WO2004035538A1

WO2004035538A1 - Process for making azetidine-3-carboxylic acid

Info

Publication number: WO2004035538A1
Application number: PCT/US2003/032074
Authority: WO
Inventors: Ross Miller; Fengrui Lang; Zhiguo Jake Song; Daniel Zewge
Original assignee: Merck & Co., Inc.
Priority date: 2002-10-15
Filing date: 2003-10-10
Publication date: 2004-04-29
Also published as: AU2003279915A1

Abstract

The present invention is directed to an improved process for synthesizing azetidine-3-carboxylic acid, comprising triflating diethylbis(hydroxymethyl)malonate followed by azetidine ring-formation by intramolecular cyclization using an amine, decarboxylation to give the mono acid azetidine and hydrogenation to give the title compound. Azetidine-3-carboxylic acid is useful as an intermediate for making certain S1P?1#191/Edg1 receptor agonists, which are immunosupressive agents.

Description

PROCESS FOR MAKING AZETIDINE-3-CARBOXYLIC ACID

BACKGROUND OF THE INVENTION The present invention is related to an improved process for synthesizing azetidine-

3-carboxylic acid, which is an intermediate useful for making certain SlPi/Edgl agonists. Compounds that are SlPi/Edgl receptor agonists have immunosuppressive activities by producing lymphocyte sequestration in secondary lymphoid tissues. SlPi/Edgl agonists are disclosed, for example, in WO 03/061567, WO 03/062248 and WO 03/062252, all of which published on July 31 , 2003.

Immunosuppressive agents have been shown to be useful in a wide variety of autoimmune and chronic inflammatory diseases, including systemic lupus erythematosis, chronic rheumatoid arthritis, type I diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis and other disorders such as Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves ophthalmopathy, atopic dermatitis and asthma. They have also proved useful as part of chemotherapeutic regimens for the treatment of cancers, lymphomas and leukemias.

Although the underlying pathogenesis of each of these conditions may be quite different, they have in common the appearance of a variety of autoantibodies and/or self-reactive lymphocytes. Such self-reactivity may be due, in part, to a loss of the homeostatic controls under which the normal immune system operates. Similarly, following a bone-marrow or an organ transplantation, the host lymphocytes recognize the foreign tissue antigens and begin to produce both cellular and humoral responses including antibodies, cytokines and cytotoxic lymphocytes which lead to graft rejection. One end result of an autoimmune or a rejection process is tissue destruction caused by inflammatory cells and the mediators they release. Anti-inflammatory agents such as NS AIDs act principally by blocking the effect or secretion of these mediators but do nothing to modify the immunologic basis of the disease. On the other hand, cytotoxic agents, such as cyclophosphamide, act in such a nonspecific fashion that both the normal and autoimmune responses are shut off. Indeed, patients treated with such nonspecific immunosuppressive agents are as likely to succumb to infection as they are to their autoimmune disease.

Cyclosporin A is a drug used to prevent rejection of transplanted organs. FK-506 is another drug approved for the prevention of transplant organ rejection, and in particular, liver transplantation. Cyclosporin A and FK-506 act by inhibiting the body's immune system from mobilizing its vast arsenal of natural protecting agents to reject the transplant's foreign protein. Cyclosporin A was approved for the treatment of severe psoriasis and has been approved by

European regulatory agencies for the treatment of atopic dermatitis.

Though they are effective in delaying or suppressing transplant rejection,

Cyclosporin A and FK-506 are known to cause several undesirable side effects including nephrotoxicity, neurotoxicity, and gastrointestinal discomfort. Therefore, an immunosuppressant without these side effects still remains to be developed and would be highly desirable.

The immunosuppressive compound FTY720 is a lymphocyte sequestration agent currently in clinical trials. FTY720 is metabolized in mammals to a compound that is a potent agonist of sphingosine 1 -phosphate receptors. Agonism of sphingosine 1 -phosphate receptors induces the sequestration of lymphocytes (T-cells and B-cells) in lymph nodes and Peyer's patches without lymphodepletion. Such immunosuppression is desirable to prevent rejection after organ transplantation and in the treatment of autoimmune disorders.

Sphingosine 1 -phosphate is a bioactive sphingolipid metabolite that is secreted by hematopoietic cells and stored and released from activated platelets. Yatomi, Y., T. Ohmori, G. Rile, F. Kazama, H. Okamoto, T. Sano, K. Satoh, S. Kume, G. Tigyi, Y. Igarashi, and Y. Ozaki.

2000. Blood. 96:3431-8. It acts as an agonist on a family of G protein-coupled receptors to regulate cell proliferation, differentiation, survival, and motility. Fukushima, N., I. Ishii, J.J.A.

Contos, J.A. Weiner, and J. Chun. 2001. Lysophospholipid receptors. Annu. Rev. Pharmacol.

Toxicol. 41:507-34; Hla, T., M.-J. Lee, N. Ancellin, J.H. Paik, and M.J. Kluk. 2001. Lysophospholipids - Receptor revelations. Science. 294:1875-1878; Spiegel, S., and S. Milstien.

2000. Functions of a new family of sphingosine- 1 -phosphate receptors. Biochim. Biophys. Acta.

1484:107-16; Pyne, S., and N. Pyne. 2000. Sphingosine 1-phosphate signalling via the endothelial differentiation gene family of G-protein coupled receptors. P arm. & Therapeutics.

88:115-131. Five sphingosine 1-phosphate receptors have been identified (SlPi, S1P2, SIP3, SIP4, and SIP5, also known as endothelial differentiation genes Edgl, Edg5, Edg3, Edg6,

Edg8), that have widespread cellular and tissue distribution and are well conserved in human and rodent species (see Table). Binding to SIP receptors elicits signal transduction through Gq-,

Gi/o, G12-, G13-, and Rho-dependent pathways. Ligand-induced activation of SlPχ and SIP3 has been shown to promote angiogenesis, chemotaxis, and adherens junction assembly through Rac- and Rho-, see Lee, M.-J., S. Thangada, K.P. Claffey, N. Ancellin, CH. Liu, M. Kluk, M. Volpi, R.I. Sha'afi, and T. Hla. 1999. Cell. 99:301-12, whereas agonism of SIP2 promotes neurite retraction, see Nan Brooklyn, J.R., Z. Tu, L.C. Edsall, R.R. Schmidt, and S. Spiegel. 1999. J. Biol. Chem. 274:4626-4632, and inhibits chemotaxis by blocking Rac activation, see Okamoto, H., Ν. Takuwa, T. Yokomizo, Ν. Sugimoto, S. Sakurada, H. Shigematsu, and Y. Takuwa. 2000. Mol. Cell. Biol. 20:9247-9261. SIP4 is localized to hematopoietic cells and tissues, see Graeler, M.H., G. Bernhardt, and M. Lipp. 1999. Curr. Top. Microbiol. Immunol. 246:131-6, whereas SIP5 is primarily a neuronal receptor with some expression in lymphoid tissue, see Im, D.S., C.E. Heise, N. Ancellin, B.F. O'Dowd, G.J. Shei, R.P. Heavens, M.R. Rigby, T. Hla, S. Mandala, G. McAllister, S.R. George, and K.R. Lynch. 2000. /. Biol. Chem. 275:14281-6.

Administration of sphingosine 1-phosphate to animals induces systemic sequestration of peripheral blood lymphocytes into secondary lymphoid organs, thus resulting in therapeutically useful immunosuppression, see Mandala, S., R. Hajdu, J. Bergstrom, E. Quackenbush, J. Xie, J. Milligan, R. Thornton, G.-J. Shei, D. Card, C. Keohane, M. Rosenbach, J. Hale, C.L. Lynch, K. Rupprecht, W. Parsons, H. Rosen. 2002. Science. 296:346-349.

However, sphingosine 1-phosphate also has cardiovascular and bronchoconstrictor effects that limit its utility as a therapeutic agent. Intravenous administration of sphingosine 1-phosphate decreases the heart rate, ventricular contraction and blood pressure in rats, see Sugiyama, A., N.N. Aye, Y. Yatomi, Y. Ozaki, and K. Hashimoto. 2000. Jpn. J. Pharmacol. 82:338-342. hi human airway smooth muscle cells, sphingosine 1-phosphate modulates contraction, cell growth and cytokine production that promote bronchoconstriction, airway inflammation and remodeling in asthma, see Ammit, A.J., A.T. Hastie, L. C. Edsall, R.K. Hoffman, Y. Amrani, N.P. Krymskaya, S.A. Kane, S.P. Peters, R.B. Penn, S. Spiegel, R.A. Panettieri. Jr. 2001, FASEB J. 15:1212-1214. The undesirable effects of sphingosine 1-phosphate are associated with its non- selective, potent agonist activity on all SIP receptors.

Compounds which are agonists of the SlPi/Edgl receptor having selectivity over the SlP3 Εdg3 receptor are described in the following patent applications: U.S. No. 60/350,000, filed January 18, 2002; U.S. No. 60/349,991, filed January 18, 2002; U.S. No. 60/362,566, filed March 7, 2002; U.S. No. 60/382,933 filed May 23, 2002 and U.S. No. 60/389,173, filed June 17, 2002, all of which are hereby incorporated by reference in their entirety. An SlPi/Edgl receptor selective agonist has advantages over current therapies and extends the therapeutic window of lymphocytes sequestration agents, allowing better tolerability with higher dosing and thus improving efficacy as monotherapy. While the main use for immunosuppressants is in treating bone marrow, organ and transplant rejection, other uses for such compounds include the treatment of arthritis, in particular, rheumatoid arthritis, insulin and non-insulin dependent diabetes, multiple sclerosis, psoriasis, inflammatory bowel disease, Crohn's disease, lupus erythematosis and the like.

Azetidine-3-carboxylic acid is an intermediate useful in the preparation of certain SlPi/Edgl receptor agonists described in the above patent applications. Known methods for making azetidine-3-carboxylic acid and related compounds are described in Anderson, et. al., J. Org. Chem., 1972, 3953, JP 62081367, EP 0165636, EP 0199413, EP 0190786 and EP 0169603. However, since the productivity of these known processes are not high and rely on the use of highly toxic reagents, it was impractical for large scale preparation of this compound. The present invention, however, provides for an improved process for synthesizing azetidine-3- carboxylic acid, which avoids the use of toxic chemicals, such as cyanide and epi chlorohydrin. The improved process is also shorter in length, operationally more simple and uses readily- available reagents that are economically viable as compared to the processes known described in the art.

SUMMARY OF THE INVENTION

The present invention is directed to an improved process for synthesizing azetidine-3-carboxylic acid, comprising triflating diethylbis(hydroxymethyl)malonate followed by azetidine ring-formation by intramolecular cyclization using an amine, decarboxylation to give the mono acid azetidine and hydrogenation to give the title compound. Azetidine-3- carboxylic acid is useful as an intermediate for making certain SlPj/Edgl receptor agonists, which are immunosupressive agents.

DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses a method for making a compound of formula A

comprising:

1) reacting a compound of formula B

B wherein Ra and Rb are each independently selected from the group consisting of:

(1) Ci-ioalkyl,

(2) C2-10alkenyl,

(3) C3-ioalkynyl,

(4) C3-6cycloalkyl

(5) phenyl or naphthyl, and

(6) HETl,

wherein items (1) to (4) above are each optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, hydroxy, cyano, C3_6cycloalkyl, phenyl, naphthyl, HET2 and Cj^alkoxy, said C3_6cycloalkyl, phenyl, naphthyl, HET2 and C^alkoxy groups optionally substituted with 1-3 substituents independently selected from halo, hydroxy, nitro, cyano, Cι_4alkoxy and Cι_4alkylthio, said phenyl, naphthyl and HET2 further optionally substituted with C i _4alkyl ;

and items (5) and (6) above are optionally substituted with 1-5 substituents independently selected from the group consisting of: halo, hydroxy, nitro, cyano, Cι_4alkyl, Cι_4alkoxy and Ci_4alkylthio;

HETl and HET2 are each independently selected from the group consisting of: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4- dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, with a chloronating agent, bromonating agent, iodonating agent, R^c-S(O)2-halo or R^c-S(O)2-O- S(O)2-R^c, wherein Re is Cι_4alkyl, optionally substituted with 1-3 halo groups, or R^c is phenyl, optionally substituted with 1-3 groups selected from methyl and halo, to yield a compound of formula C

C wherein Xl is chloro, bromo, iodo, or -O-S(O)2-R^c,

2) reacting the compound of formula C with a compound of formula D

R-NH2 D wherein R is selected from the group consisting of: allyl or benzyl, the phenyl portion of benzyl being optionally substituted with 1-5 substituents independently selected from the group consiting of: Cι_4alkyl, haloCχ_4alkyl, halo, hydroxy, cyano, nitro, Ci_4alkoxy, and Ci-4alkylthio,

under basic conditions to yield a compound of formula E

E

3) hydrolyzing the compound of formula E under acidic, basic or neutral conditions to yield a compound of formula G

G 4) heating the compound of formula G to an elevated temperature under neutral or acidic conditions to yield a compound of formula H

H 5) reacting the compound of formula H with an hydrogenating agent in the presence of a catalyst to yield a compound of formula A.

For purposes of this Specification, the following terms have the indicated meanings: The term "halogen" or "halo" includes F, CI, Br, and I.

The term "alkyl" means linear or branched structures and combinations thereof, having the indicated number of carbon atoms. Thus, for example, Ci-βalkyl includes methyl, ethyl, propyl, 2-propyl, s- and t-butyl, butyl, pentyl, hexyl, 1,1-dimethylethyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "haloalkyl" means alkyl defined as above with one or more hydrogen atoms substituted with a halo group as defined above. The halo groups can be the same or different.

The term "alkoxy" means alkoxy groups of a straight, branched or cyclic configuration having the indicated number of carbon atoms. Ci-βalkoxy, for example, includes methoxy, ethoxy, propoxy, isopropoxy, and the like.

The term "alkylthio" means alkylthio groups having the indicated number of carbon atoms of a straight, branched or cyclic configuration. Cι_6alkylthio, for example, includes methylthio, propylthio, isopropylthio, and the like.

The term "alkenyl" means linear or branched structures and combinations thereof, of the indicated number of carbon atoms, having at least one carbon-to-carbon double bond, wherein hydrogen may be replaced by an additional carbon-to-carbon double bond. C2-6alkenyl, for example, includes ethenyl, propenyl, 1-methylethenyl, butenyl and the like.

The term "alkynyl" means linear or branched structures and combinations thereof, of the indicated number of carbon atoms, having at least one carbon-to-carbon triple bond. C3- galkynyl' f°^r example, includes, propenyl, 1-methylethenyl, butenyl and the like. The term "cycloalkyl" means mono-, bi- or tri-cyclic structures, optionally combined with linear or branched structures, the indicated number of carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cycloheptyl, adamantyl, cyclododecylmethyl, 2-ethyl-l- bicyclo[4.4.0]decyl, and the like. The terms "acidic condition," "neutral condition" and "basic condition" mean that the pH during the reaction is adjusted accordingly by adding, for example, an acid or a base. The selection of the appropriate acid or base is well within the skill of one having ordinary skill in the art and exemplified in the example below. For example, in step 2) basic conditions can be achieved by adding N,N-disopropylethylamine. In step 1), the compound of formula B is commercially available or can be made by procedures known in the art. For example, bis(hydroxymethyl)malonate is commercially available or easily made from diethylmalonate. See Block, P.F. Organic Synthesis, vol. 5, 1973, 380. Compounds of formula B can also be prepared by following the procedures in Gazaeau, et al., Synthesis, 1987, 1281. The terms "chloronating agent", "bromonating agent" and "iodonating agent" mean compounds that are capable of providing chlorine, bromine or iodine to replace the hydroxy group in the compound of formula B. Examples of these agents are hydrogen halides or phosphorous halides. One skilled in the art can readily prepare alkyl halides from alcohols. Such techniques are disclosed, for example, in Larock, R.C., Comprehensive Organic Transformations, 2nd ed., 1999, pp. 689-701.

The compounds RC-S(O)2-halo or R^c-S(O)2-O-S(O)2-R^c are also commercially available or can be readily made by utilizing procedures known in the art. Examples include p- tolunesulfonyl chloride or trifluoromethanesulfonic acid anhydride. Methods for making the compounds RC-S(O)2-halo or RC-S(O)2-O-S(O)2-R^c are described in, for example, Stang, P.J. et al., Synthesis, 1982, pp. 82-126.

The compounds R-NH2, for example benzylamine, are also either commercially available or can be made by procedures known in the art, as described in, for example, Larock, R.C., Comprehensive Organic Transformations, 2nd ed., 1999, pp. 753-880.

Procedures for hydrolyzing the ester portions of the compound of formula E are well understood and known by persons having ordinary skill in the art. Such procedures that can be used in the present invention are described, for example, in Larock, R.C., Comprehensive Organic Transformations, 2nd ed., 1999, pp. 1959-1968. For example, the compound of formula E can be hydrolyzed with NaOH in methanol followed by acidification.

The term "elevated temperature" means above about 50 °C, preferably in the range of about 50 °C to about 200 °C, more preferably in the range of about 90 °C to about 100 °C. , _____

WO 2004/035538

The term "hydrogenating agent in the presence of a catalyst" is well understood by one having skill in the art for replacing the group R in the compound of formula H with hydrogen. Examples include molecular hydrogen in the presence of Pd(OH)2 or formic acid in the presence of palladium. Other techniques for hydrogenation that can be utilized in the present invention are described in Rylander, P.N., Catalytic Hydrogenation in Organic Syntheses, 1979, pp. 271-285.

An embodiment of the invention encompasses the above method wherein the compound of formula B is reacted with RC-S(O)2-O-S(O)2-R^c in step 1) to yield a compound of formula C wherein l is -O-S(O)2-R^c- Within this embodiment is encompassed the above emthod wherein R^c is selected from -toluene, /?-bromophenyl, methyl or trifluoromethyl. Also within this embodiment is encompassed the above method wherein the compound of formula B is reacted with R^c-S(O)2-O-S(O)2-R^c in step 1) in a first polar aprotic solvent selected from the group consisitng of: acetonitrile, dimethylsulfoxide, N,N-dimethylformamide, N,N- dimethylacetamide and N-methylpyrrolidone, or a mixture thereof, to yield a compound of formula C. Further within this embodiment is encompassesd the above method wherein the compound of formula C in step 2) is reacted with a compound of formula D in in a second polar aprotic solvent selected from the group consisitng of: acetonitrile, dimethylsulfoxide, N,N- dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone, or a mixture thereof, to yield a compound of formula E. Also within this embodiment is encompassed the above method wherein the first polar aprotic solvent and second polar aprotic solvent are acetonitrile. Also within this embodiment is encompassed the above method wherein the compound of formula C in step 2) is reacted with the compound of formula D without isolation from step 1). Also within this embodiment is encompassed the above method wherein step 1) and step 2) are conducted at a low temperature in the range of about -20 °C to about 0 °C. Another embodiment of the invention encompasses the above method wherein R is benzyl.

Another embodiment of the invention encompasses the above method wherein R^a and Rb are each independently Ci-6alkyl.

Another embodiment of the invention encompasses the above method wherein the compound of formula E is hydrolyzed under basic conditions to yield a compound of Formula G by reacting the compound of formula E with an inorganic base and isolating the product salt as a compound of formula F

F wherein Z is the corresponding cation of the inorganic base,

reacting the compound of formula F with an acid to yield a compound of formula G, and isolating the compound of formula G.

The definition of Z as the "corresponding cation of the inorganic base" is well understood by the ordinarily skilled artisan, typically meaning the alkali metal or alkaline earth metal portion of the inorganic base. For example, if the inorganic base is NaOH, then Z is Na. If the inorganic base is KOH, Z is K.

The inorganic base can be a basic salt of an alkali metal or an alkaline earth metal. For example, the inorganic base can be selected from the group consisting of alkali metal hydroxides, oxides, carbonates, and bicarbonates. Exemplary bases include LiOH, NaOH, KOH, L1HCO3, NaHCO3, KHCO3, Na2θ, K2O, Li2CO3, Na2CO3, and K2CO3. The inorganic base can be in the form of a hydrate or it can be anhydrous (e.g., anhydrous LiOH). Within this embodiment of the invention is encompassed the above method wherein the inorganic base is selected from the group consisting of: LiOH, NaOH, KOH, LiHCO3, NaHCO3, KHCO3, Na2θ, K2O, Li2CO3, Na2CO3, and K2CO3. Also within this embodiment is encompassed the above method wherein the inorganic base is NaOH and is reacted with the compound of formula E in an alcohol solvent. Also within this embodiment is encompassed the above method wherein the alcohol solvent is methanol.

The invention also encompasses the above method wherein the acid reacted with the compound of formula F is selected from the group consisting of: acetic acid, formic acid, hydriodic acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, nitric acid, hypochlorous acid, chlorous acid chloric acid, perchloric acid, phosphoric acid, sulfuric acid and sulfurous acid. Another embodiment of the invention encompasses the above method wherein the acid is hydrochloric acid.

Another embodiment of the invention encompasses the above method wherein the elevated temperature is in the range of about 50 °C to about 200 °C. Another embodiment of the invention encompasses the above method wherein the elevated temperature is in the range of about 90 °C to about 100 °C. Another embodiment of the invention encompasses the above method wherein the hydrogenating agent is molecular hydrogen and the catalyst is Pd(OH)2-

Another embodiment of the invention encompasses the above method wherein the hydrogenating agent is formic acid and the catalyst is palladium. The invention also encompasses a method for making azetidine-3-carboxylic acid comprising

1) reacting diethyl bis(hydroxymethyl) malonate with trifluoromethanesulfonic acid anhydride in acetonitrile to yield a compound of formula CI

CI

2) reacting the compound of formula CI without isolation with a benzylamine under basic conditions to yield a compound of formula El

El

3) reacting the compound of formula El with sodium hydroxide in methanol to yield a compound of formula FI

FI reacting the compound of formula FI with hydrochloric acid in an aqueous solvent to yield a compound of formula Gl, and isolating the compound of formula Gl,

Gl

4) heating the compound of formula Gl to an elevated temperature in the range of about 90 °C to about 100 °C in an aqueous solvent to yield a compound of formula HI

HI

5) reacting the compound of formula HI with molecular hydrogen in the presence of a Pd(OH)2 in an aqueous solvent to yield azetidine-3-carboxylic acid. Within this embodiment is encompassed the above method wherein the elevated temperature is about 96 °C.

Another embodiment of the invention encompasses a process for making a compound of formula π

II or a pharmaceutically acceptable salt or hydrate thereof, wherein: n is O;

Y is a bond, -O- or -S(O)k-, wherein k is 0, 1 or 2;

each R3 is independently selected from the group consisting of: hydrogen and Cι_4alkyl, said Ci-4alkyl optionally substituted with from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, hydroxy, Ci-4alkoxy and carboxy;

each R4 is independently selected from the group consisting of: halo, hydroxy, Cχ_4alkyl and Cj^alkoxy, said C^alkyl and Ci^alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo;

each R is independently selected from the group consisting of:

(a) halo,

(b) cyano,

(c) hydroxy,

(e) Cχ-6alkyl,

(f) C2-6alkenyl,

(g) C3_6alkynyl

(h) Cι_6alkoxy

(i) Ci-6alkyl-S(O)k-, wherein k is 0, 1 or 2,

(D C3_6cycloalkyl,

(k) phenyl, and

(1) HETl;

wherein items (e) to (j) above are each optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy and Cj^alkoxy, said Cj^alkoxy group optionally substituted from one up to the maximum number of substitutable positions with halo, and

wherein items (k) and (1) above are each optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy, Ci^alkyl and C^alkoxy, said Cj^alkyl and Cj^alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo;

R6 is selected from the group consisting of: (1) hydrogen

(2) halo,

(3) cyano,

(4) Cl-ioalkyl,

(5) C2-10alkenyl,

(6) C3-ioalkynyl,

(7) C3-6cycloalkyl

(8) phenyl, and

(9) HET2;

wherein items (4) to (6) above are each optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy, C3_6cycloalkyl, phenyl, HET3 and Cj^alkoxy, said C3_ βcycloalkyl, phenyl, HET3 and Cj^alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo,

wherein item (7) above is optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy, phenyl, HET4 and Cι_3alkoxy, said phenyl, HET4 and Ci^alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo, and

wherein items (8) and (9) above are each optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy, Cι_4alkyl and Cj^alkoxy, said C]i -4alkyl and Cj^alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo,

with the proviso, that R6 is not halo or cyano when Y is -O- or -S(O)k~; or R6 and one R5 group or two R5 groups may be joined together to form a five or six-membered monocyclic ring optionally containing 1 or 2 heteroatoms selected from the group consisting of: O, S, or N(R7),

each R7 is independently hydrogen or Cl-4alkyl, said Cι_4alkyl optionally substituted substituted from one up to the maximum number of substitutable positions with halo; and

HETl, HET2, HET3 and HET4 are each independently selected from the group consisting of: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4- dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl,

comprising reacting a compound of formula A-ii

with azetidine-3-carboxylic acid made according to any of the above processes and a reducing agent in a compatible solvent to yield a compound of Formula H Within this embdiment is encompassed the above process wherein the reducing agent is selected from the group consisiting of: sodium cyanoborohydride, sodium triacetoxyborohydride and sodium borohydride, and the compatible solvent is selected from the group consisitng of: methanol, ethanol, acetonitrile and methylene chloride. Another embodiment of the invention encompasses a process for making a compound of Formula II

II or a pharmaceutically acceptable salt or hydrate thereof, wherein:

n is 0;

Y is a bond, -O- or -S(O)k-, wherein k is 0, 1 or 2;

each R3 is independently selected from the group consisting of: hydrogen and Cι_4alkyl, said Cι_4alkyl optionally substituted with from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, hydroxy, Ci_4alkoxy and carboxy;

each R4 is independently selected from the group consisting of: halo, hydroxy, Cj^alkyl and Cχ_3alkoxy, said C^alkyl and C^alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo;

each R5 is independently selected from the group consisting of:

(a) halo,

(b) cyano,

(c) hydroxy,

(e) Cι_6alkyl,

(f) C2-6alkenyl,

(g) C3_6alkynyl

(h) Cι_6alkoxy (i) Cι_6alkyl-S(O)k-, wherein k is 0, 1 or 2,

(j) C3_6cycloalkyl,

(k) phenyl, and

(1) HETl;

wherein items (e) to (j) above are each optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy and Cj^alkoxy, said C^alkoxy group optionally substituted from one up to the maximum number of substitutable positions with halo, and

wherein items (k) and (1) above are each optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy, Cj^alkyl and Cj^alkoxy, said Cj^alkyl and Cj^alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo;

R6 is selected from the group consisting of: (1) hydrogen

(2) halo,

(3) cyano,

(4) Ci-ioalkyl,

(5) C2-10alkenyl,

(6) C3_ιoalkynyl,

(7) C3-6cycloalkyl

(8) phenyl, and

(9) HET2;

wherein items (4) to (6) above are each optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy, C3_6cycloalkyl, phenyl, HET3 and Cj^alkoxy, said C3- βcycloalkyl, phenyl, HET3 and Cj^alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo,

wherein item (7) above is optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy, phenyl, HET4 and Cj^alkoxy, said phenyl, HET4 and Cj^alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo, and

wherein items (8) and (9) above are each optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy, Cj^alkyl and Cj^alkoxy, said Cj^alkyl and C^alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo,

with the proviso that R6 is not halo or cyano when Y is -O- or -S(O)k-; or

R6 and one R5 group or two R groups may be joined together to form a five or six-membered monocyclic ring optionally containing 1 or 2 heteroatoms selected from the group consisting of: O, S, or N(R7),

each R7 is independently hydrogen or Cι_4alkyl, said Cι_4alkyl optionally substituted substituted from one up to the maximum number of substitutable positions with halo; and

HETl, HET2, HET and HET4 are each independently selected from the group consisting of: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4- dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl,

comprising reacting a compound of formula A-iv

wherein X is selected from the group consisting of: Br, CI, I, -O-Rd, wherein Rd is tosyl, brosyl, mesyl or trifyl,

with azetidine-3-carboxylic acid made according to any of the above processes and a weak base in a compatible solvent at or above about room temperature to yield a compound of Formula II. Within this embodiment is encompassed the above process wherein the weak base is selected from the group consisting of: sodium carbonate, potassium carbonate, triethylamine, and N,N- diisopropylethylamine and the compatible solvent is selected from the group consisting of: methanol, ethanol and acetonitrile.

Another embodiemnt of the invention encompasses a process for making a compound of Formula I

or a pharmaceutically acceptable salt or hydrate thereof, wherein:

Ar is phenyl or naphthyl;

m = 0;

n = 0;

A is -CO2H; Rl and R2 are each hydrogen;

R is selected from the group consisting of: hydrogen and Cι_4alkyl, optionally substituted with from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo and hydroxy;

each R4 is independently selected from the group consisting of: halo, C_j^alkyl and C_j^alkoxy, said Cχ~4alkyl and C 1-3 alkoxy optionally substituted from one up to the maximum number of substitutable positions with halo,

C is selected from the group consisting of:

(1) Ci-8alkyl, C__8alkoxy, -(C=O)-Cι .galkyl or -CHOH-Cι_6alkyl, said Ci_

8alkyl, Cι_8alkoxy, -(C=O)-C₁_₆alkyl and -CHOH-Cι_6alkyl optionally substituted with phenyl, and

(2) phenyl or HET, each optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, phenyl, C -

4alkyl and Cj^alkoxy, said Cj^alkyl and Cj^alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from halo and hydroxy, and said phenyl optionally substituted with 1 to 5 groups independently selected from the group consisting of : halo and Cι_4alkyl, optionally substituted with 1-3 halo groups, or C is not present;

when C is not present then B is selected from the group consisting of: phenyl, C5-ιgalkyl, C5-

₁₆alkenyl, C₅-₁₆alkynyl, -CHOH-C₄-₁5alkyl, -CHOH-C₄-₁₅alkenyl, -CHOH-C₄-₁₅alkynyl,

C4-l5^alkoxy, -O-C4_i5alkenyl, -O-C4_χ5alkynyl, C4_j5alkylthio, -S-C4_χ5alkenyl, -S-C4_

15alkynyl, -CH2-C3.^alkoxy, -CH2-O-C3_i4alkenyl, -CH2-O-C3_i4alkynyl, -(C=O)-C4_ i5alkyl,

-(C=O)-O-C₃_₁₄alkyl, -(C=O)-O-C₃_

₁₄alkenyl,

-(C=O)-N(R6)(R7)-C3_

14alkenyl, -(C=O)-N(R6)(R7)-C3_i4alkynyl, -N(R6)(R7)-(C=O)-C3_i4alkyl, -N(R6)(R7)_

(C=O)-C3_i4alkenyl and -N(R6)(R7).(C=O)-C3_i4alkynyl, when C is phenyl or HET then B is selected from the group consisting of: Cj-galkyl, Cχ_ ₅alkoxy, -(C=O)-C₁_₅alkyl,

phenyl and HET, and

when C is Ci_8alkyl, Cι_8alkoxy,

or -CHOH-Cι_6alkyl then B is phenyl; and

R6 and R7 are independently selected from the group consisting of: hydrogen, Ci-9alkyl and - (CH2)p-phenyl, wherein p is 1 to 5 and phenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of: Ci-3alkyl and Ci_3alkoxy, each optionally substituted with 1-3 halo groups,

comprising reacting a compound of formula ii

11

with azetidine-3-carboxylic acid made according to any of the above processes and a reducing agent in a compatible solvent to yield a compound of Fomiula I. Within this embodiment is encompassed the above process wherein the reducing agent is selected from the group consisiting of: sodium cyanoborohydride, sodium triacetoxyborohydride and sodium borohydride, and the compatible solvent is selected from the group consisitng of: methanol, ethanol, acetonitrile and methylene chloride. Another embodiment of the invention encompasses a process for making a compound of Formula I

or a pharmaceutically acceptable salt or hydrate thereof, wherein:

Ar is phenyl or naphthyl;

m = 0;

n = 0;

A is -CO2H;

Rl and R2 are each hydrogen;

R3 is selected from the group consisting of: hydrogen and Cι_4alkyl, optionally substituted with from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo and hydroxy;

each R4 is independently selected from the group consisting of: halo, Ci^alkyl and Cj^alkoxy, said Cj^alkyl and Cj^alkoxy optionally substituted from one up to the maximum number of substitutable positions with halo,

C is selected from the group consisting of:

(1) Cι_8alkyl, Cι_salkoxy,

or -CHOH-Cι_6alkyl, said Cχ_ 8alkyl, Ci-8alkoxy, -(C=O)-Cι_6alkyl and -CHOH-Cι_6alkyl optionally substituted with phenyl, and

(2) phenyl or HET, each optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, phenyl, C\-

4alkyl and Cj^alkoxy, said C^alkyl and Ci^alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from halo and hydroxy, and said phenyl optionally substituted with 1 to 5 groups independently selected from the group consisting of : halo and Ci-4alkyl, optionally substituted with 1-3 halo groups, or C is not present;

when C is not present then B is selected from the group consisting of: phenyl, C5-i6alkyl, C5- Iβalkenyl, Cs-igalkynyl, -CHOH-C₄-₁5alkyl, -CHOH-C₄-i5alkenyl, -CHOH-C -₁₅alkynyl, C4-15alkoxy, -O-C4_i5alkenyl, -O-C4_i5alkynyl, C4_χ5alkylthio, -S-C4_ 15 alkenyl, -S-Gψ. 15_Jkynyl, -CH2-C3_j4alkoxy, -CH2-O-C3_ι₄alkenyl, -CH2-O-C3_i4alkynyl, -(C=O)-C _ l₅alkyl,

-(C=O)-O-C₃_ l alkenyl,

-(C=O)-N(R6)(R7)-C3_ 14alkenyl, -(C=O)-N(R6)(R7)-C3_i4alkynyl, -N(R6)(R7)_(C=O)-C3_i4alkyl, -N(R6)(R7)_ (C=O)-C3_i4alkenyl and -N(R6)(R7).(C=O)-C3_i4alkynyl,

when C is phenyl or HET then B is selected from the group consisting of: Cj^alkyl, Cχ_ ₅alkoxy, -(C=O)-C₁_₅alkyl,

C_halky!

when C is Ci-8alkyl, Cι_8alkoxy,

or -CHOH-Cι_6alkyl then B is phenyl; and

R6 and R7 are independently selected from the group consisting of: hydrogen, Ci-9alkyl and - (CH2)p-phenyl, wherein p is 1 to 5 and phenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of: Cι-3alkyl and Cι_3alkoxy, each optionally substituted with 1-3 halo groups,

comprising reacting a compound of formula iv

IV

with azetidine-3-carboxylic acid made according to any of the above methods and a weak base in a compatible solvent at or above about room temperature to yield a compound of Formula I. The invention also encompasses the above process wherein wherein the weak base is selected from the group consisting of: sodium carbonate, potassium carbonate, triethylamine, and N,N- diisopropylethylamine and the compatible solvent is selected from the group consisting of: methanol, ethanol and acetonitrile.

For purpose of this Specification the following abbreviations have the indicated meanings:

Et ethyl Tf trifyl (-SO2-CF3)

The invention is exemplified by the following non-limiting example:

61% isolated 90% isolated yield from 3 yield from 7 All solvents and reagents were purchased from commercial sources and used without purification. Preparation of azetidine malonate 5 Into a 100 L RBF were charged diethyl bis(hydroxymethyl) malonate 3 (3.5kg,

15.89 mol) followed by 52 L of acetonitrile. Under a nitrogen atmosphere, the solution was cooled to -20 °C and triflic anhydride (5.61 L, 33.37 moles, 2.1 eq) was charged via addition funnel over 50 min while keeping temperature below -10 °C. N,N-Diisopropylethylamine (5.14 kg, 39.72 mol, 2.5 equivalents) was then addeded to the reaction mixture via addition funnel while maintaining temperature of reaction mixture below -10 °C. The process is very exothermic and the actual addition took 1.5 h. Fuming over the head space of the reaction mixture was observed during the addition. Bis-triflate 4 formed cleanly as checked by NMR. While the reaction mixture was still at -10 °C, more N,N-disopropylethylamine (5.14 kg, 39.72 mol, 2.5 equivalents) was added via an addition funnel over 10 min. This addition is not exothermic, so it was added rather quickly. Benzylamine (2.60 L, 23.84 moles, 1.5 eq) was then charged over 5 min. The reaction mixture was heated to 70 °C (mild reflux) and aged over 2 hr. Completion of cyclization reaction is confirmed by HPLC (< 2 A% bistrifiate 4). The batch was cooled to room temperature and transferred to a workup container containing 52 L of toluene, and washed with 2 x 60 L of water. Quantitative assay of the toluene layer gave a yield of 86% (AR). pH of aqueous layer was 9-10, loss in aqueous layers was less than 2%. Organic layer was concentrated to 20 % of its original volume at 45 °C under reduced pressure, and 3 x 20 L of MeOH used for solvent switch. Batch final volume was 40 L. Amount of toluene at the end of solvent switch was determined to be 6 v % by GC (AR). The methanol solution of diester 5 was directly used in the subsequent step.

Preparation of azetidine disodium malonate 6

To the methanol solution of diester 5 (quantitative assay showed 3.98 kg 5) total volume 40 L at room temperature, was added 4.0 L 10 N NaOH, all added in one portion. Reaction mixture temperature raised by about 15 °C during addition. Reaction mixture was then heated to 50 °C and aged over 45 minutes. A slurry resulted during this time. The slurry was cooled to room temperature and sampled for assay, which showed the hydrolysis was incomplete, so an additional 400 mL 10 N NaOH was added. Slurry was aged at 50 °C over an additional 30 min and cooled to room temperature. The slurry was filtered and a dark brown-colored mother liquor collected, displacement wash followed using 16 L of MeOH. The wet solid was mixed with 28 L methanol and stirred overnight at room temperature. The solid was filtered and washed with 2x12L methanol. The solid was dried in vacuum oven at room temperature overnight, giving 3.61 kg (approx 90wt% pure, 3.25 kg pure basis) disodium salt 6 as an off- white solid.

Preparation of azetidine malonic diacid 7

Solid disodium salt 6 (3.33 kg) was mixed with 12 L of water, stirred at room temperature over 10 minutes, upon which the slurry becomes a homogeneous solution. 5 N HC1 (4.77 L) was then added via an addition funnel over 45 minutes without cooling, temperature rose +7 °C to 30 °C during the addition. It became a slurry at the end of addition. The batch was then cooled with an ice/water bath, aged for 1 hr and filtered. The solid was washed with 14 L of MeOH. The solid was left to dry under nitrogen atmosphere overnight. A total of 2.12 kg solid 7 was collected 98 wt%, 83% yield (corrected for purity). Preparation of N-benzyl azetidine monoacid 8

To 2.12 kg (9.01 mol) of diacid 7 was charged 20 L of GMP water and the suspension was warmed up to a mild reflux (internal temperature 96 °C). The slurry became homogeneous after ca. 3 h. After a total of 6 h at 96 °C the reaction was complete by HPLC analysis (remaining diacid <1 A%). Reaction solution was then cooled to room temperature. Small amount of solid particles was seen at bottom of flask. Solution was filtered via in-line filter and used directly in the next hydrogenation step.

Preparation of Azetidine-3-Carboxylic Acid 1

To the monoacid 8 solution in water from the previous step was added ethanol (4.8 L). Pd(OH)₂/C (20 wt%, 212 g) added and reaction mixture subjected to hydrogenation at 60 °C and 40 psi over 16 h. Sample filtered after 16 h indicates reaction is complete by NMR analysis. Reaction mixture was filtered through Solka Floe, and the cake washed with 20 L of water. The filtrate and washes were combined and concentrated under reduced pressure to a minimum volume of approximately 5L and then ethanol was added slowly over 30 min, upon which a slurry resulted The distillation was continued to remove more water. KF of slurry checked, when the wt % of water is less than 2%, slurry filtered, and cake washed with 12 L of ethanol. Mother liquor loss was 1.67 %, and loss during wash was 0.20 %. Total loss was less than 2 %. Wet solid was dried overnight under nitrogen affording 806.2 g of white solid. Purity of the isolated solid was found to be 96.8 wt % (AR). As reported Anderson, et. al., J. Org. Chem., 1972, 3953, double displacement of dibromide (2) with benzhydrylamine gave only monodisplacement and elimination products.

None Observed

2

In order to prevent this facile elimination to an acrylate, they chose to alkylate with epichlorohydrin instead, followed by a one carbon-extension with cyanide. This elimination problem is circumvented in the instant invention however by having the azetidine ring protected as a malonate ester during ring forming step and subsequently decarboxylate. The required starting material diethyl bis(hydroxymethyl)malonate (3) is commercially available or easily made from diethylmalonate. See Block, P. F. Organic Synthesis Vol. 5, 1973, 380. Conversion to the crystalline bis mesylate proceeded in high yield using Hunigs base and mesyl chloride. Attempted azetidine formation using benzylamine or ammonia gave either starting material or complex mixtures. The mesylate was stable under a variety of conditions tested so a more reactive leaving group was sought. Conversion of (3) to the bis triflate (4) proceeded in high yield using triflic anhydride (<5 % oxetane detected). Addition of benzylamine and heating to reflux induced cyclization to the azetidine. Since the bis triflate slowly decomposed at room temperature during storage, a one-pot process combining the first two steps was developed with no loss of yield. The azetidine malonate was not sufficiently crystalline to isolate, therefore the malonate was hydrolyzed directly to the highly crystalline bis sodium salt using methanolic sodium hydroxide in 74% overall yield from (1). Acidification with HC1 gave the crystalline diacid in 61% isolated yield from diethyl (bis)hydroxymethylmalonate.

Initial studies on the decarboxylation showed that elimination to the acrylate would be a competing pathway and also that this pathway was less competitive if the benzyl group was still in place. Also azetidine-3-carboxylic acid is highly water soluble and as such it is advantageous an extractive workup after formation. Therefore hydrogenative debenzylation that would only require a filtration of the catalyst was choosen as the last step. Decarboxylation was carried out from the isolated diacid 7 by heating a slurry in water at reflux (96C). After about 6 hrs, the reaction was completed and could be cooled to room temperature and used directly in the debenzylation step. Debenzylation was best carried out using palladium hydroxide on alumina under 40psi hydrogen pressure at 60°C. Alternatively, transfer hydrogen with formic acid and palladium on carbon was also found to be successful. Isolation of the water soluble azetidine was carried out by azeotropic distillation of the ethanol-water mixture until <2% water remained at which time the slurry was filtered to isolated the crystalline 1. The isolated azetidine carboxylic acid was obtained in high weight percent and purity in this way.

The instant process is useful for making compounds that are SlPi/Edgl receptor agonists. For example, U.S. No. 60/350,000, filed on January 18, 2002, published as WO 03/062252 on July 31, 2003, discloses compounds of Formula I:

or a pharmaceutically acceptable salt or hydrate thereof, wherein:

Ar is phenyl or naphthyl;

m = 0 or 1 ;

n = 0 or 1;

A is selected from the group consisting of: -CO2H, -PO3H2, -PO2H, -SO3H, -PO(C!-3alkyl)OH and lH-tetrazol-5-yl;

Rl and R2 are each independently selected from the group consisting of: hydrogen, halo, hydroxy, -CO2Η and Ci-4alkyl, optionally substituted from one up to the maximum number of substitutable positions with halo; R3 is selected from the group consisting of: hydrogen and Ci-4alkyl, optionally substituted with from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo and hydroxy;

each R is independently selected from the group consisting of: halo, C^alkyl and C_j^alkoxy, said Cj^alkyl and C 1-3 alkoxy optionally substituted from one up to the maximum number of substitutable positions with halo,

C is selected from the group consisting of: (1) C salkyi, Cι_8alkoxy,

or -CHOH-Cι_6alkyl, said Cι_

8alkyl, Cι_8alkoxy,

and -CHOH-Cι_6alkyl optionally substituted with phenyl, and

(2) phenyl or HET, each optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, phenyl, C_j- 4alkyl and C^alkoxy, said Cj^alkyl and Cj^alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from halo and hydroxy, and said phenyl optionally substituted with 1 to 5 groups independently selected from the group consisting of : halo and Ci-4alkyl, optionally substituted with 1-3 halo groups, or C is not present;

when C is not present then B is selected from the group consisting of: phenyl, C5-ιgalkyl, C5- ₁₆alkenyl, Cs-igalkynyl, -CHOH-C₄-i5alkyl, -CHOH-C4-i5alkenyl, -CHOH^-j^alkynyl, C4_i5alkoxy, -O-C4_ ^alkenyl, -O-C4_i5alkynyl, 04. ^alkylthio, -S-C4_i5 lkenyl, -S-C__j._ 15alkynyl, -CH2-C3_i4alkoxy, -CH2-O-C3_i4alkenyl, -CH2-O-C₃_₁ alkynyl, -(C=O)-C4_ ₁₅alkyl, -(C=O)-C4_ ^alkenyl, -(C=O)-C4_₁₅alkynyl, -(C=O)-O-C₃_i4alkyl, -(C=O)-O-C _ ₁₄alkenyl, -(C=O)-O-C₃_₁₄alkynyl, -(C=O)-N(R6)(R7)_C3_₁4alkyl, -(C=0)-N(R6)(R7)_C3_ 14alkenyl, -(C=O)-N(R6)(R7)_C3_i4alkynyl, -N(R6)(R7)-(c=O)-C3_i4alkyl, -N(R6)(R7)- (C=O)-C3_i4alkenyl and -N(R6)(R7)-(C=O)-C3_i4alkynyl,

when C is phenyl or HET then B is selected from the group consisting of: C_j-βalkyl, C_j_ ₅alkoxy, -(C=O)-Cι _₅alkyl,

C_halky!

phenyl and HET, and

when C is Cι_8alkyl, Cι_8alkoxy, -(C=O)-Cj_6alkyl or -CHOH-Ci_6alkyl then B is phenyl; and

R6 and R7 are independently selected from the group consisting of: hydrogen, Cι~αalkyl and - (CH2)p-phenyl, wherein p is 1 to 5 and phenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of: Ci~3alkyl and Cι_3alkoxy, each optionally substituted with 1-3 halo groups.

Further examples of compounds that can be made by utilizing azetidine-3- carboxylic acid are compounds of Formula II disclosed in U.S. No. 60/389,173, filed on June 17, 2002:

II

or a pharmaceutically acceptable salt or hydrate thereof, wherein:

n is 0 or 1 ;

Y is a bond, -O- or -S(O)k-, wherein k is 0, 1 or 2;

each R3 is independently selected from the group consisting of: hydrogen and Cι_4alkyl, said Ci-4alkyl optionally substituted with from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, hydroxy, Cι_4alkoxy and carboxy;

each R4 is independently selected from the group consisting of: halo, hydroxy, C_j^alkyl and C^alkoxy, said C^alkyl and Cj^alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo;

each R5 is independently selected from the group consisting of:

(a) halo,

(b) cyano,

(c) hydroxy,

(e) Cι_6alkyl,

(f) C2-6alkenyl,

(g) C3,6 lkynyl

(h) Cι_6alkoxy

(i) Ci_6alkyl-S(O)k-, wherein k is 0, 1 or 2,

(j) C3_6cycloalkyl,

(k) phenyl, and

(1) HETl;

wherein items (e) to (j) above are each optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy and C^alkoxy, said C^alkoxy group optionally substituted from one up to the maximum number of substitutable positions with halo, and

wherein items (k) and (1) above are each optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy, C^alkyl and C^alkoxy, said C^alkyl and Cj^alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo;

R6 is selected from the group consisting of:

(1) hydrogen

(2) halo, (3) cyano, (4) Ci-ioalkyl,

(5) C2-10alkenyl,

(6) C3_ιoalkynyl,

(7) C3_6cycloalkyl

(8) phenyl, and

(9) HET2;

wherein items (4) to (6) above are each optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy, C3_6cycloalkyl, phenyl, HET3 and Cj^alkoxy, said C3- όcycloalkyl, phenyl, HET3 and Cj^alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo,

wherein items (8) and (9) above are each optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy, C^alkyl and C^alkoxy, said C^alkyl and Cj_3alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo,

with the provso that R6 is not halo or cyano when Y is -O- or -S(O)k-; or

R6 and one R5 group or two R5 groups may be joined together to form a five or six-membered monocyclic ring optionally containing 1 or 2 heteroatoms selected from the group consisting of: O, S, or N(R7),

each R7 is independently hydrogen or Cι_4alkyl, said Ci_4alkyl optionally substituted substituted from one up to the maximum number of substitutable positions with halo; and

HETl, HET2, HET3 and HET4 are each independently selected from the group consisting of: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4- dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyiimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl.

The compounds of Formula π can be synthesized by the following synthetic routes:

Two general methods that can be employed to prepare compounds in the current invention are depicted in Scheme 1. Intermediates A-i may be available from commercial sources (e.g., azetidine-3 -carboxylic acid where n = 0) or they can be prepared according to published procedures (e.g., representative syntheses of pyrrolidine-3-(R)-carboxylic acid and pyrrolidine-3-(S)-carboxylic acid (n = 1) are described by Gmeiner, O., et. al. in Synthesis, 1998, 1491). Combining A-i with aldehyde A-ii in the presence of an appropriate reducing agent (e.g., sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride) in a compatible solvent (e.g., methanol, ethanol, acetonitrile, methylene chloride) can afford compounds of Formula II. Alternatively, intermediates A-i can be combined with a benzyl halide or sulfonate ester A-iv in the presence of an appropriate base (e.g., sodium carbonate, potassium carbonate, triethylamine, N,N-diisopropylethylamine) in a compatible solvent solvent (e.g., methanol, ethanol, acetonitrile) at or above room temperature to give compounds of Formula II. In cases where a carboxylic acid in structure A-i would interfere with the transformation to the compound of Formula II, an appropriate protecting group (Greene & Wuts, eds., "Protecting Groups in Organic Synthesis", John Wiley & Sons, Inc.) that would mask the carboxylic acid and allow for its liberation after coupling with either A-ii or A-iv can be employed. In cases where Formula II contains asymmetric centers, the individual stereoisomers of Formula II can obtained by methods known to those skilled in the art which include (but are not limited to): stereospecific synthesis, resolution of salts of Formula II or any of the intermediates used in its preparation with enantiopure acids or bases, resolution of Formula II or any of the intermediates used in its preparation by HPLC employing enantiopure stationary phases.

Scheme 1

Base, solvent X = -CI, -Br, -I, or -OS0₂R

Methods that can be used to prepare compounds that can be employed as intermediate A-ii in Scheme 1 above are shown in Scheme 2. Many benzonitriles A-v are commercially available and can be combined with hydroxylamine • HC1 in the presence of a neutralizing base (e.g., tiiethylamine, sodium bicarbonate) in an appropriate solvent (methanol, ethanol, N,N-dimethyl formamide) at or above room temperature to afford N-hydroxy benzami dines A-vi. Benzoic acids A-vii can be activated with a carbodiimide (e.g. N,N'- dicyclohexylcarbodiimide, l-(3-dimethylaminopropyl)-3-ethylcarbodiimide) and 1- (hydroxy)benzotriazole in an appropriate solvent (acetonitrile, THF, N,N-dimethyl formamide) and then treated with vi at or above room temperature to afford 1,2,4-oxadiazoles A-viii. An alternative method to activate the benzoic acid A-vii would be to convert it to the corresponding benzoyl chloride (e.g., by warming A-vii in the presence of thionyl chloride or by treating A-vii with oxalyl chloride and catalytic N,N-dimethyl formamide in a suitable solvent). Intermediate A-ii is then obtained by converting A in A-viii to an aldehyde (R³ = H) or ketone. If A is an alcohol, carboxylic acid ester, acetal, hemiacetal, nitrile or N-alkoxyl-N-alkyl carboxamides this can be done using methods known by those skilled in the art (see Larock, "Comprehensive Organic Transformations, A Guide to Functional Group Preparations", VCH Publishers, Inc.).

Scheme 2

H₂NOHΉCI A-vii

base, alcohol, Δ EDC, HOBT, solvent, Δ

_R3 ^ _R3 ^ _R3

A = ?— [ > I—— Ao₀RR i I-—f ΛθH l—C0₂R l—CN — CON(OR')R"

OH RO RO

Many of the benzoic acids A-vii that can be used to prepare intermediates A-ii are available from commercial sources. Some methods that can be employed to prepare benzoic acids A-vii are depicted in Scheme 3. In cases where R is alkyl and Y is -O-, phenol A-ix can be treated with an alkyl halide or alkyl sulfonate ester in the presence of base (e.g., triethylamine, sodium bicarbonate, potassium carbonate) in a suitable solvent (e.g., THF, acetonitrile, methanol, ethanol) at or above room temperature to afford ether A-x. Since a free carboxylic acid might interfere with this transformation, it may be desirable to use A-ix in which the carboxylate is masked as B (e.g., B could be a carboxylate ester, aldehyde, nitrile, etc.) which would then be subsequently transformed to a carboxylic acid using methods known to those skilled in the art (see Larock, "Comprehensive Organic Transformations, A Guide to Functional Group Preparations", VCH Publishers, Inc.). Alternative methods to prepare A-x (and therefore A-xi) could involve treating A-ix with an alcohol, triphenylphosphine and a dialkyl azodicarboxylate (e.g., diethyl azodicarboxylate or diisopropyl azodicarboxylate) in a suitable solvent (THF, CH₂C1₂, toluene) to give A-x. Another method to prepare A-x could be to treat aryl fluoride A- xii with an alcohol and a strong base (NaH, KH, lithium diisopropylamide) in a suitable solvent (THF, 1,2-dimethoxyethane) to give A-x. These methods would also be applicable if it were desirable to have any of R5 be alkoxy.

There are many methods useful for preparing benzoic acids A-vii in which R6 is alkyl and Y is a bond; one useful one is depicted in Scheme 3. Treating aryl bromide, iodide or triflate A-xiii with an alkyl magnesium bromide in the presence of a nickel catalyst in a suitable solvent (THF, 1,2-dimethoxyethane) can afford alkyl benzene A-xiv. Since a free carboxylic acid might interfere with this transformation, it may be desirable to use A-ix in which the carboxylate is masked as B (e.g., B could be nitrile, vinyl, aldehyde acetal, etc.) which would then be subsequently transformed to a carboxylic acid using methods known to those skilled in the art (see Larock, "Comprehensive Organic Transformations, A Guide to Functional Group Preparations", VCH Publishers, Inc.).

Scheme 3

R⁶ is alkyl and Y is -O-

X = -CI, -Br, -I, -OS0₂R'

A-ix A-x A-xi

A-ix A-xii

R⁶ is alkyl and Y is a bond

THF

A-xiii A-xiv A-xv

The following compounds of Formula II may be made by employing azetidine-3- carboxylic acid:

Methods for preparing the above compounds are further illustrated in the following examples. Alternative routes will be easily discernible to practitioners in the field.

GENERAL

Concentration of solutions was carried out on a rotary evaporator under reduced pressure. Conventional flash chromatography was carried out on silica gel (230-400 mesh). Flash chromatography was also carried out using a Biotage Flash Chromatography apparatus (Dyax Corp.) on silica gel (32-63 mM, 60 A pore size) in pre-packed cartridges of the size noted. NMR spectra were obtained in CDC1₃ solution unless otherwise noted. Coupling constants (J) are in hertz (Hz). Abbreviations: diethyl ether (ether), triethylamine (TEA), N,N- diisopropylethylamine (DIEA) sat'd aqueous (sat'd), rt (rt), hour(s) (h), minute(s) (min).

HPLC CONDITIONS LC-1: Waters Xterra MS C18, 5 μ, 4.6 x 50 mm column, 10:90 to 95:5 v/v CH₃CN/H₂O + 0.05% TFA over 4.5 min, hold 1 min, PDA detection 200-600 nm, flow rate = 2.5 mL/min.

LC-2: YMC-Pack Pro C18 S-5μM 20 x 100 mm column or Kromasil KR100-10-C8 20 x 100 mm column; 10:90 to 90:10 v/v CH₃CN/H₂O + 0.05% TFA over 12 min, hold 4 min, UN detection at either 220 or 254 nM, flow rate = 10 mL/min.

PREPARATION OF ALDEHYDE INTERMEDIATES

Aldehyde A-l 4-(5-(4-(2-Methylpropyl)phenyl)-l,2,4-oxadiazol-3-yl)benzaldehyde

Step A: N-Hydroxy-4-(hydroxymethyl)benzamidine

A solution of 25.0 g (150 mmol) of 4-(hydroxymethyl)benzonitrile, 20.8 g (300 mmol) of hydroxyamine hydrochloride and 50.4 g (600 mmol) of sodium bicarbonate in 250 mL of methanol was heated to reflux and stirred for 20 h. The reaction mixture was cooled to rt and filtered. The solid was washed with 100 mL of methanol. The combined methanol solution was concentrated to dryness to afford 31.0 g (99 %) of the title compound: lH NMR (400 Mhz, CD₃OD) 54.63 (s, 2H), 7.39 (d, J= 8.0, 2H), 7.62 (d, J= 8.0, 2H).

Step B: 4-(5-(4-(2-Methylpropyl)phenyl)-1.2.4-oxadiazol-3-yl)phenylmethanol

A solution of 10.0 g (56.2 mmol) of 4-(2-methylpropyl)benzoic acid, 10.8 g (56.2 mmol) of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 7.6 g (56.2 mmol) of 1- hydroxybenzotriazole hydrate in 70 mL of DMF was stirred at rt for 30 min. N-Hydroxy-4- (hydroxymethyl)benzamidine (9.3 g, 56.2 mmol, from Step A) was added to the reaction mixture at rt and the resulting slurry was stirred at 140 °C for additional 2 h. The reaction was cooled to rt and quenched with 50 mL of water. The aqueous layer was extracted with 200 mL of ethyl acetate. The organic layer was washed with 0.5 N HCl solution, saturated NaHCO₃ solution and water and then was concentrated to dryness to afford 16.5 g of the title compound: lH NMR (400 Mhz, CD₃OD) δ 0.95 (d, J=6.7, 6H), 1.96 (m, IH), 2.61 (d, J=7.3, 2H), 7.42 (d, J= 8.0, 2H), 7.54 (d, J= 8.2, 2H), 8.13 (m, 4H).

Step C: 4-(5-(4-(2-Methylpropyl)phenyl)-l,2,4-oxadiazol-3-yl)benzaldehyde

A solution of 9.8 mL (112.4 mmol) of oxalyl chloride in 300 mL of dichloromethane was treated with 12 mL (168.6 mmol) of DMSO at -78 °C. To the reaction mixture, 16.5 g of 4-(5- (4-(2-methylpropyl)phenyl)-l,2,4-oxadiazol-3-yl)phenylmethanol (from Step B) was added followed by 78 mL (450 mmol) of N,N-diisopropylethylamine at -78 °C. The reaction mixture was allowed to warm to rt over 1 h. Dichloromethane was removed under reduced pressure and the residue was partitioned between ethyl acetate and 0.5 N KHSO₄ solution. The organic layer was washed with 1 N HCl solution, saturated NaHCO₃ and water and then was concentrated to dryness. The crude product was recrystallized from hexanes to afford 11.9 g of the title compound: lH NMR (400 Mhz) 5 0.97 (d, J= 6.7, 6H), 1.97 (m, IH), 2.61 (d, J= 7.0, 2H), 7.37 (d, J= 8.0, 2H), 8.06 (d, J=8.2, 2H), 8.16 (d, J= 8.2, 2H), 8.39 (d, J=8.0, 2H), 10.14 (s, IH); ESI- MS 307 (M+H); LC-1: 4.5 min.

Aldehyde A-2

4-(5-(4-Butylphenyl)-l,2,4-oxadiazol-3-yl)benz aldehyde

The title compound was prepared using a procedure analogous to Aldehyde A-l substituting 4-butylbenzoic acid for 4-(2-methylpropyl)benzoic acid in Step B: ESI-MS 307 (M+H); LC-1: 4.6 min.

Aldehyde A-3 4-(5-(4-Hexylphenyl)- 1 ,2,4-oxadiazol-3-yl)benzaldehyde

The title compound was prepared using a procedure analogous to Aldehyde A-l substituting 4-hexylbenzoic acid for 4-(2-methylpropyl)benzoic acid in Step B: ESI-MS 335 (M+H); LC-1: 5.0 min. Aldehyde A-4 4-(5-(4-Cyclohexylρhenyl)-l,2,4-oxadiazol-3-yl)benzaldehyde

The title compound was prepared using a procedure analogous to Aldehyde A-l substituting 4-cyclohexylbenzoic acid for 4-(2-methylpropyl)benzoic acid in Step B: ESI-MS 333 (M+H); LC-1: 4.8 min.

Aldehyde A-5 4-(5-(4-Propylphenyl)- 1 ,2,4-oxadiazol-3-yl)benzaldehyde

The title compound was prepared using a procedure analogous to Aldehyde A-l substituting 4-propylbenzoic acid for 4-(2-methylpropyl)benzoic acid in Step B: ESI-MS 293 (M+H); LC-1: 4.4 min.

Aldehyde A-6

4-(5-(4-Isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)benzaldehyde

The title compound was prepared using a procedure analogous to Aldehyde A-l substituting 4-isopropoxybenzoic acid for 4-(2-methylpropyl)benzoic acid in Step B: ESI-MS 309 (M+H); LC-1: 4.0 min.

Aldehyde A-7 4-(5-( 1 , 1 -Biphen-4-yl)- 1 ,2,4-oxadiazol-3-yl)benzaldehyde

The title compound was prepared using a procedure analogous to Aldehyde A-l substituting l,l'-biphenyl-4-carboxylic acid for 4-(2-methylpropyl)benzoic acid in Step B: ESI- MS 327 (M+H); LC-1: 4.3 min.

Aldehyde A-8 4-(5-(4-(2-Furyl)ρhenyl)-l,2,4-oxadiazol-3-yl)benzaldehyde

The title compound was prepared using a procedure analogous to Aldehyde A-l substituting 4-(2-furyl)benzoic acid for 4-(2-methylpropyl)benzoic acid in Step B: ESI-MS 317 (M+H); LC-1: 4.1 min. Aldehyde A-9 4-(5-(4-Cyclopentylphenyl)- 1 ,2,4-oxadiazol-3-yl)benzaldehyde

The title compound was prepared using a procedure analogous to Aldehyde A-l substituting 4-cyclopentylbenzoic acid for 4-(2-methylpropyl)benzoic acid in Step B: ESI-MS 319 (M+H); LC-1: 4.6 min.

Aldehyde A-10 (±)-4-(5-(4-(l-Methylpropyl)phenyl)-l,2,4-oxadiazol-3-yl)benzaldehyde

The title compound was prepared using a procedure analogous to Aldehyde A-l substituting (±)-4-(l-methylpropyl)benzoic acid for 4-(2-methylpropyl)benzoic acid in Step B: ESI-MS 307 (M+H); LC-1: 4.5 min.

Aldehyde A-11 4-(5-(4-( 1 , 1 -Dimethylpropyl)phenyl)- 1 ,2,4-oxadiazol-3-yl)benzaldehyde

The title compound was prepared using a procedure analogous to Aldehyde A-l substituting 4-(l , l-dimethylpropyl)benzoic acid for 4-(2-methylpropyl)benzoic acid in Step B : ESI-MS 321 (M+H); LC-1: 4.6 min.

Aldehyde A-12 4-(5-(4-(l,l-Dimethylethyl)phenyl)-l,2,4-oxadiazol-3-yl)benzaldehyde

The title compound was prepared using a procedure analogous to Aldehyde A-l substituting 4-(l,l-dimethylethyl)benzoic acid for 4-(2-methylpropyl)benzoic acid in Step B: ESI-MS 307 (M+H); LC-1: 4.4 min.

Aldehyde A-13

4-(5-(4-(Trifluoromethyl)phenyl)-l,2,4-oxadiazol-3-yl)benzaldehyde

The title compound was prepared using a procedure analogous to Aldehyde A-l substituting 4-(trifluoromethyl)benzoic acid for 4-(2-methylpropyl)benzoic acid in Step B: ESI- MS 319 (M+H); LC-1: 3.9 min. Aldehyde A-14 4-(5-(2,3-Dihydrobenzofuran-5-yl)-l,2,4-oxadiazol-3-yl)benzaldehyde

The title compound was prepared using a procedure analogous to Aldehyde A-l substituting 2,3-dihydrobenzofuran-5-carboxylic acid for 4-(2-methylpropyl)benzoic acid in Step B: ESI-MS 293 (M+H); LC-1: 3.5 min.

Aldehyde A-15

4-(5-(4-(2,2-Dimethylpropyl)phenyl)-l,2,4-oxadiazol-3-yl)benzaldehyde

Step A: 4-(2.2-Dimethylpropyl)-4-ethenylbenzene

To a solution of 0.8 g (33.10 mmol) of magnesium turnings and 2.0 g (13.2 mmol) of 1- bromo-2,2-dimethylpropane in 10 mL diethyl ether was added a solution of 1.42 g (7.76 mmol) of 4-bromostyrene and 69 mg (0.13 mmol) of Ni(dppf)Cl₂ . The resulting reaction mixture was heated at refluc for 8 h. The reaction was quenched with 50% saturated NH₄CI, and was extracted with MTBE (2 x 150 mL). The combined extractions were washed with water, dried and concentrated. Flash chromatography on a Biotage 40M cartridge with hexanes as the eluant afforded 1.74 g of the title compound: 1H NMR (500 Mhz) δ 0.93 (s, 9H), 2.49 (s, 2H), 5.20 (d, J = 10.9, IH), 5.73 (d, J = 17.6, IH), 6.72 (dd, Jj = 17.6, J₂ = 10.8, IH), 7.10 (d, J = 8.2, 2H), 7.33 (d, J = 8.0, 2H); ESI-MS 161 (M+H); LC-1: 4.4 min.

Step B: 4- (2,2-Dimethylpropyl)benzoic acid

To a solution of 1.74 g (7.76 mmol) of 4-(2,2-dimethylpropyl)-4-ethenylbenzene (from Step A) in 10 mL EtOAc and 10 mL H₂O was added 8.30 g (38.8 mmol) of NaIO₄ and 1 mg (0.0078 mmol) RuO₂. The reaction mixture was heated to 40°C for 30 min. The reaction mixture was cooled and stirred at rt for 16 hr. To the reaction mixture was added H₂O and EtOAc, and layers were separated. The organic layer was dried and concentrated to dryness to provide 776 mg of the title compound: 1H NMR (500 Mhz) δ 0.91 (s, 9H), 2.53 (s, 2H), 7.12 (d, J = 8.0, 2H), 7.84 (d, J = 8.0, 2H); ESI-MS 193 (M+H); LC-1: 3.2 min.

Step C: 4-(5-(4-(2,2-Dimethylpropyl)phenyl)-l,2,4-oxadiazol-3- vDbenzaldehvde The title compound was prepared using a procedure analogous to Aldehyde A-l substituting 4-(2,2-dimethylpropyl)benzoic acid (from Step B above) for 4-(2- methylpropyl)benzoic acid in Aldehyde A-l, Step B: ESI-MS 321 (M+H); LC-1: 4.7 min.

Aldehyde A- 16 4-(5-(4-(3,3,3-Trifluoropropyl)phenyl)-l,2,4-oxadiazol-3-y)benzaldehyde The title compound was prepared using procedures analogous to those described for Aldehyde A-15 substituting l-bromo-3,3,3-trifiuoropropane for l-bromo-2,2-dimethylpropane in Step A: ESI-MS 347 (M+H); LC-1: 4.0 min.

Aldehyde A-17 4-(5-(4-(3,3,3-Trifluorobutyl)phenyl)-l,2,4-oxadiazol-3-y)benzaldehyde

The title compound was prepared using procedures analogous to those described for Aldehyde A-15 substituting l-bromo-3,3,3-trifluorobutane for l-bromo-2,2-dimethylpropane in Step A: ESI-MS 361 (M+H); LC-1: 4.5 min.

Aldehyde A-18 4-(5-(4-(2-Methylpropyl))-l,2,4-oxadiazol-3-yl)-3-methylbenzaldehyde

Step A: 3-(4-Bromo-2-methylphenyl)-5-(4-(2-methylpropyl)phenyl)-l ,2,4- xadiazole

The title compound was prepared using a procedure analogous to described to prepare 4-(5-(4-(2-methylpropyl)phenyl)-l,2,4-oxadiazol-3-yl)phenylmethanol (Aldehyde A-l, Step B) substituting N-hydroxy-(4-bromo-2-methyl)benzamidine for N-hydroxy-(4- hydroxymethyl)benzamidine: lH NMR (400 Mhz, CC1₃D) δ 0.98 (d, J= 6.6, 6H), 1.98 (m, IH), 2.62 (d, J= 7.1, 2H), 2.72 (s, 3H), 7.37 (d, J= 8.1, 2H), 7.52 (d, J=8.4, IH), 7.56 (s, IH), 8.02 (d, J=8.4, IH), 8.16 (d, J= 8.1, 2H); ESI-MS 371 (M+H); LC-1: 5.3 min.

Step B: 4-(5-(4-(2-Methylpropyl)phenyl)-l,2,4-oxadiazol-3-yl)-3-methyl benzonitrile

A solution of 2.3 g (6.2 mmol) of 3-(4-bromo-2-methylphenyl)-5-(4-(2- methylpropyl)phenyl)-l,2,4-oxadiazole (from Step A), 1.46 g (12.4 mmol) of zinc cyanide and 2.15 g (1.86 mmol) of Pd(PPh₃)₄ in 20 mL of DMF was stirred at 100 °C for 20 h. The reaction was cooled and quenched with 10 mL of sat'd NaHCO₃. The quenched mixture was extracted with 100 mL of dichloromethane. The extract was dried and concentrated to afford 1.40 g of the title compound which was used without further purification: ESI-MS 318 (M+H); LC-1: 4.8 min.

Step C: 4-(5-(4-(2-Methylpropyl)phenyl)-l,2,4-oxadiazol-3-yl)-3- methyl benzaldehvde

A solution of 1.40g (4.4 mmol) of 4-(5-(4-(2-methylpropyl)phenyl)-l,2,4- oxadiazol-3-yl)-3-methyl benzonitrile (from Step B) in 20 mL of toluene was treated with 8.8 mL (8.8 mmol) of DIBALH (1.0 M in dichloromethane) at -78 °C. The resulting mixture was stirred at -78 °C for 30 min and quenched with 0.3 mL of acetic acid and 5 mL of water. The quenched mixture was allowed to warm to rt and was extracted with 50 mL of ethyl acetate. The extract was dried and concentrated to afford 1.0 g of the title compound: ESI-MS 321 (M+H); LC-1: 4.7 min.

Aldehyde A-19

4-(5-(4-(2-Methylpropyl)phenyl)-l,2,4-oxadiazol-3-yl)-3-chlorobenzaldehyde

The title compound was prepared using procedures analogous to those described for Aldehyde A-18 substituting N-hydroxy-(4-bromo-2-chloro)benzamidine for N-hydroxy-(4- bromo-2-methyl)benzamidine in Step A: ESI-MS 341 (M+H); LC-1: 4.6 min.

Aldehyde A-20 4-(5-(4-(2-Methylpropyl)phenyl)-l,2,4-oxadiazol-3-yl)-3-fluorobenzaldehyde

The title compound was prepared using procedures analogous to those described for Aldehyde A-18 substituting N-hydroxy-(4-bromo-2-fluoro)benzamidine for N-hydroxy-(4- bromo-2-methyl)benzamidine in Step A: ESI-MS 325 (M+H); LC-1: 4.4 min.

Aldehyde A-21 4-(5-(4-(2-(S)-Butoxy)-3-trifluoromethylphenyl)- 1 ,2,4-oxadiazol-3-yl) benzaldehyde

Step A: 3-Trifluoromethyl-4-(2-(S)-butoxy)benzonitrile

A solution of 1.1 g (5.9 mmol) of 4-fluoro-3-trifluoromethylbenzonitrile and 485 mg (6.5 mmol) of (S)-(+)-2-butanol in 10 mL of THF at -10 °C was treated with 235 mg (5.9 mmol) of sodium hydride. The resulting mixture was stirred cold for 2 h, then quenched with 10 mL of H₂O. The quenched solution was extracted with 30 mL of Et O, dried over MgSO₄ and concentrated. Chromatography on a Biotage 40M cartridge using 4: 1 v/v hexanes/EtO Ac as the eluant afforded 550 mg of the title compound: 1H NMR (500 Mhz) δ 0.99 (t, J=7.6, 3H), 1.35 (d, J=6.2, 3H), 1.58-1.83 (m, 2H), 4.51 (septet, IH), 7.04 (d, J=8.7, IH), 7.75 (d, J=8.7, IH), 7.85 (s, IH).

Step B: 3-Trifluoromethyl-4-(2-(S)-butoxy)benzoic acid

A solution of 550 mg (2.2 mmol) of 3-trifluoromethyl-4-(2-(S)- methylpropyloxy)benzonitrile (from Step A) in 5 mL of EtOH was treated with 1.5 mL of 5.0 N NaOH and was heated to 80 °C for 3 h. The reaction was then concentrated, treated with 2 N HCl, extracted with 30mL of EtOAc, dried over MgSO₄ and concentrated which afforded 600 mg of the title compound: 1H NMR (500 Mhz) δ 0.99 (t, J=7.3, 3H), 1.43 (d, J=5.9, 3H), 1.73- 1.83 (m, 2H), 4.54 (septet, IH), 7.02 (d, J=8.9, IH), 8.21 (d, J=8.9, IH), 8.32 (s, IH).

Step C: 4-(5-(4-(2-(S)-Butoxy)-3-trifluoromethylphenyl)- 1,2,4- oxadiazol-3-yl)phenylmethanol

A solution of 600 mg (2.2 mmol) of 3-trifluoromethyl-4-(2-(S)- methylpropyloxy)benzoic acid (from Step B), 542 mg (2.2 mmol) of EDC and 357 mg (2.2 mmol) of HOBT in 6mL of DMF were stirred at rt for 1 h. The reaction was subsequently treated with 350 mg (2.2 mmol) of N-hydroxy-4-(hydroxymethyl)benzamidine (from Aldehyde A-l, Step A) and heated to 80 °C for 12 h. The reaction mixture was cooled and purified via chromatography on a Biotage 40M cartridge using 2:1 v/v hexanes/EtOAc as the eluant affording 510 mg of the title compound: 1H NMR (500 MHz) δ 1.01 (t, J=7.3, 3H), 1.38 (d, J=5.9, 3H), 1.73-1.83 (m, 2H), 4.55 (septet, IH), 4.79 (s, 2H), 7.12 (d, J=8.9, IH), 7.51 (d,. J=8.2, 2H), 8.15 (d,. J=8.2, 2H), 8.30 (d, J=8.9, IH), 8.43 (s, IH).

Step D: 4-(5-(4-(2-(S)-Butoxy)-3-trifluoromethylphenyl)-l,2,4-oxadiazol-3- vPbenzaldehyde

A mixture of 510 mg (1.3 mmol) of 4-(5-(4-(2-(S)-methylpropyloxy)-3- trifluoromethylphenyl)-l,2,4-oxadiazol-3-yl)phenylmethanol (from Step C), 153 mg (1.3 mmol) of 4-methylmorpholine N-oxide and 510 mg of 4 A molecular sieves in 8 mL of CH₃CN was treated with 13 mg (0.04 mmol) of tetrapropylammonium perruthnate and the resulting mixture was stirred ar rt for 2 h. The solids were filtered and the filtrate was concentrated. Chromatography on a Biotage 40 S cartridge using 9:1 v/v hexanes/EtOAc (IL) as the eluant afforded 330 mg of the title compound: 1H NMR (500 Mhz) δ 1.01 (t, J=7.3, 3H), 1.38 (d, J=5.9, 3H), 1.73-1.83 (m, 2H), 4.56 (sextet, IH), 7.14 (d, J=8.9, IH), 8.02 (d,. J=8.2, 2H), 8.30 (d,. J=8.2, 2H), 8.32 (d, J=8.9, IH), 8.44 (s, IH), 10.1 (s, IH).

Aldehyde A-22 4-(5-(4-(2-(S)-Butoxy)-3-fluorophenyl)-l,2,4-oxadiazol-3-yl)benzaldehyde

Step A: 3-Fluoro-4-(2-(S)-butoxy)benzaldehvde

A solution of 750 mg (5.4 mmol) of 3-fluoro-4-hydroxybenzaldehyde, 403 mg (5.4 mmol) of (R)-(-)-2-butanol and 2 g (7.5 mmol) triphenylphosphine in 10 mL of THF was treated with 1.5 mL of diisopropylazodicarboxylate. The resulting solution was stirred at rt for 14 h, cooled to rt and concentrated. Chromatography on a Biotage 40M cartridge using 4: 1 v/v hexanes/Et₂O as the eluant afforded 130 mg of the title compound: 1H NMR (500 Mhz) δ 0.99 (t, J= 7.6, 3H), 1.35 (d, J= 6.2, 3H), 1.58-1.83 (m, 2H), 4.47 (m, IH), 7.05 (t, J= 8.2, IH), 7.59 (d, J= 8.2, IH), 7.61 (s, IH), 9.84 (s, IH).

Step B: 3-Fluoro-4-(2-(S)-butoxy)benzoic acid

A solution of 130 mg (0.66 mmol) of 3-fluoro-4-(2-(S)-butoxy)benzaldehyde in 1 mL of acetone was treated with a 73 mg (0.73 mmol) of chromium (VI) oxide in a 3: 1 v/v mixture of water/sulfuric acid at 0 °C. The reaction was allowed to warm to rt and was stirred for 2 hr then extracted with 10 mL of EtOAc, washed with brine, dried over MgSO₄ and concentrated to afford 130 mg of the title compound: 1H NMR (500 Mhz) δ 1.00 (t, J= 7.6, 3H), 1.36 (d, J= 6.2, 3H), 1.70 (m, IH), 1.82 (m, IH), 4.44 (m, IH), 6.99 (t, J= 8.2, IH), 7.79 (d, J= 8.2, IH), 7.85 (s, IH).

Step C: 4-(5-(4-(2-(S)-Butoxv)-3-fluoroρhenyl)-l,2.4-oxadiazol-3-vl) benzaldehvde

The title compound was prepared using procedures analogous to those described for Aldehyde A-21, Steps C and D substituting 3-fluoro-4-(2-(S)-butoxy)benzoic acid (from Step B) for 3-trifiuoromethyl-4-(2-(S)-butoxy)benzoic acid in Aldehyde 21, Step C.

Aldehyde A-23 4-(5-(4-(2-(S)-Butoxy)-3,5-difluorophenyl)-l,2,4-oxadiazol-3-yl)benzaldehyde Step A: 1 -Bromo-3.5-difluoro-4-(2-(S)-butoxy)benzene

The title compound was prepared using procedure analogous to that described in

Aldehyde A-22, Step A substituting 4-bromo-2,6-difluorophenol for 3-fluoro-4- hydroxybenzaldhyde.

Step B: 3,5-Difluoro-4-(2-(S)-butoxy)benzonitrile

A solution of 400 mg (1.5 mmol) of l-bromo-3,5-difluoro-4-(2-(S)-butoxy)benzene (from

Step A), 106 mg (0.9 mmol) of zinc cyanide, 69 mg of tris(dibenzylideneacetone)dipalladium(0) and 100 mg (0.18 mmol) of l,l'-bis(diphenylphosino)ferrocene in 3 mL of DMF and 30 μL of water. The resulting solution was heated to 80 °C for 1 h and then cooled and concentrated.

Chromatography on a Biotage 40M cartridge using 20:1 v/v hexanes/EtOAc as the eluant afforded 280 mg of the title compound: 1H NMR (500 Mhz) δ 1.01 (t, J=7.6, 3H), 1.35 (d,

J=6.2, 3H), 1.68 (m, IH), 1.79 (m, IH), 4.47 (m, IH), 7.25 (d, 2H).

Step C: 3 ,5-Difluoro-4-(2-(S)-butoxy)benzoic acid

The title compound was prepared using procedure analogous to that described in Aldehyde A-21, Step B substituting 3,5-difIuoro-4-(2-(S)-butoxy)benzonitrile (from Step B) for 3-trifluoromethyl-4-(2-(S)-butoxy)benzonitrile: 1H NMR (500 Mhz) δ 1.0 (t, J=7.3, 3H), 1.32 (d, J=5.9, 3H), 1.68 (m, IH), 1.79 (m, IH), 4.45 (m, IH), 7.65 (d, J=8.3, 2H).

Step D: 4-(5-(4-(2-(S)-Butoxy)-3,5-di-fluorophenyl)-l,2,4-oxadiazol-3-yl) benzaldehvde

The title compound was prepared using procedures analogous to those described for Aldehyde A-21, Steps C and D substituting 3,5-difluoro-4-(2-(S)-butoxy)benzoic acid (from Step C) for 3-trifluoromethyl-4-(2-(S)-butoxy)benzoic acid in Aldehyde A-21, Step C.

Aldehyde A-24 4-(5-(4-(2-(S)-Butoxy)phenyl)-l,2,4-oxadiazol-3-yl)benzaldehyde

Step A: Methyl 4-(2-(S)-butoxy)benzoate

The title compound was prepared using procedure analogous to that described in Aldehyde A-22, Step A substituting methyl 4-hydroxybenzoate for 3-fluoro-4- hydroxybenzaldehyde. Step B: 4-(2-(S)-Butoxy)benzoic acid

A solution of 1.0 g (4.8 mmol) of methyl 4-(2-(S)-butoxy)benzoate in 15 mL of MeOH was treated with 1 mL of 5.0 N NaOH at rt for 1 h. The solution was concentrated, acidified with 6 mL of 2 N HCl , extracted with EtOAc, dried over MgSO and concentrated to afford 800 mg (86%) of the title compound.

Step C: 4-(5-(4-(2-(S)-Butoxy)phenyl)-1.2.4-oxadiazol-3-yl)benzaldehvde

The title compound was prepared using procedures analogous to those described for Aldehyde A-21, Steps C and D substituting 4-(2-(S)-butoxy)benzoic acid (from Step B) for 3- trifluoromethyl-4-(2-(S)-butoxy)benzoic acid in Aldehyde 21, Step C.

Aldehyde A-25 4-(5-(4-(2-(R)-Butoxy)phenyl)-l,2,4-oxadiazol-3-yl)benzaldehyde

The title compound was prepared using procedures analogous to those described for Aldehyde A-24 substituting 2-(S)-butanol for 2-(R)-butanol in Step A.

Aldehyde A-26 4-(5-(4-(Cyclobutoxy)phenyl)-l,2,4-oxadiazol-3-yl)benzaldehyde

The title compound was prepared using procedures analogous to those described for Aldehyde A-24 substituting cyclobutanol for 2-(R)-butanol in Step A.

PREPARATION OF EXAMPLES

EXAMPLE A-l l-(4-(5-(4-(3-Methylpropyl)phenyl)-l,2,4-oxadiazol'-3-yl)benzyl)azetidine-3-carboxylic acid

A solution of 3.06 g (10.0 mmol) of Aldehyde A-l, 1.06 g (10.5 mmol) of 3-azetidine carboxylic acid and 5 mL of acetic acid in 150 mL of methanol was stirred for 20 min at rt. A solution of sodium cyanoborohydride (380 mg, 5.0 mmol) in 20 mL of methanol was added. The reaction mixture was stirred for 1 h then was filtered. The solids were washed with 30 ml of methanol and dried to afford 2.88 g (74%) of the title compound: lH NMR (400 Mhz, CD₃OD) δ 0.95 (d, J= 6.6, 6H), 1.96 (m, IH), 2.62 (d, J= 7.3, 2H), 3.42 (m, IH), 4.19 (m, 4H), 4.41 (s, 2H), 7.43 (d, J= 8.0, 2H), 7.64 (d, J=8.2, 2H), 8.14 (d, J= 8.0, 2H), 8.23 (d, J=8.2, 2H); ESI-MS 392 (M+H); LC-1: 3.0 min.

EXAMPLE A-2 l-(4-(5-(4-(l ,1-Dimethylethyl)phenyl)-1 ,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid

A solution of 103.7 mg (0.34 mmol) Aldehyde A-12 and 37.7 mg (0.37 mmol) of azetidine-3-carboxylic acid was stirred at rt for 15 min and then was treated with 86.5 mg (0.408 mmol) of sodium triacetoxyborohydride. The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with MeOH and directly purified by LC-2 to afford the title compound: 1H NMR (500 Mhz) δ 1.38 (s, 9H), 3.65-3.72 (m, IH), 4.32-4.39 (m, 4H), 4.50 (s, 2H), 7.64-7.68 (m, 4H), 8.13-8.16 (m, 2H), 8.24-8.25 (m, 2H); ESI-MS 392 (M+H); LC-1: 2.9 min.

The following Examples were prepared using a procedure analogous to that described for Example 2 substituting the appropriate Aldehyde for Aldehyde A-12.

EXAMPLE A-30 (+)-l-(l-(4-(5-(4-(l,l-Dimethylethyl)phenyl)-l,2,4-oxadiazol-3-yl)phenyl)ethyl) azetidine-3- carboxylic acid

Step A: (±)-4-(5-(4-(2-Methylpropyl)phenyl)-l,2,4-oxadiazol-3-yl)-l-(l- hvdroxyethvDbenzene

A solution of 0.5 g (1.63 mmol) of Aldehyde A-l in 10 mL of THF was treated with 1.1 mL (3.3 mmol) of methylmagnesium iodide (3.0 M in diethyl ether) at -78 °C and was allowed to warm to rt over 30 min. The resulting mixture was quenched with 5 mL of 1 N HCl and was extracted with 30 mL of ethyl acetate. The extract was washed, dried and concentrated to afford the title compound: ESI-MS 323 (M+H); LC-1: 4.2 min.

Step B: 4-(5-(4-(2-Methylpropyl)phenyl)-1.2,4-oxadiazol-3-yl)acetophenone The title compound was prepared using a procedure analogous to that described in

Aldehyde A-l, Step C_. substituting (±)-4-(5-(4-(2-methylpropyl)phenyl)-l,2,4-oxadiazol-3-yl)-l- (l-hydroxyethyl)benzene (from Step A) for 4-(5-(4-(2-methylpropyl)phenyl)-l,2,4-oxadiazol-3- yl)phenylmethanol: ESI-MS 321 (M+H); LC-1: 4.6 min. Step C: aVl-α-r4-(5-(4-(l.l-Dimethvlethvl)phenvlV1.2.4-oxadiazol-3-yl)phenyl)ethvD azetidine-3-carboxylic acid

The title compound was prepared using a procedure analogous to that described in Example A-2 substituting 4-(5-(4-(2-methylpropyl)phenyl)-l,2,4-oxadiazol-3-yl) acetophenone for Aldehyde A-12: ESI-MS 406 (M+H); LC-1: 3.5 min.

The formulas above use the following definitions unless otherwise indicated.

The term "aryl" is defined as a mono- or bi-cyclic aromatic ring system and includes, for example, phenyl, naphthyl, and the like. The term "aralkyl" means an alkyl group as defined above of 1 to 6 carbon atoms with an aryl group as defined above substituted for one of the alkyl hydrogen atoms, for example, benzyl and the like.

The term "aryloxy" means an aryl group as defined above attached to a molecule by an oxygen atom (aryl-O) and includes, for example, phenoxy, naphthoxy and the like. The term "aralkoxy" means an aralkyl group as defined above attached to a molecule by an oxygen atom (aralkyl-O) and includes, for example, benzyloxy, and the like.

The term "arylthio" is defined as an aryl group as defined above attached to a molecule by an sulfur atom (aryl-S) and includes, for example, thiophenyoxy, thionaphthoxy and the like.

The term "aroyl" means an aryl group as defined above attached to a molecule by an carbonyl group (aryl-C(O)-) and includes, for example, benzoyl, naphthoyl and the like.

The term "aroyloxy" means an aroyl group as defined above attached to a molecule by an oxygen atom (aroyl-O) and includes, for example, benzoyloxy or benzoxy, naphthoyloxy and the like.

The term "HET" is defined as a 5- to 10-membered aromatic, partially aromatic or non-aromatic mono- or bicyclic ring, containing 1-5 heteroatoms selected from O, S and N, and optionally substituted with 1-2 oxo groups. Preferably, "HET" is a 5- or 6-membered aromatic or non-aromatic monocyclic ring containing 1-3 heteroatoms selected from O, S and N, for example, pyridine, pyrimidine, pyridazine, furan, thiophene, thiazole, oxazole, isooxazole and the like, or heterocycle is a 9- or 10-membered aromatic or partially aromatic bicyclic ring containing 1-3 heteroatoms selected from O, S, and N, for example, benzofuran, benzothiophene, indole, pyranopyrrole, benzopyran, quionoline, benzocyclohexyl, naphtyridine and the like. "HET" also includes the following: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomo holinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl.

A preferred group of HET is as follows:

Claims

WHAT IS CLAIMED IS:

A method for making a compound of formula A

comprising:

1) reacting a compound of formula B

B

wherein R^a and Rb are each independently selected from the group consisting of:

(1) Cl-ioalkyl,

(2) C2-10alkenyl,

(3) C3_ιoalkynyl,

(4) C3_6cycloalkyl

(5) phenyl or naphthyl, and

(6) HETl,

wherein items (1) to (4) above are each optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, hydroxy, cyano, C3_6cycloalkyl, phenyl, naphthyl, HET2 and Cj^alkoxy, said C3_6cycloalkyl, phenyl, naphthyl, HET2 and C^alkoxy groups optionally substituted with 1-3 substituents independently selected from halo, hydroxy, nitro, cyano, Cχ_4alkoxy and Ci_4alkylthio, said phenyl, naphthyl and HET2 further optionally substituted with Cι_4alkyl;

and items (5) and (6) above are optionally substituted with 1-5 substituents independently selected from the group consisting of: halo, hydroxy, nitro, cyano, Ci_4alkyl, Cχ_4alkoxy and Ci_4alkylthio;

HETl and HET2 are each independently selected from the group consisting of: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4- dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl,

with a chloronating agent, bromonating agent, iodonating agent, RC-S(O)2-halo or RC-S(O)2-O- S(O)2-R^c, wherein Re is Cι_4alkyl, optionally substituted with 1-3 halo groups, or R^c is phenyl, optionally substituted with 1-3 groups selected from methyl and halo, to yield a compound of formula C

wherein Xl is chloro, bromo, iodo, or -O-S(O)2-R^c, 2) reacting the compound of formula C with a compound of formula D

R-NH2 D

wherein R is selected from the group consisting of: allyl or benzyl, the phenyl portion of benzyl being optionally substituted with 1-5 substituents independently selected from the group consiting of: Cι_4alkyl, haloCi_4alkyl, halo, hydroxy, cyano, nitro, Cχ_4alkoxy, and Cχ_ 4alkylthio,

under basic conditions to yield a compound of formula E

E

H

5) reacting the compound of formula H with an hydrogenating agent in the presence of a catalyst to yield a compound of formula A.

2. The method according to Claim 1 wherein the compound of formula B is reacted with R^c-S(O)2-O-S(O)2-R^c in step 1) to yield a compound of formula C wherein Xl is -

O-S(O2)-Rc.

3. The method according to Claim 2 wherein R^c is selected from p-toluene, p-bromophenyl, methyl or trifluoromethyl.

4. The method according to Claim 3 wherein the compound of formula B in step 1 is reacted with R^c-S(O)2-O-S(O)2-R^c in a first polar aprotic solvent selected from the group consisitng of: acetonitrile, dimethylsulfoxide, N,N-dimethylformamide, N,N- dimethylacetamide and N-methylpyrrolidone, or a mixture thereof, to yield a compound of formula C.

5. The method according to Claim 4 wherein the compound of formula C in step 2) is reacted with a compound of formula D in a second polar aprotic solvent selected from the group consisitng of: acetonitrile, dimethylsulfoxide, N,N-dimethylformamide, N,N- dimethylacetamide and N-methylpyrrolidone, or a mixture thereof, to yield a compound of formula E.

6. The method according to Claim 5 wherein the first polar aprotic solvent and second polar aprotic solvent are acetonitrile.

7. The method according to Claim 6 wherein the compound of formula C in step 2) is reacted with the compound of formula D without isolation from step 1).

8. The method according to Claim 7 wherein step 1) and step 2) are conducted at a low temperature in the range of about -20°C to about 0°C.

9. The method according to Claim 1 wherein R is benzyl.

10. The method according to Claim 1 wherein Ra and Rb are each independently Ci_6alkyl.

11. The method according to Claim 1 wherein the compound of formula E is hydrolyzed under basic conditions to yield a compound of formula G by reacting the compound of formula E with an inorganic base and isolating the product salt as a compound of formula F

F wherein Z is the corresponding cation of the inorganic base,

followed by reacting the compound of formula F with an acid to yield a compound of formula G, and isolating the compound of formula G.

12. The method according to Claim 11 wherein the inorganic base is selected from the group consisting of: LiOH, NaOH, KOH, LiHCO3, NaHCO3, KHCO3, Na2θ, K2O, Li2CO3, Na2CO3, and K2CO3.

13. The method according to Claim 12, wherein the inorganic base is NaOH and is reacted with the compound of formula E in an alcohol solvent.

14. The method according to Claim 13 wherein the alcohol solvent is methanol.

15. The method according to Claim 11 wherein the acid is selected from the group consisting of: acetic acid, formic acid, hydriodic acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, nitric acid, hypochlorous acid, chlorous acid chloric acid, perchloric acid, phosphoric acid, sulfuric acid and sulfurous acid.

16. The method according to Claim 15 wherein the acid is hydrochloric acid.

17. The method according to Claim 1 wherein the elevated temperature is in the range of about 50 °C to about 200 °C.

18. The method according to Claim 17 wherein the elevated temperature is in the range of about 90 °C to about 100 °C.

19. The method according to Claim 1 wherein the hydrogenating agent is molecular hydrogen and the catalyst is Pd(OH)2-

20. The method according to Claim 1 wherein the hydrogenating agent is formic acid and the catalyst is palladium.

21. A method for making azetidine-3 -carboxylic acid comprising

CI 2) reacting the compound of formula CI without isolation with a benzylamine under basic conditions to yield a compound of formula El

El

FI

reacting the compound of formula FI with hydrochloric acid in an aqueous solvent to yield a compound of formula Gl, and isolating the compound of formula Gl,

Gl 4) heating the compound of formula Gl to an elevated temperature in the range of about 90 °C to about 100 °C in an aqueous solvent to yield a compound of formula HI

HI

5) reacting the compound of formula HI with molecular hydrogen in the presence of a Pd(OH)2 in an aqueous solvent to yield azetidine-3-carboxylic acid.

22. The method according to Claim 21 wherein the elevated temperature is about 96 °C.

23. A process for making a compound of Formula π

II

or a pharmaceutically acceptable salt or hydrate thereof, wherein:

n is 0;

Y is a bond, -O- or -S(O)k-, wherein k is 0, 1 or 2; each R3 is independently selected from the group consisting of: hydrogen and Cj-4alkyl, said Ci_4alkyl optionally substituted with from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, hydroxy, Cι_4alkoxy and carboxy;

each R4 is independently selected from the group consisting of: halo, hydroxy, Cχ_4alkyl and Cχ_3alkoxy, said Cχ_4alkyl and Cχ_3alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo;

each R5 is independently selected from the group consisting of:

(a) halo,

(b) cyano,

(c) hydroxy,

(e) Cι_6alkyl,

(f) C2-6alkenyl,

(g) C3_6alkynyl

(h) Ci-βalkoxy

(i) Ci_6alkyl-S(O)k-, wherein k is 0, 1 or 2,

(j) C3_6cycloalkyl,

(k) phenyl, and

(1) HETl;

wherein items (e) to (j) above are each optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy and C^alkoxy, said Cχ_3alkoxy group optionally substituted from one up to the maximum number of substitutable positions with halo, and

wherein items (k) and (1) above are each optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy, Cχ_4alkyl and Ci^alkoxy, said Cχ_4alkyl and Cχ_3alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo;

R6 is selected from the group consisting of: (1) hydrogen (3) cyano,

(4) Ci-ioalkyl,

(5) C2-10alkenyl,

(6) C3-10alkynyl,

(7) C3-6cycloalkyl

(8) phenyl, and

(9) HET2;

wherein items (4) to (6) above are each optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy, C3_6cycloalkyl, phenyl, HET3 and Cj^alkoxy, said C3_ βcycloalkyl, phenyl, HET3 and Cχ_3alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo,

wherein item (7) above is optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy, phenyl, HET4 and Cχ_3alkoxy, said phenyl, HET4 and Cχ_3alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo, and

wherein items (8) and (9) above are each optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy, Cχ_4alkyl and Cχ_3alkoxy, said Cχ_4alkyl and Cχ_3alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo,

with the proviso that R6 is not halo or cyano when Y is -O- or -S(O)k or

R6 and one R5 group or two R5 groups may be joined together to form a five or six-membered monocyclic ring optionally containing 1 or 2 heteroatoms selected from the group consisting of: O, S, orN(R7),

each R7 is independently hydrogen or Cι_4alkyl, said Cχ-4alkyl optionally substituted substituted from one up to the maximum number of substitutable positions with halo; and HETl, HET2, HET3 and HET4 are each independently selected from the group consisting of: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4- dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl,

comprising reacting a compound of formula A-ii

with azetidine-3 -carboxylic acid made according to the process of Claim 1 and a reducing agent in a compatible solvent to yield a compound of Formula H

24. The compound according to Claim 23 wherein the reducing agent is selected from the group consisiting of: sodium cyanoborohydride, sodium triacetoxyborohydride and sodium borohydride, and the compatible solvent is selected from the group consisitng of: methanol, ethanol, acetonitrile and methylene chloride.

25. A process for making a compound of Formula π

II

or a pharmaceutically acceptable salt or hydrate thereof, wherein:

n is 0;

Y is a bond, -O- or -S(O)k-, wherein k is 0, 1 or 2;

each R is independently selected from the group consisting of: hydrogen and Ci_4alkyl, said Cι_4alkyl optionally substituted with from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, hydroxy, Cι_4alkoxy and carboxy;

each R is independently selected from the group consisting of: halo, hydroxy, Cχ-4alkyl and Cχ_3alkoxy, said Cχ_4alkyl and Cj^alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo;

each R5 is independently selected from the group consisting of:

(a) halo,

(b) cyano,

(c) hydroxy,

(e) Cι_6alkyl,

CO C2-6alkenyl,

(g) C3_6alkynyl

(h) Ci-βalkoxy

(i) Cι_6alkyl-S(O)k-, wherein k is 0, 1 or 2,

(j) C3_6cycloalkyl, (k) phenyl, and (1) HETl;

wherein items (e) to (j) above are each optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy and C -3 alkoxy, said Cj^alkoxy group optionally substituted from one up to the maximum number of substitutable positions with halo, and

wherein items (k) and (1) above are each optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy, Cj^alkyl and Cχ_3alkoxy, said Cj^alkyl and Cj^alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo;

R6 is selected from the group consisting of: (1) hydrogen

(2) halo,

(3) cyano,

(4) Ci-ioalkyl,

(5) C2-10alkenyl,

(6) C3_ιoalkynyl,

(7) C3_6cycloalkyl

(8) phenyl, and

(9) HET2;

wherein items (4) to (6) above are each optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy, C3_6cycloalkyl, phenyl, HET3 and Cχ_3alkoxy, said C3_

6cycloalkyl, phenyl, HET3 and Cχ_3alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo,

wherein item (7) above is optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy, phenyl, HET4 and Cj^alkoxy, said phenyl, HET4 and Cj^alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo, and wherein items (8) and (9) above are each optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy, Cj^alkyl and Cχ-3alkoxy, said Cj^alkyl and Cχ_3alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo,

with the proviso that R6 is not halo or cyano when Y is -O- or -S(O)k-; or

R6 and one R group or two R5 groups may be joined together to form a five or six-membered monocyclic ring optionally containing 1 or 2 heteroatoms selected from the group consisting of: O, S, or N(R7),

each R7 is independently hydrogen or Cι_4alkyl, said Cχ_4alkyl optionally substituted substituted from one up to the maximum number of substitutable positions with halo; and

comprising reacting a compound of formula A-iv

with azetidine-3-carboxylic acid made according to the process of Claim 1 and a weak base in a compatible solvent at or above about room temperature to yield a compound of Formula U.

26. The process according to Claim 25 wherein the weak base is selected from the group consisting of: sodium carbonate, potassium carbonate, triethylamine, and N,N- diisopropylethylamine and the compatible solvent is selected from the group consisting of: methanol, ethanol and acetonitrile.

27. A process for malting a compound of Formula I

or a pharmaceutically acceptable salt or hydrate thereof, wherein:

Ar is phenyl or naphthyl;

m = 0;

n = 0; A is -CO2H;

Rl and R2 are each hydrogen;

R is selected from the group consisting of: hydrogen and Cχ_4alkyl, optionally substituted with from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo and hydroxy;

each R4 is independently selected from the group consisting of: halo, Cχ-4alkyl and C 1-3 alkoxy, said Cχ-4alkyl and Cχ-3alkoxy optionally substituted from one up to the maximum number of substitutable positions with halo,

C is selected from the group consisting of:

(3) Cχ_8alkyl, Ci_8alkoxy, -(C=O)-Cχ_6alkyl or -CHOH-C _6alkyl, said Cχ_ 8alkyl, Cχ_8alkoxy, -(C=O)-Cι_6alkyl and -CHOH-Cχ_6alkyl optionally substituted with phenyl, and

(4) phenyl or HET, each optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, phenyl, Cχ~

4alkyl and Cj^alkoxy, said Cj^alkyl and Cχ~4alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from halo and hydroxy, and said phenyl optionally substituted with 1 to 5 groups independently selected from the group consisting of : halo and Cχ_4alkyl, optionally substituted with 1-3 halo groups, or C is not present;

when C is not present then B is selected from the group consisting of: phenyl, C5-χ6alkyl, C5- Xgalkenyl, C5-χ6alkynyl, -CHOH-C4-χ5alkyl, -CHOH-C4- ^alkenyl, -CHOH-C₄-i5alkynyl, C4_ 5alkoxy, -O-C4_χ5alkenyl, -O-C4_χ5alkynyl, C4_χ5alkylthio, -S-C4_ ^alkenyl, -S-G4_ 5alkynyl, -CH2-C₃_₁ alkoxy, -CH2-O-C3_χ alkenyl, -CH2-O-C₃_χ4alkynyl, -(C=O)-C4_ l₅alkyl,

-(C=O)-O-C₃_ ₁₄alkenyl, -(C=O)-O-C₃_₁₄alkynyl, -(C=O)-N(R6)(R7)-C3_i4alkyl, -(C=O)-N(R6)(R7)_C _ 4alkenyl, -(C=O)-N(R6)(R7)-C₃-l4alkynyl, -N(R6)(R7)_(c=O)-C₃-14alkyl, -N(R6)(R7)- (C=O)-C3-14alkenyl and -N(R6)(R7)-(C=O)-C3_χ4alkynyl, when C is phenyl or HET then B is selected from the group consisting of: Cx-_β lkyl, Cχ_ ₅alkoxy, -(C=O)-C₁_₅alkyl, -(C=O)-O-C _₄alkyl, -(C=O)-N(R6)(R7)_C _₄alkyl,

when C is Cχ_8alkyl, Cχ_8alkoxy, -(C=O)-Cχ_6alkyl or-CHOH-C _6alkyl then B is phenyl; and

R6 and R7 are independently selected from the group consisting of: hydrogen, Cχ-9alkyl and - (CH2)p-phenyl, wherein p is 1 to 5 and phenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of: Cχ-3alkyl and Cχ_3alkoxy, each optionally substituted with 1-3 halo groups,

comprising reacting a compound of formula ii

n with azetidine-3-carboxylic acid made according to the process of Claim 1 and a reducing agent in a compatible solvent to yield a compound of Formula I.

28. The compound according to Claim 27 wherein the reducing agent is selected from the group consisiting of: sodium cyanoborohydride, sodium triacetoxyborohydride and sodium borohydride, and the compatible solvent is selected from the group consisitng of: methanol, ethanol, acetonitrile and methylene chloride.

29. A process for making a compound of Formula I

or a pharmaceutically acceptable salt or hydrate thereof, wherein:

Ar is phenyl or naphthyl;

m = 0;

n = 0;

A 1S -CO2H;

Rl and R2 are each hydrogen;

R3 is selected from the group consisting of: hydrogen and Cχ_4alkyl, optionally substituted with from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo and hydroxy;

each R4 is independently selected from the group consisting of: halo, Cj^alkyl and Cχ-3alkoxy, said Cχ-4alkyl and C 1-3 alkoxy optionally substituted from one up to the maximum number of substitutable positions with halo,

C is selected from the group consisting of:

(3) Cχ_8alkyl, Cι_8alkoxy, -(C=O)-Cι .galkyl or -CHOH-Cχ_6alkyl, said C__

8alkyl, Cχ_8alkoxy, -(C=O)-C _6alkyl and -CHOH-Cχ_6alkyl optionally substituted with phenyl, and

4alkyl and Cχ-4alkoxy, said Cχ-4alkyl and Cχ-4alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from halo and hydroxy, and said phenyl optionally substituted with 1 to 5 groups independently selected from the group consisting of : halo and Cχ_4alkyl, optionally substituted with 1-3 halo groups, or C is not present;

when C is not present then B is selected from the group consisting of: phenyl, C5- 6alkyl, C5- ₁₆alkenyl, C₅-₁₆alkynyl, -CHOH-C₄-₁₅alkyl, -CHOH-C₄-₁₅alkenyl, -CHOH-C₄-₁₅alkynyl, C4_χ5alkoxy, -O-C4_ 15 alkenyl, -O-C4_χ5alkynyl, C4_χ5alkylthio, -S-C4_χ5alkenyl, -S-C4_ 15_lkynyl, -CH2-C _i4alkoxy, -CH2-O-C3_χ4alkenyl, -CH2-O-C₃_χ₄alkynyl, -(C=O)-C4_ ₁₅alkyl, -(C=O)-C₄_₁₅alkenyl, -(C=O)-C₄_ι₅alkynyl, -(C=O)-O-C₃_₁₄alkyl, -(C=O)-O-C₃_ 4alkenyl,

14alkenyl, -(C=O)-N(R6)(R7)-C₃_i4alkynyl, -N(R6)(R7)_(c=O)-C3_i4alkyl, -N(R6)(R7)- (C=O)-C3_χ4alkenyl and -N(R6)(R7).(C=O)-C3_χ4alkynyl,

when C is phenyl or HET then B is selected from the group consisting of: C -galkyl, Cχ_ ₅alkoxy, -(C=O)-Cχ_5alkyl,

phenyl and HET, and

when C is Cχ_8alkyl, Cι_8alkoxy, -(C=O)-C _6alkyl or -CHOH-Cχ_6alkyl then B is phenyl; and

R6 and R7 are independently selected from the group consisting of: hydrogen, Cχ-9alkyl and - (CH2)p-ρhenyl, wherein p is 1 to 5 and phenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of: Cχ-3alkyl and Cχ_3alkoxy, each optionally substituted with 1-3 halo groups,

comprising reacting a compound of formula iv

iv

with azetidine-3-carboxylic acid made according to the process of Claim 1 and a weak base in a compatible solvent at or above about room temperature to yield a compound of Formula I.

30. The process according to Claim 29 wherein the weak base is selected from the group consisting of: sodium carbonate, potassium carbonate, triethylamine, and N,N- diisopropylethylamine and the compatible solvent is selected from the group consisting of: methanol, ethanol and acetonitrile.