MX2008006603A - S1p receptor modulating compounds and use thereof - Google Patents

Abstract

The present invention relates to compounds of the general formula (I) that have activity as SlP receptor modulating agents and the use of such compounds to treat diseases associated with inappropriate SlP receptor activity. The compounds may be used as immunomodulators, e.g., for treating or preventing diseases such as autoimmune and related immune disorders including systemic lupus erythematosus, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, type I diabetes, uveitis, psoriasis, myasthenia gravis, rheumatoid arthritis, non-glomerular nephrosis, hepatitis, Behcet's disease, glomerulonephritis, chronic thrombocytopenic purpura, hemolytic anemia, hepatitis and Wegner's granuloma;and for treating other conditions.

Description

COMPOUNDS THAT MODULATE THE RECEIVER OF ESFINGOSIN-1-PHOSPHATE AND USE THEREOF RELATED APPLICATIONS This application claims priority benefit under 35 U.S.C. 119 (e) of copending U.S. Provisional Application No. 60 / 784,549, filed on March 21, 2006, the total content of which is incorporated herein by reference.

FIELD OF THE INVENTION The present invention relates to compounds having activity as agents that modulate the S1P receptor and the use of such compounds to treat diseases associated with inappropriate activity of the S1P receptor.

BACKGROUND OF THE INVENTION Sphingosin-1-phosphate (S1P) has been shown to induce many cellular effects, including those that result in platelet aggregation, cell proliferation, cell morphology, invasion of tumor cells, chemotaxis of endothelial cells and angiogenesis of endothelial cells in vi tro. The S1P receptors are therefore good targets for therapeutic applications such as wound healing and inhibition of tumor growth. The S1P signals the cells in part, via a set of G protein-coupled receptors called S1P1, S1P2, S1P3, S1P4 and S1P5 (formerly called EDG-1, EDG-5, EDG-3, EDG-6 and EDG- 8, respectively). These receptors share 50-55% identity of amino acids and clusters with three other receptors (LPA1, LPA2 and LPA3 (formerly EDG-2, EDG-4 and EDG-7)), for structurally related lysophosphatidic acid (LPA). A conformational change is induced in the Protein G Coupled Receptor (GPCR) when the ligand binds to that receptor, causing the GDP to be replaced by GTP in the a subunit of the associated G proteins and the subsequent release of the G proteins. in the cytoplasm. The subunit a then dissociates from the β subunit, and each subunit can then be associated with the effector proteins, which activate the second messengers that lead to a cellular response. Finally, the GTP in the G proteins is hydrolyzed to GDP, and the subunits of the G proteins re-anneal with each other and then with the receptor. Amplification plays a major role in the overall GPCR trajectory. The binding of a ligand to a receptor leads to the activation of many G proteins, each capable of associating with many effector proteins, leading to an amplified cellular response.

SIP receptors are good targets for drugs, because individual receptors are both tissue-specific and responsive. The tissue specificity of SIP receptors is important, because the development of a selective agonist or antagonist for a receptor localizes the cellular response in the tissues that contain that receptor, limiting unwanted side effects. The specificity of the response of SIP receptors is also important because it allows the development of agonists or antagonists that initiate or suppress certain cellular responses without affecting other things. For example, the specificity of SIP receptor response would allow a SIP mimic to initiate platelet aggregation without affecting cell morphology. SIP is formed as a metabolite of sphingosine in its reaction with sphingosine kinase, and is abundantly stored in platelet aggregates, where there are high levels of sphingosine kinase and lack of sphingosine lyase. SIP is released during the aggregation of platelets, accumulates in the serum and is also found in the malignant ascitos. The biodegradation of SIP proceeds most likely via hydrolysis by ectophosphohydrolases, specifically the phosphohydrolases of sphingosine 1-phosphate.

SUMMARY OF THE INVENTION The present invention relates to the use of novel compositions including S1P modulators, eg, agonists, partial agonists, inverse agonists and antagonists, to treat, prevent or cure various conditions related to the S1P receptor. The invention features compounds that are modulators of the S1P receptor; in one embodiment, such compounds include those that have the formula and their pharmaceutically acceptable salts. In formula I, A may be an aryl heteroaryl group, optionally substituted with one, two or three substituents which may include halogen, hydroxyl, SR2, S (0) 2R2, S (0) 2NR2, NHS (0) 2R2, COR2 , C02R2, cyano, amino, alkylamino / arylamino / Ci-5 heteroarylamino / Ci-6 alkyl, Ci-5 alkylthio, Ci-5 alkoxy, Ci-6 alkyl substituted with halogen and Ci-5 alkoxy substituted with halogen. Optionally, two adjacent substituents of A can be taken with Z1 and the ring A to which they are attached, to form a fused ring which may optionally contain one or more heteroatoms. R2 can be independently selected from hydrogen, hydroxyl, amino, alkylamino / arylamino, Ci-6 alkyl, Ci-5 alkoxy, Ci-5 alkylthio, Ci-6 alkyl substituted with halogen and Ci-5 alkoxy substituted with halogen; or aryl / heteroaryl. A may, desirably, be a cyclic ring of Ci-6 (alicyclic or aromatic), optionally with one or more heteroatoms. B and C are at least partially a partially aromatic bicyclic ring system, for example, bicycloaryl, bicycloheteroaryl, aryl and dihydrobicyclic or tetrahydrobicyclic heteroaryl. The bicyclic ring system can be substituted with 1 to 5 substituents, for example, Ci-6 alkyl, Ci-5 alkylthio, Ci-5 alkoxy, halogen, hydroxyl, cyano, Ci-6 alkyl substituted with halogen and alkoxy of Ci-5 substituted with halogen. Z1 and Z2 can be selected independently from 0, NR3, S, S (0), S (0) 2, S (0) 2NR3, (CR4R5) n, C = 0, C = S, C = N-R3 or a direct link. R3 may be hydrogen, hydroxyl, Ci-6alkyl, Ci-5alkoxy, Ci-5alkylthio, Ci-6alkyl substituted with halogen and Ci-5alkoxy substituted with halogen; aryl or heteroaryl. R 4 and R 5 can independently be hydrogen, halogen, hydroxyl, cyano, C 1-6 alkyl, Ci-5 alkoxy, Ci-5 alkylthio, Ci-6 alkyl substituted with halogen and Ci-5 alkoxy substituted with halogen; aryl or heteroaryl or together form "C = 0"; n can be 0, 1, 2 or 3. In a mode wherein Z2 is a direct bond, R3 can be a C3-C6 ring optionally containing a heteroatom. R1 may be Ci-6 alkyl, C2-e alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, Ci-5 alkoxy, Ci-5 alkylamino, aryl or heteroaryl. R1 may be optionally substituted with, for example, hydroxyl, halogen, cyano, amino, alkylamino, arylamino, heteroarylamino groups, and the aryl and heteroaryl groups may be optionally substituted with 1-5 substituents, for example, hydroxyl, halogen, cyano, C1-S alkyl, Ci-5 alkylthio, Ci-5 alkoxy, C3-6 cycloalkyl. X can be C (0) OR6a, WP (0) R6bR6c, WS (0) 2OH, WCONHSO3H or lH-tetrazol-5-yl. W can be a direct bond, oxygen or Ci-4 alkyl with substituents independently selected from the group consisting of halogen, hydroxyl, cyano, amino, alkylamino, arylamino, heteroarylamino, Ci-4 alkoxy and; R6a may be hydrogen or C1-4alkyl; R6b and R6c may be hydrogen, hydroxyl, Ci-4 alkyl or C1-4 alkyl substituted with halogen. And it can be a remainder of formula (a), where the left and right asterisks indicate the point of union.- where Q can be a direct link, C = 0, C = S, S02, C = ONR or (CR ^ R11) ^ - m can be 0, 1, 2 or 3; R7 and R8 can independently be hydrogen, halogen, amino, Ci-5 alkylamino, hydroxy, cyano, Ci-6 alkyl, Ci-6 hydroxyalkyl (for example, hydroxy-terminated alkyl), Ci-5 alkylthio , Ci-5 alkoxy, Ci-6 alkyl substituted with halogen and Ci-5 alkoxy substituted with halogen; or R7 and R8 can be linked with the atoms to which they are attached to form a 4- to 7-membered ring, which optionally has a heteroatom. R9 can be hydrogen, halogen, hydroxyl, cyano, Ci-6 alkyl, Ci-5 alkylthio, Ci-5 alkoxy, Ci-6 alkyl substituted with halogen or Ci-5 alkoxy substituted with halogen; R10 and R11 can individually be hydrogen, halogen, hydroxyl, cyano, Ci-6 alkyl, Ci-5 alkoxy, Ci-5 alkylthio, Ci-6 alkyl substituted with halogen or Ci-5 alkoxy substituted with halogen In another embodiment, the invention includes compounds of formula (II): wherein A can be an aryl or heteroaryl group; X is -C (0) OR6a, wherein R6a is hydrogen or C1-4alkyl; And it's a residue of formula (a) where Q is (CR ^ R11) ,,,; m is 0, 1, 2, 3 or 4; R7 and R8 can independently be hydrogen, hydroxyl, lower alkyl; or R7 and R8, taken with the atoms to which they are attached, form a ring; R9 is selected from, for example, hydrogen, halogen, hydroxyl or cyano; and Z1 and Z2 are independently 0 or (CR4R5) n, wherein R4 and R5 are independently hydrogen, halogen, hydroxyl, cyano, Ci-6 alkyl, Ci-5 alkoxy; n is 0, 1, 2 or 3; and R1 is selected from, for example, Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl / C3-6 cycloalkyl, Ci-5 alkoxy, Ci-5f alkylamino aryl or heteroaryl; or their pharmaceutically acceptable salts. The aryl or heteroaryl group can be substituted with one, two or three substituents such as halogen, hydroxyl, S, S (0) 2R2, S (0) 2NR2, NHS (0) 2R2, COR2, C02R2, cyano, amino, alkylamino / arylamino / Ci-5 heteroarylamino, Ci-6 alkyl, Ci-5 alkylthio, Ci-5 alkoxy, Ci-6 alkyl substituted by halogen, or Ci-5 alkoxy substituted by halogen (wherein R2 is , for example, of hydrogen, hydroxyl, amino, alkylamino / arylamino, Ci-6 alkyl, Ci-5 alkoxy, Ci-5 alkylthio, Ci-6 alkyl substituted with halogen and Ci-5 alkoxy substituted with halogen or aryl / heteroaryl, or optionally, two adjacent substituents on A can, taken with Z 1 and the ring to which they are attached, form an alicyclic or heterocyclic ring R 2 can be selected from hydrogen, hydroxyl, amino, alkylamino / arylamino, Ci-6, Ci- 5 alkylthio alkoxy of Ci-5, Ci-6 alkyl substituted with halogen and Ci-5 alkoxy substituted with halogen, or aryl / heteroaryl. In the benzofuranyl ring it can be substituted with 1 to 5 substituents, for example, Ci-S alkyl, C 1-5 alkylthio, C 1-5 alkoxy, halogen, hydroxyl, cyano, Ci-6 alkyl substituted with halogen or C1-5 alkoxy substituted with halogen. R1 may be Ci-e alkyl, C2-6 alkenyl / C2-6 alkynyl, C3-6 cycloalkyl, Ci-5 alkoxy, Ci-5 alkylamino, aryl or heteroaryl; R1 may be optionally substituted with, for example, hydroxyl, halogen, cyano, amino, alkylamino, arylamino or heteroarylamino groups. (The aryl or heteroaryl groups may be substituted by one to five substituents such as hydroxyl, halogen, cyano, Ci-6 alkyl, Ci-5 alkylthio, Ci-5 alkoxy and C 3-6 cycloalkyl. relates in one embodiment to compounds according to Formula I. Preferably A is a substituted or unsubstituted aryl or heteroaryl group, which may be one illustrated below, wherein R12 is hydrogen or Ci-6 alkyl, and the left asterisks and right indicate the point of attachment in formula (I); R12 may be hydrogen, hydroxyl, amino, alkylamino or arylamino, Ci-6 alkyl, Ci-5 alkoxy, Ci-5 alkylthio, Ci-s alkyl substituted with halogen, and Ci-5 alkoxy substituted by halogen; aryl or heteroaryl; more preferably hydrogen. B and C are preferably substituted or unsubstituted aryl or heteroaryl, for example, In the groups shown in the two directly above tables, the asterisks indicate that the group can be attached to the molecule as shown, or "inverted". The groups immediately described in the foregoing of this text may desirably be present in the molecule in the orientation illustrated. wherein R is hydrogen or Ci-6 alkyl the left and right asterisks indicate the point of attachment in formula (I); W1 # W2, W3 or W4 can be C, N, C-OH, C-OR 13 or C-R 13, 13 is hydrogen or C 1-6 alkyl, Ci-5 alkylthio, C 1-5 alkoxy, halogen, hydroxyl, cyano, Ci-6 alkyl substituted with halogen and Ci-5 alkoxy substituted with halogen. Z1 and Z2 are preferably CH2, 0, S or a direct link. R3 is preferably methyl. R4 and R5 are preferably hydrogen or methyl. n is preferably 1 or 2. X may be combined with Y, for example, f O T OH \? OH 0 Optionally, two adjacent substituents on ring A with Z1 form a fused ring, which may contain one or more heteroatoms, and wherein X may be combined with Y, for example, In one aspect, the present invention provides methods for modulating the biological activity mediated by the S1P-1 receptor. The present invention also provides methods for using S1P-1 modulators (ie, agonists or antagonists) to treat or prevent diseases such as ovarian cancer, peritoneal cancer, endometrial cancer, cervical cancer, breast cancer, colorectal cancer, cancer uterine, stomach cancer, small bowel cancer, thyroid cancer, lung cancer, kidney cancer, pancreatic cancer and prostate cancer; acute lung diseases, respiratory distress syndrome in adults ("ARDS"), acute inflammatory exacerbation of chronic lung diseases, such as asthma, injury to superficial epithelial cells such as transcorneal freezing or skin burns, and cardiovascular diseases such as ischemia , in a subject in need of such treatment or prevention. In another aspect, the invention provides methods for using SlP-1 modulators to treat or prevent disorders such as, but not limited to, vasoconstriction in the cerebral arteries, autoimmune and immunity-related disorders, including systemic lupus erythematosus, inflammatory diseases of the bowel, such as Crohn's disease and ulcerative colitis, type I diabetes, uveitis, psoriasis, myasthenia gravis, rheumatoid arthritis, non-glomerular nephrosis, hepatitis, Behget's disease, glomerulonephritis, chronic thrombocytopenic purpura, hemolytic anemia, hepatitis and Wegner's granuloma . In still another aspect, the invention provides methods for using SlP-1 modulators to treat or prevent a disease or disorder in a subject, which comprises administering to a subject in need of such treatment or prevention, a therapeutically effective amount of a modulator of SlP-1, for example, an agonist, which stimulate the immune system. In certain modalities, the subject is afflicted by an infectious agent. In other modalities, the subject is immunocompromised.

In yet another aspect, the present invention provides a method for modulating a biological activity mediated by the SlP-1 receptor in a cell. A cell expressing the SlP-1 receptor is contacted with an amount of a SlP-1 receptor modulator sufficient to modulate the biological activity mediated by the SlP-1 receptor. In yet another aspect, the present invention provides a method for modulating a biological activity mediated by the SlP-1 receptor in a subject. In such a method, an amount of a SlP-1 receptor modulator effective to modulate a biological activity mediated by the SlP-1 receptor is administered to a subject. In still another aspect, the present invention provides a method for treating, preventing or alleviating a condition mediated by the SlP-1 receptor in a subject. In such a method, an amount of a SlP-1 receptor modulator effective to modulate a biological activity mediated by the SlP-1 receptor is administered to the subject. The condition mediated by the SlP-1 receptor can be, for example, transplant rejection (transplantation of solid organs and islet cells); transplant rejection (tissue); Cancer; autoimmune / inflammatory diseases; rheumatoid arthritis; lupus; insulin-dependent diabetes (Type I); diabetes not dependent on insulin (Type II); multiple sclerosis; psoriasis; Ulcerative colitis; inflammatory bowel disease; Crohn's disease; acute and chronic lymphocytic leukemias and lymphomas.

DETAILED DESCRIPTION OF THE INVENTION The features and other details of the invention will now be described more particularly. It will be understood that the particular embodiments described herein are shown by way of illustration and not as limitations of the invention. The main features of this invention can be employed in various embodiments without departing from the scope of the invention. All parts and percentages are by weight unless otherwise indicated.

Definitions For convenience, certain terms used in the specification and examples are collected here. "Treat", include any effect, for example, decrease, reduce, modulate or eliminate, which results in the improvement of the disease condition, disorder, etc. "Alkyl" includes saturated aliphatic groups, for example, straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl; branched chain alkyl groups (e.g., isopropyl, tert-butyl and isobutyl); cycloalkyl (alicyclic) groups such as cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl); alkyl-substituted cycloalkyl groups; and alkyl groups substituted with cycloalkyl. The "alkyl" groups may also optionally include heteroatoms, ie, wherein the oxygen, nitrogen, sulfur or phosphorus atoms replace one or more carbon atoms of the hydrocarbon backbone, particularly where the substitution does not adversely impact the effectiveness of the resulting compound. Linear or branched alkyl groups may have six or fewer carbon atoms in their main chain (eg, Ci-C6 for a straight chain, C3-C6 for a branched chain), and most preferably four or less. Preferred cycloalkyl groups have from three to eight carbon atoms in their ring structure, and most preferably five or six carbons in the ring structure. "Ci-C6" includes alkyl groups containing one to six carbon atoms. "Substituted alkyls" refer to alkyl portions having substituents that replace a hydrogen at one or more carbons of the hydrocarbon backbone. Such substituents may include alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alquilarainocarbonilo, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, cyano, amino, acylamino, amidino, imino, sulfhydryl, alkylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido or heterocyclyl. "Aryl" includes groups with aromaticity, including 5 and 6 membered non-conjugated aromatic groups,. { that is, a single ring), which may include from zero to four heteroatoms, as well as conjugated (ie, multicyclic) systems having at least one ring that is aromatic. Examples of aryl groups include benzene, phenyl, tolyl and the like. Multicyclic aryl groups include tricyclic and bicyclic systems, for example, naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, naphthridine, indole, benzofuran, purine, benzofuran, desazapurine, indolizine, tetralin and methylenedioxyphenyl. Aryl groups having heteroatoms in the ring structure are also referred to as "aryl heterocycles", "heterocycles," "heteroaryls" or "heteroaromatics"; for example, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isooxazole ,. pyridine, pyrazine, pyridazine and pyrimidine. The aromatic ring can be substituted at one or more ring positions with, for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonate, phosphinate, cyano, amino, acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic portion. An "alkylaryl" or an "aralkyl" moiety is an alkyl substituted with an aryl group (e.g., phenylmethyl (benzyl)). "Alkenyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but containing at least one double bond. For example, the term "alkenyl" includes straight chain alkenyl groups (eg, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl and decenyl), branched chain alkenyl groups, cycloalkenyl groups such as cyclopropenyl, cyclopentenyl , cyclohexenyl, cycloheptenyl and cyclooctenyl; alkyl- or alkenyl-substituted cycloalkenyl groups, and alkenyl groups substituted with cycloalkyl or cycloalkenyl. The "alkenyl" groups may also optionally include heteroatoms, ie, wherein the oxygen, nitrogen, sulfur or phosphorus atoms replace one or more carbon atoms of the hydrocarbon backbone, particularly where the substitution does not adversely impact the effectiveness of the resulting compound. Linear or branched alkenyl groups may have six or fewer carbon atoms in their main chain (eg, C2-C6 for a straight chain, C3-C6 for a branched chain). Preferred cycloalkenyl groups have from three to eight carbon atoms in their ring structure, and most preferably have five or six carbons in the ring structure. The term "C2-C6" includes alkenyl groups containing from two to six carbon atoms. "Substituted alkenyls" refers to alkenyl portions having substituents that replace a hydrogen on one or more carbon atoms of the hydrocarbon backbone. Such substituents may include alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, cyano, amino, acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido or heterocyclyl. "Alkynyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but containing at least one triple bond. For example, "alkynyl" includes alkynyl groups straight chain (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), alkynyl branched chain groups, and alkynyl groups substituted with cycloalkyl or cycloalkenyl. The "alkynyl" groups may also optionally include heteroatoms, ie, wherein the oxygen, nitrogen, sulfur or phosphorus atoms replace one or more carbon atoms of the hydrocarbon backbone, particularly where the substitution does not adversely impact the effectiveness of the resulting compound. The straight or branched chain alkynyl groups may have six or fewer carbon atoms in their main chain (eg, C2-C6 for a straight chain, C3-C6 for a branched chain). The term "C2-C6" includes alkynyl groups containing from two to six carbon atoms. "Substituted alkynyls" refers to alkynyl portions having substituents that replace a hydrogen on one or more carbon atoms of the hydrocarbon backbone. Such substituents can include alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, cyano, amino ( including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido or heterocyclyl. Unless the carbon number is otherwise specified, "lower alkyl" includes an alkyl group as defined above, but having from one to ten, more preferably from one to six carbon atoms in its structure of the main chain. "Lower alkenyl" and "lower alkynyl" have chain lengths of, for example, 2-5 carbon atoms. "Acyl" includes compounds and portions that contain the acyl radical (CH3CO-) or a carbonyl group. "Substituted acyl" includes acyl groups, wherein one or more of the hydrogen atoms are replaced by, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl , aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl , alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl or an aromatic or heteroaromatic portion. "Acylamino" includes portions wherein an acyl portion is attached to an amino group. For example, the term includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups. "Alkylamino" includes portions wherein an alkyl portion is attached to an amino group; "dialkylamino", "arylamino", "diarylamino" and "alquilamino" are named analogously. In some embodiments, "amino" may include acylamino and / or alkylamino groups. "Alkoxyalkyl", "alkylaminoalkyl" and "thioalkoxyalkyl" include alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms that replace one or more carbon atoms of the hydrocarbon backbone, for example, oxygen, nitrogen or sulfur atoms. "Alkoxy" includes alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. Examples of "substituted alkoxy" groups include halogenated alkoxy groups. Alkoxy substituted groups may include alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, cyano, amino substituents. , acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido or heterocyclyl. Examples of halogen-substituted alkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and trichlororaethoxy. The terms "heterocyclyl" or "heterocyclic group" include closed ring structures, for example, rings of 3 to 10, or 4 to 7 members that include one or more heteroatoms. Heterocyclyl groups can be saturated or unsaturated and include pyrrolidine, oxolane, thiolane, piperidine, piperizine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultans, sultones and the like. The heterocyclic rings may be substituted at one or more positions with such substituents as described above, such as, for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate , phosphinate, cyano, amino, acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, or an aromatic or heteroaromatic moiety. The term "thiocarbonyl" or "thiocarboxy" includes compounds and portions containing a carbon connected with a double bond to a sulfur atom. The term "ether" includes compounds or portions containing an oxygen attached to two different carbon atoms or heteroatoms. For example, the term includes "alkoxyalkyl" which refers to an alkyl, alkenyl or alkynyl group covalently linked to an oxygen atom that is covalently bound to another alkyl group. The term "ester" includes compounds and portions that contain a carbon or a heteroatom attached to an oxygen atom that is attached to a carbon of a carbonyl group. The term "ester" includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc. The alkyl, alkenyl or alkynyl groups are as defined above. The term "thioether" includes compounds and portions that contain a sulfur atom attached to two different carbons or heteroatoms. Examples of thioethers include, but are not limited to, alkaryl alkyls, alkylalkynyls, and alkyoalkynyls. The term "Alktoalkyls" includes compounds with an alkyl, alkenyl or alkynyl group attached to a sulfur atom that is attached to an alkyl group. Similarly, the term "alkaryl alkyls" and "alkaryalkynyls" refers to compounds or moieties wherein an alkyl, alkenyl or alkynyl group is attached to a sulfur atom that is covalently attached to an alkynyl group. The term "hydroxy" or "hydroxyl" includes groups with -OH or -O-. The term "halogen" includes fluorine, bromine, chlorine, iodine, etc. The term "perhalogenated" generally refers to a portion where all hydrogens are replaced by halogen atoms. "Heteroatom" includes atoms of any element other than carbon or hydrogen. Examples of heteroatoms include nitrogen, oxygen, sulfur and phosphorus. "Bicyclic ring system at least partially aromatic", means a bicyclic ring system in which either or both of the rings that form the bicycles are aromatic. It will be noted that the structure of some of the compounds of the invention includes asymmetric carbon atoms. It will be understood accordingly that isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of the invention, unless otherwise indicated. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. In addition, the structures and other compounds and portions discussed in this application also include all tautomers thereof. Alkenes can include either the E or Z geometry, where appropriate. "Combination therapy" (or "therapy"), includes the administration of a SIP receptor modulator of the invention and at least one second agent as part of a specific treatment regimen intended to provide the beneficial effect of the coercion of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, the pharmacokinetic or pharmacodynamic coercion resulting from the combination of therapeutic agents. The administration of these therapeutic agents in combination is typically carried out for a defined period of time (usually, minutes, hours, days or weeks depending on the combination seed). The "combination therapy" may, but is not generally intended to encompass the administration of two or more of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present invention. The "combination therapy" is intended to encompass the administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as the administration of these therapeutic agents, or at least two of the agents therapeutic, in a substantially simultaneous manner. Substantially simultaneous administration can be achieved, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple capsules alone for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route, including, but not limited to, oral routes, intravenous routes, intramuscular routes and direct absorption through the tissues of the mucous membrane. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the seed combination can be administered by intravenous injection, while the other therapeutic agents of the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally or all therapeutic agents can be administered by intravenous injection. The sequence in which the therapeutic agents are administered is not critical. The "combination therapy" may also encompass the administration of the therapeutic agents as described above, in a further combination with other biologically active ingredients and non-drug therapies (e.g., surgery or radiation treatment). Where the combination therapy also comprises a treatment that is not with drugs, said treatment can be carried out at any suitable time provided that the beneficial effect of the coercion of the combination of the therapeutic agents and the treatment that is not with drugs is achieved. For example, in appropriate cases, the beneficial effect is achieved even when non-drug treatment is temporarily withdrawn from the administration of the therapeutic agents, perhaps for days or even weeks. An "anionic group," as used herein, refers to a group that is negatively charged at a physiological pH. Preferred anionic groups include carboxylate, sulfate, sulfonate, sulfinate, sulphamate, tetrazolyl, phosphate, phosphonate, phosphinate or phosphorothioate or functional equivalents thereof. The "functional equivalents" of the anionic groups are intended to include bioisosteres, for example, bioisosteres of a carboxylate group. Bioisosteres encompass both classical bioisostic equivalents and non-classical bioisostic equivalents. Classic and non-classical bioisosteres are known in the art (see, for example, Silverman, RB The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc .: San Diego, Calif., 1992, pp. 19-23) . A particularly preferred anionic group is a carboxylate. The term "heterocyclic group" is intended to include closed ring structures in which one or more of the atoms in the ring is a different element of carbon, for example, nitrogen or oxygen or sulfur. Heterocyclic groups can be saturated or unsaturated, and heterocyclic groups such as pyrrole and fonuran can have an aromatic character. They include fused ring structures such as quinoline and isoquinoline. Other examples of heterocyclic groups include pyridine and purine. The heterocyclic groups can also be substituted on one or more constituent atoms with, for example, a halogen, a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkylthio, a lower alkylamino, a lower alkylcarboxyl, a nitro, a hydroxyl , -CF3, -CN, or similar. An "agent that modulates S1P" includes a compound or compositions capable of inducing a detectable change in the S1P receptor in vivo or in vitro, for example, at least 10% increase or decrease in S1P activity as measured by a given test, such as the test described hereinafter. "EC50 of an agent" includes that concentration of an agent to which a given activity, including the binding of the sphingosine or other ligand of a S1P receptor and / or a functional activity of a S1P receptor (eg, an activity of signaling), is 50% maximum for that S1P receiver. In other words, the EC50 is the concentration of the agent that provides 50% activation, when the 100% activation is adjusted to the amount of S1P receptor activity that does not increase with the addition of more ligand / agonist and % activation is adjusted as the amount of activity in the assay in the absence of the added ligand / agonist. "Purified" and similar terms relate to the isolation of a molecule or compound in a form that is substantially free of contaminants normally associated with the molecule or compound in a native or natural environment. An "effective amount" includes an amount sufficient to produce a selected effect. For example, an effective amount of an S1P receptor antagonist is an amount that decreases the activity of cellular signaling of the S1P receptor. "Immunomodulation" includes the effects on the functioning of the immune system, and includes both the improvement of an immune response and the suppression thereof. The compounds of the invention and the other pharmacologically active agent can be administered to a patient simultaneously, sequentially or in combination. It will be appreciated that when a combination of the invention is used, the compound of the invention and the other pharmacologically active agent can be in the same pharmaceutically acceptable carrier and therefore, be administered simultaneously. They can be in separate pharmaceutical carriers such as in conventional oral dosage forms that are taken simultaneously. The term "combination" also refers to the case where the compounds are provided in separate dosage forms and are administered sequentially. The compounds of the invention can be administered to patients (animals and humans) in need of such treatment, in dosages that will provide optimum pharmaceutical efficacy. It will be appreciated that the dose required to be used in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient. , the concurrent medication or special diets that are being followed by the patient, and other factors that those with experience in the technique will recognize, with the appropriate dosage being finally at the discretion of the attending physician. An appropriate dosage level will generally be from about 0.001 to 50 mg per kg of body weight of the patient per day, which can be administered in single or multiple doses. Preferably, the dosage level will be from about 0.01 to about 25 mg / kg per day; more preferably from about 0.05 to about 10 mg / kg per day. For example, in the treatment or prevention of a central nervous system disorder, a suitable dosage level is from about 0.001 to 10 mg / kg per day, preferably from about 0.005 to 5 mg / kg per day, and especially from approximately 0.01 to 1 mg / kg per day.

The compounds can be administered in a regimen of 1 to 4 times per day, preferably once or twice per day. It will be appreciated that the amount of the compound of the invention required to be used in any treatment will vary not only with the particular compounds or compositions selected, but also with the route of administration, the nature of the condition being treated and the age and condition of the patient. , and finally it will be at the discretion of the attending physician. The compositions and combination therapies of the invention may be administered in combination with a variety of pharmaceutical excipients, including stabilizing agents, carriers and / or encapsulation formulations as described herein. The aqueous compositions of the present invention comprise an effective amount of the compounds of the invention, dissolved or dispersed in a pharmaceutically acceptable carrier or aqueous medium. "Pharmaceutically or pharmacologically acceptable" includes molecular entities and compositions that do not produce an adverse, allergic or other harmful reaction when administered to an animal, or a human, as appropriate. "Pharmaceutically acceptable carrier" includes any and all of solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and delaying absorption and the like. The use of such media and agents for active pharmaceutical substances is well known in the art. Except insofar as any conventional medium or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. For human administration, preparations must meet the standards of sterility, pyrogenicity, general safety and purity that are required by the standards of the FDA Biological Office. The compositions and combination therapies of the invention will generally be formulated for parenteral administration, for example, formulated for injection via the intravenous, intramuscular, subcutaneous, intralesional, or even intraperitoneal routes. The preparation of an aqueous composition containing a composition of the invention or an active ingredient or component will be known to those skilled in the art in light of the present disclosure. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions; Suitable solid forms to be used to prepare solutions or suspensions after the addition of a liquid before the injection can also be prepared; and the preparations can also be emulsified.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations that include sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that there is a facility to place it with a syringe. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. Solutions of the active compounds as free bases or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. The dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The therapeutic or pharmacological compositions of the present invention will generally comprise an effective amount of the components of the combination therapy., dissolved or dispersed in a pharmaceutically acceptable medium. The pharmaceutically acceptable medium or carriers include any and all of solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and delaying absorption and the like. The use of such media and agents for active pharmaceutical substances is well known in the art. Supplementary active ingredients may also be incorporated into the therapeutic compositions of the present invention. The preparation of the pharmaceutical or pharmacological compositions will be known to those skilled in the art in light of the present disclosure. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in a liquid before injection; as tablets or other solids for oral administration; as temporary release capsules; or in any other form currently used, including creams, lotions, mouthwashes, inhalants and the like. Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with several of the other ingredients listed above, as required, followed by sterilization by filtration. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle containing the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze drying techniques which provide a powder of the active ingredient plus any additional desired ingredient of a solution thereof sterilized by prefiltration. . The preparation of more concentrated solutions for intramuscular injection is also contemplated. In this regard, the use of DMSO as a solvent is preferred, since it will result in extremely rapid penetration, delivering high concentrations of the active compounds or agents to a small area. The use of sterile formulations, such as washes based on physiological saline by surgeons, doctors or health care workers to clean a particular area in the field of operation, can also be particularly useful. Therapeutic formulations according to the present invention can also be reconstituted in the form of buccal washes, or in conjunction with antifungal reagents. Inhalable forms are also considered. The therapeutic formulations of the invention may also be prepared in forms suitable for topical administration, such as creams and lotions. Suitable preservatives for use in such a solution include benzalkonium chloride, benzethonium chloride, chlorobutanol, thimerosal and the like. Suitable buffers include boric acid, sodium and potassium bicarbonate, sodium and potassium borates, sodium and potassium carbonate, sodium acetate, sodium biphosphate and the like, in sufficient quantities to maintain the pH between about pH 6 and pH 8 , and preferably, between approximately pH 7 and pH 7.5. Suitable agents for tonicity are dextran 40, dextran 70, dextrose, glycerin, potassium chloride, propylene glycol, sodium chloride and the like, so that the sodium chloride equivalent of the ophthalmic solution is in the range of 0.9 plus or minus 0.2%. Suitable antioxidants and stabilizers include sodium bisulfite, sodium metabisulfite, sodium thiosulfite, thiourea and the like. Suitable wetting and clarifying agents include polysorbate 80, polysorbate 20, poloxamer 282 and tyloxapol. Suitable viscosity-increasing agents include dextran 40, dextran 70, gelatin, glycerin, hydroxyethylcellulose, hydroxymethylpropylcellulose, lanolin, methylcellulose, petrolatum, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose and the like. After the formulation, the therapeutic agents will be administered in a manner compatible with the dosage formulation, and in such amount as to be pharmacologically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like may also be employed. In this context, the amount of the active ingredient and the volume of the composition to be administered, depends on the host animal to be treated. The precise amounts of active compound required for administration, they depend on the judgment of the practitioner, and are peculiar to each individual. A minimum volume of a composition required to disperse the active compounds is typically used. Suitable regimens for administration are also variable, but would be typified by initially administering the compound and verifying the results and then providing additional controlled doses at additional intervals. For example, for parenteral administration, an aqueous solution suitably buffered, and if necessary isotonic, would be prepared and used for intravenous, intramuscular, subcutaneous or even intraperitoneal administration. A dosage could be dissolved in 1 ml of an isotonic NaCl solution and added to 1000 ml of hypodermolysis fluid or injected at the proposed infusion site (see, for example, Remington's Pharmaceutical Sciences 15th Edition, pages 1035-1038 and 1570 -1580). In certain embodiments, the active compounds can be administered orally. This is contemplated for agents that are generally resistant, or that have become resistant to proteolysis by digestive enzymes. Such compounds are contemplated to include agents designed or chemically modified; Dextrogiratory peptides; and peptide and liposomal formulations in time-release capsules to prevent degradation by peptidase and lipase. The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol and the like), suitable mixtures thereof and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of a dispersion and by the use of surfactants. The preservation of the action of microorganisms can be caused by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with several of the other ingredients listed above, as required, followed by sterilization by filtration. Generally, dispersions are prepared by incorporating the sterilized active ingredients into a sterile vehicle containing the basic dispersion medium and the required other ingredients from those enumerated above. In case of sterile powders for the preparation of sterile injectable solutions, the preferred preparation methods are vacuum drying and freeze drying techniques which provide a powder of the active ingredient plus any additional desired ingredients of a solution thereof sterilized by prefiltration. The preparation of more concentrated solutions for direct injection is also contemplated, where the use of D SO as a solvent is considered to result in an extremely rapid penetration, delivering high concentrations of the active agents to a small area. After formulation, the solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but capsules that release the drug and the like may also be employed. For parenteral administration in an aqueous solution, for example, the solution must be suitably buffered if necessary, and the liquid diluent first becomes isotonic with sufficient physiological saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this regard, the sterile aqueous medium that can be employed will be known to those skilled in the art in the light of the present disclosure. In addition to compounds formulated for parenteral administration, such as intravenous or intramuscular injection, other pharmaceutically acceptable forms include, for example, tablets or other solids for oral administration; liposomal formulations; Temporary release capsules; and any other currently used form, including creams. Additional formulations suitable for other modes of administration include suppositories. For suppositories, traditional binders and carriers may include, for example, polyalkylene glycols or triglycerides; such suppositories can be formed from mixtures containing the active ingredient in the range of 0.5% to 10%, preferably 1% -2%. Oral formulations include such excipients normally employed, as for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate and the like. These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders. In certain defined embodiments, the oral pharmaceutical compositions will comprise an inert diluent or an edible assimilable carrier, or they may be enclosed in a hard or soft shell gelatin capsule, or they may be compressed into tablets, or they may be incorporated directly with the diet food. For oral therapeutic administration, the active compounds can be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like. Such compositions and preparations should contain at least 0.1% of the active compound. The percentage of the compositions and preparations may vary, of course, and may conveniently be between about 2 to about 75% of the unit weight, or preferably between 25-60%. The amount of the active compounds in such therapeutically useful compositions is such that an adequate dosage will be obtained. Tablets, troches, pills, capsules and the like may also contain the following: a binder, such as gum tragacanth, acacia, corn starch or gelatin; excipients, such as dicalcium phosphate; a disintegrating agent, such as corn starch, potato starch, alginic acid and the like; a lubricant, such as magnesium stearate; and a sweetening agent, such as sucrose, lactose or saccharin may be added or a flavoring agent, such as peppermint, oil of wintergreen or cherry flavoring. When the shape of the dosage unit is a capsule, they may contain, in addition to the materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For example, tablets, pills or capsules may be coated with a lacquer, sugar or both. An elixir syrup may contain the active compounds, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring, such as cherry or orange flavor. The pharmaceutical compositions of this invention can be used in the form of a pharmaceutical preparation, for example, in solid, semi-solid or liquid form, containing one or more of the compounds of the invention, as an active ingredient, in admixture with an organic carrier. or inorganic or a suitable excipient for external, inert or parenteral applications. The active ingredient can be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, granules, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The carriers that may be used are water, glucose, lactose, acacia gum, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other suitable carriers to be used. in the manufacture of the preparations, in solid, semi-solid, or liquid form, and in addition, auxiliary agents, stabilizers, thickeners and colorants and perfumes can be used. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect after the disease process or condition. To prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical carrier, for example, conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the invention, or a pharmaceutically acceptable non-toxic salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition, so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above, containing from 0.1 to about 500 mg of the active ingredient of the invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form that provides the advantage of a prolonged action. For example, the tablet or pill may comprise an internal dosage component and an external dosage component, the latter being in the form of a wrapper over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach, and allows the internal component to pass intact to the duodenum or be delayed in the release. A variety of materials can be used for such enteric coatings or coatings, such materials include various polymeric acids and mixtures of polymeric acids with such materials as lacquer, cetyl alcohol and cellulose acetate.

Liquid forms in which the compositions of the invention may be incorporated for oral administration or by injection, include aqueous solution, suitably flavored syrups, aqueous or oily suspensions and emulsions with acceptable oils such as cottonseed oil, oil sesame, coconut oil or peanut oil, or with a solubilizing agent or emulsifier suitable for intravenous use, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin. Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable solvents, aqueous or organic, or mixtures thereof and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients such as discussed above. Preferably, the compositions are administered by the oral or nasal respiratory route for a local or systemic effect. The compositions in pharmaceutically acceptable solvents, preferably sterile, can be nebulized by the use of inert gases. The nebulized solutions can be breathed directly from the nebulizing device or the nebulizing device can be attached to a face mask, tent or intermittent positive pressure breathing machine. The compositions in solution, suspension or powder can be administered, preferably orally or nasally, of devices that deliver the formulation in an appropriate manner. To treat the clinical conditions and diseases indicated above, the compound of this invention can be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional, non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term "parenteral" as used herein, includes subcutaneous injections, injection techniques or intravenous, intramuscular, intrasternal infusion. The compounds of the present invention are high affinity agonists (or antagonists) of several S1P receptors. It is also expected that the compounds of the invention cause lymphopenia when introduced into rodents, non-human primates or humans. Thus, the compounds of the invention can be used as immune modulators, and are useful for treating or preventing pathologies mediated by the actions of lymphocytes, including acute or chronic rejection of tissue grafts such as organ transplants and autoimmune diseases. Autoimmune diseases that can be treated with the compounds of the invention include: systemic lupus erythematosus, multiple sclerosis, Beh? Et's disease, glomerulonephritis, rheumatoid arthritis, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, type I diabetes, uveitis, psoriasis, myasthenia gravis, Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, hepatitis and Wegner's granuloma. The compounds of the invention are also useful for treating inflammatory disorders, including atopic asthma, inflammatory glomerular injury and ischemia-reperfusion injury. The lysophosphidids, S1P and lysophosphatidic acid (LPA), stimulate cell proliferation and affect numerous cellular functions by signaling through the receptors encoded by the gene (S1P) of endothelial differentiation coupled to the G protein. anticipates that the S1P receptor modulators of the invention have utility in immunomodulation, for example, in antiangiogenesis therapy, such as the treatment of neoplastic disease. In an embodiment of the invention, a pharmaceutical composition comprising one or more of the S1P receptor agonists of the present invention are administered to a mammalian species, including humans, to improve wound repair, improve neuronal function or improve an immune response of that species . It has also been reported that SIP inhibits fibrosis in various organs. Accordingly, the SIP receptor agonists of the invention can be used to prevent / treat diseases associated with organ fibrosis, such as pulmonary fibrosis, interstitial pneumonia, chronic hepatitis, liver cirrhosis, chronic renal failure or glomerular sclerosis of the kidney. In one embodiment, a composition comprising a SIP receptor agonist of the present invention is used to treat wounds, including burns, cuts, lacerations, surgical incisions, yagas caused by the bed and ulcers that heal slowly, such as those observed in the diabetics. In addition, it is believed that compounds of the invention that modulate SIP mobilize lymphocytes and increase their return to secondary lymphoid tissues. Thus, the present compounds can be used to direct lymphocytes away from transplanted organs, for example, allografts or healthy cells, for example, pancreatic islets as in type I diabetes, myelin sheaths (multiple sclerosis), or other tissues that they can undergo an undesirable immune response, and thus decrease the damage to such tissues of the immune system.

In another embodiment, the compounds that modulate the SIP receptor of the invention are administered to a subject to treat or prevent an abnormal cell growth and differentiation disorder. These disorders include Alzheimer's disease, aberrant corpus luteum formation, osteoporosis, anovulation, Parkinson's disease and cancer. In one embodiment, a SIP antagonist is administered to a patient to treat a disease associated with abnormal growth. In one embodiment, the compounds of the invention are used as immunomodulators to alter the activities of the immune system and prevent damage to healthy tissue that would otherwise occur in autoimmune diseases and in organ transplantation. In particular, the compounds can be administered to patients as part of the treatment associated with organ transplantation, including transplantation of pancreas, pancreatic islets, kidney, heart and lung. SIP modulators can be administered alone or in combination with known immunosuppressants such as cyclosporin, tacrolimus, rapamycin, azathioprine, cyclophosphamide, methotrexate and corticosteroids such as cortisone, deoxymethasone, betamethasone, desametasone, flunisolide, prednisolone, prednisone, amcinomide, desonide, methylprednisolone, triamcinolone and alclometasone. SIP also acts as a survival factor in many cell types. In particular, it is anticipated that the compounds of the invention having S1P antagonist activity are useful to protect cells and tissues from hypoxic conditions. According to one embodiment, the compounds of the invention are administered to a patient judged to need or actually need treatment, to treat cells and tissues exposed to hypoxic conditions, including sustained injury as a result of ischemia. According to one embodiment, the compounds of the invention which show S1P receptor antagonist activity can be used to treat reperfusion type injury by ischemia. Interference with the supply of oxygenated blood to tissues is defined as ischemia. The effects of ischemia are known to be progressive, so that over time, cellular vitality continues to deteriorate and tissues become necrotic. The total persistent ischemia, with a limited oxygen perfusion of the tissues, results in cell death and finally in the necrosis induced by coagulation despite reperfusion with arterial blood. The evidence indicates that a significant proportion of the injury associated with ischemia is a consequence of the events associated with reperfusion of ischemic tissues, hence the term reperfusion injury. Pharmaceutical compositions comprising the compounds of the invention can be administered to an individual in need by various routes, including topical, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, inter, topical , sublingual or rectal. The oral route is typically employed for most conditions that require the compounds of the invention. Preference is given to intravenous injection or infusion for acute treatments. For maintenance regimens, the oral or parenteral route is preferred, for example, intramuscular or subcutaneous. According to one embodiment, a composition comprising a compound of the invention and albumin is provided, for example, a compound of the present invention, a pharmaceutically acceptable carrier and 0.1-1.0% albumin. Albumin functions as a buffer and improves the solubility of the compounds. The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. According to a modality, a kit is provided to treat a patient in need of immunomodulation, including instructions for using the equipment. In this embodiment, the kit comprises one or more of the S1P modulators of the invention, and may also include one or more known immunosuppressants. These pharmaceutical products can be packaged in a variety of containers, for example, vials, tubes, plates with microtiter wells, bottles and the like. Other reagents can be included in separate containers and provided with the equipment; for example, positive control samples, negative control samples, buffers, cell culture media, etc. Preferably, the equipment will also include instructions for use. The activity of the compounds of the invention can be determined using an assay to detect the activity of the SIP receptor (such as the [? -35 S] GTP binding assay), and test the activity in the presence of SIP and the compound test. More particularly, in the method described by Traynor et al., 1995, Mol. Pharmacol. 47: 848-854, incorporated herein by reference, the coupling of the G protein to the membranes can be assessed by measuring the binding of labeled GTP. For example, samples comprising membranes isolated from cells expressing a SIP polypeptide can be incubated in a buffer that promotes binding of the polypeptide to the ligand (ie, SIP), in the presence of radiolabeled GTP and unlabeled GDP (e.g. , in 20 mM HEPES, pH 7.4, 100 mM NaCl, and 10 mM MgCl2, 80 pM 35S-GTPyS and 3 μM GDP), with and without a candidate modulator. The test mixture is incubated for a suitable period of time to allow receptor binding and activation (eg, 60 minutes at 30 ° C), after which unbound labeled GTP is removed (eg, by filtering on GF / B filters). The bound labeled GTP can be measured by liquid scintillation counting. A decrease of 10% or more in the binding of the labeled GTP, is measured by scintillation counting in a sample containing a candidate modulator, relative to a sample without the modulator, indicates that the candidate modulator is an inhibitor of the activity of the SIP receiver. A similar GTP binding assay can be performed without the presence of the ligand (SIP) to identify agents that act as agonists. In this case, the binding of GTP stimulated by the ligand is used as a standard. An agent is considered an agonist if it induces at least 50% of the level of GTP induced by SIP when the agent is present at 10 and less, and preferably will induce a level that is the same as, or higher than, that induced. for the ligand. The activity of GTPase can be measured by incubating cell membrane extracts containing a SIP receptor with y32P-GTP. The active GTPase will release the label as an inorganic phosphate, which can be detected by separating the free inorganic phosphate in a 5% suspension of activated carbon in 20 mM H3P04, followed by scintillation counting. The controls would include assays using membrane extracts isolated from cells that do not express an S1P receptor (eg, mock transfected cells), in order to exclude possible non-specific effects of the candidate modulator. In order to test the effect of a candidate modulator on GTPase activity regulated by S1P, samples of the cell membrane were incubated with the ligand (S1P), with and without the modulator, and a GTPase assay can be performed as described above. A change (increase or decrease) of 10% or more in the level of GTP binding or GTPase activity relative to the samples without the modulator is indicative of modulation of S1P by a candidate modulator. The identified S1P receptor agonists and antagonists can be used to treat a variety of human diseases and disorders, including, but not limited to, the treatment of infections such as bacterial, mycotic, protozoal and viral infections, particularly infections caused by HIV. -1 or HIV-2; pain; cancers; diabetes, obesity; anorexy; bulimia; asthma; Parkinson's disease; acute heart failure; hypotension; hypertension; urinary retention; osteoporosis; pectoral angina; myocardial infarction; apoplexy; ulcers; asthma; allergy; benign prostatic hypertrophy; migraine; threw up; psychotic and neurological disorders, including anxiety, schizophrenia, manic depression, depression, delirium, dementia and severe mental retardation. Pain is a complex subjective sensation that reflects a damage to the real or potential tissue and the affective response to it. Acute pain is a physiological signal that indicates a potential or real injury. Chronic pain can be somatogenetic (organic) or psychogenic. Chronic pain is often accompanied or followed by vegetative signs, which often result in depression. The somatogenetic pain may be of nociceptive, inflammatory or neuropathic origin. Nociceptive pain is judged to be consistent with the ongoing activation of nerve fibers sensitive to somatic or visceral pain. Neuropathic pain results from dysfunction in the nervous system; it is believed to be sustained by aberrant somatosensory processes in the peripheral nervous system, the CNS, or both. Chronic pain results in an individual suffering and economic social costs of a tremendous extent. The existing pharmacological therapies for pain are largely unsatisfactory both in terms of efficacy and safety. In one embodiment, the S1P modulators of the present invention are used as immunomodulators to suppress the immune system and prevent damage to healthy tissue, which would otherwise occur in autoimmune diseases and in organ transplantation. The compounds can be administered to patients as part of the treatment associated with organ transplantation, including transplantation of pancreas, pancreatic islets, kidney, heart and lung. The S1P modulators can be administered alone or in combination with known immunosuppressants such as cyclosporin, tacrolimus, azathioprine, deoxymethasone, cyclophosphamide, cortisone, betamethasone, FK 506 (an immunosuppressant of mycotic macrolide), desametasone, flunisolide, prednisolone, prednisone, amcinomide, desonide, methylprednisolone, triamcinolone, alclomethasone and methotrexate. The dosage to be used is, of course, dependent on the specific disorder to be treated, as well as on the additional factors, including age, weight, general health, severity of symptoms, frequency of treatment and if there are additional pharmaceutical products. that accompany the treatment. The dosages are generally administered several times per day, and preferably one to three times per day. The amounts of the individual active compounds are easily determined by routine procedures known to those of ordinary skill in the art. S1P also acts as a survival factor in many cell types. It is anticipated that modulators of the S1P receptor have activity to protect cells and tissues from hypoxic conditions. According to one embodiment, the compounds of the invention are administered to treat cells and tissues exposed to hypoxic conditions, including sustained injury as a result of ischemia. According to one embodiment, SIP modulators that have antagonist activity can be used to treat reperfusion type injury by ischemia. Interference with the supply of oxygenated blood to tissues is defined as ischemia. The effects of ischemia are known to be progressive, so that over time the cellular vitality continues to deteriorate, and the tissues become necrotic. Total persistent ischemia, with limited oxygen perfusion of tissues, results in cell death and finally in coagulation-induced necrosis despite reperfusion with arterial blood. The compounds of the invention and the other pharmacologically active agent can be administered to a patient simultaneously, sequentially or in combination. It will be appreciated that when a combination of the invention is used, the compound of the invention and the other pharmacologically active agent can be in the same pharmaceutically acceptable carrier and therefore, be administered simultaneously. They can be in separate pharmaceutical carriers such as in conventional oral dosage forms that are taken simultaneously. The term "combination" also refers to the case where the compounds are provided in separate dosage forms and are administered sequentially. The compounds of the invention can be administered to patients (animals and humans) in need of such treatment, in dosages that will provide optimum pharmaceutical efficacy. It will be appreciated that the dose required to be used in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration., the nature of the condition being treated, the age and condition of the patient, the concurrent medication or special diets being followed by the patient, and other factors that those skilled in the art will recognize, with the appropriate dosage being finally at discretion of the doctor who attends. An appropriate dosage level will generally be from about 0.001 to 50 mg per kg of body weight of the patient per day, which can be administered in single or multiple doses. Preferably, the dosage level will be from about 0.01 to about 25 mg / kg per day; more preferably from about 0.05 to about 10 mg / kg per day. For example, in the treatment or prevention of a central nervous system disorder, a suitable dosage level is from about 0.001 to 10 mg / kg per day, preferably from about 0.005 to 5 mg / kg per day, and especially from approximately 0.01 to 1 mg / kg per day. The compounds can be administered in a regimen of 1 to 4 times per day, preferably once or twice per day. It will be appreciated that the amount of the compound of the invention required to be used in any treatment will vary not only with the particular compounds or compositions selected, but also with the route of administration, the nature of the condition being treated and the age and condition of the patient. , and finally it will be at the discretion of the attending physician. The compositions and combination therapies of the invention may be administered in combination with a variety of pharmaceutical excipients, including stabilizing agents, carriers and / or encapsulation formulations as described herein. The aqueous compositions of the present invention comprise an effective amount of the compounds of the invention, dissolved or dispersed in a pharmaceutically acceptable carrier or aqueous medium. "Pharmaceutically or pharmacologically acceptable" includes molecular entities and compositions that do not produce an adverse, allergic or other harmful reaction when administered to an animal, or a human, as appropriate. "Pharmaceutically acceptable carrier" includes any and all of solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and delaying absorption and the like. The use of such media and agents for active pharmaceutical substances is well known in the art. Except insofar as any conventional medium or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. For human administration, preparations must meet the standards of sterility, pyrogenicity, general safety and purity that are required by the standards of the FDA Biological Office. The compositions and combination therapies of the invention will generally be formulated for parenteral administration, for example, formulated for injection via the intravenous, intramuscular, subcutaneous, intralesional, or even intraperitoneal routes. The preparation of an aqueous composition containing a composition of the invention or an active ingredient or component will be known to those skilled in the art in light of the present disclosure. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions; Suitable solid forms to be used to prepare solutions or suspensions after the addition of a liquid before the injection can also be prepared; and the preparations can also be emulsified. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations that include sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that there is a facility to place it with a syringe. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. Solutions of the active compounds as free bases or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The therapeutic or pharmacological compositions of the present invention will generally comprise an effective amount of the components of the combination therapy, dissolved or dispersed in a pharmaceutically acceptable medium. The pharmaceutically acceptable medium or carriers include any and all of solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and delaying absorption and the like. The use of such media and agents for active pharmaceutical substances is well known in the art. Supplementary active ingredients may also be incorporated into the therapeutic compositions of the present invention. The preparation of the pharmaceutical or pharmacological compositions will be known to those skilled in the art in light of the present disclosure. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in a liquid before injection; as tablets or other solids for oral administration; as temporary release capsules; or in any other form currently used, including creams, lotions, mouthwashes, inhalants and the like. Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with several of the other ingredients listed above, as required, followed by sterilization by filtration. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle containing the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze drying techniques which provide a powder of the active ingredient plus any additional desired ingredient of a solution thereof sterilized by prefiltration. . The preparation of more concentrated solutions for intramuscular injection is also contemplated. In this regard, the use of DMSO as a solvent is preferred, since it will result in extremely rapid penetration, delivering high concentrations of the active compounds or agents to a small area. The use of sterile formulations, such as washes based on physiological saline by surgeons, doctors or health care workers to clean a particular area in the field of operation, can also be particularly useful. Therapeutic formulations according to the present invention can also be reconstituted in the form of buccal washes, or in conjunction with antifungal reagents. Inhalable forms are also considered. The therapeutic formulations of the invention may also be prepared in forms suitable for topical administration, such as creams and lotions. Suitable preservatives for use in such a solution include benzalkonium chloride, benzethonium chloride, chlorobutanol, thimerosal and the like. Suitable buffers include boric acid, sodium and potassium bicarbonate, sodium and potassium borates, sodium and potassium carbonate, sodium acetate, sodium biphosphate and the like, in sufficient quantities to maintain the pH between about pH 6 and pH 8 , and preferably, between approximately pH 7 and pH 7.5. Suitable agents for tonicity are dextran 40, dextran 70, dextrose, glycerin, potassium chloride, propylene glycol, sodium chloride and the like, so that the sodium chloride equivalent of the ophthalmic solution is in the range of 0.9 plus or minus 0.2%. Suitable antioxidants and stabilizers include sodium bisulfite, sodium metabisulfite, sodium thiosulfite, thiourea and the like. Suitable wetting and clarifying agents include polysorbate 80, polysorbate 20, poloxamer 282 and tyloxapol. Suitable viscosity-increasing agents include dextran 40, dextran 70, gelatin, glycerin, hydroxyethylcellulose, hydroxymethylpropylcellulose, lanolin, methylcellulose, petrolatum, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose and the like. After the formulation, the therapeutic agents will be administered in a manner compatible with the dosage formulation, and in such amount as to be pharmacologically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like may also be employed. In this context, the amount of the active ingredient and the volume of the composition to be administered, depends on the host animal to be treated. The precise amounts of active compound required for administration, they depend on the judgment of the practitioner, and are peculiar to each individual. A minimum volume of a composition required to disperse the active compounds is typically used. Suitable regimens for administration are also variable, but would be typified by initially administering the compound and verifying the results and then providing additional controlled doses at additional intervals. For example, for parenteral administration, an aqueous solution suitably buffered, and if necessary isotonic, would be prepared and used for intravenous, intramuscular, subcutaneous or even intraperitoneal administration. A dosage could be dissolved in 1 ml of an isotonic NaCl solution and added to 1000 ml of hypodermolysis fluid or injected at the proposed infusion site (see, for example, Remington's Pharmaceutical Sciences 15th Edition, pages 1035-1038 and 1570-1580 ). In certain embodiments, the active compounds can be administered orally. This is contemplated for agents that are generally resistant, or that have become resistant to proteolysis by digestive enzymes. Such compounds are contemplated to include agents designed or chemically modified; Dextrogiratory peptides; and peptide and liposomal formulations in time-release capsules to prevent degradation by peptidase and lipase. Pharmaceutically acceptable salts include acid addition salts and which are formed with inorganic acids such as, for example, hydrochloric, hydrobromic, boric, phosphoric, sulfuric or phosphoric acids, or organic acids such as acetic, oxalic, tartaric, maleic, fumaric acids , citric, succinic, mesyl, mandelic, succinic, benzoic, ascorbic, methanesulphonic, glutaric-a-keto, a-glycerophosphoric, glucose-l-phosphoric and the like. The salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, magnesium or ferric hydroxides, and organic bases such as isopropylamine, trimethylamine, histidine, procaine and the like. Other examples of pharmaceutically acceptable salts include quaternary derivatives and internal salts such as N-oxides. The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol and the like), suitable mixtures thereof and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of a dispersion and by the use of surfactants. The prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with several of the other ingredients listed above, as required, followed by sterilization by filtration. Generally, dispersions are prepared by incorporating the sterilized active ingredients into a sterile vehicle containing the basic dispersion medium and the required other ingredients from those enumerated above. In case of sterile powders for the preparation of sterile injectable solutions, the preferred preparation methods are vacuum drying and freeze drying techniques which provide a powder of the active ingredient plus any additional desired ingredients of a solution thereof sterilized by prefiltration. The preparation of more concentrated, or highly concentrated, solutions for direct injection is also contemplated, where the use of DMSO as a solvent is considered to result in extremely rapid penetration, delivering high concentrations of the active agents to a small area. After formulation, the solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but capsules that release the drug and the like may also be employed. For parenteral administration in an aqueous solution, for example, the solution must be suitably buffered if necessary, and the liquid diluent first becomes isotonic with sufficient physiological saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this regard, the sterile aqueous medium that can be employed will be known to those skilled in the art in the light of the present disclosure. In addition to compounds formulated for parenteral administration, such as intravenous or intramuscular injection, other pharmaceutically acceptable forms include, for example, tablets or other solids for oral administration.; liposomal formulations; Temporary release capsules; and any other currently used form, including creams. Additional formulations suitable for other modes of administration include suppositories. For suppositories, traditional binders and carriers may include, for example, polyalkylene glycols or triglycerides; such suppositories can be formed from mixtures containing the active ingredient in the range of 0.5% to 10%, preferably 1% -2%. Oral formulations include such excipients normally employed, such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate and the like. These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders. In certain defined embodiments, the oral pharmaceutical compositions will comprise an inert diluent or an edible assimilable carrier, or they may be enclosed in a hard or soft shell gelatin capsule, or they may be compressed into tablets, or they may be incorporated directly with the diet food. For oral therapeutic administration, the active compounds can be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like. Such compositions and preparations should contain at least 0.1% of the active compound. The percentage of the compositions and preparations may vary, of course, and may conveniently be between about 2 to about 75% of the unit weight, or preferably between 25-60%. The amount of the active compounds in such therapeutically useful compositions is such that an adequate dosage will be obtained. Tablets, troches, pills, capsules and the like may also contain the following: a binder, such as gum tragacanth, acacia, corn starch or gelatin; excipients, such as dicalcium phosphate; a disintegrating agent, such as corn starch, potato starch, alginic acid and the like; a lubricant, such as magnesium stearate; and a sweetening agent, such as sucrose, lactose or saccharin may be added or a flavoring agent, such as peppermint, oil of wintergreen or cherry flavoring. When the shape of the dosage unit is a capsule, they may contain, in addition to the materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For example, tablets, pills or capsules may be coated with a lacquer, sugar or both. An elixir syrup may contain the active compounds, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring, such as cherry or orange flavor. The pharmaceutical compositions of this invention can be used in the form of a pharmaceutical preparation, for example, in solid, semi-solid or liquid form, containing one or more of the compounds of the invention, as an active ingredient, in admixture with an organic carrier. or inorganic or a suitable excipient for external, inert or parenteral applications. The active ingredient can be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, granules, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The carriers that can be used are water, glucose, lactose, acacia gum, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other suitable carriers to be used. in the manufacture of the preparations, in solid, semisolid, or liquid form, and in addition, auxiliary agents can be used, stabilizers, thickeners and dyes and perfumes. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect after the disease process or condition. To prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical carrier, for example, conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the invention, or a pharmaceutically acceptable non-toxic salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition, so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above, containing from 0.1 to about 500 mg of the active ingredient of the invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form that provides the advantage of a prolonged action. For example, the tablet or pill may comprise an internal dosage component and an external dosage component, the latter being in the form of a wrapper over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach, and allows the internal component to pass intact to the duodenum or be delayed in the release. A variety of materials can be used for such enteric coatings or coatings, such materials include various polymeric acids and mixtures of polymeric acids with materials such as lacquer, cetyl alcohol and cellulose acetate. Liquid forms in which the compositions of the invention may be incorporated for oral administration or by injection, include aqueous solution, suitably flavored syrups, aqueous or oily suspensions and emulsions with acceptable oils such as cottonseed oil, oil sesame, coconut oil or peanut oil, or with a solubilizing agent or emulsifier suitable for intravenous use, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin. Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable solvents, aqueous or organic, or mixtures thereof and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients such as discussed above. Preferably, the compositions are administered by the oral or nasal respiratory route for a local or systemic effect. The compositions in pharmaceutically acceptable solvents, preferably sterile, can be nebulized by the use of inert gases. The nebulized solutions can be breathed directly from the nebulizing device or the nebulizing device can be attached to a face mask, tent or intermittent positive pressure breathing machine. The compositions in solution, suspension or powder can be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner. To treat the clinical conditions and diseases indicated above, the compound of this invention can be administered orally, topically, parenterally, by spray for inhalation or rectally in dosage unit formulations containing conventional, non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term "parenteral" as used herein, includes subcutaneous injections, injection techniques or intravenous, intramuscular, intrasternal infusion. The following examples are provided for the purpose of illustrating the invention, but not to limit the scope or spirit of the invention. The compounds of the invention can be prepared as described in the following reaction schemes.

Reaction Scheme 1 Step 5 Reaction Scheme 2 100 ° C, Microwave Step 3 Step 4 Reaction Scheme 3 Br Pd (dpp1) 2Cl2, dppl ¾ O > * "NQ 100 ° C, Microwave Step 1 Step 2 100 ° C, Microwave Step 3 Step 4 Reaction Scheme 4 or polymer-PPh3 Step 1 Step 2 Reaction Scheme 5 Step 1 Step 2 Step 3 Step 5 Reaction Scheme 6 Step 1 Step 2 Reaction Scheme 7 BTJ - ° N Step 1 Step 2 Reaction Scheme 8 Heat 100 ° C, 24 hours Step 3 Reaction Scheme 9 HOHQHX X = Br or TfO 2 Step 1 NaOH (2 N) Step 2 EXAMPLES The compounds were prepared using the general procedures described below: (n, m = 0, 1, 2 respectively) A: General procedure for the C-C coupling link with the Rieke reagents The 5-bromobenzofuran (1.0 mmoles) was dissolved in a THF solution of the Rieke reagent (0.5 M, 2.9 mmol) in a microwave reaction tube. Pd (PtBu3) 2 (0.05 mmol) was added to this solution. The mixture was purged with N 2 gas for 3-5 minutes, and heated at 100 ° C for 30 minutes under microwave radiation (microwave reactor Personal Chemistry Emrys ™ Optimizer). After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with an aqueous 1N HCl solution, brine, filtered through Celite. The filtrate was dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (ISCO system), to provide a pure product.

B: General procedure for the coupling reaction of the NC link 5-bromobenzofuran (1.0 mmol), piperidine (1.2 mmol), Pd (dppf) Cl2 (0.03 mmol), dppf (0.045 mmol) and sodium tert-butoxide were mixed ( 1.5 mmol) in toluene (2 mL). The mixture was purged with N 2 gas for 3-5 minutes and heated at 120 ° C for 30 minutes under microwave radiation (microwave reactor Personal Chemistry Emrys ™ Optimizer). After the end of the reaction, the reaction mixture was loaded directly onto a column on silica gel and purified in an ISCO system (5% EtOAc in hexanes), to provide a pure product.

C: General preparative procedure for the formation of benzofuranboronic acids A solution of n-BuLi (1.2 mmol, 2.5 M solution in hexanes) was added dropwise to a solution of benzofuran compounds (1.0 mmol) in anhydrous THF (20 mM). mL) at -78 ° C. The resulting mixture was stirred at -78 ° C for 20 minutes, and treated with B (1PrO) 3 (1.5 mmoles). The reaction mixture was allowed to slowly warm to room temperature and was stirred for 1 hour. The reaction was cooled in an ice bath and quenched with 2N HC1 or saturated NH4C1, and extracted with Et20. The combined organic extracts were washed with brine, dried and concentrated under reduced pressure to provide a desired benzofuranboronic acid without further purification for the next step.

D: General procedure for coupling boronic acids with aryl halides A mixture of benzofuranboronic acid (1.1 mmoles), aryl halide (1.0 mmoles), triethylamine (20 mmoles) and bis (triphenylphosphine) aladio (II) chloride (0.05) mmoles) in ethanol (30 mL) was irradiated in a microwave instrument at 100 ° C for 20 minutes. The reaction mixture was cooled, and the solvent was removed. The residue was treated with water and extracted with ethyl acetate. The organic layer was dried and concentrated in vacuo (work of the aqueous layer is optional). Purification by chromatography on silica gel provided the desired product.

E: General procedure of reductive amination A mixture of aldehyde (1.0 mmol), acetic acid (1.5 mmol) and azetidin-3-carboxylic acid or piperidine-4-carboxylic acid (1.2-1.5 mmol) in DCM / MeOH (1: 1) , 10 mL), was stirred at room temperature for 1 hour. Sodium cyanoborohydride (0.5 mmol) was added and the reaction mixture was stirred for 2-3 hours at room temperature. After concentration of the solvent under reduced pressure, the resulting residue was dissolved in DMSO, filtered and purified by preparative reverse-phase HPLC (Phenomenex Reverse Phase 5μ Luna C18 (2) column, DI 60 x 21.2 mm, phase mobile: A = 0.05% of TFA in water; B = 0.05% TFA in acetonitrile. The flow rate was 10-12 mL / minute), to provide the desired final product with a purity greater than 95%. All final products were obtained as the TFA salts except for Compound 59. Alternatively, the crude mixture of the reductive amination can be purified by trituration with MeOH and water.

Compound 1 1- (4- (5-Phenylbenzofuran-2-yl) benzyl) azetidine-3-carboxylic acid 1- (2,2-Diethyethoxy) -4-phenylbenzene (step 1 in Reaction Scheme 1): A mixture of 4-phenylphenol (5 g, 29.4 mmol), diethyl acetal bromoacetaldehyde (4.56 mL, 29.4 mmol) and KOH (1.94 g, 29.4 mmol) in DMSO (15 mL) was stirred under reflux for 6 hours. The reaction mixture was allowed to cool to room temperature and poured onto ice containing 0.60 g of KOH and diluted to 100 mL with water. The solution is extra or with Et20 (20 mL x 3); the combined extracts were washed with a 1N NaOH solution, water and brine, dried and concentrated under reduced pressure to provide 7.97 g (94%) of a yellow oil which was used without further purification: 1 H NMR (400 MHz, CDC13 ) d 7.56-7.50 (til, 4H), 7.41 (t, 2H), 7.30 (t, 1H), 7.00 (dt, 2H), 4.86 (t, 1H), 4.05 (d, 2H), 3.82-3.74 ( m, 2H), 3.69-3.62 (m, 2H).

-Phenylbenzofuran (step 2 in Reaction Scheme 1): A mixture of 1- (2, 2-diethoxyethoxy) -4-phenylbenzene (3.52 g, 12.3 mmol) and polyphosphoric acid (2.95 g, 29.4 mmol) in benzene (60 mL) was stirred under reflux for 2 hours. The reaction mixture was cooled to room temperature, decanted from PPA and filtered through a plug of silica gel, which was washed with hexanes. The filtrate and the washing were combined and concentrated under reduced pressure to provide 2.00 g of the crude benzofuran:? NMR (400 MHz, CD3OD) d 7.79 (dd, 1H), 7.66 (d, 1H), 7.63-7.60 (m, 2H), 7.58-7.51 (m, 2H), 7.45 (t, 2H), 7.36-7.33 (m, 1H), 6.82 (dd, 1H).

-Phenylbenzofuran-2-yl-2-boronic acid (step 3 in Reaction Scheme 1): A solution of n-BuLi (2.0 mL, 2.5 M solution in hexanes) was added dropwise to a solution of 5-phenylbenzofuran (816 mg, 4.21 mmol) in anhydrous THF (20 mL) at -78 ° C. The resulting mixture was stirred at -78 ° C for 20 minutes, and treated with B (1PrO) 3 (1.46 mL, 6.31 mmol). The reaction mixture was allowed to slowly warm to room temperature and was stirred for 1 hour. The reaction was quenched with 2N HC1 and extracted with Et20. The combined extracts were washed with brine, dried and concentrated under reduced pressure to provide 1.2 g of the crude boronic acid, which was used without further purification: ?? NMR (400 MHz, CD30D) d 7.83 (dd, 1H), 7.64-7.55 (m, 4H), 7.48-7.42 (m, 3H), 7.38-7.32 (m, 1H). 4- (5-Phenylbenzofuran-2-yl) benzaldehyde (step 4 in Reaction Scheme 1): A solution of 5-phenylbenzofuran-2-yl-2-boronic acid (527 mg, 2.22 mmol), 4-bromobenzaldehyde (315 mg, 1.70 mmol), dichlorobis (triphenylphosphine) palladium (60 mg, 0.085 mmol) and triethylamine (4.74 mL, 34 mmol) in EtOH were irradiated in the microwave at 100 ° C for 1200 seconds. The precipitate that formed was filtered and rinsed with ethanol to provide 217 mg of the desired benzaldehyde: XH NMR (400 MHz, CD3OD) d 10.06 (s, 1H), 8.05 (d, 2H), 7.98 (d, 2H), 7.82 (broad s, 1H), 7.65-7.52 (m, 4H), 7.48 (dd, 2H), 7.37 (t, 1H). MS (ESI) m / z: Calculated: 298.10; Observed: 299.1 (M ++ l). 1- (4- (5-Phenylbenzofuran-2-yl) benzyl) azetidine-3-carboxylic acid (step 5 in Reaction Scheme 1): A mixture of 4- (5-phenylbenzofuran-2-yl) benzaldehyde (49 mg, 0.14 mmol) and azetidin-3-carboxylic acid (30 mg, 0.28 mmol) in MeOH (1 mL) was stirred at room temperature for 1 hour. hour. Sodium cyanoborohydride (60 mg, 0.28 mmol) was added in two portions and the reaction mixture was stirred for 16 hours. Concentration of the solvent under reduced pressure afforded a yellow solid which was dissolved in DMSO (3 mL) and filtered to give a yellow solution which was purified by HPLC to provide 3 mg of the desired product: ?? NMR (400 MHz, CD3OD) d 8.03 (d, 2H), 7.84 (broad s, 1H), 7.66-7.58 (m, 6H), 7.45 (t, 2H), 7.36-7.32 (m, 2H), 4.47 ( s, 2H), 4.40-4.32 (m, 4H), 3.72 (m, 1H). MS (ESI) m / z: Calculated: 383.15; Observed: 383.9 (M ++ l).

Compound 2 1- (4- (5-Butylbenzofuran-2-yl) phenyl) methyl) azetidin-3-carboxylic acid 1- (2,2-Diethylethoxy) -4-butylbenzene: The title compound was prepared as in the Example of Compound 1 (step 1 in Reaction Scheme 1) in the general method described above (90% yield): NMR (400 MHz, CDC13) d 7.07 (d, J = 8.8, 2H), 6.83 (d, J = 8.8, 2H), 4.83 (t, J = 5.1, 1H), 3.98 (d, J = 5.1, 2H), 3.80-3.72 (m, 2H), 3.67-3.59 (m , 2H), 2.54 (t, J = 7.7, 2H), 1.59-1.51 (m, 2H), 1.36-1.30 (m, 2H), 1.24 (t, J = 7.0, 6H), 0.91 (t, J = 7.3, 3H). - . 5-Butylbenzofuran: The title compound was prepared as in Example of Compound 1 (step 2 in Reaction Scheme 1) in the general method described above (91% yield): XU NMR (400 MHz, CDC13) d 7.58 (d, J = 2.2, 1H), 7.41-7.36 (m, 2H), 7.11 (dd, J = 8.5, 1.8, 1H), 6.70 (dd, J = 2.2, 1.1, 1H), 2.70 (t, J = 7.7, 2H ), 1.67-1.60 (m, 2H), 1.42-1.32 (m, 2H), 0.93 (t, J = 7.3, 3H).

-Butylbenzofuran-2-yl-2-boronic acid: The title compound was prepared as in the Example of Compound 1 (step 3 in Reaction Scheme 1) in the general method described above (67% yield): XH NMR (400 MHz, CDC13) d 7.43-7.31 (m , 2H), 7.22-7.14 (m, 2H), 2.70 (t, J = 7.7, 2H), 1.67-1.59 (m, 2H), 1.41-1.32 (m, 2H), 0.93 (t, J = 7.3, 3H). 4- (5-Butylbenzofuran-2-yl) benzaldehyde: The title compound was prepared as in Example 1 of Compound 1 (step 4 in Reaction Scheme 1) in the general method described above (72% yield): ?? NMR (400 MHz, CDC13) d 10.03 (s, 1H), 8.00 (d, J = 8.4, 2H), 7.94 (d, J = 8.4, 2H), 7.45-7.41 (m, 2H), 7. 17-7.15 (m, 2H), 2.71 (t, J = 7.7, 2H), 1.68-1.61 (m, 2H), 1.41-1.33 (m, 2H), 0.94 (t, J = 7.3, 3H). 1- (4- (5-Butylbenzofuran-2-yl) phenyl) methyl) azetidine-3-carboxylic acid: The title compound was prepared as in Example 1 of Compound 1 (step 5 in Reaction Scheme 1) in the general method described above (42% yield): XH NMR (400 MHz, CD3OD) d 7.98 (d, J = 8.4, 2H), 7.55 (d, J = 8.4, 2H), 7.43-7.41 (m, 2H), 7.23 (s, 1H), 7.15 (d, J = 8.8, 1H), 4.40 (s, 2H) , 4.25-4.23 (m, 4H), 3.52-3.46 (m, 1H), 2.71 (t, J = 7.7, 2H), 1.67-1.61 (m, 2H), 1.41-1.33 (m, 2H), 0.95 ( t, J = 7.3, 3H). MS (ESI) ra / z: Calculated: 363.18; Observed: 364.0 (M ++ l).

Compound 3 1- (4- (5-Butoxybenzofuran-2-yl) phenyl) methyl) azetidine-3-carboxylic acid 1- (2,2-Diethyethoxy) -4-butoxybenzene The title compound was prepared as in the Example of Compound 1 (step 1 in Reaction Scheme 1) in the general method described above (84% yield): XH NMR (400 MHz, CDC13) d 6.86-6.80 (m , 4H), 4.81 (t, J = 5.1, 1H), 3.96 (d, J = 5.1, 2H), 3.90 (t, J = 6.6, 2H), 3.79-3.72 (m, 2H), 3.67-3.59 ( m, 2H), 1.77-1.70 (m, 2H), 1.52-1.43 (m, 2H), 1.24 (t, J = 7.0, 6H), 0.96 (t, J = 7.4, 3H).

-Butoxybenzofuran: The title compound was prepared as in Example of Compound 1 (step 2 in Reaction Scheme 1) in the general method described above (81% yield): XH NMR (400 MHz, CDC13) d 7.58 (d, J = 2.2, 1H), 7.38 (d, J = 9.2, 1H), 7.05 (d, J = 2.5, 1H), 6.90 (dd, J = 2.5, 8.8, 1H), 6.69 (broad d, J = 2.2, 1H), 3.99 (t, J = 6.6, 2H), 1.82-1.75 (ra, 2H), 1.56-1.47 (m, 2H), 0.99 (t, J = 7.3, 3H).

-Phenylbenzofuran-2-yl-2-boronic acid (step 3 in Reaction Scheme 1): A solution of n-BuLi (2.5 mL, 2.5 M solution in hexanes) was added dropwise to a solution of 5-butoxybenzofuran (1.0 g, 5.21 mmol) in anhydrous THF (20 mL) at -78 ° C. The resulting mixture was stirred at -78 ° C for 20 minutes, and treated with B (iPrO) 3 (1.80 mL, 7.8 mmol). The reaction mixture was allowed to slowly warm to room temperature and was stirred for 1 hour. The reaction was quenched with 2N HC1 and extracted with Et20. The combined extracts were washed with brine, dried and concentrated under reduced pressure to provide 1.2 g of the crude boronic acid, which was used without further purification: (98% yield):? RN (400 MHz, CDC13) d 7.37 (d, 1H), 7.30 (d, 1H), 7.06 (s, 1H), 6.98 (d, 1H), 4.44 (s, 2H), 1.81-1.71 (m, 2H) ), 1.58-1.50 (m, 2H), 1.00 (t, 3H). 4- (5-Butoxybenzofuran-2-yl) benzaldehyde (step 4 in Reaction Scheme 1): A solution of 5-phenylbenzofuran-2-yl-2-boronic acid (702 mg, 3.0 mmol), 4-bromobenzaldehyde (427 mg, 2.30 mmol), dichlorobis (triphenylphosphine) palladium (80 mg, 0.11 mmol) and triethylamine (6.5 mL, 45 mmol) in EtOH (2 mL) was irradiated in the microwave at 100 ° C for 1200 seconds. The precipitate that formed was filtered and rinsed with ethanol to give 620 mg of the crude product which, after column chromatography, gave 375 mg of the desired compound (43%): H NMR (400 MHz, CDC13) d 10.03 ( s, 1H), 8.05 (d, 2H), 7.98 (d, 2H), 7.82 (d, 1H), 7.18 (d, 1H), 7.16 (d, 1H), 6.94 (s, 1H), 4.44 (s) , 2H), 1.81-1.71 (m, 2H), 1.58-1.50 (m, 2H), 1.00 (t, 3H). MS (ESI) m / z: Calculated: 294.34; Observed: 295.2 (M ++ l). 1- (4- (5-Butoxybenzofuran-2-yl) phenyl) methyl) azetidine-3-carboxylic acid (step 5 in Reaction Scheme 1): A mixture of 4- (5-butoxybenzofuran-2-yl) enzaldehyde (70 mg, 0.30 mmol), azetidine-3-carboxylic acid (46 mg, 0.45 mmol) and acetic acid (0.50 mmol) in MeOH-DCM (3: 1; 2 mL), was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (211 mg, 1.00 mmol) was added, and the reaction mixture was stirred for 16 hours. Concentration of the solvent under reduced pressure gave a yellow solid, which was dissolved in DMSO (3 mL) and filtered to give a yellow solution which was purified by HPLC to provide 6 mg of the desired product (5% yield): XH NMR (400 MHz, CD3OD) d 7.97 (d, 2H), 7.55 (d, 2H), 7.40 (d, 1H), 7.21 (s, 1H), 7.10 (d, 1H), 6.92-6.89 (dd, 1H) , 4.44 (s, 2H), 4.37 (c, 4H), 4.00 (t, 2H), 3.72-3.64 (m, 1H), 1.81-1.71 (m, 2H), 1.58-1.50 (m, 2H), 1.00 (t, 3H). MS (ESI) m / z: Calculated: 379.45; Observed: 380.3 (M ++ l).

Compound 4 1- (4- (5-Benzylbenzofuran-2-yl) phenyl) methyl) azetidine-3-carboxylic acid 1- (4- (2,2-Diethyethoxy) benzyl) benzene: The title compound was prepared as in Example 1 of Compound 1 (step 1 in Reaction Scheme 1) in the general method described above (84% yield): XU NMR (400 MHz, CDC13) d 7.30-7.25 (m , 2H), 7.20-7.15 (m, 3H), 7.09 (d, J = 8.8, 2H), 6.84 (d, J = 8.8, 2H), 4.82 (t, J = 5.5, 1H), 3.98 (d, J = 5.5, 2H), 3.92 (s, 2H), 3.79-3.72 (m, 2H), 3.66-3.59 (m, 2H), 1.24 (t, 7.1, 3H). - . 5-Benzylbenzofuran: The title compound was prepared as in Example of Compound 1 (step 2 in Reaction Scheme 1) in the general method described above (89% yield): XH NMR (400 MHz, CDC13) d 7.58 (d, J = 2.2, 1H) 3 7.42-7.40 (m, 2H), 7.31-7.7.26 (m, 3H), 7.25-7.12 (m, 3H), 6.70 (m, 1H), 4.08 (s, 2H).

-Benzylbenzofuran-2-yl-2-boronic acid: The title compound was prepared as in Example of Compound 1 (step 3 in Reaction Scheme 1) in the general method described above (66% yield): XH NMR (400 MHz, CDC13) d 7.44 (ra, 1H ), 7.42 (d, J = 8.4, 1H), 7.32-7.26 (m, 4H), 7.25-7.19 (m, 3H), 4.81 (s, 2H), .08 (s, 2H). 4 - . 4 - (5-Benzylbenzofuran-2-yl) benzaldehyde: The title compound was prepared as in Example of Compound 1 (step 4 in Reaction Scheme 1) in the general method described above (76% yield): U NMR (400 MHz, CDC13) d 10.03 (s, 1H ), 7.99 (d, J = 8.4, 2H), 7.94 (d, J = 8.4, 2H), 7.46-7.41 (m, 2H), 7. 32-7.17 (m, 6H), 7.13 (broad s, 1H), 4.08 (s, 2H). 1- ((4- (5-Benzylbenzofuran-2-yl) phenyl) methyl) azetidine-3-carboxylic acid: The title compound was prepared as in Example of Compound 1 (step 5 in Reaction Scheme 1) in the general method described above (62% yield): XH NMR (400 MHz, CD3OD) d 7.98 (d, J = 8.4, 2H), 7.55 (d, J = 8.4, 2H), 7.45-7.42 (m, 2H), 7.28-7.15 (m, 7H), 4.44 (s, 2H), 4.37-4.22 (m, 4H) , 4.06 (s, 2H), 3.72- 3.64 (m, 1H). MS (ESI) m / z: Calculated: 397.17; Observed: 398.0 (M ++ l).

Compound 5 1- (4- (7-Benzylbenzofuran-2-yl) phenyl) methyl) azetidine-3-carboxylic acid 1- (2- (2,2-Diethylethoxy) benzyl) benzene: The title compound was prepared as in the Example of Compound 1 (step 1 in Reaction Scheme 1) in the general method described above (99% yield): XH RN (400 MHz, CDC13) d 7.27-7.21 (m , 4H), 7.19-7.15 (m, 2H), 7.08 (broad d, J = 5.9, 1H), 6.90-6.83 (m, 2H), 4.78 (t, J = 5.1, 1H), 4.00-3.98 (m , 4H), 3.76-3.69 (m, 2H), 3.63-3.56 (m, 2H), 1.22 (t, J = 7.0, 6H). 7 -. 7-Benzylbenzofuran: The title compound was prepared as in Example 1 of Compound 1 (step 2 in Reaction Scheme 1) in the general method described above (84% yield): XH NMR (400 MHz, CDC13) d 7.62 (d, J = 2.2, 1H), 7.45 (d, J = 7.7, 1H), 7.36 (s, 1H), 7.29-7.26 (m, 3), 7.25-7.13 (m, 2), 7.05 (d, J = 7.4, 1H), 6.76 (d, J = 2.2, 1H), 4.27 (s, 2H). 7-Benzylbenzofuran-2-yl-2-boronic acid: The title compound was prepared as in the Example of Compound 1 (step 3 in Reaction Scheme 1) in the general method described above (67% yield):? NMR (400 MHz, CDC13) d 7.50 (dd, J = 7.7, 1H), 7.36 (s, 1H), 7.29-7.25 (m, 4H), 7.18-7.09 (m, 3H), 4.29 (s, 2H) . 4 - . 4 - (7-Benzylbenzofuran-2-yl) benzaldehyde: The title compound was prepared as in the Example of Compound 1 (step 4 in Reaction Scheme 1) in the general method described above (72% yield):? NMR (400 MHz, CDC13) d 10.04 (s, 1H), 8.00-7.94 (m, 4H), 7.50 (d, J = 9.9, 1H), 7.47-7.27 (m, 4H), 7.24-7.17 (m, 3H), 7.11 (d, J = 7.3, 1H), 4.33 (s, 2H). 1- ((4- (7-Benzylbenzofuran-2-yl) phenyl) methyl) azetidine-3-carboxylic acid: The title compound was prepared as in the Example of Compound 1 (step 5 in Reaction Scheme 1) in the general method described above (81% yield):? NMR (400 MHz, CD30D) d 7.97 (d, J = 8.0, 2H), 7.56 (d, J = 8.0, 2H), 7.48 (d, J = 7.7, 1H), 7.34-7.24 (m, 5H), 7.19-7.10 (m, 3H), 4.44 (s, 2H), 4.32-4.25 (m, 6H), 3.66-3.56 (m, 1H). MS (ESI) m / z: Calculated: 397.17; Observed: 397.9 (M ++ l).

Compound 6 1- (4- (5-Cyclohexylbenzofuran-2-yl) benzyl) azetidine-3-carboxylic acid 5-Cyclohexylbenzofuran (step 1 in Scheme 2): The 5-bromobenzofuran (500 mg, 2.55 mmol) was dissolved in a THF solution of zinc (II) cyclohexyl bromide (0.5 M, 15 mL, 7.40 mmol) in a microwave reaction tube. Pd (PtBu3) 2 (65 mg, 0.128 mmol, 0.05 equivalents) was added to this solution. The mixture was purged with N 2 gas for 3-5 minutes and heated at 100 ° C for 30 minutes under microwave radiation. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with an aqueous 1N HCl solution, brine, filtered through Celite. The filtrate was dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (ISCO system, 5% EtOAc in hexanes), to give 0.217 g of the desired product (43% yield): XH NMR (400 MHz, CDC13) d 7.57 (d , 1H), 7.41 (d, 2H), 7.15 (d, 1H), 6.72 (d, 1H), 2.58 (m, 1H), 1.92-1.74 (m, 4H), 1.51-1.35 (m, 4H), 1.31-1.25 (m, 2H).

-Cyclohexylbenzofuran-2-yl-boronic acid (step 2 in Reaction Scheme 2): A solution of n-BuLi (360 μL, 0.9 mmol, 2.5 M solution in hexanes) was added dropwise to a solution of 5-cyclohexylbenzofuran (150 mg, 0.75 mmol) in anhydrous THF (5 mL) at -78 ° C. . The resulting mixture was stirred at -78 ° C for 40 minutes, and treated with B (1PrO) 3 (260 L, 1.13 mmol). The reaction mixture was allowed to slowly warm to room temperature and was stirred for 1 hour. TLC indicated completion of the reaction. The reaction was cooled in an ice bath and quenched with 2N HC1 (3 mL) and extracted with Et20. The combined organic extracts were washed with brine, dried and concentrated under reduced pressure to provide a desired boronic acid (0.156 g, 85% yield) without further purification for the next step. 1 H NMR (400 MHz, CDC13) d 7.46 (s, 1 H), 7.43 (d, 1 H), 7.32 (s, 1 H), 7.25 (d, 1 H), 2.62 (m, 1 H), 1.93-1.85 (m, 4H), 1.78-1.75 (m, 4H), 1.34-1.22 (m # 2H). 4- (5-Cyclohexylbenzofuran-2-yl) benzaldehyde (step 3 in Reaction Scheme 2): A mixture of 5-cyclohexylbenzofuran-2-ylboronic acid (75 mg, 0.37 mmol), 4-bromobenzaldehyde (62 mg, 0.34 mmol), triethylamine (1.1 mL, 7.5 mmol) and bis (triphenylphosphine) aladine (II) chloride ( 13 mg, 0.05 mmol) in ethanol (11 mL) was irradiated in a microwave instrument at 100 ° C for 20 minutes. The reaction mixture was cooled, and the solvent was removed. The residue was purified by chromatography on silica gel in the ISCO system to provide the title compound (52 mg, 46% yield): > 95% purity by LCMS, ESI-MS: 305.2 (+ H +). U NMR (400 MHz, CDC13) d 10.03 (s, 1H), 8.00 (d, 2H), 7.95 (d, 2H), 7.46 (d, 2H), 7.19 (d, 1H), 7.16 (s, 1H) , 2.63-2.58 (m, 1H), 1.94-1.76 (m, 4H), 1.53-1.42 (m, 4H), 1.38-1.25 (m, 2H). MS (ESI) m / z: Calculated: 304.38; Observed: 305.2 (M ++ l). 1- (4- (5-Cyclohexylbenzofuran-2-yl) encyl) azetidine-3-carboxylic acid (step 4 of Reaction Scheme 2) A mixture of 4- (5-cyclohexylbenzofuran-2-yl) benzaldehyde (30 mg, 0.1 mmol), acetic acid (9 μm, 0.15 mmol) and azetidin-3-carboxylic acid (15 mg, 0.15 mmol) in DCM / MeOH (1: 1, 2 mL), was stirred at room temperature for 1 hour. Sodium cyanoborohydride (3.1 mg, 0.05 mmol) was added, and the reaction mixture was stirred for 3 hours at room temperature. After concentration of the solvent under reduced pressure, the resulting residue was dissolved in hot MeOH and filtered. The filtrate and the white solid, which was again dissolved in hot DMSO, were both purified by preparative reverse phase HPLC (Phenomenex Reverse Phase 5μ Luna C18 (2) column, DI 60 x 21.2 mm), to provide the product desired end (16 mg, 42% yield) as a white powder: > 95% purity by LCMS, ESI-MS: 459.1 (M + H) +, XH RN (400 MHz, CD3OD) d 7.95 (d, 2H), 7.56 (d, 2H), 7.45 (d, 1H), 7.42 (d, 1H), 7.24 (s, 1H), 7.19 (dd, 1H), 4.45 (s, 2H), 4.34 (dd, 4H), 3.69 (m, 1H), 2.64-2.57 (d, 1H), 1.89 (t, 4H), 1.58-1.40 (m, 4H), 1.38-1.26 (m, 2H).

Compound 7 1- (4- (5-Cyclohexylbenzofuran-2-yl) benzyl) piperidine-4-carboxylic acid A mixture of 4- (5-cyclohexylbenzofuran-2-yl) benzaldehyde (22 mg, 0.07 mmol), acetic acid (7 pL, 0.11 mmol) and piperidin-4-carboxylic acid (14 mg, 0.11 mmol) in DCM / MeOH (1: 1, 1.6 mL), was stirred at room temperature for 1 hour. Sodium cyanoborohydride (2.3 mg, 0.05 mmol) was added, and the reaction mixture was stirred for 4 hours at room temperature. After concentration of the solvent under reduced pressure, the resulting residue was dissolved in DMSO, filtered and purified by preparative reverse phase HPLC (column C18 (2) of 5μ Luna reverse phase Phenomenex, DI 60 x 21.2 mm), to provide the desired final product (15.4 mg, 51%): > 95% purity by LCMS, ESI-MS: 418.1 (M + H) +, XH NMR (400 MHz, CD3OD) d 8.00 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 1.6 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7. 26 (s, 1H), 7.21 (dd, J = 8.4 Hz, J = 1.6 Hz), 4.35 (s, 2H), 3.57 (d, J = 11.6 Hz, 2H), 3.07 (t, J = 12 Hz, 2H), 2. 64-2.53 (m, 2H), 2.24 (d, 2H), 1.19-1.86 (m, 4H), 1.79 (t, 2H), 1.58-1.42 (m, 4H), 1.38-1.26 (m, 2H).

Compound 8 1- (4- (5-Butylbenzofuran-2-yl) phenyl) methyl) piperidine-4-carboxylic acid The title compound was prepared as in the Example of Compound 1 (step 5 in Reaction Scheme 1) in the general method described above, except that piperidin-4-carboxylic acid was used (57% yield): XH NMR (400 MHz, CD3OD) d 8.00 (d, J = 8.1, 2H), 7.59 (d, J = 8.1, 2H), 7.43-7.41 (m, 2H), 7.25 (s, 1H), 7.15 (d, J = 8.8, 1H), 4.35 (s, 2H), 3.57 (broad d, J = 11.7, 2H), 3.07 (broad t, J = 12.5, 2H), 2.71 (t, J = 7.7, 2H), 2.70- 2.59 (m, 1H), 2.25 (broad d, J = 14.6, 2H), 1.93-1.79 (m, 2H), 1.67-1.61 (m, 2H), 1.43-1.33 (m, 2H), 0.95 (t, J = 13, 3H). MS (ESI) m / z: Calculated: 391.21; Observed: 392.0 (M ++ l).

Compound 9 1- (4- (5-Benzylbenzofuran-2-yl) phenyl) methyl) piperidine-4-carboxylic acid compound of the title was prepared as Example of Compound 1 (step 5 in Reaction Scheme 1) in the general method described above, except that piperidine-4-carboxylic acid was used: XH NMR (400 MHz, CD3OD) d 7.99 ( broad d, J = 8.0, 2H), 7.58 (broad d, J = 8.0, 2H), 7.44-7.42 (m, 2H), 7.28-7.16 (m, 7H), 4.34 (broad s, 2H), 4.05 ( s broad, 2H), 3.57 (broad d, J = 11.7, 2H), 3.05 (broad t, J = 12.4, 2H), 2.65-2.62 (m, 1H), 2.23 (broad d, J = 13.5, 2H) 1.89-1.80 (m, 2H). MS (ESI) m / z: Calculated: 425.20; Observed: 426.0 (M ++ l).

Compound 10 1- (4- (5-Isobutylbenzofuran-2-yl) phenyl) methyl) azetidine 3 -carboxylic acid (Reaction Scheme 2) 5-Isobutylbenzofuran (Step 1 in Reaction Scheme 2): -Bromobenzofuran (500 mg, 2.56 mmol) was dissolved in a THF solution of zinc (II) isobutyl bromide (0.5 M, 15 mL, 7.40 mmol) in a microwave reaction tube. Pd (PtBU3) 2 (65 mg, 0.128 mmol, 0.05 equivalents) was added to this solution. The mixture was purged with N 2 gas for 3-5 minutes and heated at 100 ° C for 30 minutes under microwave radiation. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with an aqueous solution of 1N HC1, brine, filtered through Celite. The filtrate was dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (ISCO system, 5% EtOAc in hexanes), to provide 0.331 g of the desired product (74% yield): XH RN (400 MHz, CDC13) d 7.59 (s) , 1H), 7.35 (d, 1H), 7.07 (d, 1H), 6.70 (s, 1H), 2.59 (d, 2H), 1.9 (ra, 1H), 0.9 (d, 6H).

-Isobutylbenzofuran-2-ylboronic acid (step 2 in Reaction Scheme 2): A solution of n-BuLi (912 pL, 2.28 mmol, 2.5 M solution in hexanes) was added dropwise to a solution of 5-isobutylbenzofuran (331 mg, 1.9 mmol) in anhydrous THF (12 mL) at -78 ° C. . The resulting mixture was stirred at -78 ° C for 40 minutes, and treated with B (1PrO) 3 (658 pL, 2.85 mmol). The reaction mixture was allowed to slowly warm to room temperature and was stirred for 1 hour. TLC indicated completion of the reaction. The reaction was cooled in an ice bath and quenched with 2N HCl (6 mL) and extracted with Et20. The combined organic extracts were washed with brine, dried and concentrated under reduced pressure to give a crude benzofuranboronic acid (0.76 g) without further purification for the next step. 4- (5-isobutylbenzofuran-2-yl) benzaldehyde (step 3 in Reaction Scheme 2): A mixture of 5-isobutylbenzofuran-2-ylboronic acid (70 mg, 0.33 mmol), 4-bromobenzaldehyde (61 mg, 0.33 mmol), triethylamine (1.7 mL, 12.6 mmol) and bis (triphenylphosphine) palladium (II) chloride ( 12 mg, 0.017 mmol) in ethanol (10 mL) was irradiated in a microwave instrument at 100 ° C for 20 minutes. The reaction mixture was cooled, and the solvent was removed. The residue was treated with water and extracted with ethyl acetate. The organic layer was dried and concentrated in vacuo (work of the aqueous layer is optional). Purification by chromatography on silica gel in an ISCO system afforded the title compound (59 mg, 65% yield): > 99% purity by LCMS, ESI-MS: 279.2 (M + H) +. 1- ((4- (5-Isobutylbenzofuran-2-yl) phenyl) methyl) -azetidine-3-carboxylic acid (step 4 in Reaction Scheme 2): A mixture of 4- (5-isobutylbenzofuran-2-yl) benzaldehyde (30 mg, 0.11 mmol), acetic acid (10 μL, 0.15 mmol) and azetidine-3-carboxylic acid (16 mg, 0.16 mmol) in DCM / MeOH (1: 1, 2 mL) was stirred at room temperature for 1 hour. Sodium cyanoborohydride (3.4 mg, 0.054 mmol) was added and the reaction mixture was stirred for 3 hours at room temperature. After concentration of the solvent under reduced pressure, the resulting residue was dissolved in an aliquot of DMSO and purified by reverse phase preparative HPLC (Phenomenex reverse phase 5μ Luna C18 (2) column, DI 60 x 21.2 mm), to provide the desired end product (25.6 mg, 65% yield) as a colorless film: >95% purity by LCMS, ESI-MS: 364.0 (M + H) +, l NMR (400 MHz, CD3OD) d 7.99 (d, 2H), 7.55 (d, 2H), 7.42 (d, 1H), 7.39 (s, 1H), 7.24 (s, 1H), 7.12 (dd, 1H), 4.44 (s, 2H), 4.33 (d, 4H), 3.68 (m, 1H), 2.57 (d, 2H), 1.90 (m, 1H), 0.92 (d, 6H).

Compound 11 1- (4- (5-Phenethylbenzofuran-2-yl) phenyl) methyl) azetidine-3-carboxylic acid The title compound was prepared in the same manner as the Compound of Example 6: > 95% purity by LCMS, ESI-MS: 411.9 (M + H) +, XH NMR (400 MHz, CD3OD) d 7.99 (d, 2H), 7.55 (d, 2H), 7.41 (d, 1H), 7.38 (s, 1H), 7.24-7.21 (m, 3H), 7.17-7.14 (m, 4H), 4.44 (s, 2H), 4.34 (d, 4H), 3.70 (m, 1H), 3.01-2.90 (m , 4H).

Compound 12 1- (4- (5- (Pyridin-3-yl) benzofuran-2-yl) benzyl) azetidine-3-carboxylic acid 3- (benzofuran-5-yl) pyridine (step 1 in Reaction Scheme 2 , except that the Suzuki coupling was used): A solution of 5-pyridin-3-ylboronic acid (390 mg, 3.18 mmol), 5-bromobenzofuran (500 mg, 2.54 mmol), dichlorobis (triphenylphosphine) palladium (111 mg, 0.16 mmol) and triethylamine (8.8 mL, 63.5 mmol) ) in EtOH was irradiated in the microwave at 100 ° C for 1200 seconds. Removal of the solvents followed by dissolution in CH2C12 and filtrate gave the residue after concentration of the solvent under reduced pressure. The compound was purified in an ISCO to provide 316 mg of the title compound as a light yellow solid: ""? NMR (400 MHz, CDC13) d 8.89 (s, 1H), 8.60 (d, 1H), 7.90 (d, 1H), 7.80 (s, 1H), 7.69 (s, 1H), 7.55 (d, 1H), 7.50 (d, 1H) 7.38 (dd, 1H), 6.85 (dd, 1H). MS (ESI) m / z: Calculated: 195.07; Observed: 196.30 (M ++ l).

- (Pyridin-3-yl) benzofuran-2-boronic acid (step 2 in Reaction Scheme 2): A solution of n-BuLi (0.76 mL, 2.5 M hexanes solution) was added dropwise to a solution 3- (benzofuran-5-yl) iridine (310 mg, 1.59 mmol) in anhydrous THF (10 mL) at -78 ° C. The resulting mixture was stirred at -78 ° C for 30 minutes, and treated with B (1PrO) 3 (0.55 mL, 2.39 mmol). The reaction mixture was allowed to slowly warm to room temperature and was stirred for 1 hour. The reaction was quenched with 2N HC1 and extracted with Et20. The aqueous layer was neutralized with 5N NaOH (pH = 6), followed by extraction with THF: ether (1: 1) three times. The combined extracts were washed with brine, dried and concentrated under reduced pressure to provide 241 mg of the crude boronic acid, which was used without further purification. 4- (5- (Pyridin-3-yl) benzofuran-2-yl) benzaldehyde (step 3 in Reaction Scheme 2): The title compound was prepared as in Example of Compound 6 in the general method described above (44% yield): ?? NMR (400 MHz, CDC13) d 10.06 (s, 1H), 8.91 (broad s, 1H), 8.61 (broad s, 1H), 8.07 (d, 2H), 7.98 (d, 2H), 7.93 (d, 1H) ), 7.65 (d, 1H), 7.55 (d, 1H), 7.82 (m, 1H), 7.39 (m, 1H), 7.27 (m, 1H). MS (ESI) m / z: Calculated: 299.09; Observed: 300.30 (M ++ l). 1- (4- (5- (Pyridin-3-yl) benzofuran-2-yl) benzyl) -azetidine-3-carboxylic acid (step 4 in Reaction Scheme 2): The title compound was prepared as in the Example of Compound 6 in the general method described above (22% yield): H NMR (400 MHz, CD3OD) d 9.11 (broad s, 1H), 8.70 (m, 2H), 8.06 (m, 3H), 7.98 (m, 1H), 7.74 (m, 2H), 7.60 (d, 2H), 7.44 (s, 1H), 4.47 (s, 2H), 4.40-4.38 (m, 4H) 3.72 (ra, 1H). MS (ESI) m / z: Calculated: 384.20; Observed: 385.00 (M ++ l).

Compound 13 1- (4- (5-Isobutylbenzofuran-2-yl) benzyl) piperidine-4-carboxylic acid A mixture of 4- (5-isobutylbenzofuran-2-yl) enzaldehyde (22 mg, 0.08 mmol), acetic acid (7 pL, 0.12 mmol) and piperidin-4-carboxylic acid (15 mg, 0.12 mmol) in DCM / MeOH (1: 1, 1.4 mL) was stirred at room temperature for 1 hour. Sodium cyanoborohydride (2.5 mg, 0.04 mmol) was added and the reaction mixture was stirred for 4 hours at room temperature. After concentration of the solvent under reduced pressure, the resulting residue was dissolved in an aliquot of DMSO and purified by preparative reverse phase HPLC (column C18 (2) 5μ Luna reverse phase Phenomenex, DI 60 x 21.2 min), to provide the desired final product (16.9 mg, 55%): > 95% purity by LCMS, ESI-MS: 392.0 (M + H) +, 1 H NMR (400 MHz, CD 3 OD) d 8.01 (d, 2 H), 7.59 (d, 2 H), 7.43 (d, 1 H), 7.39 (s, 1H), 7.26 (s, 1H), 7.13 (dd, 1H), 4.36 (s, 2H), 3.58 (m, 2H), 3.10 (m, 2H), 2.65 (m, 1H), 2.57 ( d, 2H), 1.90 (m, 1H), 0.92 (d, 6H).

Compound 14 1- (4- (5-Benzylbenzofuran-2-yl) -2-fluorophenyl) methyl) azetidin-3-carboxylic acid 4- (5-Benzylbenzofuran-2-yl) -2-fluorobenzaldehyde: The title compound was prepared as in Example of Compound 1 (step 4 in Reaction Scheme 1) in the general method described above (67% yield): H NMR (400 MHz, CDC13) d 10.35 (s, 1H ), 7.92 (dd, J = 8.1, 7.0, 2H), 7.69 (d, J = 8.5, 1H), 7.63 (d, J = 11.4, 1H), 7.46-7.42 (m, 2H), 7.33-7.19 ( m, 6H), 7.13 (s, 1H), 4.09 (s, 2H). 1- ((4- (5-Benzylbenzofuran-2-yl) -2-fluorophenyl) methyl) azetidin-3-carboxylic acid: The title compound was prepared as in Example 1 of Compound 1 (step 5, Reaction Scheme 1) in the general method described above (54% yield):? NMR (400 MHz, CD30D) d 7.78 (d, J = 8.1, 1H), 7.73 (d, J = 9.9, 1H), 7.58 (t, J = 7.7, 1H), 7.46-7.44 (m, 2H), 7.29-7.16 (m, 7H), 4.39 (s, 2H), 4.17-4.15 (m, 4H), 4.06 (s, 2H), 3.72-3.64 (ra, 1H). MS (ESI) m / z: Calculated: 415.16; Observed: 416.0 (++ l).

Compound 15 1- (4- (5-Benzylbenzofuran-2-yl) -3-fluoro-enyl) methyl) azetidin-3-carboxylic acid 4- (5-Benzylbenzofuran-2-yl) -3-fluorobenzaldehyde: The title compound was prepared as in Example 1 of Compound 1 (step 4, Reaction Scheme 1) in the general method described above (65% yield): 1 H NMR (400 MHz, CDC13) d 10.01 (s, 1H) , 8.20 (t, J = 7.7, 1H), 7.77 (d, J = 8.0, 1H), 7.68 (d, J = 11.3, 1H), 7.47-7.45 (m, 2H), 7.37-7.20 (m, 7H ), 4.10 (s, 2H). 1- ((4- (5-Benzylbenzofuran-2-yl) -3-fluorophenyl) methyl) azetidin-3-carboxylic acid: The title compound was prepared as in Example 1 of Compound 1 (step 5, Reaction Scheme 1) in the general method described above (56% yield): XH NMR (400 MHz, CD3OD) d 8.09 (t, J = 7.9, 1H), 7.47-7.45 (m, 2H), 7.40-7.37 (m, 2H), 7.28-7.16 (m, 7H), 4.34 (s, 2H), 4.17-4.15 (m, 4H), 4.07 ( s, 2H), 3.53-3.45 (m, 1H). S (ESI) m / z: Calculated: 415.16; Observed: 415.9 (M ++ l).

Compound 16 1- (4- (5-Butoxybenzofuran-2-yl) phenyl) methyl) piperidin-4- acid A mixture of 4- (5-butoxybenzofuran-2-yl) benzaldehyde (50 mg, 0.20 mmol), piperidine-4-carboxylic acid (41 mg, 0.31 mmol) and acetic acid (0.50 mmol) in eOH-DCM (3: 1; 2 mL) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (135 mg, 0.64 mmol) was added and the reaction mixture was stirred for 16 hours. Concentration of the solvent under reduced pressure afforded a yellow solid which was dissolved in DMSO (3 mL) and filtered to give a yellow solution which was purified by HPLC to provide the desired product: 1 H NMR (400 MHz, CD3OD) d 7.98 ( d, 1H), 7.97 (d, 1H), 7.58 (d, 2H), 7.40 (d, 1H), 7.24 (s, 1H), 7.11 (d, 1H), 6.90 (dd, 1H), 4.35 (s) , 2H), 4.00 (dd, 2H), 3.55 (m, 2H), 3.3 (m, 1H), 3.10 (m, 2H), 2.2 (m, 2H), 1.8 (m, 2H), 1.52 (m, 2H), 1.28 (m, 2H), 1.00 (dd, 3H). MS (ESI) m / z: Calculated: 407.21; Observed: 407.90 (M ++ l).

Compound 17 1- (6- (5-Cyclohexylbenzofuran-2-yl) pyridin-3-ylmethyl) azetidin-3-carboxylic acid The title compound was prepared in the same manner as the Compound of Example 6, except that 6-bromo-3-pyridinecarboxaldehyde was used in step 3 (Reaction Scheme 2): > 95% purity by LCMS, ESI-MS: 391.1 (M + H) +,? NMR (400 MHZ, CD3OD) d 8.81 (d, 1H), 7.94 (d, 1H), 7.65 (d, 1H), 7.59 (s, 1H), 7.50 (m, 2H), 7.35 (m, 1H), 4.44 (s, 2H), 4.45 (s, 2H), 4.34 (dd, 4H), 3.69 (m, 1H), 2.64-2.57 (d, 1H), 1.89 (t, 4H), 1.58-1.41 (m, 4H), 1.38-1.26 (m, 2H).

Compound 18 1- (4- (5- (6-Methylpyridin-2-yl) benzofuran-2-yl) benzyl) azetidine-3-carboxylic acid (Reaction Scheme 2) The title compound was prepared in the same manner as the Compound of Example 6, except that zinc (II) (6-methylpyridin-2-yl) bromide was used in step 1 (Reaction Scheme 2): > 95% purity by LCMS, ESI-MS: 391.1 (M + H) + f 1 H NMR (400 MHz, CD 3 OD) d 8.42 (t, 1 H), 8.22 (d, 1 H), 8.07-8.10 (m, 3 H) , 7.77-7.88 (m, 3H), 7.62 (d, 2H), 7.50 (dd, 1H), 4.48 (s, 2H), 4.36 (d, 4H), 3.71 (m, 1H), 2.85 (s, 3H) ).

Compound 19 1- (4- (5-Phenoxybenzofuran-2-yl) benzyl) azetidine-3-carboxylic acid 1- (2,2-diethoxy-ethoxy) -4-phenoxy-benzene: The title compound was prepared as in he Example of Compound 1 (step 1, Reaction Scheme 1) in the general method described above.

-Penoxi-benzofuran The title compound was prepared as in Example of Compound 1 (step 2, Reaction Scheme 1) in the general method described above (65% yield): H NMR (400 MHz, CDC13) d 7.63 (d, 1H) , 7.45 (d, 1H), 7.29 (m, 2H), 7.22 (d, 1H), 7.00-7.08 (m, 4H), 6.71 (m, 1H).

-Phenoxybenzofuran-2-boronic acid: The title compound was prepared as in Example 1 of Compound 1 (step 3, Reaction Scheme 1) in the general method described above (74% yield). 4 - . 4 - . 4 - (5-Phenoxybenzofuran-2-yl) benzaldehyde: The title compound was prepared as in Example 1 of Compound 1 (step 4, Reaction Scheme 1) in the general method described above (65% yield): XH NMR (400 MHz, DMS0-d6) d 10.05 (s, 1H), 8.13 (d, 2H), 8.03 (d, 2H), 7.70 (d, 1H), 7.66 (s broad, 1H), 7.39 (m, 4H), 7.10 (m, 2H), 7.00 (dd, 1 HOUR) . MS (ESI) m / z: Calculated: 314.10; Observed: 315.10 (M ++ l). 1- (4- (5-Phenoxybenzofuran-2-yl) benzyl) azetidine-3-carboxylic acid: The title compound was prepared as in Example of Compound 1 (step 5, Reaction Scheme 1) in the general method described above (7% yield): 1 H NMR (400 MHz, CD 3 OD) d 7.90 (d, 2 H), 7.55 (m, 3 H), 7.32 (m, 2H), 7.27 (s, 1H), 7.22 (d, 1H), 7.03 (m, 4H), 4.47 (s, 2H), 4.34 (m, 4H), 3.62 (m, 1H). MS (ESI) m / z: Calculated: 399.20; Served: 399.90 (M ++ l).

Compound 20 1- (4- (5-Isopentylbenzofuran-2-yl) phenyl) methyl) azetidine-3-carboxylic acid 5-Isopentylbenzofuran: The title compound was prepared as in Example of Compound 6 (step 1 in Reaction Scheme 2) in the general method described above (75% yield): XH NMR (400 MHz, CDC13) d 7.58 (d, J = 2.0, 1H), 7.41-7.39 (m, 2H), 7.11 (dd, J = 8.2, 2.0, 1H), 6.70 (broad s, 1H), 2.72-2.68 (m, 2H), 1.62-1.51 (m , 3), 0.94 (d, J = 6.6, 6H).

-Isopentylbenzofuran-2-yl-2 -boronic acid: The title compound was prepared as in Example of Compound 6 (step 2 in Reaction Scheme 2) in the general method described above (53% yield): XH NMR (400 MHz, CDC13) d 7.43-7.38 (m , 2H), 7.30 (s, 1H), 7.18 (d, J = 8.5, 1H), 2.72-2.68 (m, 2H), 1.60-1.50 (m, 3), 0.94 (d, J = 6.6, 6H) . 4 - (5-1-Solpentylbenzofuran-2-yl) benzaldehyde: The compound of the title was prepared as Example of Compound 6 (step 3 in Reaction Scheme 2) in the general method described above (79% yield): XH NMR (400 MHz, CDC13) d 10.03 (s, 1H), 8.00 (d, J = 8.5, 2H), 7.95 (d, J = 8.5, 2H), 7.46-7.42 (m, 2H), 7.18-7.15 (m, 2H), 2.73-2.69 (m, 2H), 1.62- 1.54 (m, 3), 0.95 (d, J = 6.2, 6H). 1- (4- (5-Isopentylbenzofuran-2-yl) phenyl) methyl) -zetidin-3-carboxylic acid: The title compound was prepared as in Example of Compound 6 (step 4 in Reaction Scheme 2) in the general method described above (63% yield): ?? NMR (400 MHz, CD30D) d 7.98 (d, J = 8.3, 2H), 7.55 (d, J = 8.3, 2H), 7.43-7.41 (m, 2H), 7.23 (s, 1H), 7.15 (d, J = 8.8, 1H), 4.44 (s, 2H), 4.38-4.30 (m, 4H), 3.73-3.65 (m, 1H), 2.73-2.69 (m, 2H), 1.62-1.52 (m, 3), 0.96 (d, J = 7.6, 6H). MS (ESI) m / z: Calculated: 377.2; Observed: 377.9 (M ++ l).

Compound 21 1- (4- (6-Butoxybenzofuran-2-yl) phenylmethyl) azetidine-3-carboxylic acid 1- (2,2-Diethylethoxy) -3-butoxybenzene: The title compound was prepared as in Example of Compound 1 (step 1 in Reaction Scheme 1) in the general method described above (86% yield): ¾ NMR (400 MHz, CDC13) d 7.15 (t, J = 7.4), 6.52-6.49 (m, 3H), 4.83 (t, J = 5.1, 1H), 3.99 (d, J = 5.1, 2H), 3.93 (t, J = 6.6, 2H), 3.80-3.72 ( m, 2H), 3.67-3.60 (m, 2H), 1.79-1.72 (m, 2H), 1.53-1.43 (m, 2H), 1.25 (t, J = 7.3, 6H), 0.97 (t, J = 7.3 , 3H). 6 -. 6 -Butoxybenzofuran: The title compound was prepared as in Example of Compound 1 (step 2 in Reaction Scheme 1) in the general method described above (83% yield): XH NMR (400 MHz, CDC13) d 7.52 (d, J = 2.2, 1H), 7.44 (d , J = 8.5, 1H), 7.03 (d, J = 2.2, 1H), 6.87 (dd, J = 8.8, 2.5, 1H), 6.69-6.68 (m, 1H), 4.00 (t, J = 6.6, 2H ), 1.83-1.76 (m, 2H), 1.56-1.47 (m, 2H), 0.99 (t, J = 7.4, 3H). 6-Butoxybenzofuran-2-yl-2-boronic acid: The title compound was prepared as Example of Compound 1 (step 3 in Scheme 1) in the general method described above (76% yield): XH NMR (400 MHz, CDC13) d 7.52-7.42 (m, 2H), 7.00 (s broad, 1H), 6.90-6.85 (m, 1H), 4.00 (t, J = 6.6, 2H), 1.82-1.78 (m, 2H), 1.56-1.48 (m, 2H), 0.98 (t, J = 7.3, 3H). 4 - . 4 - (6 -Butoxybenzofuran-2-yl) benzaldehyde: The title compound was prepared as in Example of Compound 1 (step 4 in Reaction Scheme 1) in the general method described above (62% yield): XH NMR (400 MHz, CDC13) d 9.94 (s, 1H), 7.94-7.89 (m, 4H ), 7.45 (d, J = 8.5, 2H), 7.10 (s, 1H), 7.05 (broad d, J = 2.2, 1H), 6.89 (dd, J = 8.5, 2.2, 1H), 4.02 (t, J) = 6.2), 1.85-1.78 (m, 2H), 1.57-1.52 (m, 2H), 1.00 (t, J = 7.3, 3H). 1- ((4- (6-Butoxybenzofuran-2-yl) phenyl) methyl) azetidine-3-carboxylic acid: The title compound was prepared as in Example of Compound 1 (step 5 in Reaction Scheme 1) in the general method described above (46% yield): 1 H NMR (400 MHz, CD 3 OD) d 7.94 (d, J = 8.4, 2H), 7.53 (d, J = 8.4, 2H), 7.47 (d, J = 8.5, 1H), 7.21 (s, 1H), 7.11 (broad d, J = 2.2, 1H), 6.88 (dd) , J = 8.5, 2.2), 4.43 (S, 2H), 4.34-4.32 (m, 4H), 4.04 (t, J = 6.2), 3.71-3.63 (m, 1H), 1.81-1.76 (m, 2H) , 1.57-1.52 (m, 2H), 1.01 (t, J = 7.3, 3H). MS (ESI) m / z: Calculated: 379.18; Observed: 379.8 (M ++ l).

Compound 22 1- (2- (5-Butoxybenzofuran-2-yl) thiazol-5-yl) methyl) azetidine-3-carboxylic acid 2- (5-Butoxybenzofuran-2-yl) thiazole-5-carbaldehyde: The title compound was prepared as in the Example of Compound 1 (step 4 in Reaction Scheme 1) in the general method described above, except that 2-bromothiazole-5-carbaldehyde (29% yield) was used: XH NMR (400 MHz, CDCl 3) d 10.07 (s, 1H), 8.46 (dd, 1H), 7.45 (dd, 2H), 7.03 (dd, 2H), 4.01 (dd, 2H), 1.74 (m, 2H), 1.54 (m, 2H), 1.01 (t, 3H). MS (ESI) m / z: Calculated: 301.10; Observed: 302.10 (M ++ l). 1- (2- (5-Butoxybenzofuran-2-yl) thiazol-5-yl) methyl) azetidine-3-carboxylic acid: The title compound was prepared as in Example of Compound 1 (step 5 in Reaction Scheme 1) in the general method described above (36% yield): XH NMR (400 MHz, CD3OD) d 8.06 (broad s, 1H), 7.344 (m, 2H), 7.18 (m, 1H), 7.01 (ddd, 1H), 4.79 (s, 2H), 4.36 (m, 4H), 3.98 (m, 2H), 3.69 (m, 1H) ), 1.75 (m, 2H), 1.50 (m, 2H), 1.00 (t, 3H). MS (ESI) m / z: Calculated: 386.13; Observed: 386.90 (M ++ l).

Compound 23 1- (4- (5-Butoxybenzofuran-2-yl) -4-fluorophenyl) methyl) azetidine-3-carboxylic acid (5 -Butoxybenzofuran-2-yl) -4-fluorobenzaldehyde: The title compound was prepared as in Example of Compound 1 (step 4 in Reaction Scheme 1) in the general method described above (36% yield): XH NMR (400 Hz, CDC13) d 10.02 (s, 1H ), 8.18 (t, J = 7.7, 1H), 7.73 (d, J "= 8.0, 1H), 7.66 (d, J = 11.2, 1H), 7.44-7.39 (m, 2H), 7.09 (d, J) = 2.4, 1H), 6.92 (dd, J = 2.4, 8.8, 1H), 4.01 (t, J = 6.2), 1.81-1.76 (m, 2H), 1.57-1.51 (m, 2H), 1.01 (t, J "= 7.2, 3H). 1- ((4- (5-Butoxybenzofuran-2-yl) -4-fluorophenyl) methyl) azetidin-3-carboxylic acid: The title compound was prepared as in Example 1 of Compound 1 (step 5 in Reaction Scheme 1) in the general method described above (51% yield): ?? NMR (400 MHz, CD3OD) d 8.08 (t, J = 7.7, 1H), 7.44-7.37 (m, 3H), 7.25 (d, J "= 3.7, 1H), 7.14 (d, J = 2.2, 1H) , 6.94 (dd, J = 8.8, 2.2), 4.35 (s, 2H), 4.18-4.15 (m, 4H), 4.01 (t, J = 6.2), 3.45-3.37 (m, 1H), 1.82-1.75 ( m, 2H), 1.57-1.49 (m, 2H), 1.00 (t, J = 7.2, 3H) MS (ESI) m / z: Calculated: 397.17; Observed: 397.9 (M ++ l).

Compound 24 1- (4- (5-Butoxybenzofuran-3-yl) -3-methoxyphenyl) azetidine-3-carboxylic acid 4- (5-Butoxybenzofuran-2-yl) -3-methoxybenzaldehyde: The title compound was prepared as in the Example of Compound 1 (step 4 in Reaction Scheme 1) in the general method described above (65% yield): ¾ NMR (400 MHz, CD3C1) d 10.03 (s, 1H ), 8.22 (d, 1H), 7.59 (S, 1H), 7.50 (s, 1H), 7.45 (d, 1H), 7.41 (s, 1H), 7.08 (d, 1H), 6.93 (d, 1H) , 4.16 (s, 3H), 4.05 (t, 2H), 1.84 (m, 2H), 1.61 (m, 2H), 1.04 (t, 3H). MS (ESI) m / z: Calculated: 324.14; Observed: 324.9 (M ++ l). 1- (4- (5-Butoxybenzofuran-2-yl) -3-methoxyphenyl) -azetidine-3-carboxylic acid: The title compound was prepared as in Example of Compound 1 (step 5 in Reaction Scheme 1) in the general method described above (36% yield): 1 H NMR (400 MHz, CD30D) d 8.04 (d, 1H ), 7.39 (s, 1H), 7.38 (s, 1H), 7.21 (s, 1H), 7.15 (d, 1H), 7.08 (s, 1H), 6.83 (d, 1H), 4.44 (s, 2H) , 4.38 (m, 7H), 4.02 (m, 2H), 3.62 (m, 1H), 1.82 (m, 2H), 1.63 (m, 2H), 1.01 (t, 3H). MS (ESI) m / z: Calculated: 409.19; Observed: 409.9 (M ++ l).

Compound 25 1- (5- (5-Butoxybenzofuran-2-yl) thiophen-2-yl) methyl) azetidine-3-carboxylic acid 5- (5-Butoxybenzofuran-2-yl) thiophene-2-carbaldehyde: The title compound was prepared as in the Example of Compound 1 (step 4 in Reaction Scheme 1) in the general method described above, except that 5-bromothiophen-2 -carbaldehyde (32% yield) was used: 1 H NMR (400 MHz, CDC13) d 9.92 (s, 1H), 7.73 (d, 1H), 7.51 (dd, 1H), 7.39 (d, 1H), 7.96 (m, 2H), 6.94 (dd, 1H), 3.98 (dd, 2H), 1.80 (m, 2H), 1.70 (ra, 2H), 1.01 (t, 3H). 1- ((5- (5-Butoxybenzofuran-2-yl) thiophen-2-yl) methyl) -zetidine-3-carboxylic acid: The title compound was prepared as in the Example of Compound 1 (step 5 in Reaction Scheme 1) in the general method described above (27% yield):? NMR (400 MHz, CD3OD) d 7.49 (broad s, 1H), 7.35 (m, 2H), 7.03 (d, 2H), 6.89 (dd, 1H), 4.67 (s, 2H), 4.35 (m, 4H) , 3.98 (m, 2H), 3.67 (m, 1H), 1.73 (m, 2H), 1.51 (m, 2H), 0.99 (t, 3H). MS (ESI) m / z: Calculated: 385.13; Observed: 385.70 (M ++ l).

Compound 26 1- (6- (5-Butoxybenzofuran-2-yl) iridin-3-yl) methyl) azetidin-3-carboxylic acid 4- (5-Butoxybenzofuran-2-yl) iridin-3-carboxaldehyde: The title compound was prepared in the same manner as described in step 4 (Reaction Scheme 1), using 6-bromo-3-pyridinecarboxaldehyde (48%): 1 H NMR (400 MHz, CDC13) d 10.10 (s, 1H), 9.08 (s, 1H), 8.24 (d, 1H), 8.01 (d, 1H), 7.56 (s, 1H), 7.47 (d, 1H), 7.02 (s, 1H), 6.99 (d, 1H) ), 4.03 (c, 4H), 1.84-1.77 (m, 2H), 1.50-1.48 (m, 2H), 1.00 (t, 3H). MS (ESI) m / z: Calculated: 295.33; Observed: 296.2 (M ++ l). 1- (6- (5-Butoxylbenzofuran-2-yl) pyridin-3-yl) methyl) -zetidin-3-carboxylic acid: The title compound was prepared as in step (Reaction Scheme 1) of the general method described at the beginning (68% yield): a? RN (400 MHz, CDC13) d 8.86 (S, 1H), 8.19 (d, 1H), 7.90 (d, 1H), 7.49 (s, 1H), 7.47 (d, 1H), 7.23 (d, 1H), 6.86 (s, 1H), 3.80 (c, 2H), 4.52-4.40 (m, 4H), 3.80 (t, 2H), 3.52-3.47 (m, 1H), 1.68-1.66 (m, 2H), 1.44- 1.37 (m, 2H), 0.94 (t, 3H). MS (ESI) m / z: Calculated: 380.44; Observed: 381.0 (M ++ l).

Compound 27 1- (4- (5-Cyclohexylbenzofuran-2-yl) -3-fluorophenyl) methyl) azetidin-3-carboxylic acid-Cyclohexylbenzofuran (step 1 in the Reaction Scheme) 2) : -Bromobenzofuran (500 mg, 2.55 mmol) was dissolved in a THF solution of zinc (II) cyclohexyl bromide (0.5 M, 15 mL, 7.40 mmol) in a microwave reaction tube. Pd (PtBu3) 2 (65 mg, 0.128 mmol, 0.05 equivalents) was added to this solution. The mixture was purged with N 2 gas for 3-5 minutes and heated at 100 ° C for 30 minutes under microwave radiation. After the end of the reaction, the reaction mixture was diluted with ethyl acetate, washed with an aqueous 1N HC1 solution, brine, filtered through Celite. The filtrate was dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (ISCO system, 5% EtOAc in hexanes), to give 0.217 g of the desired product (43% yield): XH RN (400 MHz, CDC13) d 7.57 (d , 1H), 7.41 (d, 2H), 7.15 (d, 1H), 6.72 (d, 1H), 2.58 (m, 1H), 1.92-1.74 (m, 4H), 1.51-1.35 (m, 4H), 1.31-1.25 (m, 2H).

-Cyclohexylbenzofuran-2-boronic acid (step 2 in Scheme 2): A solution of n-BuLi (360 μl, 0.9 mmol, 2.5 M solution in hexanes) was added dropwise to a solution of 5-cyclohexylbenzofuran (150 mg, 0.75 mmol) in anhydrous THF (5 mL) at -78 ° C. The resulting mixture was stirred at -78 ° C for 40 minutes, and was treated with B (1PrO) 3 (260 μm, 1.13 mmol). The reaction mixture was allowed to slowly warm to room temperature and was stirred for 1 hour. TLC indicated completion of the reaction. The reaction was cooled in an ice bath and quenched with 2N HCl (3 mL) and extracted with Et20. The combined organic extracts were washed with brine, dried and concentrated under reduced pressure to provide a desired boronic acid (0.156 g, 85% yield) without further purification for the next step. ¾ NMR (400 MHz, CDC13) d 7.46 (s, 1H), 7.43 (d, 1H), 7.32 (s, 1H), 7.25 (d, 1H), 2.62 (m, 1H), 1.93-1.85 (m, 4H), 1.78-1.75 (m, 4H), 1.34-1.22 (m, 2H). 4- (5-Cyclohexylbenzofuran-2-yl) -2-fluorobenzaldehyde (step 3 in Reaction Scheme 2): A mixture of 5-cyclohexylbenzofuran-2-ylboronic acid (75 mg, 0.30 mmol), 4-bromo-2-fluorobenzaldehyde (48 mg, 0.24 mmol), triethylamine (1.1 mL, 7.5 mmol) and bis (triphenylphosphine) aladium chloride (II) (12 mg, 0.05 mmol) in ethanol (11 mL) was irradiated in a micro-wave instrument at 100 ° C for 20 minutes. The reaction mixture was cooled, and the solvent was removed. The residue was treated with water and extracted with ethyl acetate. The organic layer was dried and concentrated in vacuo (work of the aqueous layer is optional). Purification by chromatography on silica gel in an ISCO system afforded the title compound (51 mg, 49% yield). XH NMR (400 MHz, CDC13) d 10.04 (s, 1H), 8.00-7.97 (m, 2H), 7.46 (s, 1H), 7.43 (d, 2H), 7.32 (s, 1H), 7.25 (d, 1H), 2.62 (m, 1H), 1.95-1.77 (m, 4H), 1.58-1.56 (m, 4H), 1.46-1.44 (m, 2H). MS (ESI) m / z: Calculated: 322.27; Observed: 323.2 (M ++ l). 1- (4- (5-Cyclohexylbenzofuran-2-yl) -3-fluorophenyl) -methyl) azetidine-3-carboxylic acid (step 4 in Reaction Scheme 2): A mixture of 4- (5-cyclohexylbenzofuran-2-yl) -3-fluorobenzaldehyde (40 mg, 0.12 mmol), acetic acid (10 μ, 0.15 mmol) and azetidin-3-carboxylic acid (15 mg, 0.15 mmol) ) in DCM / MeOH (1: 1, 2 mL), was stirred at room temperature for 1 hour. Sodium cyanoborohydride (3.0 mg, 0.05 mmol) was added and the reaction mixture was stirred for 3 hours at room temperature. After concentration of the solvent under reduced pressure, the resulting residue was dissolved in hot MeOH and filtered. The filtrate and the white solid, which was redissolved in hot DMSO, were both purified by preparative reverse phase HPLC (Phenomenex Reverse Phase 5μ Luna C18 (2) column, DI 60 x 21.2 mm), to provide the final product desired (12 mg, 42% yield) as a white powder: > 95% purity by LCMS, 1 H NMR (400 MHz, CD 3 OD) d 8.12 (d, 1 H), 7.47-7.38 (m, 4 H), 7.28-7.20 (m, 2 H), 4.66 (s, 2 H), 4.34 ( m, 4H), 3.72 (m, 1H), 2.61 (m, 1H), 1.95-1.82 (m, 4H), 1.60-1.56 (m, 4H), 1.42-1.40 (m, 2H). MS (ESI) m / z: Calculated: 407.48; Observed: 408.2 (M ++ l).

Compound 28: 1- (4- (5- (Thiophene-2-yl) -benzofuran-2-yl) -phi-Dimethyl) -zetidine-3-carboxylic acid 5- (thiophen-2-yl) -benzofuran: The title compound was prepared as in Example of Compound 6 (step 1 in Reaction Scheme 2) in the general method described above, except that thiophen-2-ylboronic acid (55% yield) was used. "" "H NMR (400 MHz, CD3C1) d 7.82 (s, 1H), 7.62 (s, 1H), 7.55-7.03 (m, 5H), 6.79 (d, 1H). - (thiophen-2-yl) benzofuran-2-yl-boronic acid: The title compound was prepared as in Example of Compound 6 (step 2 in Reaction Scheme 2) in the general method described above (77% yield). H NMR (400 MHz, CD3Cl) d 7.92 (s, 1H), 7.88 (s, 1H), 7.66-7.34 (m, 4H), 7:08 (d, 1H). 4- (5- (thiophen-2-yl) benzofuran-2-yl) benzaldehyde: compound of the title was prepared as Example of Compound 6 (step 3 in Reaction Scheme 2) in the general method described above (61% yield): XH NMR (400 MHz, CD3C1) d 10.01 (s, 1H), 8.19 (d, 1H), 8.01 (d, 1H), 7.82 (s, 1H), 7.62-7.24 (m, 7H), 7.16 (dd, 1H). MS (ESI) m / z: Calculated: 304.06; Observed: 304.9 (M ++ l). 1- ((4- (5- (thiophen-2-yl) benzofuran-2-yl) phenyl) methyl) -azetidin-3-carboxylic acid: The title compound was prepared as Example of Compound 6 (step 4 in Reaction Scheme 2) in the general method described above (31% yield): 1 H NMR (400 MHz, DMSO-d 6) d 8.01 (d, 2H) , 7.87 (s, 1H), 7.64-7.44 (m, 7H), 7.19 (dd, 1H), 4.25 (m, 2H), 3.55 (m, 5H). MS (ESI) m / z: Calculated: 389.11; Observed: 389.9 (M ++ l).

Compound 29 3- (6- (5-Benzylbenzofuran-2-yl) -3,4-dihydroisoquinolin-2 (1H) -yl) propanoic acid 2- (3-Bromophenyl) ethanamine (step 1 in Reaction Scheme 7) : A suspension of LiAlH4 (3.04 g, 80 rare) in Dry THF (100 mL) was cooled to -5 ° C. Concentrated H2SO4 (3.9 g, 40 mmol) was added dropwise, and the resulting mixture was stirred at -5 ° C for 1 hour. A solution of 3-bromo-benzencetonitrile (9.80 g, 50 mmol) in THF (5 ml) was added dropwise, and the reaction was allowed to warm to room temperature when the addition was complete. The reaction was stirred at room temperature for 1 hour, and then returned to 0 ° C and quenched by the addition of a 1: 1 mixture of THF: H20 (12.4 ml). Et20 (50 mL) was added, followed by a 3.6 M NaOH solution (24.4 mL). The mixture was filtered through Celite, and the solids were washed well with additional Et20. The organic phase was dried over Na 2 SO 4, filtered and concentrated in vacuo to give the title compound (9.7 g, 97%). The crude compound was used in the subsequent steps. XH NMR (400 MHz, CDC13) d 7.38-7.30 (m, 2H), 7.20-7.10 (m, 2H), (t, 2H), 2.72 (t, 2H), 1.35 (broad s, 2H). MS (ESI) Calculated: 199; Observed: 200/202 (M ++ l).

N- (3-Bromophenethyl) -2,2,2-trifluoroacetamide (step 2 in Reaction Scheme 7): A mixture of 3-bromobenzene-amine (9.70 g, 48.5 mmol) and 2,6-lutidine (5.8 mL, 50.0 mmol) in dry CH2C12 (150 mL) was cooled to 0 ° C. Trifluoroacetic anhydride (5.6 ml, 40 mmol) was added dropwise; the reaction was then allowed to warm to room temperature and allowed to stir for 24 hours. Water (120 ml) was added to the reaction, the phases were separated, and the aqueous layer was extracted with CH2C12 (2 x 100 ml). The combined organic phases were washed successively with 1N HC1 (100 mL) and saturated NaHCO3 (100 mL), then dried over Na2SO4, filtered and concentrated in vacuo to provide the title compound (12.3 g, 86% ). The crude compound was used in the subsequent steps RN (400 MHz, CDC13) d 7.40 (d, J = 8.0 Hz, 1H), 7.36 (s, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H) , 6.31 (broad s, 1H), 3.59 (c, J = 6.8 Hz, 2H), 2.87 (t, J = 7.2 Hz, 2H). 1- (6-Bromo-3,4-dihydroisoquinolin-2 (1H) -yl) -2,2,2-trifluoroethanone and 1- (8-bromo-3,4-dihydroisoquinolin-2 (1H) -yl) - 2, 2, 2 -trifluoroethanone (step 3 in Scheme 7): A mixture of glacial acetic acid (68 ml) and concentrated sulfuric acid (45 ml) was added to a mixture of N- (3-bromophenethyl) -2,2, 2-trifluoroacetamide (12.3 g, 41.54 mmol) and paraformaldehyde (2.0 g). The reaction was stirred at room temperature for 24 hours, and then poured into 300 mL of cold water. The aqueous solution was extracted with EtOAc (3 x 150 mL). The combined organic phases were washed with saturated NaHCO3 (200 ml) and water (2 x 200 ml). The organic phase was then dried over Na 2 SO 4, filtered and concentrated in vacuo. The residue was purified on an ISCO column (20% EtOAc / Hexane), to provide a mixture of the title compounds (9.6 g, 75%). ¾ NMR (400 MHz, CDC13) d 7.46 (dd, J = 2.0 Hz, J = 8.0 Hz, 0.33H), 7.38-7.31 (m, 1.33H), 7.15-7.09 (m, 0.67H), 7.05-6.98 (m, 0.67H), 4.75, 4.73, 4.69 (3 xs, 2H), 3.90-3.80 (m, 2H), 3.00-2.90 (m, 2H). MS (ESI) m / z: Calculated: 306.98; Observed: 308/310 (M ++ l). 6- (5-Benzylbenzofuran-2-yl) -1,2,3,4-tetrahydroisoquinoline (step 4 in Reaction Scheme 7): A solution of 5-benzylbenzofuran-2-ylboronic acid (252 mg, 1.0 mmol) in ethanol (3 mL) was added to a mixture of 1- (6-bromo-3,4-dihydroisoquinolin-2 (1H) -yl. ) -2, 2, 2-trifluoroethanone and 1- (8-bromo-3,4-dihydroisoquinolin-2 (1H) -yl) -2,2,2-trifluoroethanone (308 mg, 1.0 mmol), Pd (PPh3) 4, toluene and 2 M Na 2 CO 3 (3.5 ml). The resulting mixture was heated to reflux overnight. The reaction was concentrated in vacuo, and the residue was diluted with water. The aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine, dried over Na 2 SO 4, filtered and concentrated in vacuo. The residue was purified on an ISCO column (5% to 10% MeOH / CH 2 Cl 2), to give the title compounds (189 mg, 56%). ¾ NMR (400 MHz, CDC13) d 7.60 (m, 2H), 7.39 (dd, 1H), 7.37 (s, 1H), 7.25 (m, 5H), 7.10 (dd, 2H), 6.90 (s, 1H), 4.10 (s, 2H), 3.40 (s, 2H), 3.18 ( m, 2H), 2.94 (m, 2H). MS (ESI) m / z: Calculated: 339.16; Observed: 340.10 (M ++ l). 3- (6- (5-Benzylbenzofuran-2-yl) -3,4-dihydroisoquinolin-2 (1H) -yl) tert-butyl propanoate (step 5 in Reaction Scheme 6): The 6- (5-benzylbenzofuran-2-yl) -1,2,3,4-tetrahydroisoquinoline (67 mg, 0.2 mmol) was dissolved in methanol (2 mL). DIEA (0.35 ml) and tert-butyl ester of acrylic acid (51 mg, 0.4 mmol) were added. The mixture was heated at 90 ° C for 30 minutes using microwave radiation. All solvents were evaporated and the crude product of tert-butyl 3- (6- (5-benzylbenzofuran-2-yl) -3,4-dihydroisoquinolin-2 (1 H) -yl) propanoate was used in the next step without additional purification. MS (ESI) m / z: Calculated: 467.25; Observed: 468.30 (M ++ l). 3- (6- (5-Benzylbenzofuran-2-yl) -3,4-dihydroisoquinolin-2 (1 H) -yl) propanoic acid (step 6 in Reaction Scheme 7): To a solution of tert-butyl 3- (6- (5-benzylbenzofuran-2-yl) -, 4-dihydroisoquinolin-2 (1H) -yl) propanoate (40 mg, 0.086 mmol) in CH2C12 (1 mL), TFA (1 ml) was added. The mixture was stirred at room temperature for 3 hours. All solvents were evaporated. The mixture was purified by preparative reverse phase HPLC to provide the title compound (14 mg, 40%). X H NMR (400 MHz, CD 3 OD) d 7.77 (m, 2 H), 7.42 (dd, 1 H), 7.40 (s, 1 H), 7.20-7.30 (m, 5 H), 7.10 (m, 3 H), 4.50 (s, 2H), 4.04 (s, 2H), 3.64 (dd, 2H), 3.55 (dd, 2H), 3.26 (dd, 2H), 2.90 (dd, 2H). MS (ESI) m / z: Calculated: 411.18; Observed: 412.10 (M ++ l).

Compound 30 1- (4- (5-Cyclopentylbenzofuran-2-yl) benzyl) azetidine-3-carboxylic acid 5-Cyclopentylbenzofuran: The title compound was prepared as in Example of Compound 6 (step 1 in Reaction Scheme 2) in the general method described above (67% yield):? NMR (400 MHz, CDC13) d 7.58 (d, J = 2.2, 1H), 7.45 (broad d, J = 1.8, 1H), 7.41 (d, J = 8.8, 1H), 7.18 (dd, J = 8.8, 1.8, 1H), 6.71 (dd, J = 1.1, 2.2, 1H), 3.13-3.05 (ra, 1H), 2.14-2.07 (m, 2H), 1.88-1.58 (m, 6H).

-Cyclopentylbenzofuran-2-yl-2 -boronic acid: The title compound was prepared as in Example of Compound 6 (step 2 in Reaction Scheme 2) in the general method described above (yield): XH NMR (400 MHz, CDC13) d 7.50-7.45 (m, 2H) , 7.43-7.39 (m, 1H), 7.31 (s, 1H), 3.12-3.05 (m, 1H), 2.14-2.06 (m, 2H), 1.80-1.60 (m, 6H). 4 - . 4 - (5-Cyclopentylbenzofuran-2-yl) benzaldehyde: The title compound was prepared as in Example of Compound 6 (step 3 in Reaction Scheme 2) in the general method described above (95% yield):? NMR (400 MHz, CDC13) d 10.03 (s, 1H), 8.00 (d, J = 8.0, 2H), 7.94 (d, J = 8.0, 2H), 7.51-7.44 (m, 3H), 7. 15 (s, 1H), 3.14-3.06 (m, 1H), 2.20-2.10 (m, 2H), 1.88-1.62 (m, 6H). 1- (4- (5-Cyclopentylbenzofuran-2-yl) benzyl) azetidine-3-carboxylic acid (step 4 in Reaction Scheme 2): The title compound was prepared as in Example of Compound 6 (step 4 in Reaction Scheme 2) in the general method described at the start for reductive amination (71% yield). 1 H NMR (400 MHz, CD 3 OD) d 8.02 (d, 2 H), 7.57 (d, 2 H), 7.49 (s, 1 H), 7.44 (d, 1 H), 7.25 (d, 2 H), 4.56 (s, 2 H) , 4.30 (m, 4H), 3.62 (m, 1H), 3.11 (m, 1H), 2.25-2.12 (m, 2H), 1.90-1.66 (m, 6H). MS (ESI) m / z: Calculated: 375.46; Observed: 375.9 (M ++ l).

Compound 31 1- (3-Luoro-4- (5- (piperidin-1-yl) benzofuran-2-yl) benzyl) azetidin-3-carboxylic acid 1- (Benzofuran-5-yl) iperidine (step 1 of Scheme 3): -bromobenzofuran (2 g, 10 mmol), piperidine (1.2 mL, 12 mmol), Pd (dppf) Cl2 (245 mg, 0.3 mmol), dppf (250 mg, 0.45 mmol) and sodium tert-butoxide (1.44 g) , 15 mmol) were mixed in toluene (10 mL). The mixture was purged with N 2 gas for 3-5 minutes and heated at 120 ° C for 30 minutes under microwave radiation (microwave reactor Personal Chemistry Emrys ™ Optimizer). After completion of the reaction, the reaction mixture was loaded directly onto a column on silica gel and purified in an ISCO system (<2% EtOAc in hexanes), to provide 0.539 g of the desired product (27% of yield): ESI-MS: 202.3 (M + H) +, XH RN (400 MHz, CDC13) d 7.58 (s, 1H), 7.40 (d, 1H), 7.15 (s, 1H), 7.00 (d, 1H) ), 6.65 (s, 1H), 3.10 (m, 4H), 1.70 (m, 4H), 1.48 (m, 2H). Note: the title compound appears to be very volatile. The evaporation of the solvent should be carried out very carefully.

- (Piperidin-1-yl) benzofuran-2-ylboronic acid (step 2 of Reaction Scheme 3): A solution of n-BuLi (334 yL, 0.83 mmol, 2.5 M solution in hexanes) was added dropwise to a solution of 1- (benzofuran-5-yl) piperidine (140 mg, 0.70 mmol) in anhydrous THF (5 mg). mL) at -78 ° C. The resulting mixture was stirred at -78 ° C for 40 minutes, and treated with B (iPrO) 3 (241) i ~ L, 1.04 mmol). The reaction mixture was allowed to slowly warm to room temperature and was stirred for 1 hour. TLC indicated completion of the reaction. The reaction was cooled in an ice bath and quenched with saturated NH4C1 (1.5 mL) and extracted with Et20. The separated aqueous layer was neutralized to pH ~ 5. The solution became turbid, which was extracted with ethyl acetate (x 3). The combined organic extracts were concentrated in vacuo, affording the desired boronic acid as brown solids (0.16 g, 94% yield) without further purification for the next step. ESI-MS: 246.3 (M + H) +. 3-Fluoro-4- (5- (piperidin-1-yl) benzofuran-2-yl) benzaldehyde (step 3 of Reaction Scheme 3): A mixture of 5- (piperidin-1-yl) benzofuran-2-ylboronic acid (50 mg, 0.204 mmol), 4-bromo-3-fluorobenzaldehyde (37 mg, 0.184 mmol), triethylamine (0.56 mL, 4.1 mmol) and bis (triphenylphosphine) palladium (II) chloride (14 mg, 0.02 mmol) in ethanol (5 mL), was irradiated in a microwave instrument at 100 ° C for 20 minutes. The reaction mixture was cooled, and the solvent was removed. The residue was purified by chromatography on silica gel in the ISCO system to provide the title compound (15 mg, 15% yield). ESI-MS: 324.2 (M + H) +, XH RN (400 MHz, CDC13) d 10.00 (s, 1H), 8.19 (t, 1H), 7.75 (d, 1H), 7.67 (d, 1H), 7.43 (d, 1H), 7.35 (d, 1H), 7.14-7.11 (m, 2H), 3.13 (m, 4H), 1.77 (m, 4H), 1.59 (m, 2H).

Salt of trifluoroacetic acid acid 1- (3-fluoro-4- (5- (piperidin-1-yl) benzofuran-2-yl) benzyl) azetidine-3-carboxylic acid (step 4 of Reaction Scheme 3): A mixture of 3-fluoro-4- (5- (piperidin-1-yl) benzofuran-2-yl) benzaldehyde (9 mg, 0.028 mmol), acetic acid (2.5 μ? ^ 0.042 mmol) and azetidin-3-acid carboxylic acid (4.2 mg, 0.042 mmol) in DCM / MeOH (2: 1, 0.9 mL) was stirred at room temperature for 1 hour. Sodium cyanoborohydride (1.0 mg, 0.014 mmol) was added and the reaction mixture was stirred for 3 hours at room temperature. After concentration of the solvent under reduced pressure, the resulting residue was dissolved in DMSO, and purified by preparative reverse phase HPLC (column C18 (2) of 5μ Luna reverse phase Phenomenex, DI 60 x 21.2 mm, mobile phase: A = 0.05% of TFA in water; B = 0.05% TFA in acetonitrile. The flow rate was 12 mL / minute. The time gradient was 2% B to 52% B over 25 minutes), to provide the desired final product (10.3 mg, 70% yield) as a white powder (ditrifluroacetic acid salt): > 95% purity by LCMS, ESI-MS: 409.1 (M + H) +, XH NMR (400 MHz, CD3OD) d 8.17 (t, 1H), 8.02 (d, 1H), 7.81 (d, 1H), 7.66 (dd, 1H), 7.49-7.47 (m, 3H), 4.50 (s, 2H), 4.39 (dd, 4H), 3.72-3.70 (m, 5H), 2.08 (m, 4H), 1.84 (m, 2H ).

Compound 32 1- (6- (5-Benzylbenzofuran-2-yl) pyridin-3-ylmethyl) azetidine-3-carboxylic acid 6- (5-Benzylbenzofuran-2-yl) nicotinaldehyde: The title compound was prepared as in the Compound of Example 1 (step 4 in Reaction Scheme 1) in the general method described above, except that 6-bromo-3-pyridinecarboxaldehyde (53% yield) was used: XH NMR (400 MHz, DMSO-de) d 10.13 (s, 1H), 9.15 (s, 1H), 8.36 (d, 1H), 8.14 (m, 1H), 7.76 (d, 1H), 7.62 (m, 2H) , 7.29 (m, 6H), 4.07 (s, 2H). MS (ESI) m / z: Calculated: 313.11; Observed: 314.20 (M ++ l). 1- (6- (5-Benzylbenzofuran-2-yl) iridin-3-yl) methyl) azetidin-3-carboxylic acid: The title compound was prepared as in the Example of Compound 1 (step 5 in Reaction Scheme 1) in the general method described above (33% yield):? NMR (400 MHz, CD30D) d 8.68 (s, 1H), 8.01 (broad s, 2H), 7.45 (m, 3H), 7.16 (m, 6H), 4.50 (s, 2H), 4.35 (m, 4H) , 4.04 (s, 2H), 3.70 (ra, 1H). MS (ESI) 'm / z: Calculated: 398.16; Observed: 399.00 (M ++ l).

Compound 33 1- (4- (5-Benzylbenzofuran-2-yl) -3-methoxyphenyl) methyl) azetidin-3-carboxylic acid 4- (5-Benzylbenzofuran-2-yl) -3-methoxybenzaldehyde: The title compound was prepared as in Example of Compound 1 (step 4 in Reaction Scheme 1) in the general method described above (60% yield): XH NMR (400 MHz, CDC13) d 10.03 (s, 1H ), 8.22 (d, 1H), 7.64-7.44 (m, 11H), 4.16 (m, 5H). MS (ESI) m / z: Calculated: 342.13; Observed: 342.9 (M ++ l). 1- ((4- (5-Benzylbenzofuran-2-yl) -3-methoxyphenyl) methyl) -azetidin-3-carboxylic acid: The title compound was prepared as in Example 1 of Compound 1 (step 5 in Reaction Scheme 1) in the general method described above (50% yield): ?? NMR (400 MHz, D S0-d6) d 7.98 (d, 1H), 7.42-7.07 (m, 11H), 4.18 (m, 2H), 3.82 (m, 5H), 3.57 (m, 1H), 3.14 ( m, 4H). MS (ESI) m / z: Calculated: 427.18; Observed: 427.9 (M ++ l).

Compound 34 1- (4- (5- (Piperidin-1-yl) benzofuran-2-yl) benzyl) azetidin-3-carboxylic acid 4- (5- (Piperidin-1-yl) benzofuran-2-yl) benzaldehyde (step 3 of Reaction Scheme 3): A mixture of 5- (piperidin-1-yl) benzofuran-2-ylboronic acid (90 mg, 0.367 mmol), 4-bromobenzaldehyde (62 mg, 0.330 mmol), triethylamine (1.0 mL, 7.3 mmol) and bis ( triphenylphosphine) aladium (II) (12.8 mg, 0.02 mmol) in ethanol (9 mL) was irradiated in a microwave instrument at 100 ° C for 20 minutes. The reaction mixture was cooled, and the solvent was removed. The residue was purified by chromatography on silica gel in the ISCO system to provide the title compound (31 mg, 28% yield). ESI-MS: 306.4 (M + H) +, XH NMR (400 MHz, CDC13) d 10.02 (s, 1H), 7.95 (d, 4H), 7.42 (d, 1H), 7.11 (m, 2H), 7.07 (dd, 1H), 3.13 (t, 4H), 1.78-1.74 (m, 4H), 1.62-1.56 (m, 2H). 1- (4- (5- (Piperidin-1-yl) benzofuran-2-yD-benzyl) azetidine-3-carboxylic acid (step 4 of Scheme 3): A mixture of 4- (5- (piperidin-1-yl) benzofuran-2-yl) benzaldehyde (31 mg, 0.102 mmol), acetic acid (9 μ, 0.15 mmol) and azetidin-3-carboxylic acid (12.3 mg, 0.122 mmol) in DCM / MeOH (2: 1, 1.5 mL), was stirred at room temperature for 1 hour. Sodium cyanoborohydride (3.2 mg, 0.051 mmol) was added and the reaction mixture was stirred for 3 hours at room temperature. After concentration of the solvent under reduced pressure, the resulting residue was dissolved in DMSO, and purified by preparative reverse phase HPLC (column C18 (2) of Phenomenex reverse phase 5μ Luna, DI 60 x 21.2 mm, mobile phase: A = 0.05% TFA in water, B = 0.05% TFA in acetonitrile), to provide the desired final product (29.1 mg, 57% yield) as a white powder (ditrifluroacetic acid salt): > 95% purity by LCMS, ESI-MS: 391.1 (M + H) +, XH NMR (400 MHz, CD3OD) d 8.05 (t, 3H), 7.79 (d, 1H), 7.65-7.62 (m, 3H) , 7.47 (s, 1H), 4.48 (m, 2H), 4.38-4.32 (m, 4H), 3.73-3.70 (m, 5H), 2.15 (m, 4H), 1.16 (m, 2H).

Compound 35 6- (5-benzylbenzofuran-2-yl) -2- (2-carboxyethyl) -3,4-dihydroisoquinolinio 2,2,2-trifluoroacetate (step 6 in Reaction Scheme 7); The title compound was isolated by preparative reverse phase HPLC during purification of Compound 29. JH NMR (400 MHz, CD3OD) d 9.17 (s, 1H), 8.04 (m, 2H), 7.90 (d, 1H), 7.50 (m, 3H), 7.23 (m, 6H), 4.28 (dd, 2H), 4.16 (dd, 2H), 4.08 (s, 2H), 3.34 (m, 2H), 3.03 (m, 2H). MS (ESI) m / z: Calculated: 410.18; Observed: 410.30 (M +).

Compound 36 1- (4- (5-Benzylbenzofuran-2-yl) -3-chloropheniDmethyl) azetidine-3-carboxylic acid Trifluoromethansulonate 4 - (ethoxycarbonyl) -2-chlorophenyl: Trifluoroacetic anhydride (4.6 mL, 27.2 mmol) was added dropwise to a solution of ethyl 3-chloro-4-hydroxybenzoate (5.02 g, 25.0 mmol) and pyridine (2.2 mL, 27.5 mmol) in DCM (31 mL) at -10 ° C. The reaction mixture was stirred for 1 hour at -10 ° C, allowed to warm to room temperature and stirred for an additional 2 hours. The reaction mixture was quenched with H20, and the resulting biphasic mixture was stirred for 15 minutes. The layers were separated and the organic layer was washed with 0.2 N HCl, water and brine. The final organic layer was dried (Na2SO4) and concentrated under reduced pressure to provide 6.8 g of a white solid, containing a mixture of triflate and the remaining phenol. The mixture was redissolved in DCM and passed through a plug of silica gel to provide 3.8 g (45%) of the pure triflate and 3 g of the impure product with raw material. NMR (400 MHz, CDC13) d 8.21 (d, J = 1.8, 1H), 8.03 (dd, J 1.8, 1H), 7.43 (d, J = 8.5, 1H), 4.42 (c, J "= 7.3, 2H ) (t, J = 7.3, 3H).

Ethyl 4- (5-benzylbenzofuran-2-yl) -3-chloro-benzoate (step 2 in Reaction Scheme 5): The title compound was prepared as in Example of Compound 40 (step 2 of Reaction Scheme 5) in the general method described above (94% yield): XK NMR (400 MHz, CDC13) d 8.15-8.12 (m, 2H), 8.00 (broad d, J = 8.4, 1H), 7.62 (s, 1H), 7.45-7.44 (m, 2H), 7.32-7.19 (m, 6H), 4.42 (c, J = 7.3, 2H), 4.09 (s, 2H), 1.42 (t, J = 7.3, 3H). (4- (5-Benzylbenzofuran-2-yl) -3-chlorophenyl) methanol (step 3 in Reaction Scheme 5): The title compound was prepared as in Example of Compound 40 (step 3 of Reaction Scheme 5 ) in the general method described above (66 mg of a 1: 1 mixture of primary alcohol and aldehyde which was used without further purification). 4- (5-Benzylbenzofuran-2-yl) -3-chlorobenzaldehyde (step 4 in Reaction Scheme 5): The title compound was prepared as in Example of Compound 40 (step 4 of Reaction Scheme 5) in the general method described above (63% for the two steps): XH NMR (400 MHz, CDC13) d 10.00 (s, 1H), 8.24 (d, J = 8.4, 1H), 7.99 (d, J = 1.4, 1H), 7.86 (dd, J = 8.0, 1.5), 7.69 (s, 1H), 7.47-7.45 (m, 2H ), 7.32-7.19 (m, 6H), 4.10 (s, 2H). 1- (4- (5-Benzylbenzofuran-2-yl) -3-chlorobenzyl) -azetidine-3-carboxylic acid (step 5 in Reaction Scheme 5): The title compound was prepared as in Example of Compound 40 (step 5 in Reaction Scheme 5) in the general method described above (42% yield): XH NMR (400 MHz, DMS0-d6) d 8.05 (d, J = 7.8, 1H), 7.76 -7.72 (m, 1H), 7.59-7.54 (m, 4H), 7.27-7.16 (m, 6H), 4.46-4.36 (m, 2H), 4.32-4.16 (m, 4H), 4.03 (s, 2H) 3.64-3.58 (m, 1H). MS (ESI) m / z: Calculated: 431.13; Observed: 431.9 (M ++ l).

Compound 37 3- (6- (5-Cyclopentylbenzofuran-2-yl) -3,4-dihydroisoquinolin-2 (1 H) -yl) propanoic acid 3- (6-Hydroxy-3,4-dihydroisoquinoline-2 (1H) - il) tert-butyl propanoate (step 1 in Reaction Scheme 8): A solution of 1,2,3,4-tetrahydroisoquinolin-6-ol hydrobromide (345 mg, 1.5 mmol), tert-butyl acrylate (0.44 ml, 3.0 mmol) and N-ethyl-N-isopropylpropan-2-amine (2.6 ml, 15.0 mmol) in MeOH was irradiated in a microwave at 90 ° C for 1800 seconds. Removal of the solvents gave the residue, which was purified on an ISCO column (2% to 5% MeOH / CH 2 Cl 2), to provide the title compounds (332 mg, 80%). ?? NMR (400 MHz, CD30D) d 6.85 (d, 1H), 6.55 (dd, 1H), 6.54 (s, 1H), 3.55 (s, 2H), 2.83 (m, 4H), 2.76 (m, 2H), 2.54 (dd, 2H), 1.45 (s, 9H). MS (ESI) m / z: Calculated: 277.17; Observed: 277.90 (M ++ l). 3- (6- (Trifluoromethylsulfonyloxy) -3,4-dihydroisoquinolin-2 (1H) -yl) tert-butyl-thiolate (step 2 in the Scheme of Reaction 8): Trifluorosulfonic anhydride (87 μL, 0.52 mmol) was added to the solution of tert-butyl 3- (6-hydroxy-3,4-dihydroisoquinolin-2 (1 H) -yl) propanoate (111 mg, 0.4 mmol) in pyridine ( 5 mL) at 0 ° C. The reaction mixture was stirred for 1 hour at room temperature, concentrated, purified on an ISCO column (2% to 5% MeOH / CH 2 Cl 2) to give the title compounds (93 mg, 57%). ?? NMR (400 MHz, CD3OD) d 7.20 (d, 1H), 7.12 (s, 1H), 7.10 (s, 1H), 3.68 (s, 2H), 2.94 (dd, 2H), 2.83 (dd, 2H), 2.78 (dd, 2H), 2.54 (dd, 2H), 1.44 (s, 9H). MS (ESI) m / z: Calculated: 409.12; Observed: 409.80 (++ l). 3- (6- (5-Cyclopentylbenzofuran-2-yl) -3,4-dihydroisoquinolin-2 (1H) -yl) tert-butyl propanoate (step 3 in Reaction Scheme 8): A mixture of 5-cyclopentylbenzofuran-ylboronic acid (78 mg, 0.34 mmol), 3- (6- (trifluoromethylsulfonyloxy) -3,4-dihydroisoquinolin-2 (1H) -yl) tert-butyl-butylate (93 mg, 0.23 mmol) ), triethylamine (0.95 mL, 6.8 mmol) and bis (triphenylphosphine) palladium (II) chloride (16 mg, 0.02 mmol) in ethanol (5 mL), was irradiated in a microwave instrument at 100 ° C for 20 minutes. The reaction mixture was cooled, and the solvent was removed. The residue was purified by chromatography on silica gel in the ISCO system to provide the title compound (34 mg, 34% yield). XH N (400 MHz, CDC13) 6 7.59 (m, 2H), 7.40 (d, 2H), 7.15 (dd, 1H), 7.07 (d, 1H), 6.91 (s, 1H), 3.70 (s, 2H) , 3.08 (m, 1H), 2.96 (dd, 2H), 2.85 (dd, 2H), 2.78 (dd, 2H), 2.54 (dd, 2H), 2.11 (m, 2H), 1.84 (m, 2H), 1.68 (m, 4H), 1.46 (s, 9H). MS (ESI) m / z: Calculated: 445.26; Observed: 446.00 (M ++ l). 3- (6- (5-Cyclopentylbenzofuran-2-yl) -3,4-dihydroisoquinolin-2 (1 H) -yl) propanoic acid (step 4 in Reaction Scheme 8): To a stirred solution of tert-butyl 3- (6- (5-cyclopentylbenzofuran-2-yl) -3,4-dihydroisoquinolin-2 (1H) -yl) propanoate (25 mg, 0.056 mmol) in CH2C12 (0.5 ml) ), TFA (0.5 ml) was added. The mixture was stirred at room temperature for 3 hours. Under reduced pressure, the solvents and excess TFA were removed, yielding a yellow oil, which was rinsed with a mixture of CH2Cl2 / Hexane (1: 4), followed by ether. The solvents were removed under vacuum to provide the title compound (19 mg, 90%). ?? NMR (400 MHz, CD3OD) d 7.82 (m, 2H), 7.47 (s, 1H), 7.40 (d, 1H), 7.30 (d, 1H), 7.20 (d, 1H), 7.19 (s, 1H), 4.54 (broad, 2H), 3.69 (broad, 2H), 3.60 (dd, 2H), 3.28 (m, 2H), 3.10 (m, 1H), 2.96 (dd, 2H), 2.10 (m, 2H), 1.85 (m, 2H), 1.74 (m, 2H), 1.65 (m, 2H). MS (ESI) m / z: Calculated: 389.2; Observed: 390.20 (M ++ l).

Compound 38 1- (4- (5- (Cyclopentylmethoxy) benzofuran-2-yl) -3-fluorobenzyl) azetidin-3-carboxylic acid 5-Hydroxybenzofuran (step 1 of Reaction Scheme 4): To an ice cooled solution of 5-methylbenzofuran (0.5 g, 3.37 mmol) in DCM (7 mL) was added boron tribromide (3.4 mL, 3.37 mmol, 1M in DCM). The light brown solution was stirred at 0 ° C for 1 hour, then another equivalent of boron tribromide (3.4 mL) was added. The mixture was stirred at room temperature for 2 hours. TLC analysis indicated completion of the reaction. The mixture was poured into ice and the pH adjusted to 7 with Na 2 CO 3. The aqueous layer was extracted with DCM (x2). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated. The resulting light brown solid gave a satisfactory purity without further purification for the next step: 0.36 g (79.6% yield), 1 H NMR (400 MHz, CD3OD) d 7.59 (d, J = 2.0 Hz, 1H), 7.35 (d , J = 9.2 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.82 (dd, J = 8.8 Hz, J = 2.8 Hz, 1H), 6.67 (m, 1H), 4.73 (s, 1H) ).

- (Cyclopentylmethoxy) benzofuran (step 2 of Scheme 4) Slowly add DEAD (362 mg, 2.09 mmol) to a solution of 5-hydroxybenzofuran (200 mg, 1.49 mmol), triphenylphosphine (547 mg, 2.09 mmol) and cyclopentyl-methanol (203 mg, 2.02 mmol) in 3 mL of THF . The mixture was stirred at room temperature for 16 hours. The solvent was removed and the residue was purified by chromatography on an ISCO column using 0-5% AcOEt in Hexanes. The title compound was obtained as a white solid (0.208 g, 65% yield): 84% pure by HPLC; X H NMR (400 MHz, CD 3 OD) d 7.58 (d, 1 H), 7.38 (d, J = 8.4 Hz, 1 H), 7.06 (s, 1 H), 6.91 (d, J = 9.2 Hz, 1 H), 6.69 (m , 1H), 3.82 (d, 2H), 2.39 (m, 1H), 1.85 (m, 2H), 1.63 (m, 4H), 1.39 (m, 2H).

- (Cyclopentylmethoxy) benzofuran-2-boronic acid (step 3 of Reaction Scheme 1) The title compound was prepared as in the Example of Compound 1 (step 3 in Reaction Scheme 1) by the general method C described above (94.7% yield):? NMR (400 MHz, CD30D) d 7.39 (d, J = 9.2 Hz, 1H), 7.30 (s, 1H), 7.07 (d, 1H), 6.99 (dd, J = 9.2 Hz, J = 2.4 Hz, 1H) , 3.82 (d, J = 7.0 Hz, 2H), 2.39 (m, 1H), 1.86 (m, 2H), 1.63 (m, 4H), 1.39 (m, 2H). 4- (5- (Cyclopentylmethoxy) benzofuran-2-yl) -3-fluorobenzaldehyde (step 4 of Reaction Scheme 1) The title compound was prepared as in Example 1 of Compound 1 (step 4 in Reaction Scheme 1) by the general method D described above (53% yield): ESI-MS: 339.3 (MH-H) +, XH RN (400 MHz, CD3OD) d 10.0 (S, 1H), 8.20 (t, 1H), 7.30 (s, 1H), 7.77 (d, 1H), 7.68 (d, 1H), 7.43 (d, 1H), 7.36 (d, 1H), 7.09 (s, 1H), 6.99 (dd, 1H), 3.88 (d, J = 7.0 Hz, 2H), 2.39 (m, 1H), 1.86 (m, 2H), 1.63 (m , 4H), 1.39 (m, 2H). 1- (4- (5- (Cyclopentylmethoxy) benzofuran-2-yl) -3-fluorobenzyl) azetidine-3-carboxylic acid (step 5 of Scheme 1) The title compound was prepared as in the Example of Compound 1 (step 5 in Reaction Scheme 1) by the general method E described above (79% yield): ESI-MS: 423.9 (M + H) + f XH NMR (400 MHz, CD3OD) d 8.11 (t, 1H), 7.45-7.40 (m, 3H), 7.28 (d, 1H), 7.15 (d, 1H), 6.95 (dd, 1H), 4.46 (s, 2H) ), 4.36-4.34 (m, 4H), 3.88 (d, J = 7.4 Hz, 2H), 3.68 (m, 1H), 2.38 (m, 1H), 1.85 (m, 2H), 1.65 (m, 4H) , 1.43 (m, 2H).

Compound 39 1- (4- (5- (Cyclopentylmethoxy) benzofuran-2-yl) benzyl) azetidine-3-carboxylic acid 4- (5- (Cyclopentylmethoxy) benzofuran-2-yl) benzaldehyde (step 4 of Reaction Scheme 1 ) The title compound was prepared as in the Example of Compound 1 (step 4 in Reaction Scheme 1) by the general method D described above (33% yield): ESI-MS: 321.2 (M + H) +, XH NMR (400 MHz, CD3OD) d 10.0 (s, 1H), 7.98 (dd, 4H), 7.43 (d, 1H), 7.14 (s, 1H), 7. 07 (d, 1H), 6.96 (dd, 1H), 3.88 (d, J = 7.0 Hz, 2H), 2.41 (m, 1H), 1.86 (m, 2H), 1.63 (m, 4H), 1.39 (m , 2H). 1- (4- (5- (Cyclopentylmethoxy) benzofuran-2-yl) benzyl) azetidine-3-carboxylic acid (step 5 of Scheme 1) The title compound was prepared as in Example of Compound 1 (step 5 in Reaction Scheme 1) by general method E described above (76% yield): ESI-MS: 405.9 (M + H) +, ¾ NMR (400 MHz, CD30D) d 7.97 (d, 2H), 7.55 (d, 2H), 7.40 (d, 1H), 7.23 (s, 1H), 7.11 (d.1H), 6.95 (dd, 1H), 4.44 (s, 2H), 4.35- 4.33 (m, 4H), 3.88 (d, J = 7.0 Hz, 2H), 3.69 (m, 1H), 2.38 (m, 1H), 1.87 (m, 2H), 1.65 (m, 4H), 1.43 (m , 2H).

Compound 40 1- (4- (5-Benzylbenzofuran-2-yl) -3- cyanophenyl) methyl) azetidin-3-carboxylic acid t 4- (Ethoxycarbonyl) -2-cyano-phenyl trifluoromethanesulfonate: Tí ° NC ~~ cooEt The title compound was prepared as in Example of Compound 36 in the general method described above (92% yield): XH NMR (400 MHz, CDC13) d 8.61 (s, 1H), 8.40 (d, 1H), 7.96 (d, 1H), 4.23 (c , 2H), 1.21 (t, 3H).

Ethyl-4- (5-benzylbenzofuran-2-yl) -3-cyanobenzoate (step 4, Reaction Scheme 1): The title compound was prepared as Example of Compound 1 (step 4, Reaction Scheme 1) in the general method described above (26% yield): X H NMR (400 MHz, CDC 13) d 8.42 (s, 1 H), 8.31 ( d, 1H), 8.19 (d, 1H), 7.81 (s, 1H), 7.42 (d, 2H), 7.32-7.17 (m, 6H), 4.38 (c, 2H), 4.06 (s, 2H), 1.41 (t, 3H). 2- (5-Benzylbenzofuran-2-yl) -5- (hydroxymethyl) benzonitrile (step 3, Reaction Scheme 5): A solution of ethyl 4- (5-benzylbenzofuran-2-yl) -3-cyanobenzoate (0.05 g, 0.13 mmol), sodium borohydride (0.01 g, 0.26 mmol) and calcium chloride (0.015 g, 0.13 mmol) in Ethanol (2.5 mL) was stirred at room temperature for 1 hour. Water was added and the aqueous layer was extracted with ethyl acetate (x2, 10 mL). The organic layer was washed with water and brine and dried over sodium sulfate in 75% yield: XH NMR (400 MHz, CDC13) d 8.06 (d, 1H), 7.79 (s, 1H), 7.64 (d, 1H), 7.63 (s, 1H), 7.43-7.21 (m, 8H), 4.78 (s, 2H), 4.06 (s, 3H). 2- (5-Benzylbenzofuran-2-yl) -5-formylbenzonitrile (step 4, Reaction Scheme 5): A suspension of 2- (5-benzylbenzofuran-2-yl) -5- (hydroxymethyl) benzonitrile (0.03 g, 0.09 mmol), molecular sieves of 4A (0.2 g), TPAP (0.0016 mg, 0.004 mmol) and N-morpholino oxide (0.02 g, 0.18 mmol) in acetonitrile, stirred for 1 hour and then filtered through celite. to obtain the title compound in 93% yield (step 4, Reaction Scheme 5): 1 H NMR (400 MHz, CDC13) d 10.05 (s, 1H), 8.25 (s, 1H), 8.24 (d, 1H ), 8.14 (d, 1H), 7.84 (s, 1H), 7.45 (m, 2H), 7.38-7.18 (m, 6H), 4.06 (s, 2H). 1- (4- (5-Benzylbenzofuran-2-yl) -3-cyanophenyl) methyl) -zetidine-3-carboxylic acid (step 5, Reaction Scheme 1): The title compound was prepared as in Example 1 of Compound 1 (step 5, Reaction Scheme 1) in the general method described above (28% yield): 1 H NMR (400 MHz, DMSO-d 6) d 8.18 (d, 1H), 8.09 (s, 1H), 7.82 (d, 1H), 7.64 (s, 1H), 7.61 (s, 1H), 7.59 (d, 1H), 7.38-7.18 (m, 6H), 4.85 (broad s, 2H), 4.42 (s, 2H), 4.38-4.25 (m, 4H), 4.06 (s, 2H), 3.74-3.66 (m, 1H ). MS (ESI) m / z: Calculated: 422.16; Observed: 423.0 (M ++ l).

Compound 41 1- (4- (5-Benzylbenzofuran-2-yl) -3-fluorophenyl) methyl) pyrrolidin-3-carboxylic acid The title compound was prepared as a racemic mixture according to the reductive amination procedure as described in step 5 of Reaction Scheme 1 (60% yield). XH NMR (400 MHz, CD3OD) d 8.11 (t, 1H), 7.47-7.44 (m, 4H), 7.27-7.19 (m, 7H), 4.45 (s, 2H), 4.05 (s, 2H), 3.73- 3.52 (m, 2H), 3.48-3.34 (m, 3H), 2.51-2.38 (m, 2H). MS (ESI) m / z: Calculated: 429.48; Observed: 430.0 (M ++ l).

Compound 42 1- (4- (5-Cyclopentylbenzofuran-2-yl) -3-fluorobenzyl) azetidin-3-carboxylic acid 4- (5-Cyclopentylbenzofuran-2-yl) -3-fluorobenzaldehyde (Step 3 in the Reaction Scheme) 2) : A solution of 5-cyclopentylbenzofuran-2-ylboronic acid (276 mg, 1.2 mmol), 4-bromobenzaldehyde (162 mg, 0.80 mmol), dichlorobis (triphenylphosphine) palladium (56 mg, 0.08 mmol) and triethylamine (2.2 mL, 16 mmol) ) in EtOH (5 mL), was irradiated in the microwave at 100 ° C for 20 minutes. The reaction mixture was cooled, and the solvent was removed. The residue was purified by chromatography on silica gel in the ISCO system to provide the title compound (34 mg, 34% yield). ¾ NMR (400 MHz, CDC13) d 10.0 (s, 1H), 8.21 (dd, 1H), 7.77 (d, 1H), 7.66 (d, 1H), 7.51 (S, 1H), 7.46 (d, 1H) , 7.38 (d, 1H), 7.28 (d, 1H), 3.11 (m, 1H), 2.12 (m, 2H), 1.84 (m, 2H), 1.72 (m, 2H), 1.64 (m, 2H). 1- (4- (5-Cyclopentylbenzofuran-2-yl) -3-fluorobenzyl) azetidine-3-carboxylic acid (step 5 in Reaction Scheme 1) The title compound was prepared as in the Example of Compound 1 (step 5 in Reaction Scheme 1) in the general method described above (20 mg, 18% yield):? NMR (400 MHz, CD3OD) d 8.09 (dd, 1H), 7.51 (s, 1H), 7.44 (d, 1H), 7.40 (s, 1H), 7.37 (d, 1H), 7.29 (m, 2H), 4.34 (s, 2H), 4.14 (m, 4H), 3.39 (m, 1H), 3.11 (m, 1H), 2.12 (m, 2H), 1.85 (m, 2H), 1.74 (m, 2H), 1.65 (m, 2H). MS (ESI) m / z: Calculated: 393.17; Observed: 393.90 (M ++ l).

Compound 43 1- (4- (5-Benzylbenzofuran-2-yl) -3-methylphenyl) methyl) azetidine-3-carboxylic acid; 4- (5-Benzylbenzofuran-2-yl) -3-methyl-methyl-benzoate (step 2 in Reaction Scheme 5): The title compound was prepared as in Example of Compound 40 (step 2, Reaction Scheme 5) in the general method described above (52% yield): ?? NMR (400 MHz, CDC13) d 7.89 (m, 2H), 7.61 (d, 1H), 7.42-7.17 (m, 8H), 6.95 (s, 1H), 4.06 (s, 2H), 3.82 (S, 3H) ), 2.61 (s, 3H). (4- (5-Benzylbenzofuran-2-yl) -3-methylphenyl) methanol (step 3 in Reaction Scheme 5): The title compound was prepared as in Example of Compound 40 (step 3, Reaction Scheme 5) in the general method described above (86% yield): XH NMR (400 MHz, CDC13) d 7.94 (s, 1H) , 7.82 (d, 1H), 7.48-7.07 (m, 9H), 6.85 (s, 1H), 4.67 (s broad, 1H), 4.06 (s, 4H), 2.58 (s, 3H). 4- (5-Benzylbenzofuran-2-yl) -3-methylbenzaldehyde (step 4 in Reaction Scheme 5): The title compound was prepared as in Example of Compound 40 (step 4, Reaction Scheme 5) in the general method described above (90% yield): ¾ NMR (400 MHz, CDC13) d 10.03 (s, 1H) , 8.07 (d, 1H), 7.81 (m, 2H), 7.46-7.17 (m, 8H), 7.01 (s, 1H), 4.08 (s, 2H), 2.63 (s, 3H).

Acid 1-. { (4- (5-Benzylbenzofuran-2-yl) -3-methylphenyl) -methyl) azetidine-3-carboxylic acid (step 5 in Scheme 1): The title compound was prepared as in Example 1 of Compound 1 (step 5, Reaction Scheme 1) in the general method described above (62% yield): K NMR (400 MHz, CD3OD) d 7.92 (d, 1H) , 7.51-7.17 (m, 10H), 7.03 (s, 1H), 4.84 (s broad, 2H), 4.41 (s, 2H), 4.37-4.22 (m, 4H), 4.08 (s, 2H), 3.68- 3.61 (m, 1H), 2.63 (s, 3H). MS (ESI) m / z: Calculated: 411.18; Observed: 411.9 (M ++ l).

Compound 44: 3- (6- (5-Butoxybenzofuran-2-yl) -3,4-dihydroisoquinolin-2 (1 H) -yl) ropanoic acid 3- (6- (5-Butoxybenzofuran-2-yl) -3,4 di-tert-butyl-thiohydroisoquinolin-2 (1H) -yl) -tetanoate (step 3 in Reaction Scheme 8): The title compound was prepared as in the Example of Compound 37 (step 3 in Reaction Scheme 8) in the general method described above (57 mg, 50% yield):? NMR (400 MHz, CDC13) d 7.57 (m, 2H), 7.36 (d, 1H), 7.06 (d, 1H), 7.00 (d, 1H), 6.88 (s, 1H), 6.85 (d, 1H), 3.99 (dd, 2H), 3.68 (s, 2H), 2.96 (dd, 2H), 2.85 (dd, 2H), 2.78 (dd, 2H), 2.53 (dd, 2H), 1.80 (m, 2H) , 1.56 (m, 2H), 1.45 (s, 9H), 1.00 (t, 3H). MS (ESI) m / z: Calculated: 449.26; Observed: 449.90 (M ++ l). 3- (6- (5-Butoxybenzofuran-2-yl) -3,4-dihydroisoquinolin-2 (1 H) -yl) propanoic acid (step 4 in Reaction Scheme 8): The title compound was prepared as in the Example of Compound 37 (step 4 in Reaction Scheme 8) in the general method described above (25 mg, 75% yield): XH NMR (400 MHz, CD3OD) d 7.79 ( m, 2H), 7.38 (d, 1H), 7.30 (d, 1H), 7.17 (s, 1H), 7.09 (d, 1H), 6.88 (dd, 1H), 4.54 (broad s, 2H), 4.00 ( dd, 2H), 3.68 (m, 2H), 3.60 (dd, 2H), 3.21 (m, 1H), 2.95 (dd, 2H), 1.78 (m, 2H), 1.53 (m, 2H), 1.00 (t, 2H). MS (ESI) m / z-. Calculated: 393.19; Observed: 394.20 (M ++ l).

Compound 45: 3- (5- (5-Benzylbenzofuran-2-yl) -2,3-dihydro-lH-inden-2-acid The title compound was prepared according to the reductive amination procedure as described in step 5 of Scheme 1 (60% yield) XH NMR (400 MHz, CD3CI3) d 7.80-7.74 (m, 2H), 7.54 (d, 1H), 7.40-7.22 (m, 7H), 7.18 (d, 1H ), 6.92 (s, 1H), 4.79 (s, 1H), 4.02 (s, 2H), 3.28-2.92 (m, 4H), 2.73 (t, 2H), 2.48-2.30 (m, 2H), MS ( ESI) m / z: Calculated: 411.49; Observed: 412.7 (M ++ l).

Compound 46 3- ((4- (5-Benzylbenzofuran-2-yl) -3-fluorophenyl) methylamino) -3-methylbutanoic acid: The title compound was prepared as in Example 1 of Compound 1 (step 5, in Reaction Scheme 1) in the general method described above, but using 3-amino-3-methylbutanoic acid instead of azetidin-3-acid. carboxylic (46% yield): 1 H NMR (400 MHz, CD3OD) d 8.11 (t, J = 7.8, 1H), 7.50-7.17 (m, 12H), 4.28 (a, 2H), 4.07 (s, 2H) , 1.51 (s, 6H). MS (ESI) m / z: Calculated: 431.19; Observed: 432.0 (M ++ l).

Compound 47 1- (4- (5-Cyclopentylbenzofuran-2-yl) -3-methoxyphenyl) methyl) azetidin-3-carboxylic acid 4- (5-Cyclopentylbenzofuran-2-yl) -3-methoxybenzaldehyde: The title compound was prepared as in Example 1 of Compound 1 (step 4 in Reaction Scheme 1) in the general method described above (56% yield): XH NMR (400 MHz, CDC13) d 10.04 (s, 1H ), 8.21 (d, 1H), 7.77 (d, 1H), 7.59-7.19 (m, 5H), 4.04 (s, 3H), 3.11 (m, 1H), 2.15-1.77 (m, 4H), 1.58- 1.56 (m, 4H). 1- (4- (5-Cyclopentylbenzofuran-2-yl) -3-methoxyphenyl) methyl) azetidin-3-carboxylic acid The title compound was prepared as in the Example of Compound 1 (step 5, in Reaction Scheme 1) in the general method described at the start for reductive amination (71% yield). 1 H NMR (400 MHz, CD 3 OD) d 8.16 (d, 1 H), 7.45 (s, 1 H), 7.41-7.36 (m, 2 H), 7.26-7.17 (m, 3 H), 4.85 (broad s, 2 H), 4.41 (s, 2H), 4.32 (m, 4H), 4.04 (s, 3H), 3.62 (m, 1H), 3.11 (m, 1H), 2.25-2.12 (m, 2H), 1.90-1.66 (m, 6H) ). MS (ESI) m / z: Calculated: 405.19; Observed: 405.9 (M ++ l).

Compound 48 1- (4- (5-Benzylbenzofuran-2-yl) -3,5-difluorophenyl) methyl) azetidin-3-carboxylic acid: 4- (5-Benzylbenzofuran-2-yl) -3,5-difluorobenzaldehyde : The title compound was prepared as in Example 1 of Compound 1 (step 4, Reaction Scheme 1) in the general method described above (66% yield): XH NMR (400 MHz, CDC13) d 10.04 (s, 1H) , 7.66 (S, 1H), 7.45 (d, 1H), 7.41-7.17 (m, 8H), 4.08 (s, 2H). 1- (4- (5-Benzylbenzofuran-2-yl) -3,5-difluorophenyl) -methyl) azetidine-3-carboxylic acid: The title compound was prepared as in Example of Compound 1 (step 5, Reaction Scheme 1) in the general method described above (62% yield): XH NMR (400 MHz, DMSO-d6) d 7.55 (s, 1H), 7.47 (d, 1H), 7.41-7.12 (m, 8H), 4.42 (s, 2H), 4.37-4.22 (m, 7H), 4. 06 (s, 2H), 3.72-3.64 (m, 1H). MS (ESI) m / z: Calculated: 433.15; Observed: 433.9 (M ++ l).

Compound 49 1- (4- (5- (Cyclopentylmethoxy) benzofuran-2-yl) -3-fluorobenzyl) azetidine-3-carboxylic acid 5- (Cyclopropylmethoxy) benzofuran (step 2 of Reaction Scheme 4): The title compound was prepared as in the Example of Compound 38 (step 2 in Reaction Scheme 4) by the general method described above (49% yield): XH NMR (400 MHz, CD3OD) 5 7.60 (d, 1H ), 7.38 (d, 1H), 7.05 (s, 1H), 6.94 (d, 1H), 6.69 (m, 1H), 3.84 (d, 2H), 1.31 (m, 1H), 0.66 (m, 2H) 0.37 (m, 2H).

- (Cyclopropylmethoxy) benzofuran-2-boronic acid (step 3 of Reaction Scheme 1) The title compound was prepared as in Example 1 of Compound 1 (step 3 in Reaction Scheme 1) by general method C described above (98% yield): XH NMR (400 MHz, CD30D) d 7.39 (d, 1H), 7.29 (s, 1H), 7.06 (d, 1H), 7.00 (dd, 1H), 3.83 (d, J = 6.9 Hz, 2H), 1.30 (m, 1H), 0.66 (m, 2H), 0.38 (m, 2H). 4- (5- (Cyclopropylmethoxy) benzofuran-2-yl) -3-fluorobenzaldehyde (step 4 of Reaction Scheme 1) The title compound was prepared as in the Example of Compound 1 (step 4 in Reaction Scheme 1) by the general method D described above (50% yield): ESI-MS: 311.2 (M + H) +, XU NMR (400 MHz, CD3OD) d 10.01 (s, 1H), 8.20 (t, 1H), 7.78 (d, 1H), 7.69 (d, 1H), 7.44 (d, 1H), 7.36 (d, 1H), 7.08 (s, 1H), 7.01 (d, 1H), 3.85 (d, J = 7.1 Hz, 2H), 1.32 (m, 1H), 0.68 (m, 2H), 0.38 (m, 2H). 1- (4- (5- (Cyclopentylmethoxy) benzofuran-2-yl) -3-fluorobenzyl) azetidine-3-carboxylic acid: The title compound was prepared as in Example 1 of Compound 1 (step 5 in Reaction Scheme 1) by the general method E described above (68% yield): ESI-MS: 395.9 (M + H) +, ¾ NMR (400 MHz, CD3OD) d 8.01 (t, 1H), 7.35-7.30 (m, 3H), 7.17 (d, 1H), 7.04 (d, 1H), 6.87 (dd, 1H), 4.37 (s, 2H) ), 4.28-4.25 (ra, 4H), 3.76 (d, J = 6.7 Hz, 2H), 3.60 (m, 1H), 1.18 (m, 2H), 0.54-0.51 (m, 2H), 0.28-0.26 ( m, 2H).

Compound 50 1- (4- (5-Butoxybenzofuran-2-yl) -3-chlorophenyl) methyl) azetidin-3-carboxylic acid trifluoromethanesulfonate 2-chloro-4-formylphenyl: The title compound was prepared as in Example of Compound 36 in the general method described above, but using 3-chloro-4-hydroxybenzaldehyde in place of ethyl 3-chloro-4-hydroxybenzoate (92% yield): XH NMR (400 MHz, CDC13) d 10.00 (S, 1H), 8.06 (d, J = 1.8, 1H), 7.88 (dd, J = 8.4, 1.8, 1H), 7.55 (d, J = 8.4, 1H). 4- (5-Butoxybenzofuran-2-yl) -3-chlorobenzaldehyde: The title compound was prepared as in Example of Compound 1 (step 4 in Reaction Scheme 1) in the general method described above (72% yield): XH NMR (400 MHz, CDC13) d 10.00 (s, 1H), 8.25 (d, J = 8.0 , 1H), 7.99 (d, J = 1.4, 1H), 7.86 (dd, J = 8.4, 1.5), 7.70 (s, 1H), 7.42 (d, J = 8.8), 7.10 (d, J = 2.6, 1H), 6.99 (dd, J = 8.8, 2.5), 4.01 (t, J = 6.5, 2H), 1.84-1.77 (m, 2H), 1.54-1.49 (m, 2H), 1.00 (t, J = 7.3 , 3H). 1- (4- (5-Butoxybenzofuran-2-yl) -3-chlorophenyl) methyl) -zetidine-3-carboxylic acid: The title compound was prepared as in the Example of Compound 1 (step 5 in Reaction Scheme 1) in the general method described above (66% yield): XH NMR (400 MHz, CD30D) d 8.13 (d, J = 8.4, 1H), 7.70 (d, J = 1.8, 1H), 7.57 (s, 1H), 7.53 (dd, J "= 8.4, 1.8, 1H), 7.42 (d, J" = 9.1, 1H), 7.15 (d, J = 2.5 1H), 6.95 (dd, J = 9.1, 2.5), 4.45 (s, 2H), 4.40-4.32 (m, 4H), 4.00 (t, J = 6.5, 2H), 3.74-3.66 (m, 1H), 1.81-1.74 (m, 2H), 1.58-1.49 (m, 2H), 1.00 (t, J = 7.3, 3H). Calculated: 413.14; Observed: 413.9 (M ++ l).

Compound 51 1- (3-Chloro-4- (5-cyclopentylbenzofuran-2-yl) phenyl) methyl) azetidine-3-carboxylic acid ethyl 3-chloro-4- (5-cyclopentylbenzofuran-2-yl) benzoate: The title compound was prepared as in Example of Compound 40 (step 2 in Reaction Scheme 5) in the general method described above (73% yield): XH NMR (400 MHz, CDC13) d 8.14 (d, J = 7.8, 2H), 8.00 (d, J = 8.1, 1H), 7.64 (s, 1H), 7.51-7.44 (m, 3H), 4.42 (c, J = 7.0, 2H), 3.12-3.08 (m, 1H), 2.16-2.08 (m, 2H), 1.84-1.58 (m, 6H), 1.42 (t, J = 7.3, 3H). (3-Chloro-4- (5-cyclopentylbenzofuran-2-yl) phenyl) methanol: The title compound was prepared as in Example of Compound 40 (step 3 in Reaction Scheme 5) in the general method described above (142 mg of a 1: 1 mixture of the primary alcohol and the aldehyde which was used without further purification).

The title compound was prepared as in Example of Compound 40 (step 4 of Reaction Scheme 5) in the general method described above (61% for the two steps): XH NMR (400 MHz, CDC13) d 10.00 (s, 1H), 8.25 (d, J = 8.1, 1H), 7.99 (s, 1H), 7.86 (d, J = 8.1), 7.71 (s, 1H), 7.52 (s, 1H), 7.47 (d, J = 8.8, 1H), 7.27 (d, J = 8.8, 1H), 3.16-3.06 (m, 1H), 2.18-2.06 (m, 2H), 1.88-1.60 (m, 6H). 1- ((3-Chloro-4- (5-cyclopentylbenzofuran-2-yl) phenyl) -methyl) azetidine-3-carboxylic acid The title compound was prepared as in Example of Compound 40 (step 5 of Reaction Scheme 5) in the general method described above (60% yield): 1 H NMR (400 MHz, CD 3 OD) d 8.16 (d, J = 8.1, 1H), 7.70 (d, J = 1.5, 1H), 7.61 (s, 1H), 7.55-7.53 (m, 2H), 7.45 (d, J = 8.8, 1H), 7.28 (dd, J = 8.4 , 1.5), 4.45 (s, 2H), 4.40-4.34 (m, 4H), 3.72-3.64 (m, 1H), 3.16-3.10 (m, 1H), 2.15-2.06 (m, 2H), 1.87-1.66 (m, 6H). Calculated: 409.14; Observed: 409.9 (M ++ l).

Compound 52 3- (N - ((4- (5- (Cyclopentylmethoxy) benzofuran-2-yl) -3-fluorophenyl) methyl) -N- (2-hydroxyethyl) amino) propanoic acid: The title compound was prepared as in Example 1 of Compound 1 (step 5, Reaction Scheme 1) in the general method described above, except that 3- (2-hydroxyethylamino) propanoic acid (13% yield) was used: ? NMR (400 MHz, DMSO-d6) d 7.57 (d, 1H), 7.55-7.47 (m, 2H), 7.26 (m, 2H), 7.22 (s, 1H), 6.96 (d, 1H), 4.82 (S broad, 3H), 4.42 (s, 2H), 4.06 (s, 2H), 3.92-3.65 (m, 4H), 2.75-2.33 (m, 4H), 1.95-1.31 (m, 9H). MS (ESI) m / z: Calculated: 455.21; Observed: 455.9 (M ++ l).

Compound 53 1- (3-Fluoro-4- (5-morpholinobenzofuran-2-yl) phenyl) methyl) azetidin-3-carboxylic acid 4- (Benzofuran-5-yl) morpholine: The title compound was prepared as in Example of Compound 31 (step 1, Scheme 3) in the general method described above (52% yield): 1 H NMR (400 MHz, CDC13) d 7.46 (s, 1 H), 7.36 (d, 1H), 6.95 (s, 1H), 6.81 (d, 1H), 6.58 (s, 1H), 3.78 (m, 4H), 2.95 (m, 4H).

-Morpholinobenzofuran-2-yl-2-boronic acid: The title compound was prepared as in Example of Compound 31 (step 2 Scheme 3) in the general method described above (72% yield) (ESI) m / z: Calculated: 247.1; Observed: 248.1 (M ++ l). 3 - . 3 -Fluoro-4 - (5-morpholinobenzofuran-2 -i1) benzaldehyde The title compound was prepared as in Example of Compound 31 (step 3, Scheme 3) in the general method described above (52% yield): 1 H NMR (400 MHz, CDC13) d 10.01 (s, 1H), 7.76 (d, 1H), 7.61 (d, 1H), 7.55-7.06 (m, 5H), 3.86 (m, 4H), 3.15 (m, 4H). 1- ((3-Fluoro-4- (5-morpholinobenzofuran-2-yl) phenyl) -methyl) azetidine-3-carboxylic acid The title compound was prepared as in Example 1 of Compound 1 (step 5 in Reaction Scheme 1) in the general method described above (28% yield): XH NMR (400 MHz, CD3OD) d 8.03 (t, 1H ), 7.56 (d, 1H), 7.53 (d, 1H), 7.43 (d, 1H), 7.22 (d, 1H), 7.19 (d, 1H) 7.05 (dd, 1H), 4.50 (s, 2H), 4.39 (dd, 4H), 3.72-3.70 (m, 6H), 2.08 (m, 4?), 1.84 (m, 2?). MS (ESI) m / z: Calculated: 410.1; Observed: 411.1 (M ++ l).

Compound 54 4- ((4- (5-Benzylbenzofuran-2-yl) -3-fluorophenyl) methyl) morpholin-2-carboxylic acid: The title compound was prepared as in the Example of Compound 1 (step 5 in Scheme 1) in the general method described above, but using morpholine-2-carboxylic acid instead of azetidin-3-carboxylic acid (57% yield) ):? NMR (400 MHz, CD3OD) d 8.09 (t, J = 7.8, 1H), 7.46-7.42 (m, 4H), 7.28-7.14 (m, 7H), 4.38 (broad d, J = 9.5, 1H), 4.30 -4.21 (m, 2H), 4.13-4.04 (m, 1H), 4.06 (s, 2H), 3.83 (broad t, J = 10.6, 1H), 3.53 (broad d, J = 12.4, 1H), 3.30- 3.22 (m, 1H), 3.13-3.00 (m, 2H). MS (ESI) m / z: Calculated: 445.17; Observed: 445.90 (M ++ l).

Compound 55 4- ((4- (5- (Cyclopentylmethoxy) benzofuran-2-yl) -3-fluorophenyl) methyl) morpholin-2-carboxylic acid: The title compound was prepared as in the Example of Compound 1 (step 5 in Reaction Scheme 1) in the general method described above but using morpholine-2-carboxylic acid instead of azetidine-3-carboxylic acid (57% of yield): XH NMR (400 MHz, CD3OD) d 8.06 (t, J = 7.8, 1H), 7.44-7.42 (m, 3H), 7.24 (d, J = 3.3, 1H), 7.13 (d, J = 2.5 , 1H), 6.95-6.92 (m, 1H), 4.38 (dd, J = 9.5, 2.6, 1H), 4.21-4.09 (m, 3H), 3.88 (d, J = 7.0, 2H), 3.81 (t, J = 10.2, 1H), 3.45 (broad d, J = 11.4, 1H), 3.15 (broad d, J = 12.4, 1H), 3.03-2.91 (m, 2H), 2.41-2.34 (m, 1H), 1.90 -1.83 (m, 2H), 1.71-1.57 (m, 4H), 1.46-1.37 (m, 2H). MS (ESI) m / z: Calculated: 453.20; Observed: 453.90 (M ++ l).

Compound 56 1- (5- (5-Benzylbenzofuran-2-yl) -2,3-dihydro-lH-inden-2-yl) -azetidine-3-carboxylic acid The title compound was prepared according to the reductive amination procedure as described in step 5 of Reaction Scheme 1 (69% yield). XH NMR (400 MHz, CD3Cl3) d 7.78-7.68 (m, 2H), 7.45-7.22 (m, 8H), 7.22 (d, 1H), 6.94 (s, 1H), 4.73 (s, 1H), 4.05 ( s, 2H), 3.52-3.20 (m, 2H), 3.29-2.62 (m, 7H), 2.48-2.31 (m, 2H). MS (ESI) m / z: Calculated: 423.5; Observed: 423.7 (M ++ l).

Compound 57: 3- (6- (5- (Cyclopentylmethoxy) benzofuran-2-yl) -3,4-dihydroisoquinolin-2 (1 H) -yl) propanoic acid 3- (6- (5- (Cyclopentylmethoxy) benzofuran-2 - il) -3,4-dihydroisoquinolin-2 (1H) -yl) tert-butyl propanoate (step 3 in Reaction Scheme 8): The title compound was prepared as in Example of Compound 37 (step 3 in Reaction Scheme 8) in the general method described above (73 mg, 40% yield): XH NMR (400 MHz, CDC13) d 7.57 ( m, 2H), 7.36 (d, 1H), 7.06 (d, 1H), 7.01 (d, 1H), 6.85 (m, 2H), 3.85 (d, 2H), 3.69 (s, 2H), 2.96 (dd) , 2H), 2.86 (dd, 2H), 2.79 (dd, 2H), 2.54 (dd, 2H), 2.38 (m, 1H), 1.66 (m, 2H), 1.59 (m, 4H), 1.45 (s, 9H), 1.39 (t, 2H). MS (ESI) m / z: Calculated: 475.27; Observed: 475.90 (M ++ l). 3- (6- (5- (Cyclopentylmethoxy) enzofuran-2-yl) -3,4-dihydroisoguinolin-2 (1 H) -yl) -panoic acid (step 4 in Reaction Scheme 8): The title compound was prepared as in Example of Compound 37 (step 4 in Reaction Scheme 8) in the general method described above (19 mg, 72% yield): NMR (400 MHz, CD3OD) d 7.78 (m , 2H), 7.38 (d, 1H), 7.30 (d, 1H), 7.17 (s, 1H), 7.09 (d, 1H), 6.88 (dd, 1H), 4.53 (s, 2H), 3.87 (d, 2H), 3.68 (m, 2H), 3.58 (dd, 2H), 3.27 (m, 1H), 2.93 (dd, 2H), 2.37 (m, 1H), 1.86 (m, 2H), 1.63 (m, 4H ), 1.41 (m, 2H). MS (ESI) m / z: Calculated: 419.21; Observed: 420.2 (M ++ l).

Compound 58: 3- (4- (5-Cyclopentylbenzofuran-2-yl) -3-fluorobenzylamino) propanoic acid (Step 5 in Scheme 1): The title compound was prepared as in the Example of Compound 1 (Step 5 in Scheme 1) in the general method described above (4.1 mg, 4.6% yield): 1 H NMR (400 MHz, CD30D) d 8.10 (dd, 1H), 7.50 (s, 1H), 7.42 (m, 3H), 7.25 (m, 2H), 4.30 (s, 2H), 3.25 (m, 2H), 3.10 (m, 1H), 2.25 (dd, 2H) ), 2.18 (m, 2H), 1.84 (m, 2H), 1.65 (m, 4H). MS (ESI) m / z: Calculated: 381.17; Observed: 381.80 (M ++ l).

Compound 59 3- (4- (5-Benzylbenzofuran-2-yl) -3-fluorophenoxy) propan-1,2-diol 4- (5-benzylbenzofuran-2-yl) -3-fluorophenol (step 4 in the Reaction Scheme 1) : The title compound was prepared as in the Compound of Example 1 (step 4 in Reaction Scheme 1) in the general method described above, except that 4-bromo-3-fluorophenol was used. The compound was used without further purification for the next reaction step. 3- (4- (5-Benzylbenzofuran-2-yl) -3-fluorophenoxy) propan-1,2-diol (step 2 in Reaction Scheme 9): A mixture of 4- (5-benzylbenzofuran-2-yl) -3-fluorophenol (22 mg, 0.069 mmol) and 3-bromopropan-1,2-diol (48 mg, 0.31 mmol) and 2 N NaOH (200 μ? ?) in i-PrOH (1 mL), was heated at 90 ° C overnight. After concentration of the solvents under reduced pressure, the resulting residue was dissolved in DMSO and purified by preparative reverse phase HPLC (column C18 (2) 5μ Luna reverse phase Phenomenex, DI 60 x 21.2 mm, mobile phase: A = 0.05% TFA in water, B = 0.05% TFA in acetonitrile) to provide the desired final product (4.4 mg, 16% yield) as a white powder: 1 H NMR (400 MHz, CD3OD) d 7.89 (m , 1H), 7.40 (m, 2H), 7.23 (m, 4H), 7.10 (m, 2H), 6.99 (m, 1H), 6.89 (m, 2H), 4.10 (m, 1H), 4.04 (s, 2H), 3.96 (m, 2H), 3.65 (m, 2H). MS (ESI) m / z: Calculated: 392.14; Observed: 393.20 (++ l).

Compound 60 1- (3-Fluoro-4- (5- (1- (methylsulfonyl) iperidin-4-yl) benzofuran-2-yl) phenyl) methyl) azetidin-3-carboxylic acid 4- (4- (2 , 2-Diethylethoxy) -1- (methylsulfonyl) iperidine: The title compound was prepared as in Example of Compound 1 (step 1 in Scheme 1) in the general method described above (70% yield): XH NMR (400 MHz, CDC13) d 7.07 (d, 2H), 6.82 (d, 2H), 4.81 ( t, 1H), 3.96 (d, 4H), 3.90 (t, 2H), 3.79-3.72 (m, 2H), 3.67-3.59 (m, 2H), 2.81 (s, 3H), 2.77 (t, 2H) , 2.61 (m, 1H), 1.77-1.70 (m, 2H), 1.21 (t, 6H). 4- (Benzofuran-5-yl) -1- (metils lfonyl) iperidine: The title compound was prepared as in Example 1 of Compound 1 (step 2 in Reaction Scheme 1) in the general method described above (20% yield): XR NMR (400 MHz, CDC13) d 7.45 (d, 1H ), 7.42 (s, 1H), 7.13 (d, 1H), 6.62 (s, 1H), 4.03 (m, 4H), 2.83 (s, 3H), 2.78 (t, 1H), 1.82-1.75 (m, 4H). - (1- (Methylsulfonyl) iperidin-4-yl) benzofuran-2-yl-2 -boronic acid: The title compound was prepared as in the Example of Compound 1 (step 3 in Scheme 1) in the general method described above (84% yield): MS (ESI) m / z: Calculated: 323.1; Observed: 324.1 (M ++ l). 3-Fluoro-4- (5- (1- (methylsulfonyl) piperidin-4-yl) benzofuran-2-yl) enzaldehyde: The title compound was prepared as in Example of Compound 1 (step 4 in Reaction Scheme 1) in the general method described above (62% yield): XH NMR (400 MHz, CDC13) d 10.03 (s, 1H ), 8.21 (t, 1H), 7.79 (d, 1H), 7.72 (d, 1H), 7.51-7.21 (m, 4H), 3.98 (m, 4H), 2.84 (s, 3H), 2.76 (m, 1H), 2.05-1.81 (m, 4H). 1- ((3-Fluoro-4- (5- (1- (methylsulfonyl) piperidin-4-yl) benzofuran-2-yl) phenyl) methyl) azetidine-3-carboxylic acid The title compound was prepared as in the Example of Compound 1 (step 5 in Reaction Scheme 1) in the general method described above (70% yield): X H NMR (400 MHz, DMSO-d 6) d 8.21 (t , 1H), 7.84 (d, 1H), 7.77 (d, 1H), 7.51-7.21 (m, 4H), 4.85 (s broad, 4.46 (s, 2H), 3.98 (m, 4H), 3.68 (ra, 1H), 3.62 (m, 4H), (s, 3H), 2.76 (m, 1H), 1.91-1.71 (ra, 4H), MS (ESI) Calculated: 486.1; Observed, 486.9 (++ l).

Compound 61 1- (3-Fluoro-4- (5- (tetrahydro-2Jf-pyran-4-yl) benzofuran-2-yl) phenyl) methyl) azetidin-3-carboxylic acid 4- (Benzofuran-5-yl) -tetrahydro-2H-pyran-4-ol (step 1 in Reaction Scheme 6): To a suspension of Mg (550 mg, 23.0 mmol) in dry THF (15 mL), under nitrogen atmosphere, 5-bromobenzofuran (3.9 g, 20.0 mmol) was added in one portion. An iodine crystal was added and then the contents were refluxed for 3 hours. The reaction was then allowed to reach room temperature, and then cooled to -40 ° C. Pyran-4-one (3.0 g, 30.0 mmol) was added dropwise and the resulting solution was allowed to reach room temperature. The reaction mixture was quenched by the addition of 1N HC1 (5 mL) and then diluted with ether (30 mL). This was washed with water (2 x 15 mL), and the combined organic extract was washed with brine (15 mL), dried and concentrated under reduced pressure to give the crude carbinol as a colorless oil. Purification by column chromatography using 5% EtOAc-hexanes gave the desired product as a white solid (41%). XH NMR (400 MHz, CDC13) d 7.74 (d, 1H), 7.64 (d, 1H), 7.51-7.44 (m, 2H), 6.78 (d, 1H), 4.00-3.88 (m, 4H), 2.25 ( t, 2H), 1.78-1.74 (ra, 2H).

- (Tetrahydro-2H-pyran-4-yl) benzofuran (step 2 in Reaction Scheme 6): To a solution of 4- (benzofuran-5-yl) -tetrahydro-2H-pyran-4-ol (109 mg, 0.5 mmol) in DCM (5 mL) at 0 ° C under a nitrogen atmosphere, triethylsilane was added. (175 mg, 1.5 mmol) followed by TFA (570 mg, 5.0 mmol). After stirring for 15 minutes at the same temperature, the cooling bath was removed, and the reaction mixture was allowed to reach room temperature. This was further stirred at room temperature for 6 hours and then poured into a mixture of crushed ice-water (10 mL). This was extracted with DCM (3 x 10 mL), and the combined organic layer was washed with brine (10 mL), dried and evaporated. The crude compound was purified by column chromatography using 5% EtOAc-hexanes to provide the desired product (88%). 1 H NMR (400 MHz, CDC13) d 7.61 (d, 1H), 7.44 (d, 2H), 7.15 (d, 1H), 6.73 (d, 1H), 4.11 (dd, 2H), 3.56 (t, 2? ), 2.89-2.81 (m, 1?), 1.93-1.79 (m, 4H).

- (Tetrahydro-2ff-pyran-4-yl-benzofuran-2-yl-2-boronic acid (step 3 in Reaction Scheme 1): The title compound was prepared in the same manner as described in step 3 of Reaction Scheme 1 (86%): XH NMR (400 MHz, CDC13) d 7.48-7.41 (m, 2H), 7.28 (d, 1H ), 7.20 (d, 1H), 4.10 (t, 2H), 3.60 (t, 2H), 2.98-2.94 (m, 1H), 1.97-1.80 (m, 4H). MS (ESI) m / z: Calculated: 324.35; Observed: 325.1 (M ++ l). 3-Fluoro-4- (5- (tetrahydro-2ff-pyran-4-yl-benzofuran-2-yl) benzaldehyde (step 4 in Reaction Scheme 1): The title compound was prepared in the same manner as described in step 4 of Scheme 1 (68%): 1 H NMR (400 MHz, CDC13) d 10.01 (s, 1H), 8.04 (t, 1H), 7.80 ( t, 1H), 7.74 (d, 1H), 7.52 (t, 2H), 7.40 (d, 1H), 7.22 (s, 1H), 4. 10 (t, 2H), 3.60 (t, 2H), 2.98-2.94 (m, 1H), 1.97-1.80 (m, 4H). MS (ESI) m / z: Calculated: 324.35; Observed: 325.1 (M ++ l) 1- (3-Fluoro-4- (5- (tetrahydro-2ff-pyran-4-yl) benzofuran-2-yl) phenyl) methyl) azetidine-3-carboxylic acid (step 5 in Reaction Scheme 1): The title compound was prepared according to the reductive amination procedure as described in step 5 of Scheme 1 (73% yield). 1H RN (400 MHz, CD3OD) d 8.12 (t, 1H), 7.54 (s, 1H), 7.49 (d, 1H), 7.43 (s, 1H), 7.41 (d, 1H), 7.31-7.27 (m, 2H), 4.46 (s, 2H), 4.39-4.31 (m, 4H), 4.05 (d, 2H), 3.71-3.64 (m, 1H), 3.59 (t, 2H), 1.95-1.89 (m, 4H) . MS (ESI) m / z: Calculated: 409.45; Observed: 410.0 (M ++ l).

Activity of the compounds of the invention The compounds of the invention made in accordance with the synthesis indicated above were tested for their ability to modulate the S1P-1 receptor. Therefore, the compounds are expected to be useful as modulators of the S1P-1 receptor, for example, in the treatment of a variety of clinical conditions mediated by the S1P-1 receptor. Such conditions include transplant rejection (transplantation of solid organs and islet cells); transplant rejection (tissue); Cancer; autoimmune / inflammatory diseases; rheumatoid arthritis; lupus; insulin-dependent diabetes (Type I); diabetes not dependent on insulin (Type II); multiple sclerosis; psoriasis; Ulcerative colitis; inflammatory bowel disease; Crohn's disease; lymphocytes and acute and chronic lymphocytic leukemias. To further demonstrate the suitability of the compounds of the invention as modulators of the S1P-1 receptor to treat conditions such as transplant rejection; Cancer; autoimmune / inflammatory diseases; rheumatoid arthritis; lupus; diabetes; multiple sclerosis; psoriasis; Ulcerative colitis; inflammatory bowel disease; Crohn's disease; acute and chronic lymphocytic leukemias and lymphocytes where immunosuppression is central (of which reduction of lymphopenia is thus a well-established indicator), the compounds of the invention were evaluated in laboratory animals as described below.

PROTOCOL Mice C57BL / 6J mice (B6, Jackson Laboratories, Bar Harbor, ME) were kept in a specific pathogen-free medium under a containment system with a micro-isolator. Adult and male adult mice that match age were reviewed and approved by the Animal Care and Use Committee at the University of Virginia. Each time the protocol indicated, the mice were anesthetized via intra-peritoneal injections of ketamine hydrochloride (125 mg / kg, Sanofi Winthrop Pharmaceuticals, New York, NY), xylazine (12.5 mg / kg TranquiVed, Phoenix Scientific, St. Joseph, MO) and atropine sulfate (0.025 mg / kg, Fujisawa USA, Deerfield, IL).

Preparation and analysis of flow cytometry Blood was collected from at least six mice for each measurement point of 0, 4, 8, 24, 48, 72 hours after a day, 3 days or 7 days of daily dosing with the test compound After the terminal bleeds, the brain and certain tissues were collected from all the animals subjected to the treatment. Cell counts were determined from whole blood, providing cell counts in thousands of cells per microliter (K / 1L). To identify and quantify lymphocyte subsets, cell suspensions were analyzed by flow cytometry. After lysis of the red blood cells, the cells were stained with anti-mouse monoclonal antibodies against CD3, CD4, CD8, CD19 and NK1.1 (BD Biosciences, San Jose, CA). The cells were analyzed via flow cytometry with four colors in a FACSCalibur (BD Biosciences) at the Main Facility of the Cancer Center of the University of Virginia. The subsets of lymphocytes, including B cells, total T cells, CD4 T cells, CD8 T cells, double positive thymocytes, double negative thymocytes, NK cells and NK / T cells were analyzed. The size of each cell population was calculated as the product of the total lymphocyte count recorded by Hemavet or the hemocytometer and the percentage of positive lymphocytes recorded by the flow cytometer. All data were analyzed with the Cell Quest analysis program of BD Biosciences.

Statistical analysis Statistical significance was determined using the Student's t test to compare all measurement points with the 24-hour group. The tested compounds: showed a reduction in lymphopenia that varies from 35% to 90% compared to the baseline at dosages of 0.3 to 10 mg / kg. The two final compounds in the previous table showed no reduction in lymphopenia under the conditions tested. Therefore, the compounds of the invention are expected to be useful for treating conditions such as transplant rejection; Cancer; autoimmune / inflammatory diseases; rheumatoid arthritis; lupus; multiple sclerosis; diabetes; psoriasis; Ulcerative colitis; inflammatory bowel disease; Crohn's disease; acute and chronic lymphocytic leukemias and lymphoras, where immunosuppression is central.

EQUIVALENTS Those skilled in the art will recognize or be able to determine using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of the invention. Various substitutions, alterations and modifications to the invention can be made without departing from its spirit and scope. Other aspects, advantages and modifications are within the scope of the invention. The content of all references, issued patents and published patent applications cited in this application is incorporated herein by reference. The appropriate components, processes and methods of those patents, applications and other documents may be selected for the invention and modalities thereof.

Claims (97)

1. CLAIMS: 1. A compound that has the formula wherein A is an optionally substituted aryl or heteroaryl group; B and C are at least one aromatic bicyclic ring system; X is selected from the group consisting of WC (0) OR6a, WP (0) R6bR6c, WS (0) 2OH, WCONHS03H or lH-tetrazol-5-yl; wherein W is a direct bond, oxygen or C1-4 alkyl having one or more substituents independently selected from the group consisting of halogen, hydroxyl, cyano, amino, alkylamino, arylamino, heteroarylamino, Ci-4 alkoxy groups and C002H; RSa is hydrogen or C 1-4 alkyl; and R6 and R6c are independently hydrogen, hydroxyl, Ci-4 alkyl or Ci-4 alkyl substituted with halogen; "And it's a residue of formula (a), where the left and right asterisks indicate the point of union wherein "Q is selected from the group consisting of a direct bond, C = 0, C = S, S02, C = 0NR or (CR10R1: L) m;" m is 0, 1, 2 or 3; "R7 and R8 are independently selected from the group consisting of hydrogen, halogen, amino, Ci-5 alkylamino, hydroxyl, cyano, Ci-6 alkyl, hydroxyC1-6 hydroxyalkyl (eg, hydroxy-terminated alkyl) , Ci-5 alkylthio, Ci-5 alkoxy, Ci-6 alkyl substituted with halogen and C 1-5 alkoxy substituted with halogen, or R7 and R8 can be linked with the atoms to which they are attached to form a ring of 4 to 7 members, optionally having a heteroatom, and "R9 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C1-6 alkyl, Ci-5 alkylthio, Ci-5 alkoxy, Ci alkyl -6 substituted with halogen or Ci-5 alkoxy substituted with halogen; "R10 and R12 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, Ci-6 alkyl, Ci-5 alkoxy / Ci-5 alkylthio, Ci-6 alkyl substituted with halogen or alkoxy of Ci-5 substituted with halogen and | Z1 and Z2 are independently selected from the group consisting of O, NR3, S, S (O), S (0) 2, S (0) 2NR3, (CRR5) n, C = 0, C = S, C = N-R3, or a direct bond, wherein "R3 is selected from the group consisting of hydrogen, hydroxyl, S02, C = 0, C = S, C = NH, Ci- S, Ci-5 alkoxy, Ci-5 alkylthio, Ci-6 alkyl substituted with halogen and Ci-5 alkoxy substituted with halogen; aryl or heteroaryl, or when Z2 is a direct bond, R3 is a C3-C6 ring optionally containing a heteroatom; "R4 and R5 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, Ci-6 alkyl, Ci-5 alkoxy, Ci-5 alkylthio, Ci-6 alkyl substituted with halogen and alkoxy of Ci-5 substituted with halogen, aryl or heteroaryl or together form C = 0, and "n is 0, 1, 2 or 3; and "R1 is selected from the group consisting of Ci-6 alkyl, C2-6 alkenyl / C2-6 alkynyl, C3-6 cycloalkyl, Ci-5 alkoxy, Ci-5 alkylamino, aryl or heteroaryl. The compound according to claim 1, wherein A is a cyclic ring of Ci-6 (alicyclic or aromatic) optionally having one or more heteroatoms 3. The compound according to claim 1, wherein A is substituted with one, two or three substituents selected from the group consisting of halogen, hydroxyl, SR2, S (0) 2 2, S (0) 2NR2, NHS (0) 2R2, COR2, C02R2, cyano, amino, Ci-5 alkylamino / arylamino / heteroarylamino, C 1-6 alkyl, Ci-5 alkylthio, Ci-5 alkoxy, Ci-6 alkyl substituted with halogen and Ci-5 alkoxy substituted with halogen 4. The compound according to claim 1, wherein A is substituted with two adjacent substituents which, taken with Z1 and the ring A to which they are attached, form a fused ring optionally containing one or more heteroatom 5. The compound according to claim 1, wherein A is optionally substituted with one, two or three substituents selected from the group consisting of halogen, hydroxyl, S, S (0) 2R2, S (0) 2NR2, NHS ( 0) 2R2, COR2, C02R2, cyano, amino, alkylamino / arylamino / heteroarylamino of Ci- 5, alkyl of Ci-6, alkylthio of C 1-5, alkoxy of C 1-5, C 1-6 alkyl substituted with halogen and alkoxy of Ci-5 substituted with halogen, wherein R2 is selected from the group consisting of hydrogen, hydroxy, amino, alkylamino / arylamino, Ci-6 alkyl, Ci-5 alkoxy, Ci-5 alkylthio, Ci-alkyl 6 substituted with halogen and Ci-5 alkoxy substituted with halogen; and aryl / heteroaryl; or optionally, two adjacent substituents on A can, taken with Z1 and the ring to which they are attached, form an alicyclic or heterocyclic ring. 6. The compound according to claim 1, wherein R2 is selected from the group consisting of hydrogen, hydroxyl, amino, alkylamino / arylamino, Ci-6alkyloxy Ci-5alkyl, Ci-5alkylthio, Ci-5alkyl, 6 substituted with halogen and C 1-5 alkoxy substituted with halogen; or aryl / heteroaryl. The compound according to claim 1, wherein B and C are selected from the group consisting of dihydrobicyclic and tetrahydrobicyclic bicycloaryl, bicycloheteroaryl, aryl and heteroaryl. 8. The compound according to claim 1, wherein the bicyclic ring system is optionally substituted with 1 to 5 substituents selected from the group consisting of Ci- 6 alkyl, Ci- 5 alkylthio, Ci- 5 alkoxy, halogen, hydroxyl , cyano, Cι-6 alkyl substituted with halogen and Ci-5 alkoxy substituted with halogen. The compound according to claim 1, wherein Z1 and Z2 are independently selected from the group consisting of O, NR3, S, S (O), S (0) 2, S (0) 2NR3, (CRR5) n / C = 0, C = S, C = N-R3, or a direct link. 10. The compound according to claim 1, wherein R3 is selected from the group consisting of hydrogen, hydroxyl, S (0) 2, C = 0, C = S, C = NH, Ci- 6 alkyl, Ci alkoxy - 5, Ci_5 alkylthio, Ci_6 alkyl substituted with halogen and Ci-5 alkoxy substituted with halogen; aryl or heteroaryl. 11. The compound according to claim 1, wherein R4 and R5 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, Ci- 6 alkyl, Ci- 5 alkoxy, Ci- 5 alkylthio, Ci-6 alkyl substituted with halogen and Ci-5 alkoxy substituted with halogen; aryl or heteroaryl or together form C = 0. The compound according to claim 1, wherein R 1 is selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl / C 2-6 alkynyl / C 3-6 cycloalkyl, C 1-5 alkoxy, alkylamino from ? .5? aryl or heteroaryl. The compound according to claim 1, wherein Ri is optionally substituted with groups selected from the group consisting of hydroxyl, halogen, cyano, amino, alkylamino, arylamino, heteroarylamino groups. The compound according to claim 1, wherein the aryl and heteroaryl groups are optionally substituted with one to five substituents selected from the group consisting of hydroxyl, halogen, cyano, Ci-6 alkyl, Ci-5 alkylthio, alkoxy, C1-5, C3-6 cycloalkyl. 15. The compound according to claim 1, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, maleate, citrate, fumarate, succinate, tartarate, mesylate, sodium, potassium, magnesium and calcium salts. 16. A compound having the formula wherein "A is an aryl or heteroaryl group; X is -C (0) ORea, wherein R <a> is hydrogen or C1-4alkyl;" Y is a residue of formula (a ) where X Q is (CR ^ R11) ™; "m is 0, 1, 2, 3 or 4;" R7 and R8 can independently be hydrogen, hydroxyl, lower alkyl; or R7 and R8, taken with the atoms to which they are attached, form a ring; and "R9 is selected from the group consisting of hydrogen, halogen, hydroxyl or cyano; | Z1 and Z2 are independently O or (CR4R5) n, wherein" R4 and R5 are independently hydrogen, halogen, hydroxyl, cyano , Ci-6 alkyl, Ci-5 alkoxy; and "n is 0, 1, 2 or 3, and" R1 is selected from the group consisting of Ci-6 alkyl, C2-6 alkenyl of C2- &C3-6 cycloalkyl, Ci-alkoxy, 5, Ci-5 alkylamino, aryl or heteroaryl; or a pharmaceutically acceptable salt thereof. The compound according to claim 1, wherein A is a cyclic ring of Ci-6 (alicyclic or aromatic) optionally having one or more heteroatoms. The compound according to claim 1, wherein A is substituted with one, two or three substituents selected from the group consisting of halogen, hydroxyl, SR2, S (0) 2R2, S (0) 2NR2, NHS (0) 2R2 , COR2, C02R2, cyano, amino, alkylamino / arylamino / Ci-5 heteroarylamino, Ci-6 alkyl, Ci_5 alkylthio, Ci-5 alkoxy, Ci-6 alkyl substituted with halogen, and Ci-5 alkoxy replaced with halogen. The compound according to claim 1, wherein A is substituted with two adjacent substituents which, taken with Z1 and the ring A to which they are attached, form a fused ring optionally containing one or more heteroatoms. The compound according to claim 1, wherein A is optionally substituted with one, two or three substituents selected from the group consisting of halogen, hydroxyl, S, S (0) 2R2, S (0) 2NR2, NHS (0) 2R2, COR2, C02R2, cyano, amino, alkylamino / arylamino / heteroarylamino of Ci-5, alkyl of Ci-S, alkylthio of Ci-5 (alkoxy of Ci-5, alkyl of Ci-6 substituted with halogen, and alkoxy of Ci-5 substituted with halogen, wherein R2 is selected from the group consisting of hydrogen, hydroxyl, amino, alkylamino / arylamino, Ci-6 alkyl, Ci-5 alkoxy, Ci-5 alkylthio, Ci-6 alkyl substituted with halogen and Ci-5 alkoxy substituted with halogen, and aryl / heteroaryl, or optionally, two adjacent substituents on A can, taken with Z1 and the ring to which they are attached, form an alicyclic or heterocyclic ring. according to claim 1, wherein R2 is selected from the group consisting of hydrogen, hydroxyl, amino, alkylamino / arylamino, Ci-6 alkyl, Ci-5 alkoxy, Ci-5 alkylthio, Ci-6 alkyl substituted by halogen and Ci-5 alkoxy substituted by halogen; or aryl / heteroaryl. The compound according to claim 1, wherein the benzofuranyl ring is optionally substituted with 1 to 5 substituents selected from the group consisting of Ci-6 alkyl, Ci-5 alkylthio (Ci-5 alkoxy, halogen, hydroxyl , cyano, Ci-6 alkyl substituted with halogen and Ci-5 alkoxy substituted by halogen 23. The compound according to claim 1, wherein R1 is selected from the group consisting of Ci-6 alkyl, C2- alkenyl 6, C2-6 alkynyl / C3-6 cycloalkyl, Ci_5 alkoxy, Ci-5 alkylamino, aryl or heteroaryl. 24. The compound according to claim 1, wherein Ri is optionally substituted with groups selected from the group consisting of hydroxyl, halogen, cyano, amino, alkylamino, arylamino, heteroarylamino groups. The compound according to claim 1, wherein the aryl and heteroaryl groups are optionally substituted with one to five substituents selected from the group consisting of hydroxyl, halogen, cyano, Ci-6 alkyl / Ci-5 alkylthio, alkoxy Ci-5 / C3-6 cycloalkyl. 26. The compound according to claim 1, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, maleate, citrate, fumarate, succinate, tartarate, mesylate, sodium, potassium, magnesium and calcium salts. 27. A pharmaceutical composition comprising the compound according to claim 1 or 1 in an amount effective to treat a condition mediated by the S1P-1 receptor. 28. The pharmaceutical composition according to claim 1, wherein the condition mediated by the S1P-1 receptor is selected from the group consisting of transplant rejection (transplantation of solid organs and islet cells).; transplant rejection (tissue); Cancer; autoimmune / inflammatory diseases; rheumatoid arthritis; lupus; insulin-dependent diabetes (Type I); diabetes not dependent on insulin (Type II); multiple sclerosis; psoriasis; Ulcerative colitis; inflammatory bowel disease; Crohn's disease; acute and chronic lymphocytic and lymphocytic leukemias. 29. A method for modulating the S1P-1 receptor, which comprises contacting the S1P-1 receptor with a compound according to claim 1. 30. A method for treating a condition mediated by the S1P-1 receptor, which it comprises administering to a patient in need thereof a pharmaceutical composition comprising the compound according to claim 1 or 1 in an amount effective to treat the condition. The method according to claim 1, wherein the condition mediated by the S1P-1 receptor is selected from the group consisting of transplant rejection (transplantation of solid organs and islet cells); transplant rejection (tissue); Cancer; autoimmune / inflammatory diseases; rheumatoid arthritis; lupus; insulin-dependent diabetes (Type I); diabetes not dependent on insulin (Type II); multiple sclerosis; psoriasis; Ulcerative colitis; inflammatory bowel disease; Crohn's disease; acute and chronic lymphocytic and lymphocytic leukemias. 32. An immunomodulation method, comprising administering to a patient in need thereof a pharmaceutical composition comprising the compound according to claim 1 or 1 in an amount that results in immunomodulation. The method according to claim 1, wherein the condition mediated by the SlP-1 receptor is selected from the group consisting of transplant rejection (transplantation of solid organs and islet cells); transplant rejection (tissue); Cancer; autoimmune / inflammatory diseases; rheumatoid arthritis; lupus, · insulin-dependent diabetes (Type I); diabetes not dependent on insulin (Type II); multiple sclerosis; psoriasis; ulcerative colitis, - inflammatory bowel disease; Crohn's disease; acute and chronic lymphocytic and lymphocytic leukemias. 34. A pharmaceutical composition comprising the compound according to claim 1 or 1 in an amount effective to treat a condition mediated by the SlP-1 receptor. 35. The pharmaceutical composition according to claim 1, wherein the condition mediated by the SlP-1 receptor is selected from the group consisting of transplant rejection (transplantation of solid organs and islet cells); transplant rejection (tissue); Cancer; autoimmune / inflammatory diseases; rheumatoid arthritis; lupus; insulin-dependent diabetes (Type I); diabetes not dependent on insulin (Type II); multiple sclerosis; psoriasis; Ulcerative colitis; inflammatory bowel disease; Crohn's disease; acute and chronic lymphocytic and lymphocytic leukemias. 36. A method for treating a condition mediated by the SlP-1 receptor, which comprises administering to a patient in need thereof a pharmaceutical composition comprising the compound according to claim 1 or 1 in an amount effective to treat the condition. 37. The method according to claim 1, wherein the condition mediated by the SlP-1 receptor is selected from the group consisting of transplant rejection. (transplantation of solid organs and islet cells); transplant rejection (tissue); Cancer; autoimmune / inflammatory diseases; rheumatoid arthritis; lupus; insulin-dependent diabetes (Type I); diabetes not dependent on insulin (Type II); multiple sclerosis; psoriasis; Ulcerative colitis; inflammatory bowel disease; Crohn's disease; acute and chronic lymphocytic and lymphocytic leukemias. 38. 1- (4- (5-Phenylbenzofuran-2-yl) benzyl) azetidine-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 39. 1- ((4- (5-Butylbenzofuran-2-yl) phenyl) methyl) azetidine-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 40. 1- (4- (5-Butoxybenzofuran-2-yl) phenyl) methyl) azetidine-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 41. 1- ((4- (5-Benzylbenzofuran-2-yl) phenyl) methyl) azetidine-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 42. 1- ((4- (7-Benzylbenzofuran-2-yl) phenyl) methyl) azetidin-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 43. 1- (4- (5-Cyclohexylbenzofuran-2-yl) benzyl) azetidin-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 44. 1- (4- (5-Cyclohexylbenzofuran-2-yl) benzyl) piperidin-4-carboxylic acid; or the pharmaceutically acceptable salts thereof. 45. 1- ((4- (5-Butylbenzofuran-2-yl) phenyl) methyl) piperidine-4-carboxylic acid; or the pharmaceutically acceptable salts thereof. 46. 1- ((4- (5-Benzylbenzofuran-2-yl) phenyl) methyl) piperidine-4-carboxylic acid; or the pharmaceutically acceptable salts thereof. 47. 1- ((4- (5-Isobutylbenzofuran-2-yl) phenyl) methyl) azetidine-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 48. 1- ((4- (5-Phenethylbenzofuran-2-yl) phenyl) methyl) azetidine-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 49. L- (4- (5- (Pyridin-3-yl) benzofuran-2-yl) benzyl) azetidine-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 50. 1- (4- (5-Isobutylbenzofuran-2-yl) benzyl) piperidine-4-carboxylic acid; or the pharmaceutically acceptable salts thereof. 51. 1- ((4- (5-Benzylbenzofuran-2-yl) 2-fluorophenyl) methyl) azetidin-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 52. 1- ((4- (5-Benzylbenzofuran-2-yl) -3-fluorophenyl) methyl) azetidin-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 53. 1- (4- (5-Butoxybenzofuran-2-yl) phenyl) methyl) piperidine-4-carboxylic acid; or the pharmaceutically acceptable salts thereof. 54. 1- ((6- (5-Cyclohexylbenzofuran-2-yl) pyridin-3-yl) methyl) azetidin-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 55. 1- (4- (5- (6-Methylpyridin-2-yl) benzofuran-2-yl) benzyl) azetidine-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 56. 1- (4- (5-Phenoxybenzofuran ^ -yl) benzyl) azetidin-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 57. 1- ((4- (5-Isopentylbenzofuran-2-yl) phenyl) methyl) azetidine-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 58. 1- (4- (6-Butoxybenzofuran-2-yl) phenyl) methyl) azetidine-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 59. 1- ((2- (5-Butoxybenzofuran-2-yl) thiazol-5-yl) methyl) azetidin-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 60. 1- ((4- (5-Butoxybenzofuran-2-yl) -4-fluorophenyl) methyl) azetidin-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 61. 1- (4- (5-Butoxybenzofuran-2-yl) -3-methoxyphenyl) azetidine-3-carboxylic acid or the pharmaceutically acceptable salts thereof 62. The acid 1- ((5- (5 -butoxybenzofuran-2-yl) thiophen-2-yl) methyl) azetidine-3-carboxylic acid, or the pharmaceutically acceptable salts thereof 63. 1- ((6- (5-butoxybenzofuran-2-yl) pyridine- 3-yl) methyl) azetidine-3-carboxylic acid, or the pharmaceutically acceptable salts thereof 64. 1- ((4- (5-cyclohexylbenzofuran-2-yl) -3-fluorophenyl) methyl) azetidin-3-acid carboxylic acid, or the pharmaceutically acceptable salts thereof 65. 1- ((4- (5- (thiophen-2-yl) benzofuran-2-yl) phenyl) methyl) azetidine-3-carboxylic acid; acceptable thereto 66. 3- (6- (5-Benzylbenzofuran-2-yl) -3,4-dihydroisoquinolin-2 (1H) -yl) propanoic acid or pharmaceutically acceptable salts thereof 67. The acid 1- (4- (5-cyclopentylbenzofuran-2-yl) benzyl) azetidine-3-carboxylic acid or the pharmaceutical salts technically acceptable. 68. The acid trifluoroacetic acid salt 1- (3-Fluoro-4- (5- (piperidin-1-yl) benzofuran-2-yl) encyl) -zetidine-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 69. 1- ((6- (5-Benzylbenzofuran-2-yl) pyridin-3-yl) methyl) azetidine-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 70. 1- ((4- (5-Benzylbenzofuran-2-yl) -3-methoxyphenyl) methyl) azetidin-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 71. 1- (4- (5- (Piperidin-1-yl) benzofuran-2-yl) benzyl) azetidine-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 72. The 2-, 2- (5-benzylbenzofuran-2-yl) -2- (2-carboxyethyl) -3,4-dihydroisoquinolinium trifluoroacetate. 73. 1- (4- (5-Benzylbenzofuran-2-yl) -3-chlorobenzyl) azetidine-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 74. 3- (6- (5-Cyclopentylbenzofuran-2-yl) -3,4-dihydroisoquinolin-2 (1 H) -yl) propanoic acid; or the pharmaceutically acceptable salts thereof. 75. 1- (4- (5- (Cyclopentylmethoxy) benzofuran-2-yl) -3-fluorobenzyl) -azetidine-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 76. 1- (4- (5- (Cyclopentylmethoxy) benzofuran-2-yl) benzyl) azetidine-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 77. 1- (4- (5-Benzylbenzofuran-2-yl) -3-cyanobenzyl) azetidine-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 78. 1- (4- (5-Benzylbenzofuran-2-yl) -3-fluorobenzyl) pyrrolidine-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 79. 1- (4- (5-Cyclopentylbenzofuran-2-yl) -3-fluorobenzyl) azetidine-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 80. l- (4- (5-Benzylbenzofuran-2-yl) -3-methylbenzyl) azetidin-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 81. 3- (6- (5-Butoxybenzofuran-2-yl) -3,4-dihydroisoquinolin-2 (1 H) -yl) propanoic acid; or the pharmaceutically acceptable salts thereof. 82. 3- (5- (5-Benzylbenzofuran-2-yl) -2,3-dihydro-lH-inden-1-ylamino) propanoic acid; or the pharmaceutically acceptable salts thereof. 83. 3- (4- (5-Benzylbenzofuran-2-yl) -3-fluorobenzylamino) -3-methylbutanoic acid; or the pharmaceutically acceptable salts thereof. 84. 1- (4- (5-Cyclopentylbenzofuran-2-yl) -3-methoxybenzyl) azetidine-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 85. 1- (4- (5-Benzylbenzofuran-2-yl) -3,5-difluorobenzyl) azetidin-3-carboxylic acid or the pharmaceutically acceptable salts thereof. 86. 1- (4- (5- (Cyclopropylmethoxy) benzofuran-2-yl) -3-fluorobenzyl) -acetyl-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 87. 1- (4- (5-Butoxybenzofuran-2-yl) -3-chlorobenzyl) azetidine-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 88. 1- (3-Chloro-4- (5-cyclopentylbenzofuran-2-yl) benzyl) azetidin-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 89. 3- ((4- (5- (Cyclopentylmethoxy) benzofuran-2-yl) -3-fluorobenzyl) (2-hydroxyethyl) amino) propanoic acid; or the pharmaceutically acceptable salts thereof. 90. 1- (3-Fluoro-4- (5-morpholinobenzofuran-2-yl) benzyl) azetidine-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 91. 4- (4- (5-Benzylbenzofuran-2-yl) -3-fluorobenzyl) morpholin-2-carboxylic acid; or the pharmaceutically acceptable salts thereof. 92. 4- (4- (5- (Cyclopentylmethoxy) benzofuran-2-yl) -3-fluorobenzyl) -morpholine-2-carboxylic acid; or the pharmaceutically acceptable salts thereof. 93. 3- (6- (5- (Cyclopentylmethoxy) benzofuran-2-yl) -3,4-dihydroisoquinolin-2 (1 H) -yl) propanoic acid; or the pharmaceutically acceptable salts thereof. 94. 3- (4- (5-Cyclopentylbenzofuran-2-yl) -3-fluorobenzylamino) propanoic acid; or the pharmaceutically acceptable salts thereof. 95. 3- (4- (5-Benzylbenzofuran-2-yl) -3-fluorophenoxy) propan-1,2-diol acid; or the pharmaceutically acceptable salts thereof. 96. 1- (3-Fluoro-4- (5- (1- (methylsulfonyl) piperidin-4-yl) benzofuran-2-yl) benzyl) -zetidin-3-carboxylic acid; or the pharmaceutically acceptable salts thereof. 97. l- (3-Fluoro-4- (5- (tetrahydro-2H-pyran-4-yl) benzofuran-2-yl) benzyl) azetidin-3-carboxylic acid; or the pharmaceutically acceptable salts thereof.