Field of the Invention
The present invention relates to certain spiro-heterocyclic derivatives as caspase inhibitors and to the processes for the synthesis of the same This invention also relates to pharmaceutical compositions containing the compounds of the present invention as caspase inhibitors The compounds of this invention are useful for treating wide variety of chronic and acute inflammatory disorders
Background of the invention During the last decade, numerous studies have focused on the roles played by cytokines, a unique class of intercellular regulatory proteins, in the pathogenesis of many diseases Cytokines play a crucial role in initiating, maintaining, and regulating immunological and inflammatory processes Advances in our understanding of their role in immune and inflammatory disorders have led to the development of cytokine-based therapies—that is, therapies that aim to inhibit or restore the activity of specific cytokines Today, drugs that block inflammatory cytokines, such as Tumor Necrosis Factor-alpha (TNF-a ) are among the most successful agents being introduced to the market (Carteron N L (2000) Cytokines m Rheumatoid Arthritis trials and tribulations Molecular Medicine Today, 6 315-323)
Elevated levels of proinflammatory cytokines viz TNF-a and Interleukin 1 (IL-1) are associated with the pathogenesis of many immune mediated autoimmune diseases, inflammatory disorders, including Sepsis, Rheumatoid Arthritis, Inflammatory Bowel Disease, Type-1 Diabetes, Asthma, Chronic Obstructive Pulmonary Disorder, osteoporosis, organ transplant rejection and Psoriasis The development of protein-based therapies that inhibit the activities of tumor-necrosis factor-a (TNF-a), including etanercept (Enbrel, Amgen/Wyeth), infliximab (Remicade, Centocor), and adahmumab (Humira, Abbott), has been an important advancement in the treatment of autoimmune diseases such as rheumatoid arthritis The approval of Kineret — an interleukin-1 (IL-1) receptor antagonist — further indicates the clinical utility of protein-based therapies that regulate cytokine activities However, current injectable therapies have associated limitations and risks, including the potential for increased malignancies and infections and increased congestive heart failure in addition to having parenteral route of administration (Carteron N L (2000) Cytokines in Rheumatoid Arthritis trials and tribulations Molecular Medicine Today, 6 315-323)
Studies in rodent models have provided evidence that targeting specific pathways involved in pro-inflammatory cytokine synthesis and processing are effective approaches to interrupt inflammatory cascade Oral small molecules that regulate these pathways should be the next significant advancement in the treatment of chronic inflammatory diseases when used either as a monotherapy or in combination with the current injectables / steroids (Dmarello CA (2004) Therapeutic strategies to reduce IL-1 activity in treating local and systemic inflammation Current opinion in Pharmacology, 4 378 - 385)
IL-1 is one such proinflammatory cytokine that plays a major role in a wide range of inflammatory and autoimmune diseases These include but are not restricted to proliferative disorders, degenerative diseases, inflammatory peritonitis, adult respiratory syndrome, rheumatoid arthritis (RA), osteoarthnts (OA), chronic obstructive pulmonary disease (COPD), asthma, inflammatory bowel disease (IBD) including Crohn's disease and ulcerative colitis, atherosclerosis and diseases of the central nervous system such as multiple sclerosis, Alzheimer's disease and stroke A pro-inflammatory tissue destructive role for IL-1 has been implicated in
many human diseases exemplified as above IL-1 has been demonstrated to promote leukocyte infiltration,
prostaglandin synthesis, joint swelling and tissue destruction The importance of IL-1 as a target for antiinflammatory therapy is shown by the efficacy of IL-1 receptor antagonist, Kineret in RA patients (Dinarello CA (2004) Therapeutic strategies to reduce IL-1 activity in treating local and systemic inflammation Current opinion in Pharmacology, 4 378 - 385 )
IL-1 family comprises of IL-1 P, IL-1 p (agonist forms) and IL-1 receptor antagonist IL-1 p, the major form implicated in inflammation is synthesized as a biologically inactive precursor, pro IL-1 p which is cleaved by interleukin-1 p converting enzyme (ICE) / caspase-1 between Asp-116 and Ala-117 to produce a biologically active C-terminal fragment found in human serum and synovial fluid Processing by ICE is also required to transport the mature IL-1 p through the cell membrane ICE also cleaves biologically inactive IL-18 at Asp-36 to generate a biologically active form IL-18 is a cytokine that is crucial for the development of Th-1 response that underlies diseases like RA (Braddock M and Quinn A (2004) Targeting IL-1 in inflammatory disease New opportunities for therapeutic intervention Nature Reviews Drug Discovery, 3 330-339) ICE is a Cysteine Protease localized primarily in monocytes ICE was the first human caspase to be identified and isolated but since then a total of 12 human caspases have been reported Caspases represent one of the most specific protease families yet described, since they have an absolute requirement for an aspartic acid residue in the PI position of their substrate Caspases are divided into 3 groups based upon their substrate preferences and physiological functions Group I caspases contain caspase-1, 4 and 5 are involved in processing of inflammatory cytokines These have a preference for aromatic/hydrophobic amino acid at P4 position Group II caspases contain caspase 2, 3 and7 and are known as apoptosis executioners and have strong preference for an Aspartic acid residue in the P4 position Group III caspases, which contains caspase 6, 8, 9 and 10, show greater tolerance for amino acids in the P4 position and are effectors of apoptosis (Brian T O and Lee Dennis (2004) Prospects for Caspase inhibitors Mini Review in Medicinal Chemistry, 4 153-165)
Various potent peptide and peptidyl Caspase-1 inhibitors are known However peptidic inhibitors are associated with undesirable properties such as poor oral absorption, poor stability, rapid metabolism and are also known to be less efficacious in cellular models of inflammation To improve upon the pharmacological and pharmacokinetic properties, peptidomimetic inhibitors have been reported However, there still continues to be a need for small molecule, non-peptidic Caspase-1 inhibitors that are potent and selective and membrane permeable to provide effective pharmacological response Such compounds would play an important role in treating diseases where Caspase-1 enzyme is involved
WO00/23421 discloses novel (substituted) acyl dipeptidyl inhibitors of ICE/ced-3 family of Cysteine proteases, W099/47545 discloses novel class of compounds as caspase inhibitors, WO03/72528 discloses novel (substituted) acyl dipeptidyl inhibitors of ICE/ced-3 family of Cysteine proteases, WO95/35308 discloses novel class of compounds which are inhibitors of interleukin- 1ß converting enzyme, US 20030191120 discloses compounds and pharmaceutical composition for prevention or treatment of Parkinson's diseases, WO00/01666 discloses novel oxamyl dipeptide ICE/ced-3 family inhibitors, WO97/41102 discloses carboxamide derivatives of pyrrolidine, pipendme and hexahydroazepme for treatment of thrombosis diseases, WO 95/09859 discloses boropepetide inhibitors of thrombin, WO 98/01133 discloses bone resorption inhibitor
WO2005/063290 discloses use of IL-18 binding protein in inflammations US6306820 discloses combination therapy using a TNF binding protein for treating TNF-mediated diseases WO92/10210 disclosed inhibitors of angiogenesis by IL-1 WO 2004/ 060911-combination therapy with co-stimulatory factor
Summary of the Invention The present invention provides compounds containing spiro-heterocychc ring systems as effective caspase inhibitors Also provided are processes for synthesizing such compounds
Pharmaceutical composition containing such compounds are provided together with their pharmaceutically acceptable carriers or diluents, which can be used for the treatment of caspase-1 mediated pathologies including inflammatory and autoimmune diseases such as bronchial asthma, rheumatoid arthritis, Chronic Obstructive Pulmonary Disorder, Sepsis, Inflammatory Bowel Disease, type I diabetes, multiple sclerosis, allograft rejection or psoriasis
The racemates, enantiomers, diastereomers, rotational isomers, N-oxides, polymorphs, pharmaceutically acceptable salts and pharmaceutically acceptable solvates of these compounds, prodrugs and metabolites having the same type of activity are also provided, as well as pharmaceutical compositions comprising the compounds, their metabolites, racemates, enantiomers, diastereomers, conformational isomers, N-oxides, polymorphs, solvates or pharmaceutically acceptable salts thereof, in combination with a pharmaceutically acceptable carrier and optionally included excipients
Other objects will be set forth in accompanying description which follows and in the part will be apparent form the description or may be learnt by the practice of the invention In accordance with one aspect, of the invention there are provided compounds having the structure of Formula I

(Formula Removed)

including pharmaceutically acceptable salts, pnarmaceutically acceptable solvates, enantiomers, diastereomers,
polymorphs, prodrugs, metabolites or jV-oxides thereof
G is carbon or sulphur, S=O or S(O)2
W forms an optionally substituted spiro-heterocychc ring with any one of the carbon atoms on the ring J,
Y can be independently selected from -CO-, -C(R1)(R2)-,CH(R1)CH(R2)- and -N(R1)- (wherein R1 and R2 are
independently selected from group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,
heterocyclyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl or cycloalkylalkyl, or R1 and R2 can together form a
carbocyclic/aromatic or heterocyclic / heteroaromatic ring along with the carbon atoms to which they are
bonded),
whenY is -CR1(R2)CR|(R2)- or -C(R1)(R2)-,
then Z can be a bond or can be independently selected from -CH2-, -C(=K)-, -C(=K)Rd- or -SO2 (wherein K can
be selected from oxygen or sulphur and Rj is amino, sulphonyl amino or oxygen),
when Yis-N(R|)-
then Z can be a bond or can be independently selected from -CH2-, -C(=K)-, or -SO2 wherein K can be
selected from oxygen or sulphur,
when Y is -C(=O)-
then Z can be a bond,
n can be an integer from 1-3
L is hydrogen, lower (C1-C6) alkyl, lower (C3-C8) cycloalkyi, lower (C3-C8) cycloalkylalkyl, lower (C1-C6)
aralkyl or lower (C1-C6) heterocyclylalkyi, aryl or heteroaryl
B is optionally substituted alkyl, cycloalkyi, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyi,
heteroaryl or heteroarylalkyl,

A can be
(Formula Removed)
wherein R3 is hydroxy, alkyloxy, cycloalkyloxy or ^^RpCwhererr?^1 is alkyl, alkenyl, alkynyl, cycloalkyi,
aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyi, heterocyclylalkyi or cycloalkylalkyl),
R3' is hydrogen, alkyl, fluoroalkyl, heterocyclyl or heteroaryl, -(CH2)n-NRxRy,
-C(=O)NRxRv -(CH2)n-ORx, -(CH2)n-OC(=O)NRxRy -(CH2)n-SRx, (wherein Rx can be selected from is alkyl,
alkenyl, alkynyl, cycloalkyi, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyi, heterocyclylalkyi or
cycloalkylalkyl and Ky can be either hydrogen or Rx),
When A is Formula D then R3 and R3 are interchangeable,
R4, R4 and R5 are hydrogen, CH3 or fluorine, and
R is independently selected from hydrogen, alkyl, aralkyl, cycloalkyi, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyi, and heteroarylalkyi (when R is heterocyclyl or heteroaryl, then the point of attachment to
oxygen is not through heteroatom)
R1 independently could be hydrogen, alkyl, arylalkyl, cycloalkyi, fluoroalkyl, heterocyclyl, heterocyclylalkyi or
heteroarylalkyi,
In other embodiment, the invention encompasses compounds that include, for example (S)-3-[((S)-7-{(S)-3-Methyl-2-[{naphthalene-2-carbonyl)-amino]-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butync acid (Compound No 1), (S)-3-[((S)-7-{(S)-3-Methyl-2-(-2-naphthalene-l-yl-acetylamino)-butyryl]-3-phenyI-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butync acid (Compound No 2), (S)-3-[{(S)-7-[(S)-3-Methyl-2-(-2-naphthalene-2-yl-acetylamino)-butyryl]-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 3),
(S)-3-[{(S)-7-[(S)-3-Methyl-2-(-2-p-tolyl-acetylamino)-butyryl]-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 4),
(S)-3-[{(S)-7-[(S)-3-Methyl-2-(-2-o-tolyl-acetylammo)-butyryl]-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 5),
(S)-3-[{(S)-7-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butync acid (Compound No 6), (S)-3-[((S)-3-Methyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butync acid(Compound No 7)
(S)-3-[((S)-4-Methanesulfonyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl)-amino]-4-oxo-butync acid (Compound No 08),
(S)-3-[{(S)-4-Methanesulfonyl-7-[(S)-3-methyl-2-(2-naphthalene-l-yl-acetylamino)-butyryl]-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl)-ammo]-4-oxo-butync acid (Compound No 9),
(S)-3-[{(S)-4-Acetyl-7-[(S)-3-methyl-2-(-2-o-tolyl-acetylamino)-butyryl]-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 10),
(S)-3-[{(S)-4-Acetyl-7-[(S)-3-methyl-2-(-2-naphthalene-l-yl-acetylamino)-butyryl]-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 11),
(S)-3-[{(S)-4-Acetyl-7-[(S)-3-methyl-2-(-2-thiophen-2-yl-acetylammo)-butyryl]-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 12),
(S)-3-{[(S)-4-Acetyl-7((S)-3-methyl-2-phenylacetylamino-butyryl)-l-thia-4,7-diaza-spiro[4 4] nonane-8-
carbonyl]-amino}-4-oxo-butync acid (Compound No 13),
(S)-3-[((S)-4-Acetyl-7-{(S)-3-methyl-2-[2-(-4-tnfluoromethyl-phenyl-)-acetylamino]-butyryl}-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 14),
(S)-3-({(S)-4-Acetyl-7-[(S)-3-methyl-2-(2-phenoxy-acetylamino)-butyryl]-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl}-ammo)-4-oxo-butyric acid (Compound No 15),
S)-3-[((S)-4-Acetyl-7-{(S)-2-[2-(3-fluoro-phenyl)-acetylamino]-3-methyl-butyryl}-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl]-amino)-4-oxo-butync acid (Compound No 16),
(S)-3-[((S)-4-Acetyl-7-{(S)-3-methyl-2-(2-p-tolyl-acetylamino)-butyryl}-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl]-amino)-4-oxo-butync acid (Compound No 17),
(S)-3-[((S)-4-Acetyl-7-{(S)-2-[2-(2-fluoro-phenyl)-acetylamino]-3-methyl-butyryl}-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 18),
(S)-3-[((S)-4-Acetyl-7-{(S)-2-[2-(4-methoxy-phenyl)-acetylamino]-3-methyl-butyryl}-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 19),
(S)-3-[{(S)-4-Acetyl-7-[(S)-3-methyl-2-(-2-naphthalene-2-yl-acetylamino)-butyryl]-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 20),
(S)-3-[((S)-4-Acetyl-7-{(S)-2-[2-(3-methoxy-phenyl)-acetylamino]-3-methyl-butyryl}-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl}-ammo)-4-oxo-butyric acid (Compound No 21),
(S)-3-[{(S)-4-Acetyl-7-[(S)-2-[-2-(4-chloro-phenyl)-acetylamino]-3-methyl-butyryl]-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 22),
(S)-3-[{(S)-4-Acetyl-7-[(S)-2-[-2-(4-fluoro-phenyl)-acetylamino]-3-methyl-butyryl]-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 23),
(S)-3-[{(S)-4-Acetyl-7-{(S)-2-[-2-(2-acetylamino-thiazol-4-yl)-acetylamino]-3-methyl-butyryl]-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 24),
(S)-3-[((S)-4-Acetyl-7-{(S)-3-methyl-2-[2-(2-methyl-lH-mdol-3-yl)-acetylamino]-butyryl}-l-thia-4,7-diaza-
spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 25),
(S)-3-[((S)-4-Acetyl-7-{(S)-2-(2-lH-indol-3-yl-acetylamino)-3-methyl-butyryl]-l-thia-4,7-diaza-spiro[4 4]
nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 26),
(S)-3-[((S)-4-Acetyl-7-{(S)-2-((S)-2-acetylamino-2-phenyl-acetylamino)-3-methyl-butyryl]-l-thia-4,7-diaza-
spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 27),
(S)-3-[((S)-4-Acetyl-7-{(S)-2-(S)-2-hydroxy-2-phenyl-acetylamino)-3-methyl-butyryl]-l-thia-4,7-diaza-
spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 28),
(S)-3-[((S)-4-Acetyl-7-{(S)-3-methyl-2-(3-phenyl-propionylamino)-butyryl]-l-thia-4,7-diaza-spiro[4 4]
nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 29),
(S)-3-{[(R)-8-Acetyl-4-(naphthalene-2-yl-aminooxalyl)-l-thia-4,8-diaza-spiro[4 5]decane-3-carbonyl]-amino}-
4-oxo-butync acid (Compound No 30),
(S)-3-[{(S)-7-{(S)-2-[(Isoquinohne-l-carbonyl)-amino]-3-methyl-butyryl}-3-phenyl-l-oxa-2,7-diaza-
spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butync acid (Compound No 31),
(S)-3-[{(S)-7-{(S)-2-[(Isoquinoline-l-carbonyl)-amino]-3-methyl-butyryl}-3-methyl-l-oxa-2,7-diaza-
spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butync acid (Compound No 32),
(S)-4-(7-Methoxy-benzooxazol-2-yl)-3-[((S)-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-
phenyl-1 -oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-ammo]-4-oxo-butync acid (Compound No 33),
(S)-4-[5-(2,6-Dichloro-phenyl)-oxazol-2-yl]-3-[((S)-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-
butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butync acid (Compound No
34),
(S)-3-[((S)-7-{(S)-3-Methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-phenyI-l-oxa-2,7-diaza-
spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-4-(5-pyndm-2-yl-oxazoI-2-yl)-butync acid (Compound No 35),
(S)-4-Benzooxazol-2-yl-3-[((S)-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-phenyl-l-oxa-
2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butync acid (Compound No 36),
(S)-3-[((S)-7-{(S)-3-Methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-phenyl-l-oxa-2,7-diaza-
spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-4-(5-phenyl-oxazol-2-yl)-butync acid (Compound No 37),
(S)-3-[((S)-7-{(S)-3-Methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-phenyl-l-oxa-2,7-diaza-
spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxazolo[4,5-b]pyndin-2-yl-4-oxo-butync acid (Compound No 38),
(S)-4-(4-Methoxy-benzooxazol-2-yl)-3-[((S)-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-
phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butync acid (Compound No 39),
(S)-4-(4-Methoxy-benzooxazol-2-yl)-3-[((S)-3-methyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-
butyryl}-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butync acid (Compound No 40),
(S)-3-({(S)-7-{(S)-2-[(Isoquinoline-l-carbonyl)-amino-3-methyl-butyryl}-3-methyl-l-oxa-2,7-diaza-spiro[4,4]
non-2-ene-8-carbonyl}-amino)-4-(7-methoxy-benzooxazol-2-yl)-4-oxo-butync acid (Compound No 41),
(S)-4-Benzooxazol-2-yl-3-[((S)-3-methyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-l-oxa-
2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butync acid (Compound No 42),
(S)-3-({(S)-7-{(S)-2-[(Isoquinoline-l-carbonyl)-amino-3-methyl-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4,4]
non-2-ene-8-carbonyl}-amino)-4-(7-methoxy-benzooxazol-2-yl)-4-oxo-butync acid (Compound No 43),
(S)-3-({(S)-7-{(S)-2-[(Isoquinohne-l-carbonyl)-amino-3-methyl-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4,4]
non-2-ene-8-carbonyl}-amino)-4-(4-methoxy-benzooxazol-2-yl)-4-oxo-butync acid (Compound No 44),
(S)-3-({(S)-7-{(S)-2-[(Isoquinohne-l-carbonyl)-amino]-3-methyl-butyryl}-3-methyl-l-oxa-2,7-diaza-spiro[4,4]
non-2-ene-8-carbonyl}-amino]-4-(4-methoxy-benzooxazol-2-yl)-4-oxo-butync acid (Compound No 45),
(S)-4-(7-Methoxy-benzooxazol-2-yl)-3-[((S)-3-methyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-
butyryl}-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butync acid (Compound No 46),
(S)-3-({(S)-4-Acetyi-7-[(S)-3-methyl-2-(2-naphthalen-2yl-acetylamino)-butyryl]-l-thia-4,7-diaza-
spiro[4,4]nonane-8-carbonyl}-amino)-4-(4-methoxy-benzooxazol-2-yl)-4-oxo-butync acid (Compound No 47),
(S)-3-({(S)-4-Acetyl-7-[(S)-3-methyl-2-(2-naphthalen-2yl-acetylamino)-butyryl]-l-thia-4,7-diaza-
spiro[4,4]nonane-8-carbonyl}-amino)-4-(7-methoxy-benzooxazol-2-yl)-4-oxo-butync acid (Compound No 48),
(S)-3-[((S)-4-Methanesulfonyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-l-thia-4,7-diaza-
spiro[4 4]nonane-8-carbonyl)-amino]-4-(4-methoxy-benzooxazol-2-yl)-4-oxo-butync acid (Compound No 49),
(S)-3-[((S)-4-Methanesulfonyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-l-thia-4,7-diaza-
spiro[4 4]nonane-8-carbonyl)-amino]-4-(7-methoxy-benzooxazol-2-yl)-4-oxo-butync acid (Compound No 50),
5-(Hexyl-methyl-amino)-3-[((S)-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-phenyl-l-
oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 51),
5-(2-Chloro-benzyloxy)-3-[((S)-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-phenyl-l-oxa-
2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 52),
(S)-5-(2-Chloro-benzylsulfanyl)-3-[((S)-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-
phenyl-1 -oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 53),
5-(Benzyl-methyl-amino)-3-[((S)-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-phenyl-l-
oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 54),
(S)-5-(l,3-Dioxo-l,3-dihydro-isoindol-2-yl)-3-[((S)-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-
butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound
No 55),
(S)-5-(2-Chloro-benzyloxy)-3-[((S)-7-{(S)-2-[(isoquinoline-l-carbonyl)-amino]-3-methyl-butyryl}-3-phenyl-l-
oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 56),
(S)-5-(2-Chloro-benzyloxy)-3-[((S)-3-methyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-l-
oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 57),
(S)-5-(2-Chloro-benzyloxy)-3-[((S)-7-{(S)-2-[(isoquinolme-l-carbonyl)-amino]-3-methyl-butyryI}-3-methyl-l-
oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 58),
5-(Hexyl-methyl-ammo)-3-[((S)-7-{(S)-2-[Isoquinoline-l-carbonyl)-amino]-3-methyl-butyryl}-3-methyl-l-
oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 59),
(S)-5-(Hexyl-methyl-amino)-3-[((S)-3-methyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-l-
oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 60),
(S)-3-[((S)-7-{(S)-3-Methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-phenyl-l-oxa-2,7-diaza-
spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-9-phenyl-nonanoic acid (Compound No 61),
(S)-5-(HexyI-methyl-amino)-3-[((S)-7-{(S)-2-[isoquinohne-l-carbonyl)-amino]-3-methyl-butyryI}-3-phenyl-l-
oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 62),
(S)-5-(Hexyl-methyl-amino)-3-[((S)-4-methanesulfonyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-l-thia-4,7-diaza-spiro[4 4]nonane-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 63), (S)-5-(2-Chloro-benzyloxy)-3-[((S)-4-methanesulfonyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-ammo]-butyryl}-l -thia-4,7-diaza-spiro[4 4]nonane-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 64), (S)-3-({(S)-4-Acetyl-7-[(S)-3-methyl-2-(2-naphthalen-2yl-acetylamino)-butyryl]-l-thia-4,7-diaza-spiro[4,4]nonane-8-carbonyl}-ammo)-5-(hexyl-methyl-amino)-4-oxo-pentanoic acid (Compound No 65), (S)-3-({(S)-4-Acetyl-7-[(S)-3-methyl-2-(2-naphthalen-2-yl-acetylamino)-butyryl]-l-thia-4,7-diaza-spiro[4,4]nonane-8-carbonyl}-amino)-5-(2-chloro-benzyloxy)-4-oxo-pentanoic acid (Compound No 66), (S)-5-(2-Chloro-benzyloxy)-3-[((5S,8S)-7-{(S)-2-[(isoquinohne-l-carbonyl)-amino]-3-methyl-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid tert-butyl ester (Compound No 67),
(S)-5-(2-Chloro-benzyloxy)-3-[((5R18S)-7-{(S)-2-[(isoquinoline-l-carbonyl)-amino]-3-methyl-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid tert-butyl ester (Compound No 68),
(S)-5-(2-Chloro-benzyloxy)-3-[((5S,8S)-7-{(S)-2-[(isoquinoline-l-carbonyl)-amino]-3-methyl-butyryl}-3-methyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid tert-butyl ester (Compound No 69),
(S)-5-(2-Chloro-benzyloxy)-3-[((5S,8S)-7-{(S)-2-[(isoquinohne-l-carbonyl)-amino]-3-methyl-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 70), (S)-5-(2-Chloro-benzyIoxy)-3-[((5R18S)-7-{(S)-2-[(isoquinoline-l-carbonyl)-amino]-3-methyl-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 71), (S)-5-(2-Chloro-benzyloxy)-3-[((5S,8S)-7-{(S)-2-[(isoquinoline-l-carbonyl)-amino]-3-methyl-butyryl}-3-methyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 72)
In yet other embodiment, the present invention relates to the therapeutically effective dose of a compound of
Formula 1 in combination with one or more of other therapeutic agents used for treating chronic inflammation
Examples of such therapeutic agents include, but not limited to, Interleukin inhibitors, anti-TNF agent or c-
AMP raising agent like PDE inhibitors, anticholinergics, Muscarinic receptor antagonist, (3-agonists, 5-
lipoxygenase inhibitors, leukotnene antagonists, p38 map kinase inhibitors, MMP inhibitors, dopamine receptor
agonists, corticosteroids, VLA-4 inhibitors, antihistamines, antitussives, Cox-2 inhibitors, DPP IV inhibitors,
anti angiogenic factor(s) and Cell proliferation inhibitors (B-cell and T-cell stimulation)
The following definitions apply to terms as used herein
The term "alkyl" substituent unless and otherwise specified refers to a branched or unbranched saturated
hydrocarbon chain having from 1 to 20 carbon atoms This term is exemplified by groups such as methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl, and the like It may further be
substituted with one or more substituents selected form the group consisting of alkenyl, alkynyl, alkoxy,
cycloalkyl, cycloalkenyl, acyl, acyloxy, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy,
carboxyalkyl, aryl, heterocyclyl, heteroaryl, arylthio, thiol, alkylthio, aryloxy, nitro, aminosulfonyl, -
NHC(=O)Rf, -NRfR<„ -C(=O)NRfRq, -NHC(=O)NRfRq, -C(=O)heteroaryl, C(=O)heterocyclyl, -OC(=O)NRfRq
[wherein Rt and Rq are independently selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl],-SO2R(i (wherein R6 is alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, aryl, heterocyclyl, heteroaryl, heteroarylaikyl or heterocyclylalkyl) Unless otherwise constrained by the definition, all substituents may be further substituted by 1-3 substituents chosen from alkyl, carboxy, -NR1Rq, -C(=O)NRfRq, -OC(=O) NRfRq -NHC(=O)NRfRq (wherein Rf and Rq are the same as defined earlier), hydroxy, alkoxy, halogen, CF3, cyano, and -SO2R6, (where R« are the same as defined earlier), or an alkyl group as defined above may also be interrupted by 1-5 atoms of groups independently chosen from oxygen, sulfur and -NRa- [ wherein Ra is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, acyl, aralkyl,-C(=O)ORf [wherein Rf is the same as defined earlier], -SO2R6; (where R6 is as defined earlier), -C(=O)NRfRq (wherein Rf and Rq are as defined earlier)] Unless otherwise constrained by the definition, all substituents may be further substituted by 1-3 substituents chosen from alkyl, carboxy, -NRfRq, -C (=O)NRfRq, -OC(=O)NRfR{| wherein Rf and Rq are the same as defined earlier hydroxy, alkoxy, halogen, CF3, cyano, and -SO2R6 (where R6 is same as defined earlier), or an alkyl group as defined above that has both substituents as defined above and is also interrupted by 1 -5 atoms or groups as defined above
The term "alkenyl" unless and otherwise specified refers to a branched or unbranched unsaturated hydrocarbon
group containing double bond preferably having from 2 to 20 carbon atoms with cis or trans geometry In the
event that alkenyl is attached to the heteroatom, the double bond cannot be alpha to the heteroatom
It may further be substituted with one or more substituents selected from the group consisting of alkyl, alkynyl,
alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, -NHC(=O)Rf, -NRfRq, -C(=O)NRfRq, -
NHC(=O)NRtRq, -OC(=O)NRfRq (wherein Rf and Rq are the same as defined earlier), alkoxycarbonylamino,
azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy,
heterocyclyl, heteroaryl, heterocyclyl alkyl, heteroaryl alkyl, aminosulfonyl, aminocarbonylamino,
alkoxyamino, nitro, -SO2R6 (wherein R^ are is same as defined earher) Unless otherwise constrained by the
definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy,
hydroxy, alkoxy, halogen, -CF3, cyano, -NRfRq, -C(=O)NRfRq, -OC(=O)NRfRq (wherein Rfand Rq are the same
as defined earlier) and -SO2R6 where R6 is same as defined earlier)
The term "alkynyl" unless and otherwise specified refers an unsaturated hydrocarbon containing a triple bond,
preferably having from 2 to 20 carbon atoms In the event that alkynyl is attached to the heteroatom, the triple
bond cannot be alpha to the heteroatom
It may further be substituted with one or more substituents selected from the group consisting of alkyl, alkenyl,
alkoxy, cycloalkyl, cycloalkenyl, acyl, acyloxy, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy,
arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl, nitro, heterocyclyl, heteroaryl, heterocyclylalkyl,
heteroarylaikyl, -NHC(=O)Rf -NRfRq, -NHC(=O)NRfRq,-C(=O)NRfRq, -OC(=O)NRfRq (wherein Rf and Rq are
the same as defined earlier), -SO2R6 (wherein R6 is same as defined earlier) Unless otherwise constrained by
the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl,
carboxy, carboxyalkyl, hydroxy, alkoxy, halogen, CF3, -NRfRq, -C(=O)NRfRq, -NHC(=O)NRfRq , -
C(=O)NRfRq (wherein Rt and Rq are the same as defined earlier), cyano, and -SO2R6 (where R6 is same as
defined earlier)
The term "alkyloxy" refers to a group-o-alkyl wherein alkyl is same as defined earlier
The term "cycloalkyl" refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring multiple condensed or bridged rings which may optionally contain one or more olefinic bonds, unless or otherwise constrained by the definition Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclopentenyl, and the like, or multiple ring structures such as adamantanyl, and bicyclo [2 2 1] heptane, or cyclic alkyl groups to which is fused an aryl group, for example indane, and the like
It may further be substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, carboxyalkyl, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl, aminocarbonylammo, -NRfRq, -NHC(=O)NRfRq, -NHC(=O)Rf, -C (=O)NRfRq, -OC(=O)NRfRq (wherein Rf and R<, are the same as defined earlier), nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, -SO2R6 (wherein R(, is same as defined earlier) Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, hydroxy, alkoxy, halogen, -CF3, -NRfRq, -C(=O)NRfRq, -NHC(=O)NRfR(), -OC(=O)NRfRq (wherein Rf and Rq, are the same as defined earher),cyano, and -SO2R6( where Re is same as defined earlier)
The term cycloalkyloxy refers to a group-o-cycloalkyl wherein cycloalkyl is defined earlier
"Cycloalkylalkyl" refers to alkyl-cycloalkyl group linked through alkyl portion, wherein the alkyl and cycloalkyl are the same as defined earlier
The term "aryl" herein refers to a carbocychc aromatic group, for example phenyl or naphthyl ring and the like optionally substituted with 1 to 3 substituents selected from the group consisting of halogen (F, CI, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, acyl, aryloxy, CF3, cyano, nitro, COORc (wherein Rc is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, heteroarylalkyl) , NHC(=O)Rf, -NRfRq, -C(=O)NRfRq, -NHC(=O)NRfRq, -OC(=O)NRfRq( wherein Rf and Rq, are the same as defined earlier), -SO2R6 (wherein R(, is same as defined earlier), carboxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or amino carbonyl amino The said aryl group may optionally be fused with cycloalkyl group, wherein the said cycloalkyl group may optionally contain heteroatoms selected from the group consisting of O, N, S
The term "aralkyl" refers to alkyl-aryl linked through alkyl (wherein alkyl is the same as defined above) portion and the said alkyl portion contains carbon atoms from 1-6 and aryl is as defined above The examples of aralkyl groups are benzyl and the like
The term 'heteroaryl" unless and otherwise specified refers to an aromatic ring structure containing 5 or 6
carbon atoms, or a bicyclic aromatic group having 8 to 10 carbon atoms, with one or more heteroatom(s)
independently selected from the group consisting of N, O and S, optionally substituted with 1 to 4 substituent(s)
selected from the group consisting of halogen (F, CI, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, carboxy, aryl, alkoxy, aralkyl, cyano, nitro, heterocyclyl, heteroaryl, -NRfRq, CH=NOH, -(CH2)wC(=O)Rg [wherein w is an integer from 0-4 and Rg is hydrogen, hydroxy, ORf, NRfRq, -NHORf or -NHOH], -C(=O)NRfRq and -NHC(=O)Rf, NHC(=O)NRfRq, -SO2R6 -O-C(=O)NRfRq -OC(=O)Rf, -OC(=O)ORf (wherein R6, Rf and Rq are the same as defined earlier) Unless or otherwise constrained by the definition, the substituents are attached to the ring atom, be it carbon or heteroatom
Examples of heteroaryl groups are oxazolyl, lmidazolyl, pyrrolyl, 1,2,3-tnazolyl, 1,2,4-tnazolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl, pyndinyl, pyridazinyl, pynmidinyl, thienyl, isoxazolyl, tnazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, isothiazolyl, isoquinolinyl, and the like
The term 'heterocyclyl" unless and otherwise specified refers to a non aromatic monocyclic or bicyclic cycloalkyl group having 5 to 10 atoms in which 1 to 4 carbon atoms in a ring are replaced by heteroatoms selected from the group comprising of O, S or N, and may be optionally fused to another cyclic ring system which may in turn be saturated or unsaturated and may futher contain 1-4 heteroatom selected from O, S or N Heterocyclyl or the cyclic ring fused on to it may be optionally substituted wherein the substituents are selected from the group consisting of halogen (F, CI, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, aryl, alkoxy, alkaryl, cyano, nitro, oxo, carboxy, heterocyclyl, heteroaryl, -(CH2)wC(=O)Rg [wherein w and Rg are the same as defined earlier], -OC(=O)Rf, -OC(=O)ORf -C(=O)NRfRq, -SOjRs, -OC(=O)NRfRq, -NHC(=O)NRfRq, -NRfRq (wherein R(, Rf and Rq are the same as defined earlier)or guanidmes Unless or otherwise constrained by the definition, the substituents are attached to the ring atom, be it carbon or heteroatom Also unless or otherwise constrained by the definition the said heterocyclyl ring may optionally contain one or more olefinic bond(s) Examples of heterocyclyl groups are dioxolanyl, oxazolidinyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyndinyl, dihydroisoxazolyl, dihydrobenzofuryl, azabicyclohexyl, dihydroindolyl, pipendinyl or piperazinyl
The term "spiro ring system" refers to carbocychc ring system having 3 to 7 atoms connected to the group to which they are attached through a common carbon atom for example spiro-cyclopentyl, spiro-cyclohexyl, spiro-cyclopentyl, spiro-thiazolyhdinyl, spiro-isoxazohdinyl, and spiro-oxazohdinyl
The term "spiro-heterocyclic ring system" refers to heterocychc ring system having 3 to 10 atoms connected to the group to which they are attached through a common carbon atom, in which the 1 or 2 carbon atoms in a ring are replaced by heteroatoms selected from the group comprising of O, S or N It may further be substituted with one or more substituents selected from the group consisting of halogen (F, CI, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, aryl, alkoxy, alkaryl, cyano, nitro, oxo, carboxy, heterocyclyl, heteroaryl, -(CH2)wC(=O)Rfe [wherein w and Rg are the same as defined earlier], -OC(=O)Rf, -OC(=O)ORf -C(=O)NRfRq, SO2R6, -OC(=O)NRfRq, -NHC(=O)NRfRq, -NRfRq (wherein Re Rf and Rq are the same as defined earlier) or guanidmes For example spiro-thiazolyhdinyl, spiro-isoxazohdinyl, and spiro-oxazohdinyl or spiro- pipendinyl ring system
"HeteroarylalkyI" refers to alkyl-heteroaryl group linked through alkyl portion, wherein the alkyl and heteroaryl are the same as defined earlier
"Heterocyclylalkyl" refers to alkyl-heterocyclyl group linked through alkyl portion, wherein the alkyl and heterocyclyl are the same as defined earlier
"ammo" refers to the group -NH-
"Sulphonyl amino" unless and otherwise specified refers to a group -SO2-NH-
The term 'leaving group" generally refers to groups that exhibit the desirable properties of being labile under the defined synthetic conditions and also, of being easily separated from synthetic products under defined conditions Examples of such leaving groups includes but not limited to halogen (F, CI, Br, I), triflates, tosylate, mesylates radicals and the like
The term "activated derivative of a carboxyhc acid or O-activating group", for example, that of a suitable protected amino acid, aliphatic acid or an aromatic acid refer to the corresponding acyl hahde (e g acid fluoride, acid chloride and acid bromide), corresponding activated esters (e g nitro phenyl ester, the ester of 1-hydroxybenzotnazole or the ester of hydroxysuccinimide, HOSu) or a mixed anhydride for example anhydride with ethyl chloroformate and other conventional derivatives within the skill of the art
The term "Protecting groups" is used herein to refer to known moieties which have the desirable property of preventing specific chemical reaction at a site on the molecule undergoing chemical modification intended to be left unaffected by the particular chemical modification Also the term protecting group, unless or other specified may be used with groups such as hydroxy, amino, carboxy and examples of such groups are found in T W Greene and PGM Wuts, "Protective groups in organic synthesis", 3rd ED, John Wiley and Sons, New York, N Y , which is incorporated herein by reference The species of the carboxyhc protecting groups, amino protecting groups or hydroxy protecting group employed is not so critical so long as the denvatised moieties/moiety is/are stable to conditions of subsequent reactions and can be removed at the appropriate point without disrupting the remainder of the molecule
The term "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds of Formula I are modified by making its acid or base salts Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acids salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxyhc acids, and the like
The term "pharmaceutically acceptable solvates" refers to solvates with water (i e, hydrates) or pharmaceutically acceptable solvents, for example solvates with ethanol and the like Such solvates are also encompassed within the scope of the disclosure Furthermore, some of the crystalline forms for compounds described herein may exist as polymorphs and as such are intended to be included in the scope of the disclosure
Detailed description of the Invention
The compounds disclosed herein may be prepared by techniques well known in the art and familiar to the ordinary skilled synthetic organic chemist In addition, the compounds of the present invention may be prepared by the following reaction sequences as depicted in schemes I, II, III and IV respectively

(Scheme Removed)

The compounds of Formula V can be prepared following the Scheme I,
Thus, the compound of Formula II (wherein Rz is optionally substituted alkyl, cycloalkyl, acyl, cyano, halogen, hydroxy, aryl, aralkyl, nitro, heterocyclyl, heteroaryl, E is a carboxy protecting group for example methyl, ethyl, benzyl, tert-butyl or tnmethylsilyl and P is amine protecting group, for example, t-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl or benzyloxycarbonyl) is N-deprotected to give a compound of Formula III Path A The compound of Formula III reacts with a compound of Formula IV (wherein B, Z and Ri are same as defined earlier) to form a compound of Formula V (wherein Rz, E, B, Z and Ri are same as defined earlier) Path B Alternatively, the compound of Formula III reacts with the compound of Formula XII (P and Ri are same as defined earlier) to give a compound of Formula Ilia (wherein Rz, E, P, and Ri are same as defined earlier) The compound of Formula IIIa is further N-deprotected to give a trifluoroacetate salt of compound of Formula Illb (wherein Rz, E, and R1 are same as defined earlier), which on reacting with a compound of Formula XV (wherein Z and B are same as defined earlier) forms a compound of Formula V The deprotection of the compound of Formula II to give the compound of Formula III, when P= t-butyloxycarbonyl, can be carried out in the presence of one or more mineral acids, for example, hydrochloric, hydrobromic, hydroiodic acid or in the presence of one or more organic acids, for example tnfluoroacetic acid, p-toluenesulphonic acid or camphor sulphonic acid in one or more solvents, for example, polar protic solvent (water, methanol, ethanol, propanol, isopropanol or tert-butanol), polar aprotic solvent (acetonitnle or dioxane), or chlorinated solvent (dichloromethane, chloroform or carbon tetrachloride)
The reaction of the compound of Formula III with the compound of Formula IV to give a compound of Formula V (Path A) can be carried out in a solvent for example dimethylformamide, tetrahydrofuran, dichloromethane, dioxane or diethyl ether and a base for example tnethylamine, dusopropylethylamine or N-methylmorpholme, in the presence of a additives for example hydroxybenzotnazole, 3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotnazine or l-hydroxy-7-azabenzotnazole, with a suitable condensing agent for example, dicyclohexyl carbodimide or l-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride
The reaction of the compound of Formula III with the compound of Formula XII to give a compound of Formula Ilia (Path B) can be carried under similar condition as that of conversion of compound of Formula III to give the compound of Formula V The N-deprotection of the compound of Formula IIIa (when P is t-butoxycarbonyl group) to give a compound of Formula IIIb can be carried under similar condition as that of conversion of Formula II to give the compound of Formula III The reaction of compound of Formula Illb with a compound of Formula XV to give a compound of Formula V can be carried out under similar condition as that of conversion of Formula III to give compound of Formula V
(Scheme Removed)

The compounds of Formula XI can be prepared following the Scheme II,
Thus, the compound of Formula VI (wherein E and P are same as defined earlier) reacts with (un)substituted-2-
aminoethanethiol to form a compound of Formula VII (wherein Rz, P and E are same as defined earlier) which
is further reacted with a compound of Formula VIII (wherein Q is selected form acyl, sulphonyl or carbamoyl
and T is a leaving group for example halide, triflate, tosylate, mesylates) to give a compound of Formula IX
(wherein Rz, P, Q and E are same as defined earlier) and further N-deprotected to give a compound of Formula
X (wherein Rz, Q and E are same as defined earlier)
Path a The compound of Formula X reacts with a compound of Formula IV (wherein B, Z and Ri are same as
defined earlier) to form a compound of Formula XI (wherein Rz, E, Q, B, Z and R1 are same as defined earlier)
Path b Alternatively the compound of Formula X reacts with the compound of Formula XII (wherein P and R1
are same as defined earlier) to give a compound of Formula XIII (wherein Rz, E, Q, P, and Ri are same as
defined earlier) The compound of Formula XIII is further N-deprotected to give a trifluroacetate salt of compound of Formula XIV (wherein Rz, E, Q, and Ri are same as defined earlier), which on reacting with a compound of Formula XV (wherein Z and B are same as defined earlier) forms a compound of Formula XI The reaction of compound VI with (un)substituted-2-aminoethanethiol to give a compound of Formula VII is carried out in the solvent selected form methanol, ethanol or isopropanol in the presence of molecular sieves The reaction of the compound of Formula VII with a compound of Formula VIII to give a compound of Formula IX can be carried out in the solvent, for example, dichloromethane, toluene, dichloroethane, tetrahydrofuran, ether or dioxane in the presence of a base, for example, dimethylaminopyndine, tnethylamine, dnsopropylethylamine or iV-methylmorpholine
The N-deprotection of the compound of Formula IX (when P is t-butoxycarbonyl group) to give the compound of Formula X can be carried out under same condition as that of conversion of compound of Formula II to a compound of Formula III
The reaction of the compound of Formula X with the compound of Formula IV to give a compound of Formula XI (Path a) can be carried under similar condition as that of conversion of Formula IN to give compound of Formula V
The reaction of the compound of Formula X with the compound of Formula XII to give a compound of Formula XIII (Path b) can be carried under similar condition as that of conversion of Formula III to give compound of Formula V The N-deprotection of the compound of Formula XIII (when P is t-butoxycarbonyl group) to give a compound of Formula XIV can be carried under similar condition as that of conversion of Formula II to give the compound of Formula III The reaction of compound of Formula XIV with a compound of Formula XV to give a compound of Formula XI can be carried out under similar condition as that of conversion of Formula III to give compound of Formula V
(Scheme Removed)

The compound of Formula XXI can be prepared following Scheme III Thus, the compound of Formula XVI (where L, Z and B are same as defined earlier) reacts with a compound of Formula XVII (wherein E and T are same as defined earlier) to form a compound of Formula XVIII (wherein B, Z, L and E are same as defined earlier) which is further hydrolysed to give a compound of Formula XIX (wherein B, Z and L are same as
defined earlier) which on reaction with a compound of Formula XX (wherein E is same as defined earlier)
gives a compound of Formula XXI (wherein L, Z, E and B are same as defined earlier)
The reaction of compound of Formula XVI with a compound of Formula XVII to give a compound of Formula
XVIII can be carried out in the solvent, for example, dichloromethane, toluene, dichloroethane, tetrahydrofuran,
ether or dioxane in the presence of a base, for example, dimethylaminopyndine, tnethylamine,
dnsopropylethylamine or jY-methylmorphohne
The hydrolysis of compound of Formula XVIII to give a compound of Formula XIX can be carried out in a
solvent selected from for example methanol, ethanol, tetrahydrofuran, dioxane, water or mixture(s) thereof in
the presence of a base for example lithium hydroxide, potassium hydroxide or sodium hydroxide
The reaction of the compound of Formula XIX with a compound of Formula XX to give a compound of
Formula XXI can be carried under similar condition as that of conversion of Formula III to give compound of
Formula V
(Scheme Removed)
Compounds of Formula XXVI and Formula XXVII can be prepared following the Scheme IV Thus, a compound of Formula XXII is hydrolysed to give a compound of Formula XXIII

Path C The compound of Formula XXIII is reacted with compound of Formula XXIV (wherein R and R3 are
same as defined earlier) to form a compound of Formula XXV (wherein R and R3 are same as defined earlier)
which is further deprotected to give a compound of Formula XXVI (wherein R3 is same as defined earlier)
(path a ) or a compound of Formula XXV is partially hydrolysed to give a compound of Formula XXVII
(wherein R is same as defined earlier) (path b)
Path D The compound of Formula XXIII is coupled with the compound of Formula XXIVa [wherein P, R3,
and R3'are same as defined earlier] to form a compound of Formula XXVa [wherein R3 and R3'are same as
defined earlier], which is further deprotected to give a compound of Formula XXVI
Path E The compound of Formula XXIII is reacted with the compound of Formula XXIVb [wherein P is amine
protecting group for example allyloxycarbonyl, benzyloxycarbonyl and R3, R3'are same as defined earlier] to
form a compound of Formula XXVb [wherein R3 and R3'are same as defined earlier], which is further oxidized
to give a compound of Formula XXVa [wherein R3 and R3'are same as defined earlier] The compound of
Formula XXVa is further deprotected to form a compound of Formula XXVI
The hydrolysis of the compound of Formula XXII to give a compound of Formula XXIII is carried out under
similar condition as that of conversion of Formula XVIII to Formula XIX
The reaction of the compound of Formula XXIII with a compound of Formula XXIV a to form a compound of
Formula XXV(Path C) is carried out under similar condition as that of conversion of Formula III to Formula V
The compound of Formula XXV is deprotected to form a compound of Formula XXVI (path a) using acids for
example hydrochloric acid, tnfluoroacetic acid in a solvent for example dichloromethane, tetrahydrofuran,
dioxane, water or mixtures thereof The hydrolysis of the compound of Formula XXV to give a compound of
Formula XXVII (path b) can be carried out using acids for example hydrochloric acid, tnfluoroacetic acid in a
solvent for example dichloromethane, tetrahydrofuran, dioxane or mixtures thereof
The reaction of compound of Formula XXIII with a compound of Formula XXIVa to form a compound of
Formula XXVa (Path D) is carried by in situ deprotection of amine (when P is allyloxycarbonyl) with catalytic
amount of palladium (II) or palladium (O) for example Bis (tnphenyl phosphine) palladium (II) chloride,
tetrakis (tnphenyl phosphine) palladium (O) [tns(dibenzylideneacetone)dipalladium-(chloroform)] and tnbutyl
tin hydride or dimedone in solvent such as tetrahydrofuran, toluene, or dioxane and trace of water, in the
presence of a additives for example hydroxybenzotnazole, 3-hydroxy-3,4-dihydro-4-oxo-l,2,3-benzotnazine or
1-hydroxy-7-azabenzotnazole, with a suitable condensing agent for example, dicyclohexyl carbodimide or 1-
(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride The compound of Formula XXVa is deprotected
to form a compound of Formula XXVI under similar condition as that of conversion of Formula XXV to
Formula XXVI
The coupling of compound of Formula XXIII with a compound of Formula XXIVb( when P= allyloxycarbonyl)
to form a compound of Formula XXVb (Path E) is carried out similar to conversion of Formula XXIII to
Formula XXVa in a mixture of solvent such as dichloromethane and dimethylformamide or tetrahydrofuran
alone without the presence of water The compound of Formula XXVb is oxidized to compound of Formula
XXVa in dichloromethane or chloroform with oxidizing agent such as Dess-Martin reagent Alternatively,
compound of Formula XXVb can be oxidized to form the compound of Formula XXVa using Corey-Kim
oxidation (N-chlorosuccinimide and Dimethylsulphide) or Swern oxidation (Dimethylsulphoxide and oxalyl
chloride) in presence of base such as tnethylamine, dnsopropylethylamine in solvent such as dichloromethane or toluene The compound of Formula XXVa is deprotected to form a compound of Formula XXVI under similar condition as that of conversion of Formula XXV to Formula XXVI
Compound Nos 1 to 7, 31-46, 51-62, 67-72 were prepared following Scheme I and IV Compound Nos 8 to 29, 47-50, 63-66 were prepared following Scheme II and IV Compound No 30, was prepared following Scheme III and IV
In the above schemes, where specific bases, acids, solvents, condensing agents, reducing agent, deprotecting agent, hydrolyzing agents, metal catalysts etc , are mentioned, it is to be understood that other acids, bases, solvents, condensing agents, reducing agent, deprotecting agent, hydrolyzing agents, metal catalysts etc , known to those skilled in the art may also be used Similarly, the reaction temperature and duration of the reactions may be adjusted according to the requirements that arise during the process
Examples set forth below demonstrate the general synthetic procedures for the preparation of representative compounds The examples are provided to illustrate particular aspect of the disclosure and should not be constrained to limit the scope of the present invention
Experimental Details Synthesis of starting materials Synthesis of (S)-3-Methyl-2-[(naphthalene-2-carbonyl)-amino]-butync acid
The title compound was prepared following the procedure outlined in Journal of Medicinal Chemistry, 1988
31 2092-2097 for (R)-2- Benzoylamino-3-phenylpropiomc acid by replacing benzoyl chloride with
Naphthalene-2- carbonyl chloride and (R)-2-amino-3-phenylpropionic acid with (S)-2-amino-3-methyl-butync
acid
EIMS(m/z) 272 0(M+1)
Analogues o/(S)-3-Methyl-2-[(naphthalene-2-carbonyl)-amino]-butync acid described below were prepared by
replacing Naphthalene-2-carbonyl chloride with appropriate acid chloride as applicable in each case
(S)-3-Methyl-2-(2-naphthalen-l-yl-acetylamino)-butyrw acid
(S)-3-Methyl-2-(2-naphthalen-2-yl-acetylamino)-butyric acid
Synthesis of (S)-2-[(Isoquinohne-l-carbonyl)-amino]-3-methyl-butync acid
Step a Synthesis of(S)-2-f(Isoquinoline-l-carbonvl)-aminol-3-methvl-butyric acid methyl ester
To the solution of isoquinohne-1-carboxylic acid (2 065 g) in dimethyl formamide (10 mL), N-
methylmorpholine (3 95 mL), hydroxybenzotnazole (1 77 g) and (S)-2-Amino-3-methyl-butync acid methyl
ester hydrochloride salt (2 g) was added at 0°C The reaction mixture was stirred for 10-15 mm followed by the
addition of l-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (2 5 g) and then stirred at 0°C for 1 h
and at room temperature for overnight The reaction mixture was diluted with ethyl acetate and washed with
water and brine, dried over anhydrous sodium sulphate and concentrated The crude product thus obtained was
purified by column chromatography over silica gel using 50 % ethyl acetate in hexane as eluant to furnish the
title compound (3 g)
EIMS(m/z) 287 2(M+1)
Step b Synthesis of(S)-2-f(lsoquinohne-l-carbonyl)-aminol-3-methyl-butyric acid
Lithium hydroxide monohydrate (0 48 g) was added to the solution of (S)-2-[(Isoquinohne-l-carbonyl)-amino]-3-methyl-butync acid methyl ester (2 6 g) in a mixture of solvent (20 mL) [tetrahydrofuran methanol water, (3 11)] and reaction mixture was stirred for about 3 h The reaction mixture was concentrated to obtain a crude residue that was taken in water (lOmL) and washed with ethyl acetate The aqueous layer was acidified with sodium hydrogen sulphate and extracted with ethyl acetate The combined organic extracts were washed with water, brine and dried over anhydrous sodium sulphate and concentrated to furnish the title compound (2 1 g) EIMS(m/z) 273 2(M+1)
Synthesis of trifluoroacetic acid salt of (S)-3-Phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2ene-8-carboxyhc acid methyl ester
Step a Synthesis of(S)-4-Methvlene-pvrrolidine-l,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester
The title compound was prepared following the procedure outlined in Journal of organic chemistry 1992 57
2060-2065
EIMS(m/z) 242 2(M+1)
Step b Synthesis of (S)-3-Phenyl-l-oxa-2,7-diaza-spiro[4 41non-2ene-7,8-dicarboxylic acid 7-tert-butvl ester
8-methyl ester
The title compound was prepared following the procedure outlined in Journal of organic chemistry 2002 67,
5673-5677 from benzaldehyde
EIMS(m/z) 3612(M+1)
Step c Synthesis of trifluoroacetic acid salt of(S)-3-Phenyl-l-oxa-2,7-diaza-spirof4 4]non-2ene-8-carboxylic
acid methyl ester
To the compound (0 2 g) obtained from the step b above was added a solution of 30 % trifluoroacetic acid in
dichloromethane (10 mL) at 0°C and stirred for 30 mm form 0°C to room temperature The reaction mixture
was concentrated and dried to yield the title compound (0 2 g)
Synthesis of trifluoroacetic acid salt of (S)-3-Methyl-l-oxa-2,7-diaza-spiro[4 4]non-2ene-8-carboxyhc acid methyl ester
Step a Synthesis of(S)-3-Methyl-l-oxa-2,7-diaza-spiro-[4 41non-2ene-7,8-dicarboxyhc acid-7-tert-butyl ester
8-methyl ester
To the compound (S)-4-methylene-pyrrohdine-l, 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (3 25 g)
in toluene (50 mL) was added phenyl isocyanate (3 213 g), a solution of nitro ethane (1 mL) and tnethylamine
(1 mL) in toluene (50 mL) The reaction mixture was stirred for 1 h at room temperature and then refluxed for
lh at 120°C, cooled and filtered The organic layer was concentrated and the crude was purified by column
chromatography over silica gel using 40 % ethyl acetate in hexane as eluant to furnish the title compound (2 g)
EIMS(m/z) 299 1(M+1)
Step b Synthesis of trifluoroacetic acid salt of (S)-3-Methyl-l-oxa-2,7-diaza-spirof4 41non-2ene-8-carboxylic
acid methyl ester
To the compound (2 g) obtained from the step a above was added a solution of 30 % tnfluoroacetic acid in dichloromethane (10 mL) at 0°C and stirred for 30 min from 0°C to room temperature The reaction mixture was concentrated and dried to yield the title compound (2 09 g)
Synthesis of (5S,8S)-3-Phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2ene-7,8-dicarboxyhc acid di-tert-butyl ester and (5R18S)-3-Phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2ene-7,8-dicarboxylic acid di-tert-butyl ester
Step a Synthesis of (S)-4-Methylene-pvrrolidine-1,2-dicarboxyhc acid 1-tert-butyl ester
To a solution of (S)-4-Methylene-pyrrohdine-l,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1 75 g) in
1,4-dioxane-water (70 30, 50 mL) was added 2N sodium hydroxide solution (5 35 mL) dropwise at room
temperature and stirred for 3 h Solvent was removed in vacuo, and the residue obtained was taken in water and
extracted with diethyl ether Aqueous layer was acidified with sodium hydrogen sulphate and extracted with
ethyl acetate The combined organic extracts were washed with water, brine, dried over anhydrous sodium
sulphate and concentrated to afford the title comound (1 41g)
EIMS(m/z) 228 2(M+1)
Step b Synthesis of(S)-4-Methylene-pyrrolidine-l,2-dicarboxylic acid di-tert-butyl ester
To the compound (1 41g) obtained from step a above in acetonitnle (30 mL) was added to di-tert-butyl
dicarbonate (2 03 g) and tnethylamine (1 3 mL) at room temperature The reaction mixture was cooled to 0°C
and 4-dimethylaminopyndine (0 076 g) was added to the above mixture, and stirred overnight at room
temperature The reaction mixture was concentrated in vacuo to obtain a residue which was purified by column
chromatography over silica gel using 10 % ethyl acetate in hexane as eluant to afford title compound (1 41g)
EIMS(m/z) 284 2(M+1)
Step c Synthesis of (5S,8S)-3-Phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2ene-7,8-dicarboxyhc acid di-tert-butyl
ester and (5R18S)-3-Phenyl-l-oxa-2,7-diaza-spirof4 4]non-2ene-7,8-dicarboxylic acid di-tert-butyl ester
(S)-4-Methylene-pyrrolidine-l,2-dicarboxyhc acid di-tert-butyl ester (6 8g) and benzaldehyde oxime (6 7 g)
were dissolved in dichloromethane (370 mL), and the resulting solution was cooled to 0°C Aqueous sodium
hypochlorite solution (363 mL, 4 %) was added dropwise over a period of 30 min The reaction mixture was
stirred vigorously overnight The layers were separated, and the aqueous layer was extracted with
dichloromethane The combined organic layers were dried over anhydrous sodium sulphate, and concentrated
The crude residue was purified by column chromatography over silica gel using 10 % ethyl acetate in hexane
as eluant to afford (5S,8S)-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2ene-7,8-dicarboxyhc acid di-tert-butyl
ester (3 75 g) and (5R18S)-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2ene-7,8-dicarboxylic acid di-tert-butyl ester
(1 25g)
EIMS(m/z) 403 2(M+1)
Synthesis of (5S,8S)-3-methyl-l-oxa-2,7-diaza-spiro[4 4]non-2ene-7,8-dicarboxyhc acid di-tert-butyl ester and (5R18S)-3-methyl-l-oxa-2,7-diaza-spiro[4 4]non-2ene-7,8-dicarboxyhc acid di-tert-butyl ester
To the solution of (S)-4-methylene-pyrrolidine-l,2-dicarboxylic acid di-tert-butyl ester (1 41g) in toluene (17
mL) was added phenyl isocyanate (1 15 g), a solution of nitro ethane (0 422 mL) and tnethylamine (3 drops) in
toluene (17 mL) The reaction mixture was stirred for 1 h at room temperature and refluxed for 1 h at 120°C
cooled and filtered The organic layer was concentrated and the crude was purified over silica gel column chromatography using 18 % ethyl acetate in hexane as eluant to yield (5S,8S)-3-methyl-l-oxa-2,7-diaza-spiro[4 4]non-2ene-7,8-dicarboxylic acid di-tert-butyl ester (0 72 g) and (5R18S)-3-methyI-l-oxa-2,7-diaza-spiro[4 4]non-2ene-7,8-dicarboxyhc acid di-tert-butyl ester (0 21 g) EIMS(m/z) 3412(M+1)
Synthesis of (R)-8-Acetyl-l-thia-4,8-diaza-spiro[4 5]decane-3-carboxyhc acid ethyl ester
L-Cysteine ethyl ester hydrochloride (2 62 g) was added to the solution of 1-acetyl pipendin-4-one (2 g) in ethanol (20 mL) The reaction mixture was stirred at room temperature for about 30 min and then at 60°C for about 3 h Reaction mixture was then concentrated, diluted with water and extracted with ethyl acetate solution The aqueous layer was basified with sodium hydrogen carbonate and back extracted with ethyl acetate The combined organic extracts were washed with water and brine Finally, the organic layer was dried over sodium sulphate and concentrated to obtain a crude residue which was purified by column chromatography over silica gel using 60 % ethylacetate in hexane solution to afford of the title compound (1 8 g) EIMS(m/z) 273 1(M+1)
Synthesis of Oxazolo [4,5-b] pyridine
2-amino-pyndin-3-ol (1 8 g) was dissolved in tnethylorthoformate (13 mL) and was refluxed at 180°C for about 6 h The reaction mixture was cooled to room temperature, concentrated in vacuo to obtain a residue which was purified by column chromatography over silica gel using 80 % ethyl acetate in hexane as eluant to afford the title compound (1 1 g) EIMS (m/z) 121 1(M+1)
Synthesis of (S)-3-Amino-4 4-dimethoxy-butync acid tert-butyl ester
Step a Synthesis of(S)-3-Allyloxycarbonylamino-4,4-dimethoxy butyric acid tert-butyl ester The title compound was prepared following the procedure outlined in Bioorgamc and Medicinal Chemistry Letters 1992 2(6) 613-618 EIMS (m/z) 304 2(M+1)
Step b Synthesis of (S)-3-Amino-4 4-dimethoxy-butyric acid tert-butyl ester
To a solution of (S)-3-aIlyloxycarbonylamino-4,4-dimethoxy butyric acid tert-butyl ester (0 lg) in dry tetrahydrofuran (3 mL) was added morphohne (0 188 g) and tetrakis (tnphenyl phosphine) palladium(O) (3 mg) at room temperature under nitrogen atmosphere The resulting mixture was stirred at room temperature for 2 h The reaction mixture was diluted with ethyl acetate and washed with water, sodium hydrogen carbonate solution and brine The combined organic extracts were dried over sodium sulphate and concentrated to obtain a residue which was purified by column chromatography over silica gel using 2 % methanol in dichloromethane as eluant to afford the title compound (0 098 g) EIMS (m/z) 220 27(M+1)
Synthesis of (S)-3-Allyloxycarbonylamino-4-hydroxy-4-(7-methoxy-benzooxazol-2-yl)-butyric acid tert-butyl ester
The title compound was prepared following the procedure outlined in US 5716929 EIMS(m/z) 407 3(M+1)
Analogues of (S)-3-allyloxycarbonylamino-4-hydroxy-4-(7-methoxy-benzooxazol-2-yl)-butync acid tert-butyl ester described below were prepared by replacing 7-methoxybenzoxazole with appropriate substituted oxazoles or benzoxazoles as applicable in each case
(S)-3-Allyloxycarbonylamino-4-hydroxy-4-(4-methoxy-benzooxazol-2-yl)-butyric acid tert-butyl ester (S)-3- Allyloxycarbonylamino-4-(benzooxazol-2-yl)- 4-hydroxy- butyric acid tert-butyl ester (S)-3-Allyloxycarbonylamino-4-hydroxy-4-oxazolo[4 5-b]pyridin-2-yl)-butyric acid tert-butyl ester (S)-3-Allyloxycarbonylamino-4-[5-(2,6-dichloro-phenyl)-oxazol-2-yl)-4-hydroxy-butyric acid tert-butyl ester (S)-3-Allyloxycarbonylamino-4-hydroxy-4-(5-pyridin-2-yl-oxazol-2-yl)-butyric acid tert-butyl ester (S)-3-Allyloxycarbonylamino-4-hydroxy-4-(5-phenyl-oxazol-2-yl)-butyric acid tert-butyl ester
Synthesis of (S)-3-Allyloxycarbonylamino-5-(2-chlorobenzyloxy)-4-oxo-pentanoic acid tert-butyl ester
The title compound was prepared following the procedure outlined in US 5716929 EIMS(m/z) 412 8(M+1)
Synthesis of (S)-3-Allyloxycarbonylamino-5-(2-chlorobenzylsulfanyl)-4-oxo-pentanoic acid tert-butyl ester
The title compound was prepared following the procedure outlined in US 5716929 EIMS(m/z) 428 9(M+1)
Synthesis of (S)-3-Allyloxycarbonylamino-5-(hexyl-methyl-amino)-4-oxo-pentanoic acid tert-butyl ester
To a solution of (S)-3-Allyloxycarbonylamino-5-bromo-4-oxo-pentanoic acid tert-butyl ester
(1 5 g, prepared following the procedure given in WO 93 16710) in dry tetrahydrofuran (10 mL) was added
triethyl amine (0 91 lg), N-hexyl,N-methyl amine (0 571 g) at room temperature The reaction mixture was
stirred for 2 h at room temperature The reaction mixture was concentrated and diluted with ethyl acetate The
resulting solution was washed with water and brine, dried over anhydrous sodium sulphate and concentrated to
furnish the crude product which was purified by column chromatography over silica gel using 20 % ethyl
acetate in hexane as eluant to afford the title compound (0 8 g)
EIMS(m/z) 3512(M+1)
Analogue of (3S)-Allyloxycarbonylamino-5-(hexyl-methyl-arnino)-4-oxo-pentanoic acid tert-butyl ester
described below was prepared by replacing N-hexyl, N-methyl amine with N-benzyl, N-methy 1 amine
(S)-3-Allyloxycarbonylamino-5-(benzylmethylamino)-4-oxo-pentanoic acid tert-butyl ester
Synthesis of (S)-3-AlIyloxycarbonylamino-5-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-4-oxo-pentanoic acid tert-butyl ester
Tnphenylphosphine (0 301g) and dnsopropyl azodicarboxylate (0 232 g) were added to a solution of (3S)-allyloxycarbonylamino-5-hydroxy-4-oxo-pentanoic acid tert-butyl ester (0 3 g, prepared following the
procedure given in US 5716929) in dry tetrahydrofuran (5 mL) AfterlO mm of stirring phthahmide (0 169 g)
was added to the reaction mixture at 0°C The reaction mixture was stirred for 30 min at 0°C and then at room temperature overnight The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over anhydrous sodium sulphate and concentrated to furnish the crude product, which was purified by column chromatography over silica gel using 15 % ethyl acetate in hexane as eluant to afford the title compound (0 49 g) EIMS(m/z) 417 2(M+1)
Synthesis of (S)-3- AHyloxycarbonylamino-4-hydroxy-9-phenyl nonanoic acid
Step a Synthesis of 5-Phenylpentyl magnesium bromide
Magnesium turnings (0 465 g) and iodine (catalytic) were taken in round bottom flask and connected to high vaccum Tetrahydrofuran (20 mL) was added followed by addition of (5-bromo-pentyl)-benzene (0 88 g) dropwise The reaction mixture was refluxed for 2 h, cooled and used as such for next step Step b Synthesis of(S)-3-Allvloxvcarbonvlamino-4-hvdroxy-9-phenyl-nonanoic acid tert-butyl ester 5-Phenylpentyl magnesium bromide obtained from step a above was dissolved in tetrahydrofuran (10 mL) and cooled to -78°C (S)-3-allyloxycarbonylamino-4-oxo-butync acid tert-butyl ester (0 5 g) (prepared following the procedure outlined in Bioorganic and Medicinal Chemistry Letters, 1992, 2(6), 613-618) in tetrahydrofuran (10 mL) was added dropwise The resulting mixture was stirred for 2 h at same temperature and then overnight at room temperature The reaction mixture was quenched with aqueous ammonium chloride and extracted with ethyl acetate The combined organic extracts were dried over anhydrous sodium sulphate, concentrated in vacuo and purified by column chromatography over silica gel using 20 % ethyl acetate in hexane to afford the title compound (0 21g) EIMS(m/z) 406 2(M+1)
Step c Synthesis of(S)-3-Allyloxvcarbonylamino-4-oxo-9-phenyl-nonanoic acid tert-butyl ester To a solution of compound (0 21 g) obtained from step b above in dichloromethane (10 mL) was added Dess-martin reagent (0 662 g) and stirred for about 1 h Saturated solution of sodium thiosulphate (5 mL), sodium hydrogen carbonate solution (5 mL) and ethyl acetate (10 mL) was added to the reaction mixture and stirred for about 30 min Organic layer was separated and washed with sodium thiosulphate solution, sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulphate and concentrated in vacuo to obtain a residue which was purified by column chromatography over silica gel using 50 % ethyl acetate in hexane as eluant to afford the title compound (0 235g) EIMS(m/z) 404 2(M+1)
Example 1 Synthesis of (S)-3-[((S)-7-{(S)-3-Methyl-2-[{naphthalene-2-carbonyl)-amino]-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butync acid (CompoundNo 1)
Step a Synthesis of (S)-7-{(S)-3-Methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carboxylic acid methyl ester
To the solution of trifluoroacetic acid salt of (S)-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2ene-8-carboxylic acid methyl ester (0 207 g) in dimethyl formamide (5mL) at 0°C under nitrogen atmosphere, were added N-methylmorpholine (0 18 mL), hydroxybenzotnazole (0 089 g) and (S)-3-Methyl-2-[(naphthalene-2-carbonyl)-
amino]-butync acid (0 15 g) and stirred for about 10-15 mm l-(3-dimethylaminopropyl)-3-ethylcarbodirnide
hydrochloride (0 127 g) was then added to the above mixture and further stirred at 0°C for 1 h and then at room
temperature for overnight The reaction mixture was diluted with ethyl acetate and washed with water, sodium
hydrogen sulphate, sodium hydrogen carbonate and brine, dried over anhydrous sodium sulphate and
concentrated to obtain a crude residue The crude residue was purified over silica gel column chromatography
using 50 % ethylacetate in hexane as eluant to furnish the title compound (0 1 lg)
EIMS(m/z) δ14 5(M+1)
Step b Synthesis of(S)-7-{(S)-3-Methyl-2-[(naphthalene-2-carbonvl)-amino]-butvrylj-3-phenyl-l-oxa-2,7-
diaza-spiro[4 4]non-2-ene-8-carboxylic acid
Lithium hydroxide monohydrate (0 135 g) was added to the solution of compound (0 llg) obtained from the
step a above in a mixture of tetrahydrofuran methanol water (3 1 1) (5 mL) and stirred for 2 h The reaction
mixture was concentrated to get a crude oil, which was taken in water and washed with ethyl acetate The
aqueous extract was acidified with sodium hydrogen sulphate and extracted with ethyl acetate The organic
extract was washed with water, brine and dried over anhydrous sodium sulphate and concentrated to furnish the
title compound (0 1 g)
EIMS(m/z) δ00 5(M+1)
Step c Synthesis of(S)-4,4-Dimethoxy-3-[((S)-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-
phenyl-l-oxa-2,7-diaza-spirof4 41non-2-ene-8-carbonvl)-amino]butyric acid tert-butyl esters
To the compound (0 lg) obtained from the step b above in dimethyl formamide (3 mL) at 0°C under nitrogen
atmosphere, were added N-methylmorpholine (0 07 mL), hydroxybenzotnazole (0 0324g) and (S)-3-amino-4,4-
dimethoxy-butyric acid tert-butyl ester (0 048 g) and stirred for 10-15 min To the reaction mixture was added
l-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (0 046 g) and was further stirred at 0°C for 1 h
and then room temperature for overnight The reaction mixture was diluted with ethyl acetate and washed with
water, sodium hydrogen sulphate, sodium hydrogen carbonate and brine dried over anhydrous sodium sulphate
and concentrated to furnish the title compound (0 157 g)
EIMS(m/z) 701 (M+l)
Step d Synthesis of(S)-3-[((S)-7-{(S)-3-Methyl-2-[(naphthalene-2-carbonyl)-aminol-butvryl}-3-phenvl-l-oxa-
2,7-diaza-spiro[4 4Jnon-2-ene-8-carbonyl)-amino]-4-oxo-butyric acid
To the solution of compound (0 157 g) obtained from the step c above in dichloromethane (4 mL) at room
temperature was added tnfluoroacetic acid (3 mL) and water (0 3 mL) and the reaction mixture was stirred at
room temperature for 8 h The reaction mixture was concentrated and purified by preparative thin layer
chromatography (2mm, Merck) using 12 % methanol in dichloromethane as mobile phase to afford the title
compound (0 053g)
1HNMR (DMSO-d6, 400 MHz) 8 8 59-8 54 (m, 2H), 8 03-7 97 (m, 4H), 7 67-7 63 (m, 4H), 7 47 (s, 2H), 4 54-
3 89 (m, 3H), 3 61-3 47 (m, 4H), 2 49-2 19 (m, 4H), 0 98-0 93 (m, 6H)
EIMS(m/z) 599(M+1)
Analogue o/(S)-3-[((S)7-{(S)-3-Methy]-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-phenyl-l-oxa-2,7-
diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butync acid described below was prepared by replacing
(S)-3-Methyl-2-[(naphthalene-2-carbonyl)-amino]-butync acid with (S)-3-Methyl-2-(2-naphthalene-l-yl-acetylamino]-butync acid
(S)-3-[((S)-7-{(S)-3-Methyl-2-(-2-naphthalene-l-yl-acetylamino)-butyryl]-3-phenyl-l-oxa-2 7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butyric acid (Compound No 2), EIMS(m/z) 613 (M+l)
Example 2 Synthesis of (S)-3-[{(S)-7-[(S)-3-Methyl-2-(-2-naphthalene-2-yl-acetylamino)-butyryl]-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl}-amino)-4-oxo-butyric acid (Compound No 3) Step a Synthesis of (S)-7-[(S)-3-Methyl-2-(-2-naphthalene-2-yl-acetylamino)-butyryl]-3-phenyl-l-oxa-2J-diaza-spiro[4 4]non-2-ene-8-carboxylic acid methyl ester
N-methylmorphohne (0 128g), hydroxybenzotnazole (0 068 g) and naphthalene-2-yl acetic acid (0 078g) were added to the solution of the tnfluoroacetic acid salt of (S)-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2ene-8-carboxylic acid methyl ester (0 2 g) in dimethyl formamide (3 mL) at 0°C under nitrogen atmosphere, and stirred for 10-15 mm l-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (0 097 g) was added to the reaction mixture and reaction was further stirred at 0°C for 1 h and then at room temperature for overnight The reaction mixture was diluted with ethyl acetate and washed with water, sodium hydrogen sulphate, sodium hydrogen carbonate and brine, dried over anhydrous sodium sulphate and concentrated The crude was purified over silica gel column chromatography using 50 % ethylacetate in hexane as eluant to furnish the title compound (0 26 g) EIMS(m/z) δ28 3 (M+l)
Step b Synthesis of (S)-7-[(S)-3-Methyl-2-(-2-naphthalene-2-yl-acetylamino)-butyryll-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carboxvhc acid
Lithium hydroxide monohydrate (0 03 lg) was added to the solution of compound (0 26 g) obtained from the step a above in a mixture of tetrahydrofuran methanol water (3 1 1) (10 mL) and stirred for 2 h The reaction mixture was concentrated to get a crude oil, which was taken in water and washed with ethyl acetate The aqueous extract was acidified with sodium hydrogen sulphate and extracted with ethyl acetate The organic extracts were washed with water, brine and dried over anhydrous sodium sulphate and concentrated to furnish the title compound (0 173 g) EIMS(m/z) δ14 2 (M+l)
Stepc Synthesis of(S)-4,4-Dimethoxv-3'f((S)-7-{(S)-3-methyl-2-[(naphthalen-2-yl-acetylaminol-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 41non-2-ene-8-carbonvl)-amino]butyric acid tert-butyl esters To the compound (0 173 g) obtained from the step b above in dimethyl formamide (4 mL) at 0°C under nitrogen atmosphere, were added N-methylmorpholine (0 102 g), hydroxybenzotnazole (0 0545 g) and (S)-3-amino-4,4-dimethoxy-butync acid tert-butyl ester (0 081 g) and stirred for 10-15 mm To the reaction mixture was added l-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (0 046 g) and reaction was further stirred at 0°C for 1 h and then at room temperature for overnight The reaction mixture was diluted with ethyl acetate and washed with water, sodium hydrogen sulphate, sodium hydrogen carbonate and brine, dried over anhydrous sodium sulphate and concentrated to furnish the crude title compound (0 2283 g)
EIMS(m/z) 715 3(M+1)
Step-d (S)-3-f((S)-7-f(S)-3-Methvl-2-(-2-naphthalene-2-yl-acetylamino)-butyryl]-3-phenvl-l-oxa-2J-diaza-
spiro[4 4]non-2-ene-8-carbonvU-amino)-4-oxo-butyric acid
To the solution of compound (0 2283 g) obtained from the step c above in dichloromethane (4 5 mL) at room
temperature was added trifluoroacetic acid (1 4 mL) and water (0 45 mL) and the reaction mixture was stirred at
room temperature for 8 h The reaction mixture was concentrated and purified by preparative thin layer
chromatography (2mm, Merck) using 12 % methanol in dichloromethane to afford the title compound (0 91g)
1HNMR(DMSO-d6, 400 MHz) δ 7 84-7 79 (m, 3H), 7 72 (s, 4H), 7 62-7 60 (m, 1H), 7 48-7 33 (m, 7H), 4 50-
4 25 (m, 2H), 4 20-4 00 (m, 2H), 3 80-3 20 (m, 6H), 2 90-2 65 (m, 1H), 2 45-2 30 (m, 1H), 2 20-1 85 (m, 2H)
and 0 85 (m, 6H)
EIMS(m/z) 613 1(M+1)
Analogues of (S)-3-[{(S)-7-[(S)-3-Methyl-2-(-2-naphthalene-2-yl-acetylamino)-butyryl]-3-phenyl-l-oxa-2,7-
diaza-spiro[4 4]non-2-ene-8-carbonyl}-amino)-4-oxo-butync acid described below were prepared by replacing
with naphthalene-2-yl acetic acid with appropriate acid or as applicable in each case
(S)-3-[{(S)-7-[(S)-3-Methyl-2-(-2-p-tolyl-acetylamino)-butyryl]-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-
8-carbonyl}-amino)-4-oxo-butyric acid (Compound No 4)
EIMS(m/z) δ77 1(M+1)
(S)-3-[{(S)-7-[(S)-3-Methyl-2-(-2-o-tolyl-acetylamino)-butyryl]-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-
8-carbonyl}-amino)-4-oxo-butyric acid (Compound No 5),
EIMS (m/z) δ77 2(M+1)
(S)-3-[{(S)-7-{(S)-2-[2-(2-Fluoro-phenyl) -acetylamino]-3-methyl-butyryl}-3-phenyl-l-oxa-2 7-diaza-
spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butyric acid (Compound No 6),
EIMS (m/z) δ81 1 (M+l)
Analogues of (S)-3-[{(S)-7-[(S)-3-Methyl-2-(-2-naphthalene-2-yl-acetylamino)-butyryl]-3-phenyl-l-oxa-2,7-
diaza-spiro[4 4]non-2-ene-8-carbonyl}-amino)-4-oxo-butync acid described below was prepared by replacing
with naphthalene-2-yl acetic acid with isoquinoline-1-carboxyhc acid and/ or replacing trifluoroacetic acid salt
of (S)-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2ene-8-carboxyhc acid methyl ester with appropriate amine as
applicable in each case
(S)-3-[{(S)-7-{(S)-2-[(Isoquinolme-l-carbonyl)-amino]-3-methyl-butyryl}-3-phenyl-l-oxa-2 7-diaza-
spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butyric acid (Compound No 31)
EIMS (m/z) 600 3(M+1)
(S)-3-[{(S)-7-{(S)-2-[(Isoquinohne-l-carbonyl)-amino]-3-methyl-butyryl}-3-methyl-l-oxa-2,7-diaza-
spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butyric acid (Compound No 32),
EIMS (m/z) δ38 2(M+1)
Example 3 Synthesis of (S)-3-[((S)-3-Methyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butync acid (CompoundNo 07) Step a Synthesis of(S)-3-Methvl-7-/(S)-3-methvl-2-f(naphthalene-2-carbonvl)-aminoJ-butyrvU-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carboxylic acid methyl ester
To the solution of tnfluoroacetic acid salt of (S)-3-methyl-l-oxa-2,7-diaza-spiro[4 4]non-2ene-8-carboxylic
acid methyl ester (2 093 g) in dimethyl formamide (15 mL) at 0°C under nitrogen atmosphere, were added N-
methylmorphohne (2 2 mL), hydroxybenzotnazole (1 087 g) and (S)-3-Methyl-2-[(naphthalene-2-carbonyl)-
amino]-butync acid (1 818 g) and stirred for 10-15 mm To the reaction mixture was added l-(3-
dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (1 543 g) and was further stirred at 0°C for 1 h and
then at room temperature for overnight The reaction mixture was diluted with ethyl acetate and washed with
water, sodium hydrogen sulphate, sodium hydrogen carbonate and brine, dried over anhydrous sodium sulphate
and concentrated The crude was purified over silica gel column chromatography using 50 % ethylacetate in
hexane as eluant to furnish the title compound (1 57 g)
EIMS(m/z) 452 1(M+1)
Step b Synthesis of(S)-3-Methyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonylj-amino]-butyryl}-l-oxa-2,7-
dia:a-spiro[4 4]non-2-ene-8-carboxylic acid
Lithium hydroxide monohydrate (0 219 g) was added to the solution of compound (1 57 g) obtained from the
step a above in a mixture of tetrahydrofuran methanol water (3 1 l)(50mL) The resulting mixture was stirred
for about 2 h The reaction mixture was concentrated to get a crude oil, which was taken in water and washed
with ethyl acetate The aqueous extract was acidified with sodium hydrogen sulphate and extracted with ethyl
acetate The organic extract was washed with water, brine and dried over anhydrous sodium sulphate and
concentrated to furnish the title compound (1 5 g)
EIMS(m/z) 438 1(M+1)
Stepc Synthesis of(S)-4,4-Dimethoxy-3~[((S)-3-methyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-
butyrylj-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-butyric acid tert-butyl ester
To the compound (1 5 g) obtained from the step b above in dimethyl formamide (30 mL) at 0°C under nitrogen
atmosphere, were added N-methylmorpholine (1 13 mL), hydroxybenzotnazole (0 555 g) and (S)-3-amino-4,4-
dimethoxy-butync acid tert-butyl ester (0 826 g) and stirred for 10-15 min To the reaction mixture was added
l-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (0 789 g) and was further stirred at 0°C for 1 h
and then room temperature for overnight The reaction mixture was diluted with ethyl acetate and washed with
water, sodium hydrogen sulphate, sodium hydrogen carbonate and brine, dried over anhydrous sodium sulphate
and concentrated to afford the title compound (1 5169 g)
EIMS(m/z) 639 2(M+1)
Step d Synthesis of(S)-3-[((S)-3-Methvl'7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-l-oxa-
2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butyric acid
To the solution of compound (1 5169 g) obtained from the step c above in round bottom flask was added 30 %
tnfluoroacetic acid in dichloromethane (39 4 mL) and water (3 03 mL) at 0°C and the reaction mixture was
stirred from 0°C to room temperature for 3 h The reaction mixture was concentrated, dried and purified by
preparative thin layer chromatography (2mm, Merck) using 15 % methanol in dichloromethane to furnish the
title compound (0 188 g)
1HNMR (DMSO-d6, 400 MHz) δ 8 75-8 53 (m, 2H), 8 03-7 94 (m, 4H), 7 63-7 57 (m, 2H), 4 52-4 19 (m, 3H),
3 81-3 78 (m, 2H), 3 33-3 00 (m, 2H), 2 36-2 17 (m, 4H), 1 93-1 88 (m, 3H) and 0 95-0 83 (m, 6H)
EIMS(m/z) 537(M+1)
Example 4 Synthesis of (S)-3-[((S)-4-Methanesulfonyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl)-amino]-4-oxo-butync acid (Compound No 08)
Step a Synthesis of (S)-4 -Oxo-pvrrolidine-1 2-dicarboxylic acid-1-tert-butyl ester-2-methyl ester
The title compound was prepared following the procedure given in Journal of medicinal chemistry 1996, 39
2990-3000 starting from (2S, 4R)-4-Hydroxy-pyrrolidine-l,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester
EIMS(m/z) 244 2(M+1)
Step b Synthesis of(S)-l-Thia-4,7-diaza-spiro[4,4]nonane-7,8-dicarboxvlic acid 7-tert-butyl ester 8-methyl
ester
To the compound (14 2g) obtained the step a above in dry methanol (150 mL) was added hydrochloride salt of
2-aminothiol (7 3 g) and the reaction mixture was stirred at room temperature for 30 min Powdered molecular
sieves (15 g) was added to the reaction mixture and reaction was heated at 55-60°C for 6-7 h The reaction
mixture was cooled, filtered through cehte bed and washed with methanol The organic layer was evaporated
and the product was taken in ethyl acetate and washed with sodium hydrogen carbonate, brine and dried over
anhydrous sodium sulphate and concentrated The crude was purified by column chromatography over silica gel
using 60 % ethyl acetate in hexane as eluant to furnish the title compound (12 5 g)
EIMS(m/z) 303 3(M+1)
Step c Synthesis of (S)-4-Methanesulfonyl-l-thia-4,7-dia:a-spiro[4,4]nonane-7,8-dicarboxylic acid 7-tert-butyl
ester 8-methyl ester
To the solution of compound (lg) obtained from the step b above in dichloromethane (20 mL) was added
tnethylamine (2 8 mL), followed by dropwise addition of methane sulphonyl chloride (1 08 mL) and 4-
dimethylaminopyndine (0 040 g) at 0°C and the reaction mixture was refluxed at 45°C for 7 h The reaction
mixture was cooled and diluted with dichloromethane washed with sodium hydrogen sulphate, sodium
hydrogen carbonate, brine and dried over anhydrous sodium sulphate and concentrated The crude was purified
by column chromatography over silica gel using 50 % ethyl acetate in hexane as eluant to furnish the title
compound (0 52 g)
EIMS (m/z) 381 4(M+1)
Step d Synthesis of trifluoroacetic acid salt of(S)-4-Methanesulfonyl-l-thia-4,7-diaza-spiro[4,4]nonane-
8carboxyhc acid methyl ester
To the solution of compound (0 5 g) obtained from the step c above in dichloromethane (5 mL) at 0°C was
added 30 % trifluoroacetic acid in dichloromethane (15 mL) and the reaction mixture was stirred from 0°C to
room temperature for 3 h The reaction mixture was concentrated and dried to furnish the title compound (0 54
g)
Step e Synthesis of (S)-4-Methanesulfon\l-7-{(S)-3-methyl-2-f(naphthalene-2-carbonyl)-amineol-butyryl\-l-
thia-4,7-diaza-spirof4 4]nonane-8-carboxylic acid methyl ester
N-methylmorphohne (0 23 mL), hydroxybenzotnazole (0 11 lg) and (S)-3-methyl-2-[(naphthalene-2-carbonyl)-
amino]-butync acid (0 204 g) were added to the solution of the compound (0 27 g) obtained form step d above
in dimethyl formamide (5 mL) at 0°C under nitrogen atmosphere, and stirred for 10-15 min l-(3-
dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (0 157 g) was added to the reaction mixture and was
further stirred at 0°C for 1 h and then at room temperature for overnight The reaction mixture was diluted with
ethyl acetate and washed with water, sodium hydrogen sulphate, sodium hydrogen carbonate and brine, dried
over anhydrous sodium sulphate and concentrated The crude was purified by column chromatography over
silica gel using 2 % methanol in dichloromethane as eluant to furnish the title compound (0 255 g)
EIMS(m/z) δ34 6(M+1)
Step f Synthesis of (S)-4-Methanesulfonyl-7-nS)-3-methyl-2-[(naphthalene-2-carbonyl)-amineo]-butyrylj-l-
thia-4,7-dia:a-spiro[4 4]nonane-8-carboxvlic acid
To the solution of compound (0 255 g) obtained from the step e above in a mixture of tetrahydrofuran
methanol water (3 1 1) (10 mL) was added lithium hydroxide monohydrate (0 027 g) and stirred for 2 h The
reaction mixture was concentrated to get a crude oil, which was taken in water and washed with ethyl acetate
The aqueous extract was acidified with sodium hydrogen sulphate and extracted with ethyl acetate The organic
extract was washed with water, brine and dried over anhydrous sodium sulphate and concentrated to furnish the
title compound (0 124 g)
EIMS(m/z) δ20 6(M+1)
Step g Synthesis of(S)-3-[((S)-4-Methanesulfonyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amineo]-
butyrylj-l-thia-4,7-dia:a-spiro[4 4]nonane-8-carbonyl)-amino]-4,4-dimethoxy-butyric acid tert-butyl ester
To the compound (0 124 g) obtained from the step f above in dimethyl formamide (5 mL) at 0°C under nitrogen
atmosphere, were added N-methylmorpholine (0 08 mL), hydroxybenzotnazole (0 0387 g) and (S)-3-amino-
4,4-dimethoxy-butyric acid tert-butyl ester (0 0575 g) and stirred for 10-15 mm To the reaction mixture was
added l-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (0 0547 g) and was further stirred at 0°C
for 1 h and then room temperature for overnight The reaction mixture was diluted with ethyl acetate and
washed with water, sodium hydrogen sulphate, sodium hydrogen carbonate and brine dried over anhydrous
sodium sulphate and concentrated to furnish the crude title compound (0 14 g)
EIMS(m/z) 7218(M+1)
Step h Synthesis of(S)-3-[((S)-4-Methanesulfonvl-7-{(S)-3-2-[(naphthalene-2-carbonyl)-aminol-butyryl}-l-
thia-4,7-diaza-spirol4 4]nonane -8-carbonyl)-amino]-4-oxo-butyric acid
To the solution of compound (0 14 g) obtained from the step g above at 0°C was added 30 % tnfluoroacetic
acid in dichloromethane (4 mL) and water (0 4 mL) and the reaction mixture was stirred form 0°C to room
temperature for 3 h The reaction mixture was concentrated to obtain a crude residue which was purified by
preparative thin layer chromatography (2mm, Merck) using 10 % methanol in dichloromethane as eluant to
furnish the title compound (0 05 g)
1HNMR (DMSO-d6, 400 MHz) 8 8 56-8 49 (m, 7 2Hz, 1H), 8 23-7 93 (m, 4H), 7 60-7 57 (m, 1H), 4 59-4 56
(m, 1H), 4 30-3 89 (m 4H), 3 39-3 13 (m, 9H), 2 50-2 10 (m, 3H) and 1 00-0 94 (m, 6H)
EIMS (m/z) 641 (M+23)
Analogue of (S)-3-[((S)-4-Methanesulfonyl-7-{(S)-3-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-l-thia-4,7-
diaza-spiro[4 4]nonane -8-carbonyl)-amino]-4-oxo-butync acid described below was prepared by replacing
(S)3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butync acid with (S)-3-Methyl-2-(2-naphthalene-l -yl-
acetylamino]-butync acid
(S)-3-[{(S)-4-Methanesulfonyl-7-[(S)-3-methyl-2-(2-naphthalene-l-yl-acetylamino)-butyryl]-l-thia-4 7-diaza-spiro[4 4] -nonane-8-carbonyl)-amino]-4-oxo-butyrw acid (Compound No 9), EIMS(m/z) 633 (M+l)
Example 5 Synthesis of (S)-3-( {(S)-4-Acetyl-7- [(S)-3-methyl-2-(2-o-tolyl-acetylamino)-butyryl] - l-thia-4,7-diaza-spiro[4,4]nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 10)
Step a Synthesis of~(S)-4-Acetyl-l-thia-4,7-diaza-spirof4,4Jnonane-8-carboxyhc acid 7-tert-butyl ester 8-methyl ester
To the solution of compound (3 g) obtained from the step b of the Example 04 above in dichloromethane (50 mL) was added tnethylamine (6 6 mL), acetyl chloride (1 4 mL) followed by 4-dimethylaminopyridine (0 12 g) at 0°C The reaction mixture was stirred at 0°C for 1 h The reaction mixture was quenched with water, extracted with dichloromethane, washed with sodium hydrogen sulphate, sodium hydrogen carbonate, brine and dried over anhydrous sodium sulphate and concentrated The crude product was purified by column chromatography over silica gel using 50 % ethyl acetate in hexane as eluant to furnish the title compound (3 g) EIMS(m/z) 345 4 (M+l)
Step b Synthesis of trifluoroacetate salt of'(S)-4-Acetyl-l-thia-4,7-diaza-spiro[4,4]nonane-8-carboxylic acid methyl ester
To the solution of compound (3 7 g) obtained from the step a above in dichloromethane (5 mL) at 0°C was added 30 % tnfluoroacetic acid in dichloromethane (20 mL) and the reaction mixture was stirred form 0°C to room temperature for 2 h The reaction mixture was concentrated and dried to furnish the title compound (3 2
g)
Step c Synthesis of(S)-4-Acetyl-7-((S)-2-tert-butyoxvcarbonylamino-3-methyl-butyryl)-l-thia-4,7-diaza-
spiro[4 41nonane-8-carboxylic acid methyl ester
To the solution of the compound (2 6 g) obtained form the step b above in dimethyl formamide (20 mL) at 0°C under nitrogen atmosphere, were added N-methylmorpholine (3 3 mL), hydroxybenzotnazole (1 6 g) and (S)-2-tert-butoxycarbony 1-3-methyl-butyric acid (2 g) and stirred for about 10-15 min To the reaction mixture was added l-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (2 36 g) and was further stirred at 0°C for 1 h and then at room temperature for overnight The reaction mixture was diluted with ethyl acetate and washed with water, sodium hydrogen sulphate, sodium hydrogen carbonate and brine, dried over anhydrous sodium sulphate and concentrated The crude was purified over silica gel column chromatography using 2 % methanol in dichloromethane as eluant to furnish the title compound (2 g) EIMS (m/z) 444 5 (M+l)
Step d Synthesis of trifluoroacetate salt of (S)-4-Acetvl-7-((S)-2- amino-3-methyl-butyryl)-l-thia-4,7-diaza-spiro[4 4]nonane-8-carboxylic acid methyl ester
To the solution of compound (0 7 g) obtained from the step c above in dichloromethane (5 mL) at 0°C was added 30 % tnfluoroacetic acid in dichloromethane (10 mL) and the reaction mixture was stirred from 0°C to room temperature for 2 h The reaction mixture was concentrated and dried to furnish the title compound (0 8 g)
Step e Synthesis of(S)-4-Acetvl-7-[(S)-3-methyl-2-(2-o-tolvl-acetvlamino)-butyryl]-l-thia-4,6-diaza-
spiro[4 4]nonane-8-carboxyhc acid methyl ester
To the solution of the compound (0 5 g) obtained form step d above in dimethyl formamide (5 mL) at 0°C
under nitrogen atmosphere, were added N-methylmorpholine (0 37 mL), hydroxybenzotnazole (0 16 g) and o-
tolyl-acetic acid (2 g) and stirred for about 10-15 min To the reaction mixture was added l-(3-
dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (0 24 g) and was further stirred at 0°C for 1 h and
then at room temperature for overnight The reaction mixture was diluted with ethyl acetate and washed with
water, sodium hydrogen sulphate, sodium hydrogen carbonate, and brine, dried over anhydrous sodium sulphate
and concentrated to furnish the crude title compound (0 6 g)
EIMS(m/z) 476 6(M+1)
Step f Synthesis of (S)-4-Acetyl-7-[(S)-3-methyl-2-(2-o-tolyl-acetvlamino-butyryll-l-thia-4,7-diaza-
spiro[4 4]nonane-8-carboxylic acid
To the solution of compound (0 6 g) obtained from the step e above in a mixture of tetrahydrofuran
methanol water (3 1 1) (10 mL) was added lithium hydroxide monohydrate (0 080 g) and stirred for 2 h The
reaction mixture was concentrated to get a crude oil, which was taken in water and washed with ethyl acetate
The aqueous extract was acidified with sodium hydrogen sulphate and extracted with ethyl acetate The organic
extract was washed with water, brine and dried over anhydrous sodium sulphate and concentrated to furnish the
title compound (0 315 g)
EIMS(m/z) 462 6(M+1)
Step g Synthesis of(S)-3-({S)-4-Acetvl-7[(S)-3-methyl-2-(2-o-tolyl-acetylammo-butyryll-l-thia-4,7-diaza-
spiro[4 41nonane-8-carbonylj-amino)-4,4-dimethoxv-butyric acid tert-butyl ester
To the compound (0 315g) obtained from step f above in dimethyl formamide (5 mL) at 0°C under nitrogen
atmosphere, were added N-methylmorpholine (0 33 mL), hydroxybenzotnazole (0 lg) and (S)-3-amino-4,4-
dimethoxy-butync acid tert-butyl ester (0 15 g) and stirred for about 10-15 min To the reaction mixture was
added l-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (0 15 g) and was further stirred at 0°C for
1 h and then at room temperature for overnight The reaction mixture was diluted with ethyl acetate and washed
with water, sodium hydrogen sulphate, sodium hydrogen carbonate and brine dried over anhydrous sodium
sulphate and concentrated to furnish the title compound (0 4g)
EIMS(m/z) 663 8(M+1)
Step h Synthesis of(S)-3-({(S)-4-Acetyl-7-[(S)-3-methvl-2-(2-o-tolyl-acetylamino)-butyryll-l-thia-4,7-diaza-
spiro[4,41nonane-8-carbonylj-amino)-4-oxo-butvric acid
To the solution of compound (0 4g) obtained from the step g above in dichloromethane (5 mL) at room
temperature was added 30 % trifluoroacetic acid in dichloromethane (8 mL) and water (0 8 mL) at 0°C and the
reaction mixture was stirred from 0°C to room temperature for 3 h The reaction mixture was concentrated to
afford a crude residue which was purified by preparative thin layer chromatography (2mm, Merck) using 10 %
methanol in dichloromethane to furnish the title compound (0 16 g)
1HNMR (DMSO-d6, 400 MHz) δ 8 15 (m, 1H), 7 19-7 08 (m, 4H), 4 46 (m, 1H), 4 27-4 25 (m, 2H), 3 83-3 82
(m, 2H), 3 54-3 47(m, 2H), 2 97-2 94 (m, 2H), 2 23 (s, 3H), 2 06-2 01(m, 4H) and 0 91-0 81 (m, 6H)
EIMS (m/z) δ83 1 (M+23)
Analogues of (S)-3-({(S)-4-Acetyl-7-[(S)-3-methyl-2-(2-o-tolyl-acetylamino)-butyryl]-l-thia-4,7-diaza-spiro[4,4]nonane-8-carbonyl}-amino)-4-oxo-butync acid described below were prepared by replacing o-tolyl-acetic acid with appropriate acid or as applicable in each case
(S)-3-[{(S)-4-Acetyl-7-[(S)-3-Methyl-2-(-2-naphthalene-lyl-acetylamino)-butyryl]-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butyric acid (Compound No 11), EIMS(m/z) δ97 2(M+1)
(S)-3-[{(S)-4-Acetyl-7-[(S)-3-Methyl-2-(-2-thwphen-2yl-acetylamino)-butyryl]-l-thia-4 7-diaza-spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butyric acid (Compound No 12) EIMS(m/z) δ53 2(M+1)
(S)-3-{[(S)-4-Acetyl-7((S)-3-Methyl-2-phenylacetylamino-butyryl)-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl]-amino}-4-oxo-butyric acid (Compound No 13), EIMS(m/z) δ47 2(M+1)
(S)-3-[((S)-4-Acetyl-7-{(S)-3-Methyl-2-[2-(-4-trifluoromethyl-phenyl-)-acetylamino]-butyryl}-l-thia-4 7-diaza-spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butyric acid (Compound No 14), EIMS(m/z) 615(M+1)
(S)-3-({(S)-4-Acetyl-7-[(S)-3-Methyl-2-(-2-phenoxy-acetylammo)-butyryl]-l-thia-4 7-diaza-spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butyric acid (Compound No 15) EIMS(m/z) δ63 2(M+1)
(S)-3-[((S)-4-Acetyl-7-{(S)-2-[2-(3-fluoro-phenyl)-acetylamino]-butyryl}-l-thia-4 7-diaza-spiro[4 4]nonane-8-carbonyl}-amino)-4-oxo-butyric acid (CompoundNo 16) EIMS(m/z) δ65 2(M+1)
(S)-3-[((S)-4-Acetyl-7-{(S)-3-methyl-2-(2-p-tolyl-acetylammo]-butyryl}-l-thia-4 7-diaza-spiro[4 4]nonane-8-carbonyl}-amino)-4-oxo-butyric acid (CompoundNo 17) EIMS(m/z) δ612(M+1)
(S)-3-[((S)-4-Acetyl-7-{(S)-2-[2-(2-fluoro-phenyl)-acetylamino]-3-methyl-butyryl}-l-thia-4,7-diaza-spiro[4 4]nonane-8-carbonyl}-amino)-4-oxo-butyric acid (Compound No 18), EIMS(m/z) δ65 2(M+1)
(S)-3-[((S)-4-Acetyl-7-{(S)-2-[2-(4-methoxy-phenyl)-acetylamino]- 3-methyl-butyryl}-l-thia-4 7-diaza-spiro[4 4]nonane-8-carbonyl}-amino)-4-oxo-butyric acid (Compound No 19) EIMS(m/z) δ77 2(M+1)
(S)-3-[{(S)-4-Acetyl-7-[(S)-3-Methyl-2-(-2-naphthalene-2-yl-acetylamino)-butyryl]-l-thia-4 7-diaza-%piro[4 4]nonane-8-carbonyl}-amino)-4-oxo-butyric acid (Compound No 20) EIMS(m/z) δ97 2(M+1)
(S)-3-[((S)-4-Acetyl-7-{(S)-2-[2-(3-methoxy-phenyl)-acetylaminoJ- 3-methyl-butyryl}-l-thia-4 7-diaza-spiro[4 4]nonane-8-carbonyl}-amino)-4-oxo-butyric acid (Compound No 21) EIMS(m/z) δ77 2(M+1)
(S)-3-[{(S)-4-Acetyl-7-[(S)- 2-[-2-(4-chloro-phenyl)-acetylamino]- 3-Methyl -butyrylJ-l-thia-4,7-diaza-spiro[4 4]nonane-8-carbonyl}-amino)-4-oxo-butyric acid (Compound No 22) EIMS(m/z) δ812(M+1)
(S)-3-[{(S)-4-Acetyl-7-[(S)- 2-[-2-(4-fluoro-phenyl)-acetylamino]- 3-Methyl -butyrylJ-l-thia-4 7-diaza-
spiro[4 4]nonane-8-carbonylj-amino)'-4-oxo-butyrw acid (Compound No 23)
EIMS (m/z) δ65 2(M+1)
(S)-3-[{(S)-4-Acetyl-7-{(S)- 2-[-2-(2-acetylamino-thazol-4-yl)-acetylamino]- 3-Methyl -butyrylJ-l-thia-4 7-
diaza-spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butyric acid (Compound No 24)
EIMS (m/z) 633(M+23)
(S)-3-[((S)-4-Acetyl-7-{(S)- 3-methyl-2-[-2-(2-methyl-lH-indol-3-yl)-acetylamino] - butyrylj-l-thia-4,7-diaza-
spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butyric acid (Compound No 25)
EIMS (m/z) 600 2(M+1)
(S)-3-[((S)-4-Acetyl-7-{(S)- 2-[-(2-lH-indol-3-yl)-acetylamino] -3-methyl-butyryl]-l-thia-4 7-diaza-spiro[4 4]
nonane-8-carbonyl}-amino)-4-oxo-butyrw acid (Compound No 26)
EIMS (m/z) δ86 2(M+1)
(S)-3-[((S)-4-Acetyl-7-{(S)- 2—((S)-2-acetylamino-2-phenyl-acetylamino)-3-methyl-butyryl]-l-thia-4,7-diaza-
spuo[4 4] nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 27)
EIMS (m/z) 604 1(M+1)
(S)-3-[((S)-4-Acetyl-7-{(S)- 2-(S)-2-hydroxy-2-phenyl-acetylamino)-3-methyl-butyrylJ-l-thia-4,7-diaza-
spuo[4 4]nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 28)
EIMS (m/z) δ63 1(M+1)
(S)-3-[((S)-4-Acetyl-7-{(S)-3-methyl- 2-(3-phenyl-propionylamino)-butyryl]-l-thia-4,7-diaza-spiro[4 4]nonane-
8-carbonyl}-amino)-4-oxo-butyric acid (Compound No 29)
EIMS (m/z) δ61 1(M+1)
Example 6 Synthesis of (S)-3-{[(R)-8-Acetyl-4-(naphthalene-2-yl-aminooxalyl)-l-thia-4,8-diaza-spiro[4 5]decane-3-carbonyl]-amino}-4-oxo-butync acid {Compound No 30) Step a Synthesis of N-naphthalene-2-yl-oxamic acid ethyl ester
To the solution of naphthalene-2-ylamine (1 15 g) in dichloromethane (20 mL) was added triethylamine (0 65 mL) in a dropwise manner at -5°C and the reaction mixture was stirred at the same temperature for 15 mm followed by dropwise addition of chloro-oxo-acetic acid ethyl ester (1 5 mL) The reaction mixture was stirred from -5°C to room temperature for 2 h, poured in water, extracted with dichloromethane, washed with aqueous solution of sodium hydrogen sulphate, aqueous solution of sodium hydrogen carbonate, water, brine and dried over anhydrous sodium sulphate and concentrated to furnish the title compound (1 16 g) EIMS (m/z) 244 1(M+1)
Step b Synthesis ofN-naphthalene-2-yl-oxamic acid
To the solution of compound (1 15 g) obtained from the step a above in a mixture of tetrahydrofuran methanol water (3 11) (20 mL) was added lithium hydroxide monohydrate (0 21 g) and stirred for 2 h The reaction mixture was concentrated to get a crude oil, which was taken in water and washed with ethyl acetate The aqueous extract was acidified with dilute sodium hydrogen sulphate and extracted with ethyl acetate The organic extract was washed with water, brine and dried over anhydrous sodium sulphate and concentrated to
furnish the title compound (1 1 g)
EIMS(m/z) 216 1(M+1)
Step c Synthesis of (R)-8-Acetyl-4-(naphthalene-2-ylaminooxalyl)-1 -thia-4,8-diaza-spiro[4 5]decane-3-
carboxylic acid ethyl ester
To the solution of the N-naphthalene-2-yl-oxamic acid (0 27 g) obtained form the step b above in
tetrahydrofuran (10 mL) at 0°C under nitrogen atmosphere, was added N-methylmorpholine (0 11 mL) and the
reaction mixture was stirred for 5 min followed by the addition of a solution (R)-8-acetyl-l-thia-4,8-diaza-
spiro[4 5]decane-3-carboxyhc acid ethyl ester (0 157 g) in tetrahydrofuran (5 mL) and stirred for lh from -15°C
to room temperature The reaction mixture was quenched with water and evaporated To the residue thus
obtained was added ethyl acetate, washed with aqueous solution of sodium hydrogen sulphate, aqueous solution
of sodium hydrogen carbonate, brine and dried over anhydrous sodium sulphate and concentrated The crude
was purified by column chromatography over silica gel using 20 % ethyl acetate in hexane as eluant to furnish
the title compound (0 225 g)
EIMS(m/z) 469 1(M+1)
Step d Synthesis of(R)-8-Acetyl-4-(naphthalene-2-ylaminooxalyl)-l-thia-4,8-diaza-spiro[4 5]decane-3-
carboxylic acid
To the solution of compound (0 225 g) obtained from the step c above in a mixture of tetrahydrofuran
methanol water (3 1 1) (10 mL) was added lithium hydroxide monohydrate (0 025 g) and stirred for 2 h The
reaction mixture was concentrated to get a crude oil, which was taken in water and washed with ethyl acetate
The aqueous extract was acidified with sodium hydrogen sulphate and extracted with ethyl acetate The organic
extract was washed with water, brine and dried over anhydrous sodium sulphate and concentrated to furnish the
title compound (0 2 g)
EIMS (mix) 441 1 (M+l)
Step e Synthesis of(S)-3-{[(R)-8-Acetyl-4-(naphthalene-2-vlaminooxalyl)-l-thia-4,8-diaza-spiro[4 5]decane-
3-carbonyl]-amino}-4 4-diemthoxy-butyric acid tert-butyl ester
To the compound (0 2 g) obtained from step d above in dimethyl formamide (10 mL) at 0°C under nitrogen
atmosphere, were added N-methylmorphohne (0 15 mL), hydroxybenzotnazole (0 07 g) and (S)-3-ammo-4,4-
dimethoxy-butyric acid tert-butyl ester (0 1 g) and stirred for 10-15 min To the reaction mixture was added 1-
(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (0 1 g) and was further stirred at 0°C for 1 h and
then at room temperature for overnight The reaction mixture was diluted with ethyl acetate and washed with
aqueous solution of sodium hydrogen sulphate, aqueous solution of sodium hydrogen carbonate, water, brine,
dried over anhydrous sodium sulphate and concentrated to furnish the crude title compound (0 2 g)
EIMS(m/z) 642 1 (M+l)
Step f Synthesis of (S)-3-{ [(R)-8-Acetyl-4-(naphthalene-2-yl-aminooxalyl)- l-thia-4,8-diaza-spiro[4 Sldecane-
3-carbonyl)'-amino}-4-oxo-butyric acid
To the solution of compound (0 1 g) obtained from the step e above in dichloromethane (5 mL) at room
temperature was added 30 % trifluoroacetic acid in dichloromethane (2 mL) and water (0 2 mL) at 0°C and the
reaction mixture was stirred form 0°C to room temperature for 3 h The reaction mixture was concentrated to
obtain a crude residue which was purified by preparative thin layer chromatography (2 mm, Merck) using 10 %
methanol in dichloromethane to furnish the title compound (0 03 g)
1HNMR (DMSO-d6, 400 MHz) δ 10 4 (1H, s), 8 27 (1H, s), 7 82 (4H, m), 7 47 (4H, m), 5 76 (1H, br s), 4 6 (1H, m), 4 0 (1H, m), 3 5-2 5 (8H, m), 2 03 (3H, s) and 2 2-16 (2H, m) EIMS(m/z) δ63 1(M+23)
Example 7 Synthesis of (S)-4-(7-Methoxy-benzooxazol-2-yl)-3-[((S)-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryI}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butync acid (Compound No 33)
Step a Synthesis of (S)-4-Hydroxy-4-(7-methoxy-benzooxazol-2-yl)-3-[((S)-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyD-aminol -butyryU-3-phenyl-1 -oxa-2J-diaza-spiro[4 41non-2-ene-8-carbonvl)-ammol-butyric acid tert-butyl ester
To a stirred solution of (S)-7-{(S)-3-Methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carboxyhc acid (0 33 g) obtained from step b of Example 1 and (S)-3-allyloxycarbonylamino-4-hydroxy-4-(7-methoxy-benzooxazol-2-yl)-butync acid tert-butyl ester (0 25 g) in dimethylformamide (3 mL) and dichloromethane (3 mL) was added bis (tnphenylphosphine) palladium (II) chloride (9 mg) followed by addition of tributyltin hydride (0 41 mL) dropwise Hydroxybenzotriazole (0 166 g) was added to the resulting mixture and reaction mixture was then cooled to 0°C l-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (0 14 g) was added and reaction mixture was allowed to warm to room temperature and stirred for 16 h The reaction mixture was diluted with ethyl acetate and washed with sodium hydrogen sulphate and with sodium hydrogen carbonate, water and brine The combined organic extracts were dried over anhydrous sodium sulphate, concentrated in vacuo and purified by column chromatography using 30 % ethyl acetate hexane as eluant to afford (0 134 g) of the title compound EIMS(m/z) 804 (M+l)
Step b Synthesis of (S)-4-(7-Methoxy-benzooxazol-2-yl)-3-[((S)-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonvl)-amino]-4-oxo-butyric acid tert-butyl ester
To a solution of compound (0 16 g) obtained from step a above in dichloromethane (10 mL) was added Dess-martin reagent (0 253 g) The resulting mixture was stirred for 1 h Saturated solution of sodium thiosulphate (5 mL), sodium hydrogen carbonate solution (5 mL) and ethyl acetate (10 mL) was added to the reaction mixture and stirred for about 30 min Organic layer was separated and washed with sodium thiosulphate solution, sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulphate and concentrated in vacuo to afford residue which was purified by column chromatography over silica gel using 50 % ethyl acetate hexane as eluant to afford the title compound (0 16 g) EIMS(m/z) 802 (M+l)
Step c Synthesis of (S)-4-(7-Methoxy-benzooxazol-2-yl)-3-f((S)-7-{(S)-3-methyl-2-((naphthalene-2-carbonyl)-amino]-butyryU-3-phenyl-l-oxa-2,7-diaza-spirof4 41non-2-ene-8-carbonyl)-amino]-4-oxo-butvric acid The compound (0 16g) obtained from step b above was stirred with 50 % trifluoroacetic acid solution in dichloromethane (5 mL) at room temperature for 30 min The reaction mixture was concentrated and dried to give the crude product, which was purified by preparative thin layer chromatography (2mm, Merck) using 10 %
methanol in dichloromethane to afford the title compound (0 023 g)
1HNMR (CDCI3, 400 MHz) 8 8 33 (s, 1H), 7 90-6 90 (m, 14H), 5 05-4 55 (m, 3H), 4 12 (br s, 3H), 3 50-3 10 (m, 4H), 2 63 (m, 2H), 2 31 (m, 2H), 2 10-1 90 (m, 1H) and 0 85(m, 6H) EIMS(m/z) 746 04(M+1)
Analogues of (S)-4-(7-Methoxy-benzooxazol-2-yl)-3-[((S)-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-
amino]-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butync acid
described below were prepared by either retaining or replacing (S)-7-{(S)-3-Methyl-2-[(naphthalene-2-
carbonyl)-amino]-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carboxylic acid with appropriate
acid and/ or (S)-3-allyloxycarbonylamino-4-hydroxy-4-(7-methoxy-benzooxazol-2-yl)-butync acid tert-butyl
ester with appropriate alloc protected amines as applicable in each case
(S)-4-[5-(2,6-Dichloro-phenyl)-oxazol-2-yl]-3-[((S)-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-
butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butyric acid (Compound No
34)
EIMS(m/z) 8116(M+1)
(S)-3-[((S)-7-{(S)-3-Methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-phenyl-l-oxa-2 7-diaza-
spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-4-(5-pyndin-2-yl-oxazol-2-yl)-butyric acid (Compound No 35),
EIMS(m/z) 743 02(M+1)
(S)-4-Benzooxazol-2-yl-3-[((S)-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-phenyl-l-oxa-
2 7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butyric acid (Compound No 36),
EIMS(m/z) 716 05(M+1)
(S)-3-[((S)-7-{(S)-3-Methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-phenyl-l-oxa-2 7-diaza-
spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-4-(5-phenyl-oxazol-2-yl)-butyric acid (CompoundNo 37),
EIMS(m/z) 742 01(M+1)
(S)-3-[((S)-7-{(S)-3-Methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-phenyl-l-oxa-2 7-diaza-
spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxazolo[4 5-b]pyridin-2-yl-4-oxo-butyrw acid (Compound No 38),
EIMS(m/z) 738 97(M+23)
(S)-4-(4-Methoxy-benzooxa:ol-2-yl)-3-[((S)-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-
phenyl-l-oxa-2 7-diaza-spiro[4 4Jnon-2-ene-8-carbonyl)-aminoJ-4-oxo-butyric acid (Compound No 39)
EIMS(m/z) 746(M+1)
(S)-4-(4-Methoxy-benzooxazol-2-yl)-3-[((S)-3-methyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-
butyryl}-l-oxa-2 7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butync acid (Compound No 40),
EIMS(m/z) 684 88(M+1)
(S)-3-({(S)-7-{(S)-2-[(Isoquinoline-l-carbonyl)-amino-3-methyl-butyryl}-3-methyl- l-oxa-2,7-diaza-
spiro[4 4]non-2-ene-8-carbonyl}-amino)-4-(7-methoxy-benzooxazol-2-yl)-4-oxo-butyric acid (Compound No
41)
EIMS(m/z) 685 6(M+1)
(S)-4-Benzooxazol-2-yl-3-[((S)-3-methyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-1-oxa-
2 7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butyric acid (Compound No 42),
EIMS(m/z) 653 87(M+)
(S)-3-({(S)-7-{(S)-2-[(Isoquinohne-l-carbonyl)-amino-3-methyl-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl}-amino)-4-(7-methoxy-benzooxazol-2-yl)-4-oxo-butync acid (Compound No 43)
EIMS(m/z) 747 46(M+1)
(S)-3-({(S)-7-{(S)-2-[(lsoquinoline-l-carbonyl)-amino-3-methyl-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl}-ammo)-4-(4-methoxy-benzooxazol-2-yl)-4-oxo-bntync acid (Compound No 44)
EIMS(m/z) 747 53(M+1)
(S)-3-({(S)-7-{(S)-2-[(Isoquinoline-l-carbonyl)-amino]-3-methyl-butyryl}-3-methyl-l-oxa-2 7-diaza-spiro[4,4]non-2-ene-8-carbonyl}-amino]-4-(4-methoxy-benzooxazol-2-yl)-4-oxo-butyric acid (Compound No 45)
EIMS(m/z) 684 80(M+)
(S)-4-(7-Methoxy-benzooxazol-2-yl)-3-[((S)-3-methyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-l-oxa-2 7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butyric acid (Compound No 46) EIMS(m/z) 684 81(M+1)
(S)-3-({(S)-4-Acetyl-7-[(S)-3-methyl-2-(2-naphthalen-2yl-acetylamino)-butyryl]-l-thia-4 7-diaza-spiro[4 4]nonane-8-carbonyl}-amino)-4-(4-methoxy-benzooxazol-2-yl)-4-oxo-butyric acid (Compound No 47) EIMS(m/z) 744 8(M+1)
(S)-3-({(S)-4-Acetyl-7-[(S)-3-methyl-2-(2-naphthalen-2yl-acetylamino)-butyryl]-l-thia-4 7-diaza-spiro[4 4]nonane-8-carbonyl}-ammo)-4-(7-methoxy-benzooxazol-2-yl)-4-oxo-butyric acid (Compound No 48), EIMS(m/z) 744 82(M+1)
(S)-3-[((S)-4-Methanesulfonyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-l-thia-4 7-diaza-spiro[4 4]nonane-8-carbonyl)-amino]-4-(4-methoxy-benzooxazol-2-yl)-4-oxo-butyric acid (CompoundNo 49) EIMS(m/z) 766 76(M+1)
(S)-3-[((S)-4-Methanesulfonyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-l-thia-4,7-diaza-spiro[4 4]nonane-8-carbonyl)-amino]-4-(7-methoxy-benzooxazol-2-yl)-4-oxo-butyric acid (Compound No 50), EIMS(m/z) 765 7(M+)
Example 8
Synthesis of 5-(Hexyl-methyl-amino)-3-[((S)-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-
butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid
(Compound No 51)
Step a Synthesis of 5-(Hexvl-methyl-amino)-3-[((S)-7-{(S)-3-methvl-2-[(naphthalene-2-carbonyl)-aminol-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4Jnon-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid tert-butyl ester
To a solution of (S)-7-{(S)-3-MethyI-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carboxyhc acid (0 2 g) obtained from step b of Example 1 in dry tetrahydrofuran (5 mL) was added hydroxybenzotnazole (0 108 g) and l-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (0 084 g) at room temperature The mixture was stirred for about 30 min and two drops of water was added to
the reaction mixture and reaction was further stirred for 10 min To this reaction mixture (S)-3-
Allyloxycarbonylamino-5-(hexyl-methyl-amino)-4-oxo-pentanoic acid tert-butyl ester (0 153 g) in
tetrahydrofuran (2 mL) was added, followed by bis (tnphenyl phosphine) palladium (II) chloride (0 025 g) and
tnbutyl tin hydride (0 174 g) drop wise at room temperature The reaction mixture was stirred for over night at
room temperature The reaction mixture was concentrated, diluted with ethyl acetate and washed with aqueous
sodium hydrogen sulphate solution, aqueous sodium hydrogen carbonate solution and brine, dried over
anhydrous sodium sulphate and concentrated The crude was purified by column chromatography over silica gel
using ethyl acetate as eluant to furnish the title compound (0 06 g)
EIMS (m/z) 782 (M+l)
Step b Synthesis of 5-(Hexyl-methvl-aminoj-3-[((S)-7-{(S)-3-methyl-2-[(naphthalene-2-carbonvl)-aminol-
butyryll-3-phenyl-l-oxa-2,7-diaza-spirof4 41non-2-ene-8-carbonyl)-aminol-4-oxo-pentanoic acid
The compound (0 06 g) obtained from step a above was stirred with 30 % tnfluoroacetic acid in
dichloromethane (3 mL) at room temperature for 2 h The reaction mixture was concentrated and dried to give
the crude product, which was purified by preparative thin layer chromatography (2 mm, Merck) using 10 %
methanol in dichloromethane as eluant to afford the title compound (0 04 g)
1HNMR (DMSO-d6, 400 MHz) δ 8 55-8 30 (m,3H), 7 98 (br s, 4H), 7 63 (br, d, J = 21 Hz, 4H), 7 47 (s, 3H),
4 52-4 45 (m, 4H), 2 90-2 35 (m, 3H), 2 45 (s, 1H), 2 35-2 05 (m, 6H), 1 50-0 82 (m, 15H), 0 79(m, 6H)
EIMS (m/z) 726 17 (M+l)
Analogues q/"5-(Hexyl-methyl-amino)-3-[((S)-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-
phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid described below were
prepared by either retaining or replacing (S)-7-{(S)-3-Methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-
phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carboxyhc acid with appropriate acid and/ or (S)-3-
allyloxycarbonylamino-5-(hexyl-methyl-amino)-4-oxo-pentanoic acid tert-butyl ester with appropriate alloc
protected amines as applicable in each case
5-(2-Chloro-benzyloxy)-3-[((S)-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-phenyl-l-oxa-
2 7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 52)
EIMS (m/z) 754(M+1)
(S)-5-(2-Chloro-benzylsulfanyl)-3-[((S)-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-
phenyl-l-oxa-2 7-dia:a-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (CompoundNo 53)
EIMS (m/z) 770 3(M+1)
5-(Benzyl-methyl-amino)-3-[((S)-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-phenyl-l-
oxa-2 7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 54)
EIMS (m/z) 732(M+1)
(S)-5-(l 3-Dioxo-l 3-dihydro-isoindol-2-yl)-3-[((S)-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-ammo]-
butyryl}-3-phenyl-l-oxa-2 7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound
No 55)
EIMS (m/z) 758 7(M+1)
(S)-5-(2-Chloro-benzyloxy)-3-[((S)-7-{(S)-2-[(isoquinoline-l-carbonyl)-ammo]-3-methyl-butyryl}-3-phenyl-l-
oxa-2 7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 56),
EIMS (m/z) 755 75 (M+l)
(S)-5-(2-Chloro-benzyloxy)-3-[((S)-3-methyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyrvl}-l-oxa-2 7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 57), EIMS (m/z) 692 1(M+1)
(S)-5-(2-Chloro-benzyloxy)-3-[((S)-7-{(S)-2-[(isoquinohne-l-carbonyl)-amino]-3-methyl-butyryl}-3-methyl-l-oxa-2 7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 58) EIMS (m/z) 693 1(M+1)
5-(Hexyl-methyl-amino)-3-[((S)-7-{(S)-2-[Isoquinohne-l-carbonyl)-amino]-3-methyl-butyryl}-3-methyl-l-oxa-2 7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 59) EIMS (m/z) 665(M+1)
(S)-5-(Hexyl-methyl-amino)-3-[((S)-3-methyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyrylj-l-oxa-2 7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 60), EIMS (m/z) 664(M+1)
(S)-3-[((S)-7-{(S)-3-Methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-phenyl-l-oxa-2 7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-ammo]-4-oxo-9-phenyl-nonanoic acid (Compound No 61), EIMS (m/z) 745 26(M+1)
(S)-5-(Hexyl-methyl-amino)-3-[((S)-7-{(S)-2-[isoquinohne-l-carbonyl)-amino]-3-methyl-butyryl}-3-phenyl-l-oxa-2 7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 62) EIMS (m/z) 727 8(M+1)
(S)-5-(Hexyl-methyl-amino)-3-[((S)-4-methanesulfonyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-ammo]-butyryl}-l-thia-4 7-diaza-spiro[4 4]nonane-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 63) EIMS (m/z) 746 88(M+1)
(S)-5-(2-Chloro-benzyloxy)-3-[((S)-4-methanesulfonyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-aminoJ-butyrylj-l-thia-4,7-diaza-spiro[4 4]nonane-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 64) EIMS (m/z) 774 76(M+1)
(S)-3-({(S)-4-Acetyl-7-[(S)-3-methyl-2-(2-naphthalen-2yl-acetylamino)-butyryl]-l-thia-4 7-diaza-spiro[4 4]nonane-8-carbonyl}-amino)-5-(hexyl-methyl-amino)-4-oxo-pentanoic acid (Compound No 65) EIMS (m/z) 724 9(M+1)
(S)-3-({(S)-4-Acetyl-7-[(S)-3-methyl-2-(2-naphthalen-2-yl-acetylamino)-butyryl]-l-thia-4 7-diaza-spiro[4 4]nonane-8-carbonyl}-amino)-5-(2-chloro-benzyloxy)-4-oxo-pentanoic acid(Compound No 66), EIMS (m/z) 752 2(M+1)
Example 9 Synthesis of (S)-5-(2-Chloro-benzyloxy)-3-[((5S,8S)-7-{(S)-2-[(isoquinohne-l-carbonyl)-amino]-3-methyl-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid tert-butyl ester (Compound No 67)
Step a Synthesis of (5S,8S)-3-Phenvl-l-oxa-2J-diaza-spiro[4 4Jnon-2-ene-8-carboxylic acidmethyl ester hydrochloride To a solution of (5S, 8S)-3-Phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-7,8-dicarboxyhc
acid di-tert-butyl ester (0 15 g) in dry methanol was added thionyl chloride (0 3 mL) dropwise at 0°C The
reaction mixture was stirred at room temperature for overnight The solvent was evaporated to afford the title
compound (0 1 lg)
Step b Synthesis of (5S,8S)-7-{(S)-2-f(Isoquinolme-l-carbonylj-aminoJ-3-methyl-butyryll-3-phenyl-l-oxa-2,7-
diaza-spiro[4 41non-2-ene-8-carboxyhc acid methyl ester
To the solution of (5S,8S)-3-Phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carboxyhc acid methyl ester
hydrochloride (Oil g) in dimethyl formamide (5 mL) and at 0°C under nitrogen atmosphere, was added N-
methylmorpholine (0 25 mL), hydroxybenzotriazole (0 06 g) and (S)-2-[(Isoquinoline-l-carbonyl)-amino]-3-
methyl-butync acid (0 111 g) The reaction mixture was stirred for 10-15 min followed by the addition of l-(3-
dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (0 085 g) and stirred at 0°C for 1 h and at room
temperature for overnight The reaction mixture was diluted with ethyl acetate and washed with water, sodium
hydrogen sulphate, sodium hydrogen carbonate and brine, dried over anhydrous sodium sulphate and
concentrated The crude was purified by column chromatography over silica gel using 66 % ethyl acetate in
hexane as eluant to furnish the title compound (0 14 g)
EIMS(m/z) δ15 2(M+1)
Step c Synthesis of (5S,8S)-7-{(S)-2-[(lsoquinolme-l-carbonyl)-aminol-3-methyl-butyryU-3-phenyl-l-oxa~2,7-
dia:a-spiro[4 4]non-2-ene-8-carboxyhc acid
To the solution of (5S,8S)-7-{(S)-2-[(Isoquinohne-l-carbonyl)-amino]-3-methyl-butyryl}-3-phenyl-l-oxa-2,7-
diaza-spiro[4 4]non-2-ene-8-carboxyhc acid methyl ester (0 12 g) in a mixture of solvent (10 mL)
[tetrahydrofuran methanol water (3 1 1)] was added lithium hydroxide monohydrate (0 042 g) and stirred for
about 3 h The reaction mixture was concentrated to obtain a crude oil that was taken in water (10 mL) and
washed with ethyl acetate The aqueous layer was acidified with sodium hydrogen sulphate and extracted with
ethyl acetate The organic extract was washed with water brine and dried over anhydrous sodium sulphate and
concentrated to furnish the title compound (0 116 g)
EIMS(m/z) δ012(M+1)
Step d Synthesis of (S)-5-(2-Chloro-benzyloxy)-3-[((5S,8S)-7-{(S)-2-[(isoquinoline-l-carbonyl)-amino]-3-
methvl-butyrvll-3-phenvl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid tert-
butyl ester
To a solution of (5S,8S)-7-{(S)-2-[(Isoquinohne-l-carbonyl)-amino]-3-methyl-butyryl}-3-phenyl-l-oxa-2,7-
diaza-spiro[4 4]non-2-ene-8-carboxyhc acid (0 116 g) in dry tetrahydrofuran (3 mL) was added
hydroxybenzotriazole (0 063 g) and l-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (0 053 g) at
room temperature The mixture was stirred for about 30 min and two drops of water was added to the reaction
mixture and further stirred for 10 min To this reaction mixture (S)-3-allyloxycarbonylamino-5-(2-chloro-
benzyloxy)-4-oxo-pentanoic acid tert-butyl ester (0 095 g) was added followed by addition of bis (triphenyl
phosphine) palladium (II) chloride (4 mg) and tnbutyl tin hydride (0 06 mL) drop wise at room temperature
The reaction mixture was stirred for over night at room temperature The organic layer was evaporated, diluted
with ethyl acetate and washed with dilute aqueous sodium hydrogen sulphate solution, aqueous sodium
hydrogen carbonate solution and brine, dried over anhydrous sodium sulphate and concentrated The crude was
purified by column chromatography over silica gel using ethyl acetate as eluant to furnish the title compound
(0 115g)
1HNMR (CDCU, 400 MHz) δ 9 52-9 43 (dd, J = 8 Hz and 28 Hz, IH), 8 85-8 77 (m, IH), 8 51-8 42 (m, IH),
7 86-7 77 (m, 2H), 7 74-7 62 (m, 5H), 7 47-7 33 (m, 5H), 7 29-7 15 (m, IH), 4 90-4 75 (m, 2H), 5 75-4 70 (m,
IH), 4 61-4 19 (m, 5H), 4 02-3 81 (m, IH), 3 50-3 40 (m, 2H), 2 82-2 50 (m, 4H), 1 34 and 1 30 (s, 9H), 1 15-
1 03 (m, 6H)
EIMS(m/z) 810 (M+l)
Analogues of (S)-5-(2-Chloro-benzyloxy)-3-[((5S,8S)-7-{(S)-2-[(isoquinohne-l-carbonyl)-amino]-3-methyl-
butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid tert-butyl
ester described below were prepared by replacing (5S,8S)-3-Phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-7,8-
dicarboxylic acid di-tert-butyl ester with appropriate esters as applicable in each case
(S)-5-(2-Chloro-benzyloxy)-3-[((5R8S)-7-{(S)-2-[(isoquinohne-l-carbonyl)-amino]-3-methyl-butyryl}-3-
phenyl-1-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonvl)-amino]-4-oxo-pentanoic acid tert-butyl ester
(Compound No 68)
EIMS(m/z) 811(M+1)
(S)-5-(2-Chloro-benzyloxy)-3-[((5S,8S)-7-{(S)-2-[(isoquinohne-l-carbonyl)-amino]-3-methyl-butyryl}-3-
methyl-1-oxa-2 7-diaza-spiro[4 4Jnon-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid tert-butyl ester
(Compound No 69)
EIMS(m/z) 748(M+)
Example 10
Synthesis of (S)-5-(2-Chloro-benzyloxy)-3-[((5S,8S)-7-{(S)-2-[(isoquinohne-l-carbonyl)-amino]-3-methyl-
butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid
(Compound No 70)
(S)-5-(2-ChIoro-benzyloxy)-3-[((5S,8S)-7-{(S)-2-[(isoquinohne-l-carbonyl)-amino]-3-methyl-butyryl}-3-phenyl-1-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid tert-butyl ester( 0 lg) obtained from step d of Example 9 was stirred with 50 % trifluoroacetic acid solution in dichloromethane (3 mL) at room temperature for 2 h The reaction mixture was concentrated and dried to give the crude product, which was purified by preparative thin layer chromatography (2mm, Merck) using 10 % methanol in dichloromethane as mobile phase, to afford the title compound (0 055 g)
1HNMR (DMSO-d6, 400 MHz) δ 9 00 (d, 8 7 Hz, IH), 8 85 (d, 8 7 Hz, IH), 8 56 (d, 4 Hz, IH), 8 056-7 90 (m, 21 7 85-7 50 (m, 3H) 7 48-7 27 (m, 8H), 4 75-4 25 (m, 7H), 3 97 (m, IH), 3 70-3 20 (m, 3H), 2 85-2 10 (m, 5H) a 0 85(m, 6H) EIMS(m/z) 754 (M+)
Analogues of (S)-5-(2-Chloro-benzyloxy)-3-[((5S,8S)-7-{(S)-2-[(isoquinohne-l-carbonyl)-amino]-3-methyl-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid described below were prepared by replacing (S)-5-(2-Chloro-benzyloxy)-3-[((5S,8S)-7-{(S)-2-[(isoquinoline-l-carbonyl)-amino]-3-methyl-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid tert-butyl ester with appropriate esters as applicable in each case
(S)-5-(2-Chloro-benzyloxy)-3-[((5R8S)-7-{(S)-2-[(isoquinolme-l-carbonyl)-ammo]-3-methyl-butyryl}-3-phenyl-l-oxa-2 7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanow acid (Compound No 71), EIMS(m/z) 755(M+1)
(S)-5-(2-Chloro-benzyloxy)-3-[((5S,8S)-7-{(S)-2-[(isoquinohne-l-carbonyl)-amino]-3-methyl-butyryl}-3-methyl-l-oxa-2 7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 72) EIMS(m/z) 692(M+)
Invitro activity data
ICE Inhibition Assays
The assay employs the caspase-1 specific colorimetnc substrate Ac-YVAD-pNA that upon cleavage with Caspasel exhibits increased absorption at 405 nm, which is monitored in the presence and absence of inhibitor Percent inhibition is calculated in a dose response curve and IC50 values calculated using PRISM-Graph Pad
Cell based Assay for IL-lfi release
Method of isolation of Human Peripheral Blood Mononuclear Cells(PBMNCs)
Human whole blood was collected in vacutainer tubes containing heparin as an anti coagulant A blood sample
(5 mL) was diluted with equal amount of RPMI-1640 media and layered over 4 mL Ficoll Hypaque-1077
(Sigma) in a 15 mL centrifuge tubes The sample was centrifuged at 450-500 x g for 30 minutes in a swinging
bucket rotor at room temperature After centrifugation the buffy interface of cells was removed and washed 3
times with PBS The cells were centrifuged at 400x g for 10 mm at room temperature The cells were
resuspended in RPMI media at concentration of 1 million cells / mL
LPS stimulation of Human PBMs
PBMNCs (0 1 mL, 1 million/ mL) were co-incubated with 20uL of compound at various concentrations for 30 mm in flat bottom 96 well microtiter plates Compounds were dissolved in DMSO initially and further dilutions were made in RPMI LPS was then added at volume of 50uJ (final concentration of lµg/ml) Plates were incubated for 20 min at room temperature on rotatory shaker at 200 rpm 30 \x\ of RPMI 1640 with 10% FCS was added to all wells to make up the volume to 200fo.I Cultures were incubated overnight at 37°C Supernatant were then removed and tested by ELISA for IL17 release Viability was analyzed using MTT After 0 1 mL supernatant was collected, 0 1 mL of 0 25 mg/mL of MTT was added to the remaining 0 1 mL of cells The cells were incubated at 37°C for 4 h, and then the O D was measured at 540 nm.

WE CLAIM:
1 A compound having the structure of Formula I
(Formula Removed)
including pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers,
polymorphs, prodrugs, metabolites or jV-oxides thereof
wherein
G is carbon or sulphur, S=O or S(O)2
W forms an optionally substituted spiro-heterocychc ring with any one of the carbon atoms on the ring J,
Y can be independently selected from -CO-, -C(R1)(R2)-,CH(R1)CH(R2)- and -N(R1)- (wherein R1 and R2 are
independently selected from group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,
heterocyclyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl or cycloalkylalkyi, or R1 and R2 can together form a
carbocyclic/aromatic or heterocyclic / heteroaromatic ring along with the carbon atoms to which they are
bonded)
when Y is -CR1(R2)CR1(R2)- or -C(R1)(R2)-,
then Z can be a bond or can be independently selected from -CH2-, -C(=K)-, -C(=K)Rd- or -SO2 (wherein K can
be selected from oxygen or sulphur and Rd is amino, sulphonyl amino or oxygen),
when Y is -N(R1)-
then Z can be a bond or can be independently selected from -CH2-, -C(=K)-, or -SO2 wherein K can be
selected from oxygen or sulphur,
when Y is -C(=O)-
then Z can be a bond,
n can be an integer from 1-3
L is hydrogen, lower (C1-C6) alkyl, lower (C1-C8) cycloalkyl, lower (C3-C8) cycloalkylalkyi, lower (C1-C6)
aralkyl or lower (C|-C6) heterocyclylalkyl, aryl or heteroaryl
B is optionally substituted alkyl, cycloalkyl, cycloalkylalkyi, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl or heteroarylalkyl,
A can be
(Formula Removed)
wherein R3 is hydroxy, alkyloxy, cycloalkyloxy or NHS02Rp (wherein RP is alkyl, alkenyl, alkynyl, cycloalkyl,
aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl or cycloalkylalkyl),
R3' is hydrogen, alkyl, fluoroalkyl, heterocyclyl or heteroaryl, -(CH2)„-NRxRy,
-C(=O)NRxRy, -(CH2)n-ORx, -(CH2)n-OC(=O)NRxRy -(CH2)n-SRx, (wherein RX can be selected from is alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl or
cycloalkylalkyl and Ry can be either hydrogen or Rx),
When A is Formula D then R3 and R3 are interchangeable,
R4, R4 and Rs are hydrogen, CH3 or fluorine, and
R is independently selected from hydrogen, alkyl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, and heteroarylalkyl (when R is heterocyclyl or heteroaryl, then the point of attachment to
oxygen is not through heteroatom)
Rt independently could be hydrogen, alkyl, arylalkyl, cycloalkyl, fluoroalkyl, heterocyclyl, heterocyclylalkyl or
heteroarylalkyl
2 A compound selected from
(S)-3-[((S)-7-{(S)-3-Methyl-2-[{naphthalene-2-carbonyl)-amino]-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butync acid (Compound No 1), (S)-3-[((S)-7-{(S)-3-Methyl-2-(-2-naphthalene-l-yl-acetylamino)-butyryl]-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butync acid (Compound No 2), (S)-3-[{(S)-7-[(S)-3-Methyl-2-(-2-naphthalene-2-yl-acetylamino)-butyryl]-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 3),
(S)-3-[{(S)-7-[(S)-3-Methyl-2-(-2-p-tolyl-acetylamino)-butyryl]-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 4),
(S)-3-[{(S)-7-[(S)-3-Methyl-2-(-2-o-tolyl-acetylamino)-butyryl]-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 5),
(S)-3-[{(S)-7-{(S)-2-[2-(2-Fluoro-phenyl)-acetylammo]-3-methyl-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butync acid (Compound No 6), (S)-3-[((S)-3-Methyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-ammo]-4-oxo-butync acid(Compound No 7)
(S)-3-[((S)-4-Methanesulfonyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl)-amino]-4-oxo-butync acid (Compound No 08),
(S)-3-[{(S)-4-Methanesulfonyl-7-[(S)-3-methyl-2-(2-naphthalene-l-yl-acetylammo)-butyryl]-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl)-amino]-4-oxo-butync acid (Compound No 9),
(S)-3-[{(S)-4-Acetyl-7-[(S)-3-methyl-2-(-2-o-tolyl-acetylamino)-butyryl]-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 10),
(S)-3-[{(S)-4-Acetyl-7-[(S)-3-methyl-2-(-2-naphthalene-l-yl-acetylamino)-butyryl]-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 11) (S)-3-[{(S)-4-Acetyl-7-[(S)-3-methyl-2-(-2-thiophen-2-yl-acetylamino)-butyryl]-l-thia-4,7-diaza-spiro[4 4]
nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 12),
(S)-3-{[(S)-4-Acetyl-7((S)-3-methyl-2-phenylacetylamino-butyryl)-l-thia-4,7-diaza-spiro[4 4] nonane-8-
carbonyl]-amino}-4-oxo-butync acid (Compound No 13),
(S)-3-[((S)-4-Acetyl-7-{(S)-3-methyl-2-[2-(-4-tnfluoromethyl-phenyl-)-acetylamino]-butyryl}-l-thia-4 7-diaza-spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 14),
(S)-3-({(S)-4-Acetyl-7-[(S)-3-methyl-2-(2-phenoxy-acetylamino)-butyryl]-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 15),
(S)-3-[((S)-4-Acetyl-7-{(S)-2-[2-(3-fluoro-phenyl)-acetylamino]-3-methyl-butyryl}-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyI]-amino)-4-oxo-butync acid (Compound No 16),
(S)-3-[((S)-4-Acetyl-7-{(S)-3-methyl-2-(2-p-tolyl-acetylamino)-butyryl}-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl]-amino)-4-oxo-butync acid (Compound No 17),
(S)-3-[((S)-4-Acetyl-7-{(S)-2-[2-(2-fluoro-phenyl)-acetylamino]-3-methyl-butyryl}-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 18),
(S)-3-[((S)-4-Acetyl-7-{(S)-2-[2-(4-methoxy-phenyl)-acetylamino]-3-methyl-butyryl}-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 19),
(S)-3-[{(S)-4-Acetyl-7-[(S)-3-methyl-2-(-2-naphthalene-2-yl-acetylamino)-butyryl]-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 20),
(S)-3-[((S)-4-Acetyl-7-{(S)-2-[2-(3-methoxy-phenyI)-acetylamino]-3-methyl-butyryl}-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 21),
(S)-3-[{(S)-4-Acetyl-7-[(S)-2-[-2-(4-chloro-phenyl)-acetylamino]-3-methyl-butyryl]-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 22),
(S)-3-[{(S)-4-Acetyl-7-[(S)-2-[-2-(4-fluoro-phenyl)-acetylamino]-3-methyl-butyryl]-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 23),
(S)-3-[{(S)-4-Acetyl-7-{(S)-2-[-2-(2-acetylamino-thiazol-4-yl)-acetylamino]-3-methyl-butyryl]-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 24),
(S)-3-[((S)-4-Acetyl-7-{(S)-3-methyl-2-[2-(2-methyl-lH-indol-3-yl)-acetylamino]-butyryl}-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 25),
(S)-3-[((S)-4-Acetyl-7-{(S)-2-(2-lH-mdol-3-yl-acetylamino)-3-methyl-butyryl]-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 26),
(S)-3-[((S)-4-Acetyl-7-{(S)-2-((S)-2-acetylammo-2-phenyl-acetylamino)-3-methyl-butyryl]-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 27),
(S)-3-[((S)-4-Acetyl-7-{(S)-2-(S)-2-hydroxy-2-phenyl-acetylamino)-3-methyl-butyryl]-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 28),
(S)-3-[((S)-4-Acetyl-7-{(S)-3-methyl-2-(3-phenyl-propionylammo)-butyryl]-l-thia-4,7-diaza-spiro[4 4] nonane-8-carbonyl}-amino)-4-oxo-butync acid (Compound No 29),
(S)-3-{[(R)-8-Acetyl-4-(naphthalene-2-yl-aminooxalyl)-l-thia-4,8-diaza-spiro[4 5]decane-3-carbonyl]-amino}-4-oxo-butync acid (Compound No 30),
(S)-3-[{(S)-7-{(S)-2-[(Isoquinoline-l-carbonyl)-amino]-3-methyl-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyI)-amino]-4-oxo-butync acid (Compound No 31),
(S)-3-[{(S)-7-{(S)-2-[(Isoquinoline-l-carbonyl)-ammo]-3-methyl-butyryl}-3-methyl-l-oxa-2,7-diaza-
spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butync acid (Compound No 32),
(S)-4-(7-Methoxy-benzooxazol-2-yl)-3-[((S)-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-
phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butync acid (Compound No 33),
(S)-4-[5-(2,6-Dichloro-phenyl)-oxazol-2-yl]-3-[((S)-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-
butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butync acid (Compound No
34),
(S)-3-[((S)-7-{(S)-3-Methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-phenyl-l-oxa-2,7-diaza-
spiro[4 4]non-2-ene-8-carbonyl)-ammo]-4-oxo-4-(5-pyridin-2-yl-oxazol-2-yl)-butync acid (Compound No 35),
(S)-4-Benzooxazol-2-yl-3-[((S)-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-phenyl-l-oxa-
2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butync acid (Compound No 36),
(S)-3-[((S)-7-{(S)-3-Methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-phenyl-l-oxa-2,7-diaza-
spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-4-(5-phenyI-oxazol-2-yl)-butync acid (Compound No 37),
(S)-3-[((S)-7-{(S)-3-Methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-phenyl-l-oxa-2,7-diaza-
spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxazolo[4,5-b]pyndin-2-yl-4-oxo-butync acid (Compound No 38),
(S)-4-(4-Methoxy-benzooxazol-2-yl)-3-[((S)-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-
phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butync acid (Compound No 39),
(S)-4-(4-Methoxy-benzooxazol-2-yl)-3-[((S)-3-methyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-
butyryl}-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butync acid (Compound No 40),
(S)-3-({(S)-7-{(S)-2-[(Isoquinoline-l-carbonyl)-amino-3-methyl-butyryl}-3-methyl-l-oxa-2,7-diaza-spiro[4,4]
non-2-ene-8-carbonyl}-amino)-4-(7-methoxy-benzooxazol-2-yl)-4-oxo-butync acid (Compound No 41),
(S)-4-BenzooxazoI-2-yl-3-[((S)-3-methyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-l-oxa-
2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butync acid (Compound No 42),
(S)-3-({(S)-7-{(S)-2-[(Isoquinoline-l-carbonyl)-amino-3-methyl-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4,4]
non-2-ene-8-carbonyl}-amino)-4-(7-methoxy-benzooxazol-2-yl)-4-oxo-butync acid (Compound No 43),
(S)-3-({(S)-7-{(S)-2-[(Isoquinohne-l-carbonyl)-amino-3-methyl-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4,4]
non-2-ene-8-carbonyl}-amino)-4-(4-methoxy-benzooxazol-2-yl)-4-oxo-butync acid (Compound No 44),
(S)-3-({(S)-7-{(S)-2-[(Isoquinohne-l-carbonyl)-amino]-3-methyl-butyryl}-3-methyl-l-oxa-2,7-diaza-spiro[4,4]
non-2-ene-8-carbonyI}-amino]-4-(4-methoxy-benzooxazol-2-yl)-4-oxo-butync acid (Compound No 45),
(S)-4-(7-Methoxy-benzooxazol-2-yl)-3-[((S)-3-methyI-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-
butyryl}-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-butync acid (Compound No 46),
(S)-3-({(S)-4-Acetyl-7-[(S)-3-methyl-2-(2-naphthalen-2yl-acetylamino)-butyryl]-l-thia-4,7-diaza-
spiro[4,4]nonane-8-carbonyl}-amino)-4-(4-methoxy-benzooxazol-2-yl)-4-oxo-butync acid (Compound No 47),
(S)-3-({(S)-4-Acetyl-7-[(S)-3-methyl-2-(2-naphthalen-2yl-acetylamino)-butyryl]-l-thia-4,7-diaza-
spiro[4,4]nonane-8-carbonyl}-amino)-4-(7-methoxy-benzooxazol-2-yl)-4-oxo-butync acid (Compound No 48),
(S)-3-[((S)-4-Methanesulfonyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-l-thia-4,7-diaza-
spiro[4 4]nonane-8-carbonyI)-amino]-4-(4-methoxy-benzooxazol-2-yl)-4-oxo-butync acid (Compound No 49),
(S)-3-[((S)-4-Methanesulfonyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryI}-l-thia-4,7-diaza-
spiro[4 4]nonane-8-carbonyl)-amino]-4-(7-methoxy-benzooxazol-2-yl)-4-oxo-butync acid (Compound No 50),
5-(Hexyl-methyl-amino)-3-[((S)-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 51), 5-(2-Chloro-benzyloxy)-3-[((S)-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 52), (S)-5-(2-Chloro-benzylsulfanyl)-3-[((S)-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 53), 5-(Benzyl-methyl-amino)-3-[((S)-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 54), (S)-5-(l,3-Dioxo-l,3-dihydro-isoindol-2-yl)-3-[((S)-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 55),
(S)-5-(2-Chloro-benzyloxy)-3-[((S)-7-{(S)-2-[(isoquinohne-l-carbonyl)-amino]-3-methyl-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 56), (S)-5-(2-ChIoro-benzyloxy)-3-[((S)-3-methyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 57), (S)-5-(2-Chloro-benzyloxy)-3-[((S)-7-{(S)-2-[(isoquinoline-l-carbonyl)-amino]-3-methyl-butyryl}-3-methyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 58), 5-(Hexyl-methyl-amino)-3-[((S)-7-{(S)-2-[Isoquinoline-l-carbonyl)-amino]-3-methyl-butyryl}-3-methyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 59), (S)-5-(Hexyl-methyl-amino)-3-[((S)-3-methyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 60), (S)-3-[((S)-7-{(S)-3-Methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-9-phenyl-nonanoic acid (Compound No 61), (S)-5-(Hexyl-methyl-amino)-3-[((S)-7-{(S)-2-[isoquinohne-l-carbonyl)-amino]-3-methyl-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 62), (S)-5-(HexyI-methyl-amino)-3-[((S)-4-methanesulfonyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-l -thia-4,7-diaza-spiro[4 4]nonane-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 63), (S)-5-(2-Chloro-benzyloxy)-3-[((S)-4-methanesulfonyl-7-{(S)-3-methyl-2-[(naphthalene-2-carbonyl)-amino]-butyryl}-l-thia-4,7-diaza-spiro[4 4]nonane-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 64), (S)-3-({(S)-4-Acetyl-7-[(S)-3-methyl-2-(2-naphthalen-2yl-acetylamino)-butyryl]-l-thia-4,7-diaza-spiro[4,4]nonane-8-carbonyl}-amino)-5-(hexyl-methyl-amino)-4-oxo-pentanoic acid (Compound No 65) (S)-3-({(S)-4-Acetyl-7-[(S)-3-methyl-2-(2-naphthalen-2-yl-acetylamino)-butyryl]-l-thia-4,7-diaza-spiro[4,4]nonane-8-carbonyl}-amino)-5-(2-chloro-benzyloxy)-4-oxo-pentanoic acid (Compound No 66), (S)-5-(2-Chloro-benzyloxy)-3-[((5S,8S)-7-{(S)-2-[(isoquinohne-l-carbonyl)-amino]-3-methyl-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid tert-butyl ester (Compound No 67),
(S)-5-(2-Chloro-benzyloxy)-3-[((5R18S)-7-{(S)-2-[(isoquinoline-l-carbonyl)-amino]-3-methyl-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid tert-butyl ester
(Compound No 68),
(S)-5-(2-Chloro-benzyloxy)-3-[((5S,8S)-7-{(S)-2-[(isoquinohne-l-carbonyl)-amino]-3-methyl-butyryl}-3-methyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-ammo]-4-oxo-pentanoic acid tert-butyl ester (Compound No 69),
(S)-5-(2-Chloro-benzyloxy)-3-[((5S,8S)-7-{(S)-2-[(isoquinohne-l-carbonyl)-amino]-3-methyl-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 70), (S)-5-(2-Chloro-benzyloxy)-3-[((5R,8S)-7-{(S)-2-[(isoquinoline-l-carbonyl)-amino]-3-methyl-butyryl}-3-phenyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 71), (S)-5-(2-Chioro-benzyloxy)-3-[((5S,8S)-7-{(S)-2-[(isoquinoline-l-carbonyl)-amino]-3-methyl-butyryl}-3-methyl-l-oxa-2,7-diaza-spiro[4 4]non-2-ene-8-carbonyl)-amino]-4-oxo-pentanoic acid (Compound No 72)
3 A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of the proceeding claims together with pharmaceutically acceptable carrier, excipients or diluents or mixture thereof
4 A method of treating caspase-1 mediated pathologies including inflammatory and autoimmune diseases such as bronchial asthma, rheumatoid arthritis, Chronic Obstructive Pulmonary Disorder, Sepsis, Inflammatory Bowel Disease, type I diabetes, multiple sclerosis, allograft rejection or psoriasis which comprises administering to said mammal an effective amount of a compound or a pharmaceutical composition according to any one of the claims 1-3

5 A pharmaceutical composition of claim 3 in combination with one or more of other therapeutic agents used for treating chronic inflammation selected from, interleukin inhibitors, anti-TNF agent or c-AMP raising agent like PDE inhibitors, anti-chohnergics, Muscarinic receptor antagonist, (3-agonists, 5-lipoxygenase inhibitors, leukotnene antagonists, p38 map kinase inhibitors, MMP inhibitors, dopamine receptor agonists, corticosteroids, VLA-4 inhibitors, antihistamines, antitussives, Cox-2 inhibitors, DPP IV inhibitors, anti angiogenic factor(s) and Cell proliferation inhibitors (B-cell and T-cell stimulation)
6 A process for preparing a compound of Formula V
(Formula Removed)
comprising of
reacting a compound of Formula III
(Formula Removed)

with a compound of Formula IV
(Formula Removed)
to give a compound of Formula V alternatively, comprising the steps of
(a) reacting a compound of Formula III with a compound of Formula XII
(Formula Removed)
to give a compound of Formula Ilia

(Formula Removed)
(b) deprotecting a compound of Formula IIIa to give a compound of Formula IIIb

(Formula Removed)
(c) reacting a compound of Formula IIIb with a compound of Formula XV
(Formula Removed)
to give a compound of Formula V
wherein
P is amine protecting group for example t-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl or benzyloxycarbonyl,
Rz is optionally substituted alkyl, cycloalkyi, acyl, cyano, halogen, hydroxy, aryl, aralkyi, nitro, heterocyclyl, heteroaryl,
B is optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl or heteroarylalkyl,
Z can be a bond or can be independently selected from -CH2-, -C(=K)-, -C(=K)Rd- or -SO2 (wherein K can be
selected from oxygen or sulphur and Rd is amino, sulphonyl amino or oxygen),
Ri can be independently selected from group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl or cycloalkylalkyl, or R1 and R2 can
together form a carbocyclic/aromatic or heterocyclic / heteroaromatic ring along with the carbon atoms to which
they are bonded),
E is a carboxy protecting group for example methyl, ethyl, benzyl, tert-butyl or tnmethylsilyl
7 A process for preparing a compound of Formula XI
(Formula Removed)
comprising of
reacting a compound of Formula X

(Formula Removed)
with a compound of Formula IV
(Formula Removed)
to give a compound of Formula XI
alternatively, comprising the steps of
(a) reacting a compound of Formula X with a compound of Formula XII
(Formula Removed)

to give a compound of Formula XIII
(Formula Removed)
(b) deprotecting a compound of Formula XIII to form a compound of Formula XIV

(Formula Removed)
(c) reacting a compound of formula XIV with a compound of Formula XV

(Formula Removed)
to give a compound of Formula XI
wherein
P is amine protecting group for example t-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl or benzyloxycarbonyl,
Rz is optionally substituted alkyl, cycloalkyl, acyl, cyano, halogen, hydroxy, aryl, aralkyl, nitro, heterocyclyl, heteroaryl,
B is optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyi,
heteroaryl or heteroarylalkyl,
Z can be a bond or can be independently selected from -CH2-, -C(=K)-, -C(=K)R