FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
NOVEL DERIVATIVES OF ACYL CYANOPYRROLIDINES
SUN PHARMA ADVANCED RESEARCH COMPANY LTD.
A company incorporated under the laws of India having their office at 17/B, MAHAL INDUSTRIAL ESTATE, MAHAKALI CAVES ROAD, ANDHERI (E), MUMBAI-400093, MAHARASHTRA, INDIA.
The following specification describes the nature of this invention

The present invention relates to novel derivatives of acyl cyanopyrrolidines as dipeptidyl peptidase IV (DPP -IV) inhibitors which are effective in conditions mediated by DPP-IV.
BACKGROUND ART
Dipeptidyl peptidase IV (Enzyme Commission number 3.4.14.5) is a member of a family of serine protease that catalyses the cleavage of N-terminal dipeptides from a peptide chain containing, in general, a proline or an alanine residue in the penultimate position. It is widely expressed in mammalian tissue as a type II integral membrane protein. The protease is expressed on the surface of differentiated epithelial cells of the intestine, liver, kidney proximal tubules, prostate, corpus luteum, and on leukocyte subsets such as lymphocytes and macrophages. A soluble form of the enzyme is found in serum that has structure and function identical to the membrane-bound form of the enzyme but lacks the hydrophobic transmembrane domain. In the human immune system the enzyme is expressed almost exclusively by activated T-lymphocytes of the CD4+ type where the enzyme has been shown to be synonymous with the cell-surface antigen CD26.
In addition to DPP-IV, the serine protease family encompasses other members for example dipeptidyl peptidase-II (DPP-II), dipeptidyl peptidase IV beta, dipeptidyl peptidase 8, dipeptidyl peptidase 9, aminopeptidase P, fibroblast activating protein alpha (seprase), prolyl tripeptidyl peptidase, prolyl oligopeptidase (endoproteinase Pro-C), attractin (soluble dipeptidyl-aminopeptidase), acylaminoacyl-peptidase (N-acylpeptide hydrolase; fMet aminopeptidase) and lysosomal Pro-X carboxypeptidase (angiotensinase C, prolyl carboxypeptidase). All these enzymes have preference for cleavage after H2N-X-Pro in vitro, and thus are likely to be involved in at least some of the increasing number of biological processes that appear to be regulated by proline-specific NH2-terminal processing.
A number of bioactive peptides are substrates of DPP-IV. Several of these peptides are neuropeptides, for eg., Substance P, gastrin releasing peptide (GRP), Neuropeptide Y (NPY) and pituitary adenylate cyclase activating polypeptide (PACAP). Some other substrate of DPP-IV are involved in immune responses, such as macrophage-derived chemokine (MDC) , monocyte chemoactive protein (MCP) and regulated-on-activation normal T-cell expressed and secreted (RANTES) protein. Some other DPP-IV substrates are oligopeptides involved in digestion and metabolism, such as enterostatin and insulin-like growth factor-1 (IGF-1). Several gastrointestinal hormones are substrates for DPP-IV such as peptide YY (PYY), glucagons-like peptide-1 (GLP-1), glucagons-like peptide-2 (GLP-2) and glucose dependent insulinotropic polypeptide (GIP). Thus DPP-IV is a wide spread enzyme with activity to cleave the two N-terminal amino


acids of a number of biologically active peptides involved in different functions in immunology, gastroenterology and endocrinology.
GLP-1(7-36) is a 29 amino acid peptide derived by post translational processing of proglucagon in the small intestine. It is known to have physiological actions such as an accelerating action on insulin secretion from the pancreas, decreases hepatic glucose production, gastric emptying, and food intake. Based on physiological profile, the actions of GLP-l(7-36) are expected to have direct beneficial effects on glucose disposal such as in the prevention and treatment of type II diabetes and potentially obesity. DPP -IV has been shown to be the primary degrading enzyme of GLP-1(7-3 6) in vivo and is degraded efficiently by DPP -IV to GLP-1(9-36), which has been speculated to act as a physiological antagonist. Inhibitors of DPP-IV enzyme preserve GLP-1 function for a longer time which leads to an increase in GLP-1 action, enhancement of insulin action and improvement of glucose metabolism which promotes satiety, weight loss, and the antidiabetic effects of GLP-1. For example, inhibition of DPP-IV with the known compound NVP-DPP728 increases plasma GLP-1 concentrations and improves oral glucose tolerance in obese Zucker rats. Both subcutaneously and intravenously administered GLP-1 is rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. DPPIV inhibition is therefore expected to be useful in treating type 2 diabetes mellitus.
Inhibitors of DPP-IV are described inter alia in WO2003000180, WO200000181, WO200004498, WO2003082817, WO2004032836, WO2004007468, EP1679069 and WO2005121089. Several groups have disclosed inhibitors of DPP-IV. While some leads have been found from random screening programs, the majority of the work in this field has been directed towards the investigation of substrate analogs. Inhibitors of DPP-IV that are substrate analogs are disclosed in, for example, U.S. Pat. No. 5,462,928, U.S. Pat. No. 5,543,396, WO95/15309 (equivalent to U.S. Pat. No. 5,939,560 and EP 0731789), W098/19998 (equivalent to U.S. Pat. No. 6,011,155), W099/46272 and W099/61431.
Some of the DPP-IV inhibitors known in the art are exemplified in the table below.

While not being limited thereby, the compounds of the present invention are believed to be useful for the treatment of a variety of metabolic, gastrointestinal, viral, and inflammatory diseases, including, but not limited to, diabetes, obesity, hyperlipidemia, dermatological or mucous membrane disorders, psoriasis, intestinal distress, constipation, autoimmune disorders such as encephalomyelitis, complement mediated disorders such as glomerulonepritis, lipodystrophy, and tissue damage, psychosomatic, depressive, and neuropsychiatric disease such as anxiety, depression, insomnia, schizophrenia, epilepsy, spasm, and chronic pain, HIV infection, allergies, inflammation, arthritis, transplant rejection, high blood pressure, congestive heart failure, tumors, and stress-induced abortions, for example cytokine-mediated murine abortions.
DESCRIPTION OF THE INVENTION
The first aspect of the invention relates to DPP-IV inhibitor compounds of formula I


or a tautomeric form, regioisomer, stereoisomer, solvate, N-oxide or pharmaceutically acceptable salts
thereof;
wherein
"a" is a substituted or unsubstituted heterocycloalkyl ring;

y is a member selected from -0-, -CO-, -S02-, thioalkyl, sulfinylalkyl, aminoalkyl or wherein,
Rw is hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cyclocalkyl, aryl, heteroaryl; x is a member selected from -0-, -S-, -SO-, -S02- , amide and -NR^-, or x and y together represent a chemical bond; Rd is hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cyclocalkyl, aryl, heteroaryl;
R and R' is independently selected from hydrogen, halogen, hydroxy, cyano, alkyl, alkoxy, alkoxyalkyl, alkoxyallyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, heterocycloalkyl, hydroxyalkyl, oxo, hydroxyiminocarbonyl, alkoxyiminocarbonyl, or an alkylidene group with 1-5 carbon atoms. Further, R and R' can form, together with the Carbon atoms to which they are attached a C3.7 cycloalkyl or hetercycloalkyl ring when x and y together do not represent a chemical bond;
Z is selected from -CH-, -N-, -S-;
R" is selected from hydrogen, alkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl;
Pi is 0, 1 or 2 and p2 is 0, 1 or 2 provided that the sum of p, and p2 is not 1;
m and n are integers selected from 0, 1 or 2;
t is an integer selected from 1 to 4;
with the proviso that when y = -CO-, x is not NRd;
In a preferred embodiment, the invention relates to a compound of formula I, wherein "a" is a heterocycloalkyl ring containing at least one oxygen atom. Other variables have the meaning as defined above. The groups represented by a can be exemplified by tetrahydrofuran, tetrahydropyran.
In a more preferred embodiment, the invention relates to a compound of formula I, wherein "a" is a carbohydrate moiety.
More preferably, the invention relates to a compound of formula I, wherein "a" is a carbohydrate moiety; comprising hexoses and pentoses with partial or full protection of the hydroxyl functionality that is present in the carbohydrate moiety.


In an especially preferred embodiment the invention relates to a compound of formula I, wherein "a" is a carbohydrate moiety, represented by formula II

wherein
q is 0 or 1, when q is 0, R3 and R4 are connected to the two oxygen atoms., when q is 1, R3 and R4 is
connected to b.
b is selected from group consisting of-C(R3,R4)-, -C(R3R4)CO-, -C(R3R4)-CH2 -, -CH2-C(R3R4)-CH2-
R1, R2, R3, R4, R5, R6 and R7 are independently selected from the group consisting of
hydrogen, , alky], substituted alkyl, alkenyl, alkynyl,.cycloalkyl, alkoxy, haloalkoxy, aryloxy, aryl, biayrl,
alkylaryl, heterocycloalkyl, heteroaryl, alkylamino, dialkyalmino, alkoxy, aryloxy, alkoxyalkyl, alkanoyl,
cycloalkanoyl, aroyl, biaroyl, heteroaroyl, alkoxycarbonylalkyl, cycloalkyloxy, alkylthio, cycloalkylthio,
arylthio, heterocycloalkylthio, heteroarylthio, arylalkylthio, cycloalkylalkylthio, heterocycloalkylalkylthio,
heteroarylalkylthio, alkylsulfinyl, alkylsulfonyl, cycloalkylsulfinyl, arylsulfinyl, heterocycloalkylsulfinyl,
heteroarylsulfinyl, arylalkylsulfinyl, cycloalkylalkylsulfinyl, arylsulfonyl, heterocycloalkylsulfonyl,
heteroarylsulfonyl, arylalkylsulfonyl, cycloalkylalkylsulfonyl, heterocycloalkylalkylsulfonyl,
heteroarylalkylsulfonyl, alkoxysulfinyl, alkoxysulfonyl, arylalkoxy, arylalkyl, cycloalkylsulfinyl,
cycloalkylsulfonyl, N(Rd)2CO-, wherein Rd having same meaning as described above.
or R3, R4 may together form =0, =S , =N-ORw, wherein Rw is as defined above.
or Ri and R2 or R3 and R4 together with the carbon atom to which they are attached may form a (C4.7) spirocycloalkyl or (C4-7 )spiroheterocycloalkyl ring;

or R5 and R; may form, together with the oxygen atoms to which they are attached, a 1,3-dioxolane ring when reacted with R5-CO-R6, or a spirocycloalkyl (C4-6)-substituted 1,3-dioxolane ring.
or R6 and R7 may form, together with the oxygen atoms to which they are attached, a 1,3-dioxolane ring when reacted with R6-CO-R7, or a spirocycloalkyl(C4-6)-substituted 1,3-dioxolane ring.
The alkyls, substituted alkyls, cycloalkyls selected for R,, R2, R3, R4, R5, R6, and R7 may optionally contain one or more unsaturations or hetero atoms or carbonyls or oxime in the moieties.
Other variables, namely, t, x, y, z, p,, p2, R", m, n, q, R and R' have the meaning as described above.
The compounds of the invention can exist in different forms, such as free acids, free bases, esters and other
prodrugs, salts and tautomers, and the disclosure includes all these variant forms of the compounds
A second aspect of the present invention is use of the compounds of the invention in therapy.
A third aspect of the present invention is method of treatment of conditions mediated by DPP-4 by administering a therapeutically effective amount of compound of the present invention.
Another aspect of the present invention is a composition comprising a compound of the invention and, optionally, a diluent or a carrier.
A further aspect of the present invention is a product comprising a compound of the invention and a therapeutic agent; as a combined preparation for simultaneous, separate or sequential use in therapy.
As used throughout this specification and the appended claims, the following terms have the following meanings:
The term "alkyl" as used herein includes reference to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include , but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert- butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-diemthylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl.
The term "alkenyl", as employed herein either alone or as a part of another group, denoted both straight and branched chain, optionally substituted radicals, for example containing 2-12 carbons atoms in a chain , which contains at least one carbon-carbon double bond.


The term "alkynyl", as employed herein either alone or as a part of another group, denoted both straight
and branched chain, optionally substituted radicals, for example containing 2-12 carbons atoms in a chain ,
which contains at least one carbon-carbon triple bond.
The term "alkylidene" as used herein refers to a straight or branched chain alkyl radical which is attached
via a carbon-carbon double bond.
The terms "alkoxy" as used refers to an alkyl group, as defined herein, appended to the parent molecular
moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to,
methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy.
The terms "alkoxyalkyl" as used refers to an alkoxy group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxy include,
but are not limited to, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, 1-methoxypropyl, 2-
methoxypropyl, 1-ethoxypropyl, l-(l-propyloxy)propyl, l-(2-propyloxy)propyl.
The term "cycloalkyl," as used herein, refers to a saturated cyclic hydrocarbon group containing from 3 to 8
carbon atoms. Examples of the cycloalkyl ring systems include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, and cyclooctyl.
The term "cycloalkylalkyl" as used herein, refers to a cycloalkyl group, as defined herein, appended to the
parent molecular moiety through a alkyl group, as defined herein.
The term "spirocycloalkyl" refers to saturated bicyclic hydrocarbons having one carbon common to both
rings, including for example spirocyclopropyl, spirocyclobutyl, spirocyclopentyl and spirocyclohexyl.
The term "alkylcarbonyl," as used herein, refers to an alkyl group, as defined herein, appended to the parent
molecular moiety through a carbonyl group. Representative examples of alkylcarbonyl include, but are not
limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-l-oxopropyl, 1-oxobutyl, and 1-oxopentyl.
The term "cycloalkylcarbonyl," as used herein, refers to cycloalkyl group, as defined herein, appended to
the parent molecular moiety through a carbonyl group.
The term "alkoxylcarbonyl," as used herein, refers to an alkoxygroup, as defined herein, appended to the
parent molecular moiety through a carbonyl group.
The term "aryl," as used herein, refers to an aromatic ring system. Representative examples of aryl include,
but are not limited to, phenyl, and naphthyl, anthracenyl, phenanthrenyl.
The term "arylalkyl," as used herein, refers to an aryl group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkyl include,
but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-naphth-2-ylethyl.
The term "arylcarbonyl," as used herein, refers to an aryl group, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein. Representative examples of arylcarbonyl
include, but are not limited to, benzoyl and naphthoyl.


The term "heterocycloalkyl" as used herein includes reference to a saturated heterocyclic moiety having 3-
12 ring carbon atoms and 1-7 ring heteroatoms selected from nitrogen, oxygen, phosphorus and sulphur.
Unless otherwise specified, it can be monocyclic, bicyclic or a polycyclic ring system. This term includes
reference to groups such as azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxiranyl, piperazinyl,
thiazolidinyl, morpholinyl, thiomorpholinyl, quinolizidinyl, tetrahydropyranyl and the like.
The term "Heterocycloalkylalkyl", as used herein, refers to a heterocycloalkyl group, as defined herein,
appended to the parent molecular moiety through a alkyl group, as defined herein.
The term "heterocycloalkylcarbonyl," as used herein, refers to an heterocycloalkyl group, as defined herein,
appended to the parent molecular moiety through a carbonyl group, as defined herein.
The term "heteroaryl" as used herein includes reference to an aromatic heterocyclic ring system having 5-
10 ring atoms, at least one of which is selected from nitrogen, oxygen and sulphur. The group may be a
polycyclic ring system, having two or more rings, at least one of which is aromatic. This term includes
reference to groups such as pyridazinyl, pyrimidinyl, furanyl, benzo[b]thiophenyl, thiophenyl, pyrrolyl,
imidazolyl, pyrrolidinyl, pyridinyl, benzo[b]furanyl, pyrazinyl, purinyl, indolyl, benzimidazolyl, quinolinyl,
phenothiazinyl, triazinyl, phthalazinyl, 2H-chromenyl, oxazolyl, isoxazolyl, thiazolyl, isoindolyl, indazolyl,
purinyl, isoquinolinyl, quinazolinyl, pteridinyl and the like.
The term "imino" as denotes a nitrogen atom containing one substituent such as hydrido, hydroxy or alkyl
and having two covalent bonds available for bonding to single atom such as carbon. Examples of such
imino radicals include =NH, =NOH, =NOCH3
The term "iminocarbonyl" as used herein denotes a carbon radical having two of the four covalent bond
sites shared with an imino group. Representative examples of such iminocarbonyl radicals include -C=NH,
-C=NCH3 (an alkyliminocarbonyl group).
The term "N-hydroxyiminocarbonyl refers to a -C=N-OH group.
The term "N-alkoxyiminocarbonyl refers to a -C=N-OR9, wherein R9 is an alkyl group.
The term "carbohydrate moiety" refers to a monosaccharide, oligosaccharide, pseudosugar or derivative,
and their optical isomers, diastereomers, enantiomers, hydrates, pharmaceutically acceptable salts, and
mixtures thereof. The sugars that comprise the sugar derivative, can exist as 6-membered pyranose or 5-
membered furanose forms.
Suitable monosaccharides include, but are not limited to, any of sugars (in the L or D configuration),
typically having 5 or 6 carbons (a pentose monosaccharide or a hexose monosaccharide), as well as 7
carbons (heptose monosaccharide). Included are sugar derivatives for example the sulfate and/or phosphate
derivatives of monosaccharides, amino sugars in which a hydroxyl substituent on the simple sugar is
replaced with an amino group or sugars having a double bond between two adjacent carbon atoms, (e.g.
glucosamine, 5-thio-D-glucose, nojirimycin, deoxynojirimycin, 1,5-anhydro-D-sorbitol, 2,5-anhydro-D-
mannitol, 2-deoxy-D-galactose, 2-deoxy-D-glucose, 3-deoxy-D-glucose, allose, arabinose, arabinitol,


fucitol, fucose, galactitol, glucitol, iditol, lyxose, mannitol, levo-rhamnitol, 2-deoxy-D-ribose, ribose,
ribitol, ribulose, rhamnose, xylose, xylulose, allose, altrose, fructose, galactose, glucose, gulose, idose,
levulose, mannose, psicose, sorbose, tagatose, talose, galactal, glucal, fucal, rhamnal, arabinal, xylal,
valienamine, validamine, valiolamine, valiol, valiolon, valienol, valienone, glucuronic acid, galacturonic
acid, N-acetylneuraminic acid, gluconic acid D-lactone, galactonic acid gamma-lactone, galactonic acid,
delta.-lactone, mannonic acid, gamma.-lactone, D-altro-heptulose, D-manno-heptulose, D-glycero-D-
manno-heptose, D-glycero-D-gluco-heptose, D-allo-heptulose, D-altro-3-heptulose, D-glycero-D-manno-
heptitol, D-glycero-D-altro-heptitol and the like). The hydroxyl groups on monosaccharides may optionally
be replaced with hydrogen, alkoxy (e.g. 2-O-methyl-D-fructose), alkanoate or halogen groups.
Suitable oligosaccharides include, but are not limited to, carbohydrates having from 2 to 10 or more
monosaccharides linked together. The constituent monosaccharide unit may be, for example, a pentose
monosaccharide, a hexose monosaccharide or a pseudosugar (including a pseudoaminosugar).
Oligosaccharides do not include bicyclic groups that are formed by fusing a monosaccharide to a benzene
ring, a cyclohexane ring, or a heterocyclic ring.
Pseudosugars that may be used in the invention are members of the class of compounds wherein the ring
oxygen atom of the cyclic monosaccharide is replaced by a methylene group.
The term "halogen" as used herein includes reference to F, CI, Br or I. In a particular, halogen may be F or
CI, of which F is more common.
The term "substituted" as used herein in reference to a moiety means that one or more, especially up to 5,
more especially 1, 2 or 3, of the hydrogen atoms in said moiety are replaced independently of each other by
the corresponding number of the described substituents. Commonly used substitutents include halogen,
hydroxyl, alkyl, alkenyl, alkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl,
alkylcarbonyloxy, alkylsulfonyl, alkylthio, carboxy, cyano, cyanoalkyl, nitro, formyl, halogen, , haloalkyl,
hydroxyl, alkoxycarbonylamino, amino, alkylamino, dialkylamino, heterocycle, heterocyclicalkyl,
hydroxyalkyl, mercapto and phenyl.
The term "protecting group" refers to a group which, when bound to one or more group(s), limits reactions
occurring at these group(s) and which protecting groups can be removed by conventional chemical or
enzymatic steps to reestablish the group(s). The particular removable protecting group employed is
determined by the nature of the compounds and chemical processes being utilized. For example an amine
group can be protected by protecting group P as follows
—N-H —N-P
I I
P or P
(a) (b)
In (b) the amine group is completely protected from eracting with another moiety whereas in (a) the amine
group is partially protected to limit the invention to the available hydrogen.


For example N-protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-
butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl,
alpha.-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl
groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as
benzyloxycarbonyl(Cbz), p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-
nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-
dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-
methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-
trimethoxybenzyloxycarbonyl, l-(p-biphenylyl)-l-methylethoxycarbonyl, .alpha.,.alpha.-dimethyl-3,5-
dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl (Boc),
diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl (Fmoc), allyloxycarbonyl(Alloc), cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, Fmoc, Boc and Cbz.
The term "pharmaceutically acceptable" as used herein includes reference to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings or animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. This term includes acceptability for both human and veterinary purposes.
Where two or more moieties are described as being "each independently" selected from a list of atoms or groups, this means that the moieties may be the same or different. The identity of each moiety is therefore independent of the identities of the one or more other moieties.
The compounds of the invention can be exemplified by the following compounds.

The compounds of the invention can be produced as a mixture of isomers or racemic mixtures or as optically pure compounds. The compositions of the invention may similarly contain mixtures of stereoisomers, mixtures of one or more stereoisomers, or be enriched for one or more stereoisomers. All of these forms are specifically included in this invention and are intended to be included in the claims.
Preparation of compounds of the invention
Another aspect of the invention is the process of preparation of compounds of formula I The compounds of the invention can be prepared by reacting a compound of formula IV

wherein R, R', m, and n have the meaning as defined above and L is a leaving group such as, but not limited to, a halogen, an alkylsulfonyloxy group or an arylsulfonyloxy group, preferably a halogen such as chlorine, bromine or iodine; with a primary amine compound of formula V

wherein the substitutions have the meaning as defined above.
or salts thereof, and optionally, making the product into pharmaceutically acceptable salt.
The reaction of the compound of formula IV with the compound of formula V can be carried out in presence of a solvent or the mixture of solvents. As the solvent, any solvent may be used as long as it does

not adversely effect the reaction, and can be, for example, acetonitrile, methanol, ethanol, isopropyl alcohol, propyl alcohol, acetone, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, ether, dioxane, ethyl acetate, toluene, dichloromethane, chloroform or mixed solvents thereof. Preferred being dimethylformamide, dimethylsulfoxide. dimethylacetamide.
Further the reaction may be carried out in presence of a base such as inorganic or an organic base. Preferably, the reaction may be carried out in presence of an organic bases such as , but not limited to triethylamine, N-methylmorpholine, pyridine, picolines, quinolines, etc, most preferably in presence of N,N-diisopropylethylamine.
Alternatively, the compounds of formula I may be prepared by a process comprising the following steps. Step 1 comprises reacting a compound of formula IV with a compound of formula VI

In the compounds of formula IV, V, VI and VII wherein a, t, x, y, z, p,, p2 and R" have the meaning as defined in claim 1, P is a nitrogen protecting group.
Step 1, can be carried out in presence of a suitable solvent or a mixture of solvents. Additionally, the reaction can be carried out in presence of a base. Suitable bases for the reaction are for example, triethylamine, potassium carbonate, sodium carbonate, pyridine, picolines, quinoline, N-methylmorpholine, potassium tertiarybutoxide, sodium hydride, etc, preferred being N,N-diisopropylethylamine , triethylamine.

Step 2 involves treating the compound resulting from step 1 with a deprotecting agent sufficient to remove the protecting group to give the compound of formula V. The reagents and the conditions used for the reaction depends on the type of protecting agents used, and the methods, in general, are known in the art. T W Greene, P G Wuts, "Protective groups in Organic Synthesis, 3 sup. Ed". (John Wiley & Sons, New York 1999)..For example, the formation of Boc-protected amines and amino acids is conducted under either aqueous or anhydrous conditions, by reaction with a base and the anhydride Boc20. The deprotection is done under acidic conditions; Fmoc group can be removed in basic conditions (usually 20% piperidine in DMF) ; the Cbz group can be removed using either HBr/acetic acid or catalytic hydrogenation process; the alloc group can be removed using tetrakis(triphenylphosphine)palladium(0) along with mixture of chloroform, acetic acid, and N-methylmorpholine (NMM). Thus a suitable protecting and deprotectiog agent can be chosen based on the desired reaction conditions.
Further, the compounds of formula V and/or VI can be prepared by a process as illustrated in Scheme I-Scheme IV below, however, it should be understood that the method of synthesis is not limited to these processes Scheme I


In the compounds of formula VI, VIII and IX, the terms m, n, p,, p2, R", a, t, x, y, z, have the meaning as described above; P represents a nitrogen protecting group as defined above. L] in formula VIII is, independently, a leaving group, such as, but not limited to, halogens, sulfonate esters, phenolates, preferred being, chlorine, bromine, triflate, mesylate, 4-nitrophenolate.
Step 1, as depicted in Scheme I, may be carried out in presence of a suitable solvent or a mixture of solvents. Additionally, the reaction can be carried out in presence of a base. Suitable bases for the reaction are for example, triethylamine, potassium carbonate, sodium carbonate, pyridine, picolines, quinoline, N-methylmorpholine, potassium tertiarybutoxide, sodium hydride, preferred being N,N-diisopropylethylamine , triethylamine. Step 2 involves treating the compound resulting grom step 1 with a deprotecting agent sufficient to remove the protecting group to give the compound of formula V. The reagents and the conditions used for the reaction depends on the type of protecting agents used, and the methods, in general, are known in the art.
Scheme II



Scheme I-IV demonstrates process for preparing compounds of formula VI. The reaction can be carried out in presence of a solvent and a base. Suitable bases that can be used in this reaction are as described in Scheme I above. Additionally the product form can be isolated in the form of a salt.
The compounds of the invention as well as their intermediates can exist as salts. The salts can be prepared during the final isolation and purification of the compounds or in a separate reaction of the compounds with acid or a base.

The compounds with basic groups can be treated with an acid to prepare the acid addition salts, especially pharmaceutically acceptable acid addition salts. Without limiting the scope of the invention, the representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric, and the like. The amino groups of the compounds can also be quaternized with alkyl chlorides, bromides, and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl, and the like.
Alternatively, basic addition salts can be prepared by reaction of a carboxyl group with a suitable base such as, but not limited to, hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine. Quaternary amine salts derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributlyamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,Ndibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like, are contemplated as being within the scope of the present invention.
The present compounds can also exist as therapeutically acceptable prodrugs. The term "therapeutically acceptable prodrug," refers to those prodrugs or zwitterions which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use. The term "prodrug," refers to compounds that are rapidly transformed in vivo to the parent compounds of formula (1) for example, by facile metabolism.
Asymmetric centers can exist in the present compounds. Individual stereoisomers of the compounds can be prepared by synthesis from chiral starting materials or by preparation of racemic mixtures and separation by conversion to a mixture of diastereomers followed by separation, chromatographic techniques, or direct separation of the enantiomers on chiral chromatographic columns.
Geometric isomers can exist in the present compounds. The invention contemplates various geometric isomers and mixtures thereof resulting from the disposition of substituents around a carbon-carbon double


bond, a cycloalkyl group, or a heterocycloalkyl group. Substituents around a carbon-carbon double bond are designated as being of Z or E configuration and substituents around a cycloalkyl or heterocycloalkyl are designated as being of is or trans configuration.
The compounds of the invention possess important utility as in pharmaceuticals, especially in the treatment of medical conditions which can be alleviated by inhibition of DPP IV. The instant compounds can be used for treating diabetes, especially type II diabetes, as well as impaired glucose homeostasis, impaired glucose tolerance, infertility, polycystic ovary syndrome, growth disorders, arthritis, allograft rejection in transplantation, autoimmune disease (such as scleroderma and multiple sclerosis), various immunomodulatory diseases, AIDS, intestinal diseases, inflammatory bowel syndrome, chemotherapy induced intestinal mucosal atrophy or injury, anorexia nervosa, osteoporosis, syndrome X, dysmetabolic syndrome, diabetic complications, hyperinsulinemia, obesity, atherosclerosis, as well as inflammatory bowel disease such as Chron's disease and ulcerative colitis.
The ability of the compounds of the instant invention to bind to, and inhibit DPP IV further renders the compounds of the invention useful in a variety of diagnostic and research applications. For example, in vitro techniques can be used to identify and characterize cellular components or chemical compounds that interact with DPP IV in a cell-free environment, as would be the case when a compound of the invention is used to competitively bind to, or inhibit, DPP IV in the presence of such other chemical compound or cellular component. Further, compounds of the invention may be labeled with a suitable radioisotope and in such form utilized for determining the cellular or tissue distribution of DPP IV in a given tissue sample, or utilized as a diagnostic medical imaging agent for the visualization of e.g. tumors which express high levels of DPP
Further, it is known in the art that other members of the serine peptidase family, other than DPPIV, as mentioned above, notably, DPP8 and DPP9, share the common catalytic triad with the DPP-IV and thus compounds that inhibit DPP-IV may inhibit DPP8 and DPP9 as well. Simultaneous inhibition of each enzyme, however, has proven undesirable. Toxicity studies in rat and dog have shown that DPP8 and DPP9 inhibition produces toxicity, including alopecia, thrombocytopenia, anemia, enlarged spleen, multiple histological pathologies, bloody diarrhea, emesis, tenesmus, and mortality. DPP8 and DPP9 inhibition has been shown to produce mortality in both wild type and DPP-IV deficient mice, confirming that the toxicity is not a result of DPP-IV inhibition. Since inhibition of DPP8 and DPP9 is associated with toxicities, selective inhibition of DPP-IV is necessary for an acceptable safety and tolerability profile. Accordingly, the compounds of the present invention were found to be selective in their ability to inhibit DPP-IV and not inhibit DPP8 or DPP9.