate and concentrated under vacuum. This material was thoroughly dried under vacuum. 80-90% yield of the desired acid was obtained. The acid in this step was directly used for the next step without further purification Step 3: N-(1-(cyanomethylcarbamoyl)-3-methylbutyl)quinoline-6-carboxamide
To a 50 ml_ single neck RB flask material from step 2 (0.280 g, 0.979 mmol), was added 2-Aminoacetonitrile hydrochloride (54 mg, 0.979 mmol), HATU (0.373 g, 0.979 mmol) and DMF (10 ml_). The contents were stirred for 5 mins. After clear solution formation DIPEA (0.36 ml_, 1 .958 mmol) was added and the reaction mass stirred for 16h at 20-30°C. After 16 h, the completion of the reaction was confirmed by TLC/LCMS, and worked-up. Ice-cold water (20 ml_) was added slowly to the reaction mixture with stirring. The product was extracted with ethyl acetate (2x20 ml_). The ethyl acetate extracts were separated washed with (1 x20 ml_) water, separated the organics, dried over anhydrous sodium sulphate and distilled off the volatiles under reduced pressure to get the crude product. This crude material was subjected to purification using preparative RP HPLC. The pure material thus obtained yielded 50-60% yield of the product of desired purity. The compounds outlined in Table 1 were synthesized following the procedures outlined above or variations thereof typically by variation of the starting materials used.
Table 1 Spectral data of compounds: Spectral data of compounds:
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
J=2.93 Hz, 1 H) 7.45 (d, J=2.93 Hz,
1 H) 7.54 (d,J=8.71 Hz, 1 H) 7.72 (d, J= 8.62 Hz, 1 H) 8.22 (s, 1 H) 8.38
(d, J=7.70 Hz, 1 H) 8.65 (t, J=5.46
Hz, 1 H)
(300 MHz, DMS0-d6) δ ppm : 0.91 417.1
— ( -NH
(dd, J=13.02, 6.33 Hz, 6 H) 1 .00 - 1 .14 (m, 2 H) 1 .21 - 1 .33 ( m, 2 H)
1 .48 - 1 .86 (m, 3 H) 3.04 - 3.20(m, 1
H) 4.14 (d, J=5.59 Hz, 2 H) 4.48 - 4.64 (m, 1 H) 6.97 (d, J=3. 67 Hz, 1
H) 7.71 (d, J=3.58 Hz, 1 H) 7.89 - 8.00 (m, 2 H) 8.31 (s, 1 H) 8.67
(d,J=7.98 Hz, 1 H) 8.77 (t, J= 5.55
Hz, 1 H)
(300 MHz, DMS0-d6) δ ppm : 0.91 405.15 (dd, J=13.20, 6.24 Hz, 6 H) 1 .04
(t,J=7.29 Hz, 3 H) 1 .49 - 1 .8 6 (m, 3
H) 3.67 (q, J=7.24 Hz, 2 H) 4.14(d,
J=5.59 Hz, 2 H) 4.46 - 4.62 (m, 1 H)
6.91 - 7.02 (m, 1 H) 7.71 (d, J=3.58
Hz, 1 H) 7.84 - 8.00 (m, 2 H) 8.25 - 8.34 (m, 1 H) 8.64 (d, J=7.89 Hz,1
H) 8.72 (t, J=5.59 Hz, 1 H)
(300 MHz, DMS0-d6) δ ppm : 1 .26 - 383.2 1 .81 (m, 8 H) 2.17 (d, J=13.20 Hz, 2
° NH H) 3.20 (s, 3 H) 3.66 (t, J=5.09 Hz, 2
H) 4.06 (d, J=5.50 Hz, 2H) 4.38 (t,
J=5.04 Hz, 2 H) 6.56 (d, J=3.03 Hz,
1 H) 7.44 (d, J=3.12 Hz, 1 H) 7.54
(d, J=8.62 Hz, 1 H) 7.68 (d,J=8.71
Hz, 1 H) 7.84 (s, 1 H) 8.13 -8.28 (m,
2 H)
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
37 (300 MHz, DMSO-d6) δ ppm: 0.80 - 411.2
0.98 (m, 6 H) 1.12 (br. s., 2 H) 1.32 -
1.55 (m, 6 H) 1.70 (d, J=10.45 Hz, 2 H)4.47 (d, J=6.97 Hz, 3 H) 6.86 (br.
s., 1 H) 7.81 (br. s., 1 H) 7.91 (d, J
=8.34 Hz, 1 H) 8.15 (d, J=8.62 Hz, 1
H) 8.25 (br. s., 1 H) 8.55 (d, J=7.34
Hz, 1H) 9.00 (br. s., 1 H)
38 (300 MHz, DMS0-d6) δ ppm: 0.91 433.15
(d, J=6.60 Hz, 12 H) 1.47 - 1.84 (m,
3 H) 1.92 (d, J=5.50 Hz, 1 H) 3.54
H ° (d, J=5.04 Hz,2 H) 4.15 (br. s., 2 H)
4.55 (br. s., 1 H) 6.97 (br. s., 1 H)
7.72 (br. s., 1 H) 7.85 - 8.01 (m, 2 H) 8.31 (br. s., 1 H) 8.65 (d, J=7.15 Hz, 1 H) 8.74 (br. s.,1 H
39 (300 MHz, DMS0-d6) δ ppm: 0.91 459.2
O ,N
(d, J=5.69 Hz, 12 H) 1.12 (br. s., 2
H) 1.49 (br. s., 3 H) 1.70 ( d, J=11.19 Hz, 2 H) 1.93 (br. s., 1 H) 3.54 (d,
J=3.67 Hz, 2 H) 4.46 (br. s., 1 H)
6.97 (br. s ., 1 H) 7.71 (br. s., 1 H)
7.92 (br. s., 2 H) 8.29 (br. s., 1 H)
8.59 (d, J=7.15 Hz, 1 H) 9.00 (br. s., 1 H)
40 (300 MHz, DMS0-d6) δ ppm: 0.83 - 371.15
0.97 (m, 6 H) 1.48 - 1.85 (m, 3 H)
4.02 (s, 3 H) 4.14 (d, J=5.59 Hz, 2
H) 4.46-4.62 (m, 1 H) 6.87 (d,
J=3.76 Hz, 1 H) 7.81 (d, J=3.76 Hz,
1 H) 7.92 (dd, J=8.71 , 1.56 Hz, 1 H) 8.16 (d, J=8.71 Hz, 1 H) 8.26 (d,
J=1.28 Hz, 1 H)8.62 (d, J=7.98 Hz, 1 H) 8.74 (t, J=5.55 Hz, 1 H)
41 (300 MHz, DMS0-d6) δ ppm: 0.83 - 397.2
0.96 (m, 6 H) 1.07- 1.17 (m, 2 H)
1.42- 1.57 (m, 3 H) 1.59 - 1.59 (m, 1 H) 1.60- 1.82 (m, 2 H) 3.94 -4.08
Figure imgf000069_0001
Figure imgf000070_0001
J=7.24 Hz, 1 H) 8.03 (s, 1 H) 8.68 (s,
1 H) 8.78 (t, J=5.50 Hz, 1 H)
50 (300 MHz, DMSO-d6) δ ppm: 0.92 (t, 417.15
J=6.24 Hz, 6 H) 1.02 - 1.12 (m, 2 H)
1.21 -1.30 (m,2H) 1.46- 1.82 (m,3 H) 3.02 -3.17 (m, 1 H)4.17(s, 2 H)
4.51 - 4.65 (m, 1 H) 7.22 (d, J=3.67
Hz, 1 H) 7.46 (t, J=7.93 Hz, 1 H)
7.70 (d, J=3.67 Hz, 1 H) 7.78(d,
J=7.34Hz, 1 H) 8.06 (d, J=8.34 Hz, 1 H) 8.66 (d, J=7.98 Hz, 1 H) 8.77 (t,
J=5.64 Hz, 1 H)
51 (300 MHz, DMS0-d6) δ ppm: 0.92 (t, 405.15
J=6.33 Hz, 6 H) 1.05 (t, J=7.29 Hz, 3 H) 1.48- 1.82 (m, 3 H) 3.64 (q,
J=7.24 Hz, 2 H) 4.17 (d, J=5.59 Hz,
2 H) 4.51 -4.65(m, 1 H) 7.22 (d,
J=3.58 Hz, 1 H) 7.46 (t, J=7.98 Hz, 1 H) 7.70 (d, J=3.67 Hz, 1 H) 7.79 (d,
J=7.24 Hz, 1 H) 8.02 (d, J=8.25 Hz,
1 H) 8.67 (d, J=7.98 Hz, 1 H) 8.79 (t, J=5.55 Hz, 1 H)
52 (300 MHz, DMS0-d6) δ ppm: 0.92 (t, 355.15
J=6.14 Hz, 6 H) 1.48- 1.83 (m, 3 H)
2.68 (s, 3 H) 4.17 (d, J=5.59 Hz, 2
H) 4.49 - 4.68 (m, 1 H) 7.14 (s, 1 H)
7.34 - 7.50 (m, 1 H) 7.76 (d, J=7.24
Hz, 1 H) 7.97 (s, 1 H) 8.51 (d,
J=8.25 Hz, 1 H) 8.62 (d, J=7.98 Hz,
1 H) 8.77 (t, J=5.55 Hz, 1 H)
53 (300 MHz, DMS0-d6) δ ppm: 0.92 (t, 385.15
J=5.96 Hz, 6 H) 1.41 (t, J=7.06 Hz, 3 H) 1.50- 1.83 (m, 3 H) 4.17 (d,
J=5.32 Hz, 2 H) 4.38 - 4.65 (m, 3 H)
7.15 (d, J=3.48 Hz, 1 H) 7.44 (t,
J=7.89 Hz, 1 H) 7.69 - 7.86 (m, 2 H)
8.29 (d, J=8.25 Hz, 1 H) 8.63 (br. s., 1 H) 8.77 (t, J=5.14 Hz, 1 H) (300 MHz, DMSO-d6) δ ppm: 1.69 389.1
N 0 (m, 4 H) 1.97 - 2.24 (m, 4 H) 3.47 (s,
3 H) 4.05 (d, J=5.41 Hz, 2 H) 6.96
(d, J=3.48 Hz, 1 H) 7.69 (d, J=3.48
Hz, 1 H) 7.83-7.97 (m, 21-1)8.31
(br. s., 2 H) 8.52 (s, 1 H)
(300 MHz, DMSO-d6) δ ppm: 1.29 403.15 (m, 1 H) 1.55 (br. s., 5 H) 1.66- 1.85 (m, 2 H) 2.16 (d, J=12.84 Hz, 2 H)
3.48 (s, 3 H) 4.07 (d, J=5.50 Hz, 2
H) 6.97 (d, J=3.58 Hz, 1 H) 7.69 (d,
J=3.58 Hz, 1 H) 7.90 (s, 2 H) 8.08 (s, 1 H) 8.17 -8.33 (m, 2 H)
(300 MHz, DMSO-d6) δ ppm: 0.92 (t, 398.2 J=6.28 Hz, 6 H) 1.23 (d, J=6.60 Hz,
6H) 1.48-1.81 (m, 3 H) 4.03 (dq,
J=13.54, 6.71 Hz, 1 H)4.16(d,
J=5.59 Hz, 2 H) 4.51 - 4.63 (m, 1 H)
7.08 (d, J=3.58 Hz, 1 H) 7.34 (d,
J=7.98 Hz, 1 H) 7.68 (d, J=7.24 Hz,
1 H) 7.93 - 8.06 (m, 2 H) 8.42 (s, 1
H) 8.55 (s, 1 H) 8.75 (t, J=5.50 Hz, 1 H)
(300 MHz, DMSO-d6) δ ppm: 0.91 398.2 (dd, J=11.37, 6.33 Hz, 6 H) 1.25 (d, o* NH I T H %N J=6.51 Hz, 6 H) 1.48 - 1.83 (m, 3 H)
A ' 3.97-4.11 (m, 1 H) 4.16 (s, 2 H)
4.50 - 4.61 (m, 1 H) 6.73 (d, J=3.48
Hz, 1 H) 7.62 - 7.68 (m, 1 H) 7.72 - 7.79 (m, 1 H) 7.98 -8.06 (m, 2 H)
8.57 (d, J=7.98 Hz, 1 H) 8.72 (t,
J=5.59 Hz, 1 H) 8.76 (s, 1 H)
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
BIOLOGICAL ACTIVITY
The pharmacological activities of the compound of this present invention were confirmed by the following experiments.
(a) Measurement of Human Cathepsin K, L, V and S Inhibitory Activity:
All assays for cathepsin K was carried out with human recombinant enzyme (purchased from Enzo Lifesciences). Assays for cathepsins L, S and V were carried out with human recombinant enzyme (purchased from RnD Systems). Standard assay conditions for the determination of kinetic constants used a fluorogenic peptide substrate, typically (5S,8S)-13- amino-5-benzyl-13-imino-3-methylene-N-(4-methyl-2-oxo-2H-chromen-7-yl)-6-oxo-1 -phenyl-2- oxa-4,7, 12-triazatridecane-8-carboxamide (Cbz-Phe-Arg-AMC) for Cat K and were determined in 50 mM sodium acetate at pH 5.5 containing 1 m M dithiothreitol, 2.5 mM EDTA and 0.01 % TritinX-1 00. For Cat L, S And V, the substrate used was benzyl N-[1 -[[5- (diam inomethylideneamino)-1 -[(4-methyl-2-oxochromen-7-yl)amino]-1 -oxopentan-2-yl]amino]-4- methyl-1 -oxopentan-2-yl]carbamate (Cbz-Leu-Arg-AMC). A stock substrate solution of Cbz- Phe-Arg-AMC or Cbz-Leu-Arg-AMC was prepared at a concentration of 50 mM in dimethyl sulfoxide. This substrate was diluted into the assay for a final substrate concentration of 10 μΜ in all the assays. The Km value for Cbz-Phe-Arg-AMC on human Cat K is 12 μΜ. The Km value for Cbz-Leu-Arg-AMC on human Cat S is 32 μΜ, on human Cat L is 4 μΜ and on human cathepsin V is 7 μΜ. The total reaction time was 60 min for human Cat K, L and V (final protein concentrations were 0.3 nM, 0.1 nM and 5 nM respectively) ; for human Cat S it was 30 min (final protein concentration was 1 .25 nM). Prior to the addition of substrate, different concentrations of the inhibitor ranging from
1 00 μΜ to 0.2 nM were pre-incubated for 15 min with each enzyme to allow the establishment of the enzyme-inhibitor complex. Substrate was then added and the enzyme activity measured from the increase of fluorescence measured (Aex (excitation wavelength) =355 nm , Aem (fluorescence wavelength) =460 nm). The final volume of the reaction was 100 L. Assays were performed in 96-well plate format and the plate read using an Envision (Perkin Elmer) plate reader. The percent inhibition of the reaction was calculated from a control reaction containing only vehicle. IC50 curves were generated by fitting percent inhibition values to a four parameter logistic model (PRISM). (ii) Measurement of Rat Cathepsin K Inhibitory Activity
All assays for rat cathepsin K was carried out with rat recombinant enzyme (purchased from Biovision Inc.). Standard assay conditions for the determination of kinetic constants used a fluorogenic peptide substrate, typically (5S,8S)-13-amino-5-benzyl-13-imino-3-methylene-N-(4- methyl-2-oxo-2H-chromen-7-yl)-6-oxo-1 -phenyl-2-oxa-4,7,12-triazatridecane-8-carboxamide (Cbz-Phe-Arg-AMC) and were determined in 100 mM sodium acetate at pH 5.5 containing 10 mM dithiothreitol and 120 mM sodium chloride. A stock substrate solution of Cbz-Phe-Arg-AMC was prepared at a concentration of 50 mM in dimethyl sulfoxide. This substrate was diluted into the assay for a final substrate concentration of 30 μΜ in the rat cathepsin K assay. The Km value for Cbz-Phe-Arg-AMC on rat cathepsin K is 27 μΜ. The total reaction time was 120 min for rat Cat K (final protein concentrations was 50 nM).
Prior to the addition of substrate, different concentrations of the inhibitor ranging from 100 μΜ to 0.2 nM were pre-incubated for 15 min with each enzyme to allow the establishment of the enzyme-inhibitor complex. Substrate was then added and the enzyme activity measured from the increase of fluorescence measured (Aex (excitation wavelength) =355 nm, Aem (fluorescence wavelength) =460 nm). The final volume of the reaction was 100μΙ_. Assays were performed in 96-well plate format and the plate read using an Envision (PerkinElmer) plate reader. The percent inhibition of the reaction was calculated from a control reaction containing only vehicle. IC50 curves were generated by fitting percent inhibition values to a four parameter logistic model (PRISM).
Results of in-vitro inhibition: Cathepsin K, S, L and V enzymes. The IC50s on isolated enzymes and aqueous solubility of compounds were categorised as follows:
Figure imgf000077_0001
SI No. IC50- IC50- IC50- IC50- Aq.sol uM IC50-Rat
CatK_nM CatS_nM CatL_nM CatV_nM CatK_nM +++ + + + +++ +++
+ + + + ++ +
++ + + + +++ +
+ + + + ++ NA
+++ ++ + + ++ +++
+++ + + + +++ +++
+++ ++ + + + +++
++ + + + +++ +++
+++ ++ + + ++ +++
++ + + + ++ +++
++ + + + +++ +++
+++ ++ NA NA + +++
+++ ++ NA NA + +++
+++ ++ + ++ + +++
++ ++ + NA ++ +++
++ + + + +++ +++
+++ ++ + NA + +++
+++ ++ + ++ ++ +++
+++ + ++ ++ +++ +++
++ + + + + +++
+++ ++ ++ NA +++ +++
+++ ++ + NA + +++
+++ ++ + NA + +++
+++ + ++ + ++ +++
+++ ++ ++ ++ +++ +++
+++ ++ ++ NA + +++
++ + + NA ++ +++
+ ++ NA NA + NA
++ ++ NA NA + NA
++ ++ NA NA + NA
++ ++ NA NA +++ +++
++ ++ NA NA + NA
++ ++ NA NA +++ NA
+++ ++ ++ ++ + +++
+++ ++ + + + +++
+++ + + + + +++
++ ++ NA NA + +++ 38 ++ ++ NA NA + +++
39 ++ ++ NA NA + +++
40 +++ ++ ++ ++ + +++
41 ++ ++ NA NA +++ NA
42 + + NA NA + +
43 + + NA NA + +
44 ++ ++ + ++ +++ +++
45 ++ + + + + +++
46 +++ ++ NA NA ++ +++
47 +++ ++ NA NA + +++
48 + ++ NA NA ++ NA
49 + ++ NA NA +++ NA
50 ++ ++ NA NA ++ NA
51 ++ ++ NA NA +++ NA
52 ++ ++ NA NA +++ NA
53 ++ ++ NA NA + NA
54 + + NA NA ++ NA
55 ++ + + + ++ NA
56 ++ ++ NA NA +++ NA
57 ++ ++ NA NA + NA
58 + + NA NA + NA
59 ++ ++ NA NA ++ NA
60 + + NA NA ++ NA
61 + + NA NA ++ NA
62 + + NA NA +++ NA
63 ++ ++ + + +++ +++
64 ++ + + + +++ +++
65 ++ ++ + + + +++
66 ++ ++ NA NA + NA
67 + + NA NA ++ NA
68 ++ + NA NA +++ NA
69 ++ ++ NA NA ++ NA
70 ++ ++ NA NA +++ NA
71 ++ ++ NA NA + NA
72 ++ ++ NA NA ++ NA
NA: not available (testing in progress) As can be seen from the table the compounds of the invention demonstrated good solubility coupled with cathepsin K activity.
(iv) Bone Resorption Inhibitory Activity using Human Osteoclast Cells
Human osteoclast precursors at -3x104 cells/cm2 (Poietics®, Lonza, Walkersville, MD,
USA) were cultured on OsteoAssay™ human bone plate (Lonza) (n=6 per condition) in differentiation media with M-CSF and RANKL according the manufacturer's protocol. Osteoclast precursor basal medium (OPBM) was supplemented by adding the FBS, L-glutamine, penicillin and streptomycin to final concentrations of 10%, 2 mM, 100 units/ml and 100 mg/ml respectively. Media were refreshed after 7 days with and without drug (inhibitor), and the culture was terminated on day 10. Aliquots from media were collected for measuring CTx (CrossLaps®, IDS, Fountain Hills, AZ, USA) and Ca+2 release (Biovision, USA). Samples were stained for tartrate-resistant acid phosphatase (TRAP) activity and for analysis of osteoclast number. These assays were performed for selected few compounds in the series. Compounds tested in this series had IC50s in the range of 200-500nm.
(v) Measurement of Aqueous solubility at pH 7.4:
A stock of 1 mM of the test compound is prepared in 100% DMSO from a 50mM stock (in 100% DMSO). This 1 mM solution is used for spectrum scan from 200 nm to 400 nm with increment of 1 nm to identify wavelength maxima of test compound. A standard curve was plotted by using serial dilution of 1 mM stock in a 96-well plate and measuring absorbance at the Amax of the test compound. To 1 ml of PBS, 0ul of 50mM stock of test compound was added and kept under mixing condition at 50rpm overnight at 25°C. After completion of the incubation, the test solution was filtered using 0.45 μ PVDF injector filters, and 150 μί of the flow through was used for quantification using UV-Vis spectrophotometer at respective Amax value. The aqueous solubility is calculated based on observed absorbance from the standard plot.
(vi) Pharmacokinetics in the Rat
The pharmacokinetics of a test representative compound was evaluated in male Sprague Dawley rats using both intravenous and oral routes (3 animals/group). Basic study design was as follows:
• Rat i. vdose: 1 mg/kg
• Time points for sampling: start(zero min), 20min, 40min, 1 h, 2h, 4h, 6h;
• Parameters measured: CL (ml/min/kg), AUC (uM.h), T1 /2 (h), Vss (L/kg).
• Rat PO dose: 5 mg/kg
• Time points for sampling : 0, 20min, 40min, 1 h, 2h, 4h, 6h;
• Parameters measured: Cmax (uM), Tmax (h), AUC (uM.h), F%. • Suspension formulation: 0.02% Tween-80, 0.5% methyl cellulose (for oral route) and Solution formulation- 5% DMSO, 5% Solutol: ethanol (1 :1 , v/v) and 90% of normal saline (for intravenous route). Following IV administration, t1 2,Bwas 0.50 h, mean systemic clearance was 4.51 L/h/Kg, and the mean Volume of distribution was 3.17 L/Kg. Following oral administration, the mean Cmax was 1010 ng/mL, the mean tmax was 0.25 h and the mean terminal t1 2,Bwas 1 .68 h. The mean absolute oral bioavailability was 52%. Discussion of Comparative Biological results
The compounds of the invention have been demonstrated to be superior to known inhibitors of cathepsin K. For example, a representative compound has a selectivity of >1000 fold over CatL and CatS, whereas its selectivity is >100 fold with respect to CatV. Known inhibitors lack >1000 fold selectivity wrt CatS compared with a known inhibitor. CatS inhibition could be a safety concern since CatS is also responsible for antigen presentation. CatS inhibition is expected to result in immunosupression, and therefore the representative compound is superior in this regard.
The potency of the representative compound and a known inhibitor against human Osteoclasts are comparable. The in-vitro IC50 on Rat CatK are also similar, though against human CatK, a known inhibitor is 10-fold more potent. This indicates differences in interaction of the two 2 compounds with Rat CatK.
The representative compound and a known inhibitor were dosed in healthy rats. Cmax levels in Rats at the same dose(10 mg/kg) is 3 fold higher for the representative compound, yielding a Cmax/CatK (rat IC50) that is ~ 2 fold higher for the representative compound compared to a known inhibitor. This may be significant to the pharmacodynamic translation in an animal model. The solubility of the representative compound is far superior to a known inhibitor; a 20- fold improvement, resulting in 5-fold better bioavailability in rats (52% vs. 10%). The improved solubility and bio-availability may help in developing a simpler oral formulation for the representative compound leading to cost advantage. LogD74 of the representative compound is <2, so it is less lipophilic and has better absorption profile.
The representative compound is also metabolically more stable in human microsomes as compared to a known inhibitor. The known inhibitor has a Cyp2D6 liability whereas the representative compound does not have the same liability, thus has a lower potential for any DDIs. The plasma protein binding which relates to the free fraction also differs and is favourable for the representative compound. The representative compound has about 50% free fraction while the known inhibitor has only 8% free fraction and the rest seems to be plasma protein bound.
The representative compound could be dosed as once a day regimen, while the known inhibitor has a longer half-life compound and is being dosed once a week. With the cost advantage, superior PK profile, stability and selectivity, the representative compound demonstrates a clear advantage over known inhibitors.
Efficacy study of a test compound in Ovariectomized rat osteoporosis model:
Abbreviations in the study/design:
• OVX -Ovariectomy
• μg - microgram
• g -Gram
• μΙ_ - microliter
• mg - milligram
• ml_ - milliliter
• SC - subcutaneous
• Kg -Kilogram
• ODN - Odanacatib
• ALN -Alendronate
• ESD -17-a-ethinyl oestradiol
• OD -Once in a day
• BID -Twice in a day
• PO - Per Oral
• MC -Methyl cellulose
• q.s. -Quantity sufficient
• DMSO -Dimethyl sulphoxide
• EDTA - Ethylenediaminetetraacetic acid
• CPCSEA - Committee for the purpose of control and supervision on experiments on animals
• IAEC - Institutional Animal Ethic Committee
• Test Compound: Compound#1 Efficacy study: Biomarkers & parameters followed:
CTx-1 : C-terminal telopeptide (or more formally, carboxy-terminal collagen crosslinks), is a telopeptide generated from Collagen type 1 by the action of CatK, used as a biomarker in the serum to measure the rate of bone turnover/CatK activity.
Osteocalcin: Osteocalcin is secreted solely by osteoblasts & is often used as a marker for the bone formation process.
P1 NP: amino-terminal propeptide (PINP), sensitive marker of bone formation.
Body weight gain: Ovariectomy is manifested by increase in body weight. Toxicity evaluation: Necropsy after treatment & visual observation during treatment. Study Design:
Species: Rat
Strain : Sprague Dawley
Sex: Female
Age, Weight : 12-13 weeks of age at study, 220-260g
No of animals per group : 10
Animals were dosed for a period of 3 weeks with test compound#1 , as PO at 30 and 100mg/kg BID. Reference drugs ODN and ALN were dosed as PO at 10 and 3mg/kg OD. ESD was dosed at 0.03mg/kg(SC dosing) OD. Results:
1 . There was no toxicityseen due to compound administration over 3 weeks. No gross pathological observation of abnormality for all organs after necropsy in all treated animals.
2. Compound#1 showed dose dependant reduction in CTx-1 levels after 3 weeks when compared to untreated OVX animals.
3. Compound#1 at 100mpk showed significant reduction in relative change (%) in body weight from day 15 onwards.
4. Compound#1 pharmacokinetics did not show any apparent accumulation or decrease in steady state concentration on repeated dosing for 3 weeks.
5. Reference drugs Estradiol (ESD) and Alendronate (ALN) showed significant CTx-1 reduction. The details of specific embodiments described in this invention are not to be construed as limitations. Various equivalents and modifications may be made without departing from the essence and scope of this invention, and it is understood that such equivalent embodiments are part of this invention.

Claims

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:
1 . A compound of formula (I)
Figure imgf000085_0001
(I)
wherein
each R1 is independently selected from the group consisting of hydrogen, C^.C6 alkyl and d-C6 haloalkyl,
each R2 is independently is selected from the group consisting of hydrogen, C^.C6 alkyl and C6 haloalkyl, or
R1 and R2 when taken together with the carbon atoms to which they are attached form a C3.C8 cycloalkyl group;
R3 is selected from the group consisting of hydrogen, optionally substituted d-C6 alkyl and C6 haloalkyl,
R4 is selected from the group consisting of hydrogen and optionally substituted d-C6 alkyl, or R3 and R4 when taken together with the carbon atoms to which they are attached form a C3.C8 cycloalkyl group;
R5 is selected from the group consisting of hydrogen, halogen, OH, N02, CN, SH, NH2, Ci-C6 alkyl, C^.C6 haloalkyl, C^.C6 alkyloxy and d-C6 haloalkyloxy;
V1 is C or N ; and
V2 and V3 are independently selected from the group consisting of CR6, N and NR6;
wherein if V1 is C then at least one of V2 and V3 is N or NR6;
each R6 is independently selected from the group consisting of H, optionally substituted Cr C12alkyl, optionally substituted C2-C12alkenyl, optionally substituted C2-C12alkynyl, optionally substituted CVC^haloalkyl, optionally substituted C2-C12heteroalkyl, optionally substituted C3- C12cycloalkyl, optionally substituted C3-C12cycloalkenyl, optionally substituted C2- C12heterocycloalkyl, optionally substituted C2-C12heterocycloalkenyl, optionally substituted C6- C18aryl, optionally substituted CrC18heteroaryl, optionally substituted C6-C18aryld-C12alkyl, optionally substituted d-C18heteroaryld-C12alkyl S03H, S02NR7R7, S02R7, SONR7R7, SOR7, COR7, COOH, COOR7, CONR7R7,acyl, and a nitrogen protecting group; each R7 is selected from the group consisting of H, optionally substituted Ci.C6alkyl, optionally substituted C3-C12cycloalkyl, optionally substituted C6-C18aryl and optionally substituted Cr C18heteroaryl;
m is an integer selected from the group consisting of 0, 1 , 2 and 3;
n is an integer selected from the group consisting of 1 , 2, and 3;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 wherein the compound has the formula
Figure imgf000086_0001
wherein
each R1 is independently selected from the group consisting of hydrogen, C^.C6 alkyl and C6haloalkyl,
each R2 is independently is selected from the group consisting of hydrogen, C^.C6 alkyl and C6haloalkyl, or
R1 and R2 when taken together with the carbon atoms to which they are attached form a C3-C8 cycloalkyl group;
R3 is selected from the group consisting of hydrogen, optionally substituted C^.C6 alkyl and Cehaloalkyl,
R4 is selected from the group consisting of hydrogen and optionally substituted C^.C6 alkyl, or R3 and R4 when taken together with the carbon atoms to which they are attached form a C3.C8 cycloalkyl group;
R5 is selected from the group consisting of hydrogen, halogen, OH, N02, CN, SH, NH2, C-\.C6 alkyl, d-C6haloalkyl, Ci-C6alkyloxy and Ci-C6haloalkyloxy;
R6 is selected from the group consisting of H, optionally substituted CVC^alkyl, optionally substituted C2-C12alkenyl, optionally substituted C2-C12alkynyl, optionally substituted C C12haloalkyl, optionally substituted C2-C12heteroalkyl, optionally substituted C3-C12cycloalkyl, optionally substituted C3-C12cycloalkenyl, optionally substituted C2-C12heterocycloalkyl, optionally substituted C2-C12heterocycloalkenyl, optionally substituted C6-C18aryl, optionally substituted CrC18heteroaryl, optionally substituted CVC^arylCrC^alkyl, optionally substituted Ci-Cie eteroarylCi-Ci2alkyl S03H, S02NR7R7, S02R7, SONR7R7, SOR7, COR7, COOH, COOR7, CONR7R7,acyl,and a nitrogen protecting group;
each R7 is selected from the group consisting of hydrogen and alkyl;
m is an integer selected from the group consisting of 0, 1 , 2 and 3;
n is an integer selected from the group consisting of 1 , 2, and 3;
or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 1 wherein the compound has the formula
Figure imgf000087_0001
wherein
R1 , R2, R3, R4, R5, R6, m and n are as defined in claim 1 ,
or a pharmaceutically acceptable salt thereof.
4. A compound according to claim 1 wherein the compound has the formula
Figure imgf000087_0002
wherein
R1 , R2, R3, R4, R5, R6, m and n are as defined in claim 1 ,
or a pharmaceutically acceptable salt thereof.
5. A compound according to claim 1 wherein the compound has the formula
Figure imgf000088_0001
wherein
R1 , R2, R3, R4, R5, R6, m and n are as defined in claim 1 ,
or a pharmaceutically acceptable salt thereof.
6. A compound according to any one of claims 1 to 5 wherein n is 1 .
7. A compound according to any one of claims 1 to 6 wherein R1 is hydrogen.
8. A compound according to any one of claims 1 to 7, wherein R2 is hydrogen.
9. A compound according to any one of claims 1 to 8, wherein R1 and R2 when
together with the carbon atom to which they are attached form a cyclopropyl group.
10. A compound according to any one of claims 1 to 9, wherein R3 is hydrogen.
1 1. A compound according to any one of claims 1 to 10, wherein R4 is C^alkyl optionally substituted with methanesulfonyl-, halo- or alkoxy- groups.
12. A compound according to any one of claims 1 to 8, wherein R3 and R4 when taken together with the carbon atom to which they are attached form a cyclohexyl group.
13. A compound according to any one of claims 1 to 12, wherein R5 is hydrogen.
14. A compound according to any one of claims 1 to 13, wherein R6 is selected from the group consisting of hydrogen and a methanesulfonyl group.
15. A compound according to claim 1 , selected from the following:
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000090_0002
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 and a pharmaceutically acceptable carrier, diluent or excipient.
18. A method of treating a cathepsin dependent condition in a patient which comprises administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof.
19. A method according to claim 18 wherein the condition is selected from the group consisting of inflammation, osteoporosis, rheumatoid arthritis and osteoarthritis.
20. A method of selectively inhibiting cathepsin K activity in a patient which comprises administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof.
Use of a compound according to any one of claims 1 to 16 in the manufacture of a medicament for the treatment of cathepsin dependent conditions.
PCT/IN2015/050097 2014-08-22 2015-08-21 Bicyclic heteroaryl amides as cathepsin cysteine protease inhibitors WO2016027285A2 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3902545A4 (en) * 2018-12-24 2022-06-22 InventisBio Co., Ltd. Novel salts of selective estrogen receptor degraders

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1673336B1 (en) * 2003-08-21 2014-06-04 Merck Canada Inc. Cathepsin cysteine protease inhibitors
WO2006076796A1 (en) * 2005-01-19 2006-07-27 Merck Frosst Canada Ltd. Cathepsin k inhibitors and obesity
CN101687864A (en) * 2007-06-26 2010-03-31 阿斯利康(瑞典)有限公司 1-cyanocyclopropyl-derivatives as cathepsin K inhibitors

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3902545A4 (en) * 2018-12-24 2022-06-22 InventisBio Co., Ltd. Novel salts of selective estrogen receptor degraders
US11903931B2 (en) 2018-12-24 2024-02-20 InventisBio Co., Ltd. Salts of selective estrogen receptor degraders

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