KR101582910B1 - Novel modulators of sphingosine phosphate receptors - Google Patents

Abstract

Lt; RTI ID = 0.0 > subtype 1 < / RTI > Any compound selectively activates receptor subtype 1 relative to sphingosin-1-phosphate receptor subtype 3. The use and methods of the compounds of the invention in the treatment of abnormal symptoms mediated by activation, enrichment, inhibition or antagonism of S1P1 are provided.

Description

NOVEL MODULATORS OF SPHINGOSINE PHOSPHATE RECEPTORS < RTI ID = 0.0 >

This application claims priority to U.S. Serial No. 61 / 127,603, filed May 14, 2008, which is hereby incorporated by reference in its entirety.

About government support

The present invention has been carried out by the National Health Commission under grant number U54-AI74404-02 with government support. The Government has certain rights to the invention.

Sphingosine-1-phosphate (S1P), represented by the structure below, is a phospholipid with a wide variety of biological activities, particularly those involved in cellular signaling.

For example, S1P regulates proliferation of cells such as epithelial cells. The viability of S1P1 is mediated by a plurality of receptor subtypes. For example, receptor subtypes 1 and 3 (S1P1 and S1P3, respectively) are both expressed in endothelial cells and play a role in the action of lung and lymphatic endothelial cells. Agents of such receptors as agents of S1P1 may therefore be effective in treating abnormal conditions such as multiple sclerosis, transplant rejection and adult respiratory distress syndrome. The agonist stimulation of S1P1 is regulated by the degradation of the receptor. Ligand stimulation induces phosphorylation, internalization, polyubiquination and degradation (Gonzalez-Cabrera, Hla et al. 2007).

Oxadiazole and oxazole are disclosed for use as sphingosine-1-phosphate acceptor ligands, for example, see PCT Patent Application Nos. WO 2006/131336, WO2008 / 037476 and WO2008074821.

Matloublan, M .; Lo, C. G; Cinamon, G .; Lesneski, M. J .; Xu, Y .; Brinkmann, V .; Allende, M. L .; Proia, R. L .; Cyster, J. G. Nature 2004, 427, 355. (b) Allande, M. L .; Dreier, J. L .; Mandala, S .; Proia, R. L. J. Biol. Chem. 2004, 279, 15396. Germana, S. M .; Liao, J .; Jo, E .; Alfonso, C .; Ahn, M.-Y .; Peterson, M. S .; Webb, B .; Lefebvre, S .; Chun, J .; Gray, N .; Rosen, H. J. Biol. Chem. 2004, 279, 13839. (a) Budde, K .; Schmouder, R. L .; Nashan, B .; Brunkhorst, R .; Lucker, P. W .; Mayer, T .; Brookman, L .; Nedelman, J .; Skerjanec, A .; Bohler, T .; Neumayer, H.-H. Am. J. Transplant. 2003, 3, 846-854. (b) Budde, K .; Schmouder, R. L .; Brunkhorst, R .; Nashan, B .; Lucker, P. W .; Mayer, T .; Choudhury, S .; Skerjanec, A .; Kraus, G .; Neumayer, H. H. J. Am. Soc. Nephrol. 2002,13, 1073-1083. (c) Kahan, B. D .; Karlix, J. L .; Ferguson, R. M .; Leichtman, A. B .; Mulgaonkar, S .; Gonwa, T. A .; Skerjanec, A .; Schmouder, R. L .; Chodoff, L. Transplantation 2003, 7, 1079-1084. Yan L .; Huo P .; Hale J .; Mills S. G .; Hajdu R .; Keohane C. A .; Rosenbach M. J .; Milligan J. A .; Shei G .; Chrebet G .; Bergstrom J .; Card D .; Mandala S. M. Bioorg Med Chem Lett 2006, 16, 3684-3687. Li Z .; Chen W .; Hale J .; Lynch C. L .; Mills S. G .; Hajdu R .; Keohane C. A .; Rosenbach M. J .; Milligan J. A .; Shei G .; Chrebet G .; Parent S. A .; Bergstrom J .; Card D .; Forrest M .; Quackenbush E. J .; Wickham L. A .; Vargas H .; Evans R. M .; Rosen H .; Mandala S. J Med Chem 2005, 48, 6169-6173. Hale J. J .; Lynch C. L .; Neway W .; Mills S. G .; Hajdu R .; Keohane C. A .; Rosenbach M. J .; Milligan J. A .; Shei G .; Parent S. A .; Chrebet G .; Bergstrom J .; Card D .; Ferrer M .; Hodder P .; Strulovici B .; Rosen H .; Mandala S. J Med Chem 2004, 47, 6662-5. Gonzalez-Cabrera, P. J., T. Hla, et al. (2007). "Mapping pathways downstream of sphingosine 1-phosphate subtype 1 by differential chemical perturbation and proteomics." J Biol Chem 282 (10): 7254-64. Jo, E., M.G. Sanna, et al. (2005). "S1P1-selective in vivo-active agonists from high-throughput screening: off-the-shelf chemical probes of receptor interactions, signaling, and fate." Chem Biol 12 (6): 703-15. Wei, S. H., H. Rosen, et al. (2005). "Sphingosine 1-phosphate type 1 receptor agonism inhibits transendothelial migration of medullary T cells to lymphatic sinuses." Nat Immunol 6 (12): 1228-35

The present invention relates to a heterocycle compound designed to act as an agonist of S1P1, a receptor subtype 1, to a process for its preparation and to the use of S1P1 when treatment of an abnormal symptom mediated by S1P1 activation or treatment when S1P1 is medically mediated will be.

That is, various embodiments of the present invention provide a compound of formula (I) or a pharmaceutically acceptable salt, prodrug, fugo variant, stereoisomer, hydrate, or solvate thereof:

In the above formula (I)

The dotted line means that a single bond or a double bond may be present, provided that there are two double bonds or three single bonds in the ring containing A ¹ , A ² , and A ³ ;

A ¹ , A ² , and A ³ are each independently C or O, or N or N, wherein N is bonded to two adjacent ring atoms by a double bond or a single bond, When bonded to a ring atom, NR is H or (C ₁ -C ₆ ) alkyl, provided that A ¹ , A ² , and A ³ At least one of A ¹ , A ² , and A ³ is N or NR, and only one of A ¹ , A ² , and A ³ is O;

L ¹ and L ² are independently a bond; R 'is H or (C ₁ -C ₆₎ alkyl, n is 1, 2 or 3, (CHR') _n; Or heteroaryl selected from the group consisting of thiophenyl, phenyl, furanyl, or benzothiophenyl wherein the heteroaryl is substituted with 0-3 J;

J is independently selected from F, Cl, Br, I, OR ', OC (O) N (R') 2, CN, CF 3, OCF 3, CHF 2, NO 2, R ', O, S in each case , S (O), S (O), methylenedioxy, ethylenedioxy, N (R ') ₂ , N (R') CH ₂ CH ₂ OR ', SR', SOR ', SO ₂ R', SO _{2 N (R ') 2,} SO 3 R', C (O) R ', C (O) C (O) R', C (O) CH 2 C (O) R ', C (S) R' , C (O) OR ', OC (O) R', OC (O) OR ', C (O) N (R') 2, OC (O) N (R ') 2, C (S) N ( _{R ') 2, (CH 2} ) 0-2 NHC (O) R', (CH 2) 0-2 N (R ') 2, (CH 2) 0-2 N (R') N (R ') ₂ , N (R ') N (R') C (O) R ', N (R') N (R ') C ) ₂ , N (R ') SO ₂ R', N (R ') SO ₂ N (R') ₂ , N (R ') C , N (R ') N ( R'), N (R ') C (S) R', N (R ') C (O) N (R') 2, N (R ') C (S) N _{(R ') 2, N (} COR') COR ', N (oR') R ', C (= NH) N (R') 2, C (O) N (oR ') R', or C (= NOR ') R' wherein two J groups may together form a ring, wherein R 'is independently in each occurrence hydrogen or alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, Alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl It is substituted with 0-3 of J; Or two R 'groups may form a (C ₃ -C ₈ ) heterocyclyl substituted with 0-3 J, with one nitrogen atom or two adjacent nitrogen atoms bonded thereto; Further comprising one to three additional heteroatoms selected from the group consisting of O, N, S, S (O) and S (O) ₂ ;

R < ⁵ > is monocyclic or bicyclic cycloalkyl, aryl, heterocyclyl, or heteroaryl; Each of which is substituted with 0-5 J, wherein any cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted by one or more additional cycloalkyl; Aryl; Heterocyclyl; Heteroaryl ring, fused with a heteroaryl ring, branched or spiral, wherein any of said one or more additional cycloalkyl, aryl, heterocyclic, heteroaryl rings may be monocyclic, bicyclic or polycyclic, saturated , Partially unsaturated, or aromatic and is substituted with 0-5 J;

R ⁶ is cycloalkyl, aryl, and heterocyclyl, or heteroaryl, wherein any cycloalkyl, aryl, heterocyclyl, or heteroaryl is independently J, (C ₁ -C ₆₎ alkyl, (C ₂ - C ₆₎ alkenyl, (C ₂ -C ₆₎ alkynyl, (C ₁ -C ₆₎ haloalkyl, hydroxyl, halo, (C ₁ -C ₆₎ haloalkoxy, cycloalkyl (C ₁ -C ₆₎ alkyl, heterocyclyl (C ₁ -C ₆₎ alkyl, aryl (C ₁ -C ₆₎ alkyl, heteroaryl (C ₁ -C ₆₎ alkyl, oR ³ (R ³ is H or (C ₁ -C ₆₎ Alkyl), or NR < ⁴ > wherein each R < ⁴ > is independently H or (C ₁ -C ₆ ) alkyl; or two R ⁴ groups together with the nitrogen atom to which they are attached are optionally N, O, S , (C ₃ -C ₈ ) heterocyclyl further comprising 1 to 3 heteroatoms selected from the group consisting of S (O) and S (O) ₂ , or R ⁴ is optionally substituted cyclo Alkyl, optionally substituted aryl, optionally substituted < RTI ID = 0.0 > Interrogating heterocyclyl, or optionally substituted heteroaryl), as single or multi-substituted, and;

Any alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, R ³ , R ⁴ , cycloalkyl, aryl, heterocyclyl, or heteroaryl may be further substituted by J;

Provided that (i), (ii), (iii) or (iv) applies:

(i) L ¹ is a bond or (CHR ') _n and R ⁵ is a bicyclic ring moiety optionally substituted with 0-5 J, wherein said bicyclic ring moiety is any one of ai - a - xxviii , The wavy line represents the point of attachment):

With the proviso that when R ⁵ is a-xvii or a-xix, L ² is a bond or (CHR ') _n ;

(ii) L ¹ And L < ² > are independently a bond or (CHR ') _n ; R ⁵ is a 6-immunogenic heteroaryl ring moiety optionally substituted with 0-3 of J ^1, wherein J ¹ is _{OR ', CF 3, Cl,} Br, F, CN, O (C 1 -C 6) alkoxy , O (C ₁ -C ₆ ) cycloalkoxy, alkyl, or N (R ') ₂ , The 6-membered heteroaryl ring moiety is any one of bi to b-xiii wherein the wavy line indicates the point of attachment,

(iii) L ¹ is a bond or (CHR ') _n and L ² is heteroaryl substituted with 0-3 J, wherein heteroaryl is ci or c- ii wherein the wavy line indicates the point of attachment;

or

(iv) L ¹ is a bond or (CHR ') _n , L ² is a bond or (CHR') _n or phenyl substituted with 0-5 J; And R ⁵ and R ⁶ are independently selected from phenyl or heteroaryl, each optionally substituted with 0-5 J; Provided that when L ² is a bond and R ⁵ and R ⁶ are both phenyl, R ⁵ is 4-CN, 3-alkyl-NHR ', 3-alkyl-OR' Alkyl and R < ⁶ > is substituted with at least 4-OR ';

Provided that in the case of (ii), (iii), or (iv), the compound of formula (I)

In various embodiments, pharmaceutical compositions comprising a compound of the invention and suitable excipients are provided.

In various combinations, there is provided a pharmaceutical combination comprising a compound of the present invention and a second agent. In various embodiments, the second agent is medically prescribed for the treatment of multiple sclerosis, transplant rejection or adult respiratory distress syndrome.

Various embodiments of the present invention are directed to the use of a compound of formula (II) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament capable of treating a disorder or adverse symptom medically prescribed for the activation or inhibition of sphingosine- The invention provides the use of compounds, including pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, hydrates, or solvates thereof:

In the above formula (II)

The dotted line indicates that a single bond or a double bond may be present, provided that two double bonds and three single bonds are present in the ring including A ¹ , A ² , and A ³ ;

A ¹ , A ² , and A ³ are each independently C or O, or N (wherein N is bonded to one adjacent double ring atom with a double bond and a single bond) or NR When R is H or (C ₁ -C ₆ ) alkyl when bound to two adjacent ring atoms by a single bond, with the proviso that A ¹ , A ² , and A ³ At least one of A ¹ , A ² , and A ³ is N or NR, and only one of A ¹ , A ² , and A ³ is O;

L ¹ and L ² are independently a bond; (CHR ') _n (R' is H or (C ₁ -C ₆₎ alkyl, n is 1, 2 or 3); Or a heteroaryl selected from the group consisting of thiophenyl, phenyl, furanyl, or benzothiophenyl, said heteroaryl being substituted with 0-3 J;

J is independently selected from F, Cl, Br, I, OR ', OC (O) N (R') 2, CN, CF 3, OCF 3, CHF 2, NO 2, R ', O, S in each case , S (O), S (O), methylenedioxy, ethylenedioxy, N (R ') ₂ , N (R') CH ₂ CH ₂ OR ', SR', SOR ', SO ₂ R', SO _{2 N (R ') 2,} SO 3 R', C (O) R ', C (O) C (O) R', C (O) CH 2 C (O) R ', C (S) R' , C (O) OR ', OC (O) R', OC (O) OR ', C (O) N (R') 2, OC (O) N (R ') 2, C (S) N ( _{R ') 2, (CH 2} ) 0-2 NHC (O) R', (CH 2) 0-2 N (R ') 2, (CH 2) 0-2 N (R') N (R ') ₂ , N (R ') N (R') C (O) R ', N (R') N (R ') C ) ₂ , N (R ') SO ₂ R', N (R ') SO ₂ N (R') ₂ , N (R ') C , N (R ') N ( R'), N (R ') C (S) R', N (R ') C (O) N (R') 2, N (R ') C (S) N _{(R ') 2, N (} COR') COR ', N (oR') R ', C (= NH) N (R') 2, C (O) N (oR ') R', or C (= NOR ') R', wherein two of the J groups may together form a ring; Wherein R 'is independently in each occurrence hydrogen or alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein any alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with 0-3 Substituted or unsubstituted; Or two R 'groups In a 1 substituted with 0-3 of J with the nitrogen atoms or two adjacent nitrogen atom to which (C ₃ -C ₈₎ may form a heterocyclyl; Optionally further containing 1 to 3 additional heteroatoms selected from the group consisting of O, N, S, S (O) and S (O) ₂ ;

R < ⁵ > is monocyclic or bicyclic cycloalkyl, aryl, heterocyclyl, or heteroaryl; Each of which is substituted with 0-5 J, wherein any cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted by one or more additional cycloalkyl; Aryl; Heterocyclyl; Heteroaryl ring, fused with a heteroaryl ring, branched or spiral, wherein any of said one or more additional cycloalkyl, aryl, heterocyclic, heteroaryl rings may be monocyclic, bicyclic or polycyclic, saturated , Partially unsaturated, or aromatic and is substituted with 0-5 J;

R ⁶ is cycloalkyl, aryl, and heterocyclyl, or heteroaryl, wherein any cycloalkyl, aryl, heterocyclyl, or heteroaryl is independently J, (C ₁ -C ₆₎ alkyl, (C ₂ - C ₆₎ alkenyl, (C ₂ -C ₆₎ alkynyl, (C ₁ -C ₆₎ haloalkyl, hydroxyl, halo, (C ₁ -C ₆₎ haloalkoxy, cycloalkyl (C ₁ -C ₆₎ alkyl, heterocyclyl (C ₁ -C ₆₎ alkyl, aryl (C ₁ -C ₆₎ alkyl, heteroaryl (C ₁ -C ₆₎ alkyl, oR ³ (R ³ is H or (C ₁ -C ₆₎ including the alkyl) or NR ⁴ ₂ (each R ⁴ is independently H or (C ₁ -C ₆₎ include alkyl or; or two R ⁴ groups together with the nitrogen atom bonded thereto, optionally, N, O, (C ₃ -C ₈ ) heterocyclyl further comprising 1 to 3 heteroatoms selected from the group consisting of S, S (O) and S (O) ₂ , or R ⁴ is optionally substituted Cycloalkyl, optionally substituted aryl, optionally substituted < RTI ID = 0.0 > Heterocyclyl, or optionally substituted heteroaryl), either singly or multiply substituted;

Any alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, R ³ , R ⁴ , cycloalkyl, aryl, heterocyclyl, or heteroaryl may be further substituted by J;

Provided that (i), (ii), (iii) or (iv) applies:

(i) L ¹ is a bond or (CHR ') _n and R ⁵ is a bicyclic ring moiety optionally substituted with 0-5 J, wherein said bicyclic ring moiety is any one of ai to a- xxviii , The wavy line represents the point of attachment):

Provided that when R ⁵ is a-xvii or a-xix, L ² is a bond or (CHR ') _n ;

(ii) L ¹ And L < ² > are independently a bond or (CHR ') _n ; R ⁵ is a 6-immunogenic heteroaryl ring moiety optionally substituted with 0-3 of J ^1, wherein J ¹ is _{OR ', CF 3, Cl,} Br, F, CN, O (C 1 -C 6) alkoxy , O (C ₁ -C ₆ ) cycloalkoxy, alkyl, or N (R ') ₂ , The 6-membered heteroaryl ring moiety is any one of bi to b-xiii wherein the wavy line indicates the point of attachment:

(iii) L ¹ is a bond or (CHR ') _n and L ² is heteroaryl substituted with 0-3 J, wherein the heteroaryl is ci or c- ii wherein the wavy line indicates the point of attachment ;

;

or

(iv) L ¹ is a bond or (CHR ') _n , L ² is a bond or (CHR') _n or phenyl substituted with 0-5 J; And R ⁵ and R ⁶ are independently selected from phenyl or heteroaryl, each optionally substituted with 0-5 J; Provided that when L ² is a bond and R ⁵ and R ⁶ are both phenyl, R ⁵ is 4-CN, 3-alkyl-NHR ', 3-alkyl-OR' Alkyl and R < ⁶ > is substituted with at least 4-OR ';

Provided that in the case of (ii), (iii), or (iv), the compound of formula (I)

Various embodiments of the present invention include the steps of contacting the receptor subtype 1 with an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt, prodrug, frosundate, stereoisomer, hydrate, or solvate thereof Inhibition or antagonism of sphingosine-1-phosphate receptor subtype 1, including, but not limited to,

In the above formula (II)

The dotted line indicates that a single bond or a double bond may be present, provided that two double bonds and three single bonds are present in the ring including A ¹ , A ² , and A ³ ;

A ¹ , A ² , and A ³ are each independently C or O, or N (wherein N is bonded to one adjacent double ring atom with a double bond and a single bond) or NR When R is H or (C ₁ -C ₆ ) alkyl when bound to two adjacent ring atoms by a single bond, with the proviso that A ¹ , A ² , and A ³ At least one of A ¹ , A ² , and A ³ is N or NR, and only one of A ¹ , A ² , and A ³ is O;

L ¹ and L ² are independently a bond; (CHR ') _n (R' is H or (C ₁ -C ₆₎ alkyl, n is 1, 2 or 3); Or a heteroaryl selected from the group consisting of thiophenyl, phenyl, furanyl, or benzothiophenyl, said heteroaryl being substituted with 0-3 J;

J is independently selected from F, Cl, Br, I, OR ', OC (O) N (R') 2, CN, CF 3, OCF 3, CHF 2, NO 2, R ', O, S in each case , S (O), S (O), methylenedioxy, ethylenedioxy, N (R ') ₂ , N (R') CH ₂ CH ₂ OR ', SR', SOR ', SO ₂ R', SO _{2 N (R ') 2,} SO 3 R', C (O) R ', C (O) C (O) R', C (O) CH 2 C (O) R ', C (S) R' , C (O) OR ', OC (O) R', OC (O) OR ', C (O) N (R') 2, OC (O) N (R ') 2, C (S) N ( _{R ') 2, (CH 2} ) 0-2 NHC (O) R', (CH 2) 0-2 N (R ') 2, (CH 2) 0-2 N (R') N (R ') ₂ , N (R ') N (R') C (O) R ', N (R') N (R ') C ) ₂ , N (R ') SO ₂ R', N (R ') SO ₂ N (R') ₂ , N (R ') C , N (R ') N ( R'), N (R ') C (S) R', N (R ') C (O) N (R') 2, N (R ') C (S) N _{(R ') 2, N (} COR') COR ', N (oR') R ', C (= NH) N (R') 2, C (O) N (oR ') R', or C (= NOR ') R', wherein two of the J groups may together form a ring; Wherein R 'is independently in each occurrence hydrogen or alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein any alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with 0-3 Substituted or unsubstituted; Or two R 'groups In a 1 substituted with 0-3 of J with the nitrogen atoms or two adjacent nitrogen atom to which (C ₃ -C ₈₎ may form a heterocyclyl; Optionally further containing 1 to 3 additional heteroatoms selected from the group consisting of O, N, S, S (O) and S (O) ₂ ;

R < ⁵ > is monocyclic or bicyclic cycloalkyl, aryl, heterocyclyl, or heteroaryl; Each of which is substituted with 0-5 J, wherein any cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted by one or more additional cycloalkyl; Aryl; Heterocyclyl; Heteroaryl ring, fused with a heteroaryl ring, branched or spiral, wherein any of said one or more additional cycloalkyl, aryl, heterocyclic, heteroaryl rings may be monocyclic, bicyclic or polycyclic, saturated , Partially unsaturated, or aromatic and is substituted with 0-5 J;

R ⁶ is cycloalkyl, aryl, and heterocyclyl, or heteroaryl, wherein any cycloalkyl, aryl, heterocyclyl, or heteroaryl is independently J, (C ₁ -C ₆₎ alkyl, (C ₂ - C ₆₎ alkenyl, (C ₂ -C ₆₎ alkynyl, (C ₁ -C ₆₎ haloalkyl, hydroxyl, halo, (C ₁ -C ₆₎ haloalkoxy, cycloalkyl (C ₁ -C ₆₎ alkyl, heterocyclyl (C ₁ -C ₆₎ alkyl, aryl (C ₁ -C ₆₎ alkyl, heteroaryl (C ₁ -C ₆₎ alkyl, oR ³ (R ³ is H or (C ₁ -C ₆₎ including the alkyl) or NR ⁴ ₂ (each R ⁴ is independently H or (C ₁ -C ₆₎ include alkyl or; or two R ⁴ groups together with the nitrogen atom bonded thereto, optionally, N, O, (C ₃ -C ₈ ) heterocyclyl further comprising 1 to 3 heteroatoms selected from the group consisting of S, S (O) and S (O) ₂ , or R ⁴ is optionally substituted Cycloalkyl, optionally substituted aryl, optionally substituted < RTI ID = 0.0 > Heterocyclyl, or optionally substituted heteroaryl), either singly or multiply substituted;

Any alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, R ³ , R ⁴ , cycloalkyl, aryl, heterocyclyl, or heteroaryl may be further substituted by J;

Provided that (i), (ii), (iii) or (iv) applies:

(i) L ¹ is a bond or (CHR ') _n and R ⁵ is a bicyclic ring moiety optionally substituted with 0-5 J, wherein said bicyclic ring moiety is any one of ai to a- xxviii , The wavy line represents the point of attachment):

Provided that when R ⁵ is a-xvii or a-xix, L ² is a bond or (CHR ') _n ;

(ii) L ¹ And L < ² > are independently a bond or (CHR ') _n ; R ⁵ is a 6-immunogenic heteroaryl ring moiety optionally substituted with 0-3 of J ^1, wherein J ¹ is _{OR ', CF 3, Cl,} Br, F, CN, O (C 1 -C 6) alkoxy , O (C ₁ -C ₆ ) cycloalkoxy, alkyl, or N (R ') ₂ , The 6-membered heteroaryl ring moiety is any one of bi to b-xiii wherein the wavy line indicates the point of attachment:

(iii) L ¹ is a bond or (CHR ') _n and L ² is heteroaryl substituted with 0-3 J, wherein the heteroaryl is ci or c- ii wherein the wavy line indicates the point of attachment ;

or

(iv) L ¹ is a bond or (CHR ') _n , L ² is a bond or (CHR') _n or phenyl substituted with 0-5 J; And R ⁵ and R ⁶ are independently selected from phenyl or heteroaryl, each optionally substituted with 0-5 J; Provided that when L ² is a bond and R ⁵ and R ⁶ are both phenyl, R ⁵ is 4-CN, 3-alkyl-NHR ', 3-alkyl-OR' Alkyl and R < ⁶ > is substituted with at least 4-OR ';

Provided that in the case of (ii), (iii), or (iv), the compound of formula (I)

In various embodiments, the compound inhibits sphingosine-1-phosphate receptors such as sphingosin-1-phosphate receptor subtype 3, which is higher than the level that activates, agonizes, inhibits, - activate, inhibit, inhibit or antagonize the phosphate receptor subtype 1.

In various embodiments, there is provided a method of treating an adverse symptom in a patient in which medication is prescribed to activate, energize, inhibit, or antagonize the S1P1 receptor, comprising administering to a patient an effective amount of a compound described above to provide a beneficial effect / RTI >

In various embodiments, selective activation or efficacy of the S1P1 receptor is medically prescribed relative to the S1P3 receptor. In various embodiments, the abnormal symptoms include multiple sclerosis, transplant rejection, or adult respiratory distress syndrome. In various embodiments, for example, selective inhibition or antagonism of the S1P1 receptor relative to the S1P3 receptor is medically prescribed.

Figure 1 shows the results of biochemical assays, such as those described in the Examples for S1P1 activation, which detects ubiquitination as a result of S1P1 activation. Immunoprecipitation (IP) and immunoblotting (IB) were performed using P4D1 (anti-ubiquitin) antibody to detect S1P1-ubiquitination of hemolysate from HEK 293-S1P1-GFP cells. A. S1P1-GFP ubiquitination was detected as a band of 64-82 kDa (lane 1 vehicle control, lane 2 0.5 μM AFD-R, vehicle control vehicle for lane 3 SR-917, lane 4 1 μM SR917). Localization of S1P1-GFP cells with B. Veh (vehicle control), 0.01, 0.1 and 1 [mu] M SR-917. C. S1P1-GFP cells were labeled with P32 and stimulated with agonists. S1P1-GFP was immunoprecipitated, developed with PAGE, transferred to nitrocellulose, and exposed to Kodak XAR film overnight. Lane 1 - vehicle control, lanes 2 and 3 - S1P 0.5 and 0.05 μM, lanes 4 and 5 - AFD-R 0.5 and 0.05 μM, lanes 6 and 7 - SR-917 10 and 1 μM. SR-917 is a known agonist for the S1P1 receptor and is indexed to the NIH Molecular Library Small Molecular Repository (MLMSR). Compound ID is 976135. It is commercially available from the ChemBridge Screening Library.
Figure 2 shows that compound 32 is robustly inducing internalization and ubiquitination polymerization, and these actions are blocked by the S1P1 antagonist W146R.
Figure 3 shows that compound 236 induces S1P1 ubiquitin polymerization as well as other series compounds.
Figure 4 shows that compound 236 causes lymphocyte depletion in mice. This compound was dissolved in 10% DMSO, Tween-20, and delivered via the gut.
Figure 5 shows a pharmacokinetic experiment of SR-917 1 mg / mL in DMSO / Tween / water at 10/10/80 delivered at 1 mg / kg iv.
Figure 6 shows S1P1 polar ligand binding pocket mutations. CHO cells were transformed with S1P1 cDNA constructs. Cells were left overnight serum deprived and stimulated with three-fold serial dilutions of S1P or CYM-5442. ERK1 / 2 phosphorylation was detected by phospho-ERK ELISA (cell signaling). A. S1P1 mutations E121A and R292A. B. Wild type S1P1 (wt) and S1P1 mutation R120A.

In this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

As used herein, the term "individual (as a subject of treatment) includes both mammals and non-mammals." Mammals include, for example, humans; non-human primates such as apes and monkeys; ruminants; horses; sheep; Non-mammals include, for example, fish and algae.

As used herein, the term "S1P1" is subtype 1 of the sphingosine-1-phosphate receptor and other subtypes of the sphingosine-1-phosphate receptor are referred to in the same manner, for example, sphingosine-1-phosphate receptor subtype 3 Quot; S1P3 ".

"Receptor" is a biomolecular material, generally encompassing proteins that specifically bind to ligands or a structural class of one natural ligand in a living organism, as is well known in the art, To another biological action type, for example, a cell to which a binding has been made, signals that the cell modifies its function in some way. An example of a metastasis is the receptor binding of a ligand that alters the activity of a "G-protein" coupled to a cytoplasmic receptor of living cells. Any natural or non-natural molecule that binds to a receptor and activates signal transduction is referred to as an " agonist "or" activator. &Quot; Any naturally occurring or non-naturally occurring molecule that binds to a receptor but can block the binding of an agonist and thereby signal transduction without causing signal transduction is referred to as an "antagonist ".

By "S1P1 compound" or "S1P1 agonist" or "S1P1 activator" or "S1P1 inhibitor" or "S1P1 antagonist" is meant herein a compound that interacts with S1P receptor subtype 1 in some manner. These may be agonists or activators, or antagonists or inhibitors. The "S1P1 compound" of the present invention may be selected to act on subtype 1 of the S1P receptor family, for example, the compounds of the present invention may be more effective for subtype 1 of the S1P receptor family than other subtypes of the S1P receptor family And more specifically, the "S1P compound" of the present invention may selectively act on subtype 1 receptors as compared to the action on subtype 3 or "S1P3" receptors.

In certain embodiments, the compounds of the present invention are orthostatic agonists. In certain other embodiments, the compounds of the present invention are allosteric agonists. Orthosertic agonists bind to one part of the receptor that is largely overlapped with the binding of the natural ligand, replicating the main interaction of the natural ligand with the receptor. Orthosaric agonists will be competitively antagonized by pharmacological agents, which activate the receptor by a molecular mechanism similar to the natural ligand, compete with the natural ligand, and are competitive antagonists to the natural ligand. The allosteric agonist binds to a site in the receptor that forms some significant interaction with the natural ligand, either not completely overlapping or partially overlapping. The allosteric agonist is a true agonist and not an allosteric potentiator. That is, it activates receptor signaling alone and does not require a requirement below the maximum concentration of the natural ligand. The allosteric agonist can be identified when antagonists known to be competitive to the orthoseric ligand exhibit a non-competitive antagonistic action. The allosteric agonist moiety can be mapped by receptor mutagenesis. The introduction of one point mutation in the receptor maintains receptor activation by the allosteric agonist, but the disappearance or nullification of signaling caused by the orthosicic agent, or vice versa, provides formal evidence of differences in binding interactions to provide. Orthostatic agonists make GPCRs ("G-protein coupled receptors") structures and forms unstable, but allosteric agonists can stabilize or destabilize GPCR structure and morphology. The allosteric agonists may be useful pharmacologically by differential interactions with the receptor because agonistic sites have agonist efficacy on a family of related receptor subtypes that share similar orthosicic ligands, As well as additional opportunities for selectivity. In addition, the allosteric site may require a wide variety of physical and chemical properties of the agonist as compared to the orthoseric ligand. Physico-chemical, physical properties such as hydrophobicity, aromatics, charge distribution and solubility can also provide advantages in the preparation of various agonists with pharmacokinetic, oral bioavailability, distribution and metabolic profiles that promote the development of effective pharmaceutical substances.

As used herein, the term "substantially" means fully or nearly complete, e.g., a composition in which one of the components is "substantially deficient" means that either one of the constituents is absent, Or < / RTI > Or "substantially pure" compound means that the impurities present are only minor minor quantities.

&Quot; Treating "or" treatment "as used herein means alleviating symptoms associated with a disorder, an abnormal symptom, or a disease, or inhibiting further progression or worsening of such symptoms, or preventing or preventing a disorder, abnormal symptom or disease.

The expression "effective amount" used to describe the use of a compound of the present invention in providing treatment to a patient suffering from a disorder or an abnormal condition mediated by a sphingosine-1-phosphate receptor of subtype 1 is an & An amount of a compound of the invention effective to bind as an agonist or antagonist to the S1P1 receptor in a tissue wherein the S1P1 receptor is associated with a disorder and such binding is at a level sufficient to produce a beneficial therapeutic effect for the patient. Likewise, an "effective amount" or "therapeutically effective amount" of a compound of the present invention is defined herein as a compound that alleviates all or part of a symptom associated with a disorder or adverse symptom or further stops or slows , Or an amount of a compound that prevents or prevents a disorder or aberrant symptoms. In particular, a "therapeutically effective amount" is an amount effective for the dosage and duration necessary to achieve the desired therapeutic result by acting as an agonist or activator of the sphingosine-1-phosphate receptor subtype 1 (S1P1) activity. The therapeutically effective amount is also a greater amount of the therapeutically beneficial effect than any toxic or deleterious effect of the compounds of the present invention. For example, in terms of treating the abnormal symptoms mediated by S1P1 activation, the therapeutically effective amount of S1P1 of the present invention can be adjusted by controlling the abnormal symptoms, alleviating the progress of the abnormal symptoms, . Examples of abnormal symptoms that can be treated include multiple sclerosis, graft rejection and adult respiratory distress syndrome.

In particular, all chiral, diastereoisomeric, racemic forms of the structure, unless stereochemistry or isomeric forms are specifically indicated. The compounds used in the present invention may contain optical isomers enriched or decomposed at any or all asymmetric atoms, as evident from the description provided, at any concentration level. Racemic and diastereomeric mixtures as well as individual optical isomers can be separated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners and are included within the scope of the present invention.

Isomerization and tautomerization of the compounds of the present invention

Tautification

In the present invention, it is understood that the compound of the formula I or a salt thereof can exhibit a tautomerization phenomenon in which two chemical compounds can be easily interconverted by exchanging hydrogen between two atoms for forming a covalent bond . Since the tautomeric compounds are in mobile phase equilibrium with each other, this can be regarded as different isomeric forms of the same compound. It is to be understood that the formulas of the present disclosure are capable of displaying only one of the possible taut variants. However, the invention is also understood to include any tautomeric forms that act on S1P receptors, such as the S1P subtype 1 receptor, and are not limited to any single tautomeric forms shown in the figure. It is to be understood that the formulas herein may represent only one of the possible forms of the tautomer, and that the present specification includes all possible tautomeric forms of the depicted compounds, . For example, the tautomerization may be represented by a pyrazolyl group bonded as indicated by a wavy line. Two substituents are referred to as 4-pyrazolyl groups, but it is clear that the different nitrogen atoms have hydrogen atoms in each structure.

This tautomerization can also form substituted pyrazoles such as 3-methyl, 5-methyl or 3,5-dimethylpyrazole.

Optical isomerization

When the compounds of the present invention comprise one or more chiral centers, it will be understood that the compounds exist as pure enantiomeric forms, diastereoisomeric forms or racemic mixtures and can be separated. Accordingly, the present invention includes all possible enantiomers, diastereoisomers, racemates or mixtures of the compounds of the invention that are biologically active in the treatment of S1P1 mediated diseases.

Isomers formed by the presence of a chiral center include a pair of non-overlapping entities "enantiomers ". The single enantiomer of the pure compound is optically active, i. E. It can rotate the plane of the plane polarized light. The single enantiomer is named according to the Cahn-Ingold-Prelog system. Once the priorities of the four groups are determined, the molecules are positioned such that the lowest ranking group is away from the viewer. Then, if the other groups proceed clockwise in descending order, the molecule is named (R), and if the other groups are going in the counterclockwise direction in descending order, the molecule is named (S). In Scheme 14, the Cahn - Ingold - Prelog order is A>B>C> D. The lowest ranked atom, D, is located farthest from the viewer.

(R) coordination (S) coordination

The present invention is meant to include not only diastereomers but also racemic and resolved diastereomers and enantiomerically pure forms thereof and salts thereof. The diastereomeric pairs can be separated by known separation techniques such as normal and reverse phase chromatography and crystallization.

"Isolated optical isomer" or "isolated enantiomer" refers to a compound that is substantially purified from the corresponding optical isomer of the same formula (enantiomer). Preferably, the isolated isomers are at least about 80% pure by weight, more preferably at least 90% pure, even more preferably at least 98% pure, and most preferably at least about 99% pure Do.

The separated optical isomers can be purified from the racemic mixture by well known chiral separation techniques. According to this one method, a racemic mixture or its chiral intermediates of the compounds of the present invention, by using the appropriate chiral column, for example CHIRALPAK ^® Series Column DAICEL ^® series (Daicel Chemical Industries, Ltd., Tokyo, Japan), HPLC To an optical isomer of 99% wt.% Purity. The column is operated according to the manufacturer's instructions.

Rotational isomerization

Among other types of bonds, due to the limited rotation chemistry (i. E., Resonance is indicated by the partial double bond symbol in the CN bond) for the amide bond linkage (as described below), separate rotamer species can be observed And even in some conditions, for example, these species shown below can be isolated. Certain structural elements, including steric bulk or substituents on the amide nitrogen, can separate the compound into a single stable rotamer and enhance the stability of the rotamer to a level that can exist indefinitely, do. Accordingly, the present invention includes all possible stable rotamers of the compounds of the present invention that are biologically active in treating cancer or other proliferative disease conditions.

D. positional isomerization

Preferred compounds of the present invention have a specific spatial arrangement of substituents on the aromatic ring, which is related to the radical activity relationship evidenced by the class of compounds. While such permutation arrangements are usually denoted by a numbering scheme, the numbering scheme is often not consistent among different ring systems. In a six-element aromatic system, the spatial arrangement is denoted by the general nomenclature 1,4-substitution as "para", 1,3-substitution as "meta" and 1,2-substitution as "ortho"

"Para -" "Meta -" "Oroso -"

The compounds of the present invention may comprise one or more stereogenic (chiral) or asymmetric centers, such as one or more asymmetric carbon atoms. Substitution in a double bond may exist as cis- ("Z") or trans ("E") unless otherwise stated. Substitution on the ring can also be arranged in cis or trans in different or mixed forms. The compounds of the present invention may thus exist as mixtures of stereoisomers, or preferably as substantially pure stereoisomers. Pure stereoisomers can be obtained by separating the stereoisomeric mixture or by stereoselective or stereospecific synthesis in a manner known to those skilled in the art.

It is to be understood that all structures included in the claims may be physically present, while structures represented by any combination or subcombination of optional substitutions may be physically present while maintaining a certain degree of stability, Is "chemically feasible" The chemically unrealizable structure is not included in the claimed range of the compound.

When the substitution is stated to be an atom or an atom of a specified substance or as a "bond", the coordination means that the group immediately adjacent to the specified substituent is directly connected to one another by a chemically feasible bond coordinate, if the substitution is a "bond" do.

Generally, "substituted" means that at least one bond to an included hydrogen atom is replaced by a non-hydrogen atom, such as, but not limited to, halogen (e.g., F, Cl, Br, and I); An oxygen atom in the cabin such as a hydroxyl group, an alkoxy group, an aryloxy group, an aralkyloxy group, an oxo (carbonyl) group, a carboxyl group such as a carboxylic acid, a carboxylate and a carboxylate ester; A sulfur atom in the group such as a thiol group, an alkyl and aryl sulfide group, a sulfoxide group, a sulfone group, a sulfonyl group and a sulfonamide group; Nitrogen atoms such as amines, hydroxylamines, nitriles, nitro groups, N-oxides, hydrazides, azides and enamines; ≪ / RTI > and other heteroatoms in various other < RTI ID = 0.0 > cabinets. ≪ / RTI > Examples of substituents which can be bonded to a substituted carbon (or other) atom include F, Cl, Br, I, OR ', OC (O) N (R') ₂ , CN, CF ₃ , OCF ₃ , R ', O, S, C (O), S (O), methylenedioxy, _{ethylenedioxy, N (R') 2,} SR ', SOR', SO 2 R ', SO 2 N (R') 2 _{, SO 3 R ', C (} O) R', C (O) C (O) R ', C (O) CH 2 C (O) R', C (S) R ', C (O) OR' , OC (O) R ', C (O) N (R') 2, OC (O) N (R ') 2, C (S) N (R') 2, (CH 2) 0-2 NHC ( _{O) R ', (CH 2} ) 0-2 N (R') N (R ') 2, N (R') N (R ') C (O) R', N (R ') N (R' ) C (O) OR ', N (R') N (R ') CON (R') 2, N (R ') SO 2 R', N (R ') SO 2 N (R') 2, N (R ') C (O) OR', N (R ') C (O) R', N (R ') C (S) R', N (R ') C (O) N (R') 2 , N (R ') C ( S) N (R') 2, N (COR ') COR', N (OR ') R', C (= NH) N (R ') 2, C (O) N (OR ') R', or C (= NOR ') R', but not limited to, R 'may be hydrogen or a carbon-based moiety and the carbon- .

Other substituted groups as well as substituted alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groups are also meant to include those in which at least one bond to hydrogen is replaced by a carbon atom or a group including but not limited to carbonyl (oxo), carboxyl, , Imide, urethane and urea oxygen; And a group substituted with at least one bond such as a double bond, a triple bond, etc., to a hetero atom such as imine, hydroxyimine, oxime, hydrazone, amidine, guanidine and nitrogen in nitrile.

Substituted ring groups such as substituted aryl, heterocyclyl and heteroaryl groups also include rings and fused ring systems wherein the bond to hydrogen is replaced by a bond to a carbon atom. Thus, substituted aryl, heterocyclyl and heteroaryl groups may also be substituted with alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and alkynyl groups, as defined herein, which may themselves be further substituted .

The term "heteroatom " means non-carbon and non-hydrogen atoms herein, which are capable of forming a covalent bond with the carbon, but are not limited thereto. Typical heteroatoms are N, O, and S. In the case where sulfur (S) is referred to, the sulfur may be in any oxidation state are found, and thus, except as otherwise noted sulfoxide (RS (O) -R '), and sulfone (RS (O) ₂ -R '); The term "sulfone" includes only the sulfone form of sulfur; The term "sulfide" includes only the sulfide sulfide (RS-R ') form. When the expression "heteroatom selected from the group consisting of O, NH, NR 'and S" or "[variable] is O, S ..." is used, this means that the sulfide, sulfoxide and sulfone oxidation state Are understood to include both.

The alkyl group includes straight and branched alkyl and cycloalkyl groups having from 1 to about 20 carbon atoms, typically from 1 to 12, or in some embodiments from 1 to 8 carbon atoms. Examples of the branched alkyl group include groups having 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl and 2,2-dimethylpropyl groups. Examples of substituted alkyl groups may be substituted one or more times in any of the foregoing groups such as amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy and halogen groups.

The cycloalkyl group is an alkyl group which forms a ring structure which may be substituted or unsubstituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group has 3 to 8 ring members, and in other embodiments, the number of ring carbon atoms ranges from 3 to 5, from 3 to 6, or from 3 to 7. The cycloalkyl group further includes polycyclic cycloalkyl such as norbornyl, adamantyl, boronyl, campthenyl, isopentenyl and carenyl groups, fused rings such as ditallinyl, and the like. Further, the cycloalkyl group includes a ring substituted with a straight-chain or branched-chain alkyl group as defined above. Representative substituted cycloalkyl groups include, but are not limited to, 2,2-, 2,3-, 2,4- 2,5- or < RTI ID = 0.0 > Cyclohexyl group or a mono-, di- or tri-substituted norbornyl or cycloheptyl group, which may be mono- or poly-substituted two or more times .

The terms " carbocyclic "and" carbocycle "are ring structures in which the atoms of the ring are carbon. In some embodiments, the carbocycle is a 3-8 membered ring, but in other embodiments, the number of ring carbon atoms is 4, 5, 6 or 7. Unless otherwise stated, the carbocyclic ring may be substituted with N substituents, such as amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy and halogen groups, wherein N is a carbocyclic ring .

The (cycloalkyl) alkyl group is also cycloalkylalkyl, which is an alkyl group as defined above wherein the hydrogen or carbon bond of the alkyl group is replaced by a bond to the cycloalkyl group defined above.

Alkenyl groups include straight chain and branched chain cyclic alkyl groups, as defined above except that at least one double bond is between two carbon atoms. Thus, alkenyl groups have from 2 to about 20 carbon atoms, typically from 2 to 12, and in some embodiments from 2 to 8 carbon atoms. Examples thereof include -CH = CH (CH 3), -CH = C (CH 3) 2, -C (CH 3) = CH 2, -C (CH 3) ═CH (CH 3) But are not limited to, vinyl, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl.

The term "cycloalkenyl ", alone or in combination, is a cyclic alkenyl group in which one or more double bonds are present in the ring structure. Cycloalkenyl groups include cycloalkyl groups having at least one double bond between two adjacent carbon atoms. For example, cycloalkenyl groups include cyclohexenyl, cyclopentenyl, and cyclohexadienyl groups, but are not limited thereto.

(Cycloalkenyl) alkyl group is an alkyl group according to the definition above, wherein the hydrogen or carbon bond of the alkyl group is replaced by a bond to the cycloalkenyl group as defined above.

Alkynyl groups include straight and branched chain alkyl groups wherein there is at least one triple bond between the two carbon atoms. Thus, the alkynyl group has from 2 to about 20 carbon atoms, typically from 2 to 12, in some embodiments from 2 to 8 carbon atoms. Examples are, inter alia _{-C≡CH, -C≡C (CH 3),} -C≡C (CH 2 CH 3), -CH 2 C≡CH, -CH 2 C≡C (CH 3), and -CH ₂ C≡C (CH ₂ CH ₃ ), but are not limited thereto.

The aryl group is a cyclic aromatic hydrocarbon containing no hetero atom. Examples of aryl groups include phenyl, azulenyl, heptalenyl, biphenyl, isenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl and naphthyl Butyl group, but are not limited thereto. In some embodiments, the aryl group contains 6-14 carbons in the ring portion of the group. The expression "aryl group" includes groups including fused rings such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.) Substituted aryl groups with other groups including, but not limited to, halo, amino, hydroxy, cyano, carboxy, nitro, thio or alkoxy groups. Representative substituted aryl groups may be mono-substituted or may be substituted more than once, such as 2-, 3-, 4-, 5-, or 6-membered, which may be substituted with groups that include, -Substituted phenyl or naphthyl group, but is not limited thereto.

Aralkyl groups are alkyl groups as defined above wherein the hydrogen or carbon bond of the alkyl group is replaced by a bond to an aryl group as defined above. Representative aralkyl groups include benzyl, fused (cycloalkylaryl) alkyl groups such as phenylethyl and 4-ethyl-indanyl. The aryl moiety or alkyl moiety, or both, is optionally substituted with, but not limited to, other groups such as alkyl, halo, amino, hydroxy, cyano, carboxy, nitro, thio or alkoxy groups.

Heterocyclyl groups include aromatic and non-aromatic ring compounds comprising three or more ring members, wherein at least one of the ring members is a heteroatom such as, but not limited to, N, O, S, or P. In some embodiments, the heterocyclyl group comprises 3 to 20 ring members, but such other groups include 3 to 15 ring members. One or more rings include heteroatoms, but not all rings of the polycyclic system need to include heteroatoms. For example, both the dioxolanyl ring and the benzdioxolanyl ring system (methylenedioxyphenyl ring system) are heterocyclyl groups as defined herein. The heterocyclyl group specified as C ₂ -heterocyclyl can be a pentacyclic ring having two carbon atoms and three heteroatoms, a six-membered ring having two carbon atoms and four heteroatoms, and the like. Likewise, C ₄ -heterocyclyl can be a pentacyclic ring having one heteroatom, a six-membered ring having two heteroatoms, and the like. The sum of the number of carbon atoms plus the number of heteroatoms is equal to the total number of atoms forming a ring.

The expression "heterocyclyl group " includes fused ring species such as species having fused aromatic and non-aromatic groups. This expression also includes a polycyclic ring system including, but not limited to, a heteroatom such as quinuclidil, and also includes, but is not limited to, an alkyl, halo, amino, A heterocyclyl group having a substituent such as a hydroxyl, a cyano, a carboxy, a nitro, a thiol or an alkoxy group. A heterocyclyl group as defined herein may be a heteroaryl group or may be a partially or fully saturated cyclic group comprising at least one ring heteroatom. Heterocyclyl groups include pyrrolidinyl, furanyl, tetrahydrofuranyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, Wherein the heteroaryl group is selected from the group consisting of pyridyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, , Benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphrenenyl, furanyl, zantinyl, adenyl, guanyl, quinolinyl, iso Quinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups, but are not limited thereto. The heterocyclyl group may be substituted. Representative substituted heterocyclyl groups include, but are not limited to, substituents such as those listed above such as alkyl, halo, amino, hydroxy, cyano, carboxy, nitro, thiol and alkoxy groups, 4, 5, 6 or more rings, including rings containing one or more heteroatoms, or the like.

A heteroaryl group is an aromatic ring compound comprising at least five ring members wherein at least one of the ring members is a heteroatom such as, but not limited to, N, S, O, The heteroaryl group represented by C ₂ -heteroaryl can be a pentacyclic ring comprising two carbon atoms and three heteroatoms, a six-membered ring including two carbon atoms and four heteroatoms, and the like. The maximum sum of the number of carbon atoms and the number of heteroatoms is equal to the total number of ring atoms. Examples of heteroaryl groups include pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, Benzothiazolyl, benzothiadiazolyl, imidazolylpyridinyl, isoxazolopyridinyl, thianaphthalenyl, furunyl, zantinyl, adenenyl, benzothiazolyl, benzothiazolyl, But are not limited to, guanidinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl and quinazolinyl groups. The terms "heteroaryl" and "heteroaryl group" are not necessarily all rings, and include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl and 2,3-dihydroindolyl , And the like. The term also includes heteroaryl groups attached to one of the ring members, including, but not limited to, alkyl, halo, amino, hydroxy, cyano, do. Representative substituted heteroaryl groups may be substituted one or more times with groups such as those described above.

Other examples of aryl and heteroaryl groups include phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), pyrazolyl (3-pyrazolyl), pyrazolyl Imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, Yl, 1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, Thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2- blood Pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl) Quinolyl, 8-quinolyl, isoquinolyl (1-isoquinolyl, 3-quinolyl, 4-quinolyl, Isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl and 8-isoquinolyl), benzo [b] furanyl (2-benzo [ Benzo [b] furanyl, 4-benzo [b] furanyl, 5-benzo [b] furanyl, 6- Dihydro-benzo [b] furanyl (2- (2,3-dihydro-benzo [b] furanyl) (2,3-dihydro-benzo [b] furanyl), 5- (2,3-dihydro-benzo [b] furanyl) Benzo [b] thiophenyl, 3-benzo [b] thiophenyl, 4-benzo [b] furanyl, Thiophenyl, 5-benzo [b] thiophenyl, 6- (2,3- dihydro-benzo [b] thiophenyl), 2,3-dihydro-benzo [b] thiophenyl, (2,3-dihydro-benzo [b] thiophenyl), 4- (2,3-dihydro- (2,3-dihydro-benzo [b] thiophenyl), indolyl (1-indolyl, 2- Indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl and 7-indolyl) Benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, Benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl, , 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl) (5H-dibenz [b, f] azepin-l-yl) benzoyl] 5H-dibenz [b, f] azepin-2-yl, 5H-dibenz [b, Dibenz [b, f] azepin-5-yl), 10,11-dihydro-5H-dibenz [b, f] azepine (10,11-dihydro- Dihydro-5H-dibenz [b, f] azepin-2-yl, 10,11-dihydro- Dihydro-5H-dibenz [b, f] azepin-5-yl), 10,11- And the like, but are not limited thereto.

The heterocyclylalkyl group is an alkyl group as defined above wherein the hydrogen or carbon bond of the alkyl group is replaced by a bond to the heterocyclyl group defined above. Representative heterocyclylalkylthio include furan-2-ylmethyl, furan-3-ylmethyl, pyridin-2-ylmethyl (alpha-picolyl), pyridin- 4-ylmethylgamma-picolyl), tetrahydrofuran-2-ylethyl, and indol-2-ylpropyl, but are not limited thereto. The heterocyclylalkyl group may be substituted in the heterocyclyl moiety, the alkyl moiety, or both.

A heteroarylalkyl group is an alkyl group as defined above wherein the hydrogen or carbon bond of the alkyl group is replaced by a bond to a heteroaryl group as defined above. The heteroarylalkyl group may be substituted in a heteroaryl moiety, an alkyl moiety, or both.

The term "ring system" is used herein to denote 1, 2, 3 or 4 ring systems, which may be substituted by a non-ring group or other ring system, which may be fully saturated, partially saturated, fully unsaturated or aromatic And the ring may be fused, bridged or spirocyclic when the ring system comprises two or more single rings. "Spirocyclic" means a structure type in which two rings are fused to one tetrahedraalic carbon atom, as is well known in the art.

The term "monocyclic, bicyclic or polycyclic, aromatic or partially aromatic ring" is used herein to mean a ring system, such as an unsaturated ring having 4n + 2 pi electrons or a partially reduced (hydrogenated) it means. The aromatic or partially aromatic ring may include additional fused, bridged or spiro rings, which themselves are not aromatic or partially aromatic. For example, both naphthalene and tetrahydronaphthalene are included within the meaning of a "monocyclic, bicyclic or polycyclic aromatic or partially aromatic ring". Further, for example, benzo [2.2.2] -bicyclooctane also corresponds to the meaning of a "monocyclic, bicyclic or polycyclic aromatic or partially aromatic ring" and includes a phenyl ring fused to a cross-linked bicyclic system . A fully saturated ring has no double bond and is carbocyclic or heterocyclic depending on the presence of the heteroatom within the meaning of the present application.

The term "alkoxy" is an oxygen-linked alkyl group, such as a cycloalkyl group, as defined above. Examples of the linear alkoxy group include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, n-hexyloxy and the like. Examples of the branched alkoxy include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy and the like. Examples of cyclic alkoxy include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

The terms "aryloxy" and "arylalkoxy" are an alkyl moiety in which an aryl group is bonded to an oxygen atom and an alkyl moiety in which an aralkyl group is bonded to an oxygen atom. Examples include, but are not limited to, phenoxy, naphthyloxy and benzyloxy.

The term "acyl" is used herein to denote a carbonyl moiety containing a group linked through a carbonyl carbon atom. The carbonyl carbon atom is also bonded to other carbon atoms, which may be part of an alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, . In certain instances where a carbonyl carbon atom is bound to a hydrogen, the group is a "formyl" group, referred to as the acyl group, as defined herein. Acyl groups may include from 0 to about 12-20 additional carbon atoms attached to the carbonyl group. Acyl groups may include double or triple bonds within the meaning of the present application. The acrylic oil group is an example of an acyl group. In addition, the acyl group may contain a hetero atom within the meaning of the present application. (Pyridyl-3-carbonyl) group is an example of an acyl group corresponding to the meaning of the present invention. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl and acryloyl groups. When a group containing a carbon atom bonded to a carbonyl carbon source comprises a halogen, this group is referred to as a "haloacyl" group. An example thereof is a trifluoroacetyl group.

The term "amine" refers to a primary, secondary and tertiary amine, for example, represented by the formula N (group) ₃ wherein each group is independently H or H, . Amines, R-NH _2, for example, alkyl amine, aryl amine, alkyl aryl amine; R ₂ NH (each R is independently selected), such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines, and the like; And R3N (each R is independently selected), such as, but not limited to, trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like. The term "amine" also includes ammonium ions as used herein.

An "amino" group is a substituent of the form -NH ₂ , -NHR, -NR ₂ , -NR ₃ ⁺ (each R is independently selected) and each quantized form. That is, any compound substituted with an amino group can be regarded as an amine.

"Ammonium" ions include unsubstituted ammonium ion NH ₄ ⁺ , except where otherwise noted, and also include any quantized or quaternized amine forms. That is, both trimethylammonium hydrochloride and tetramethylammonium chloride are included in the ammonium ions and amines herein.

The term "amide" (or "amido") includes C- and N-amide groups, ie, -C (O) NR ₂ , and -NRC (O) R, respectively. Thus, the amide group includes, but is not limited to, a carbamoyl group (-C (O) NH ₂ ) and a formamide group (-NHC (O) H). The "carboxy" group is a group of the formula C (O) NR ₂ , wherein R can be H, alkyl, aryl, and the like.

The term "urethane" (or "carbamyl") are N- and O- urethane group, i.e., -NRC (O) OR and -OC (O) NR ₂ group include, respectively.

The term "sulfonamide" (or "sulfonamido") includes S- and N- sulfonamide group, i.e., -SO ₂ NR ₂ and -NRSO ₂ R group, respectively. Sulfonamide group thus comprises a sulfamic one parent group (-SO ₂ NH _2), but are not limited to.

The term "amidine" or "amidino" includes groups of the formula -C (NR) NR ₂ . Typically, an amidino group -C (NH) a NH _2.

The term "guanidine" or "guanidino" include groups of formula -NRC (NR) ₂ NR. Typically, the guanidino group is -NHC (NH) a NH _2.

"Halo "," halogen "and" halide "include F, Cl, Br and I.

 The terms "including", "including", "having", and "consisting of" are used in this non-limiting term to exclude the presence of additional elements or components. In the claim element, the terms "including", "having", and "comprising" mean that the subject of a verse containing the term, whether it is, including, It does not necessarily include the element.

"Salts" include organic compounds such as carboxylic acids, sulfonic acids or amines in ionic form in combination with counterions, as is well known in the art. For example, in the anionic form, the acid may be a metal cation such as sodium, potassium, and the like; Ammonium salt such as NH ₄ ⁺ or other cation such as trimethylsulfonium and the like. "Pharmaceutically acceptable" or "pharmacologically acceptable" salts are salts formed from ions, such as chloride salts or sodium salts, which are generally non-toxic and approved for human consumption. A "positive ion" is an internal salt, as can be formed in a molecule, in which two or more ionizable groups, one is a cation and the other is balanced with an anion. For example, amino acids such as glycine may be present in the form of a positive ion. "Positive ion" corresponds to the salt meaning herein. The compounds of the present invention can take the form of a salt. The term "salt" includes the free acid of the compound of the invention or an addition salt of the free base. Salts are "pharmaceutically acceptable salts ". The term "pharmaceutically acceptable salt" refers to a salt having a toxicity profile to the extent that it imparts utility to pharmaceutical use. Pharmaceutically unacceptable salts may nonetheless have characteristics such as high crystallinity, which may be achieved by the practice of the invention, such as, for example, the utility in the synthesis, purification, or formulation of compounds of the present invention .

Suitable pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid and phosphoric acid. Suitable organic acids may be selected from aliphatic, cycloaliphatic, aromatic, aromatic aliphatic, heterocyclic, carboxyl and sulfone classes of organic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid (Pamoic acid), malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, , Methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, Beta-hydroxybutyric acid, salicylic acid, galactaric acid, and galacturonic acid. Examples of pharmaceutically unacceptable acid addition salts are, for example, perchlorate and tetrafluoroborate.

Suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include, for example, metallic salts such as alkali metals, alkaline earth metals and transition metal salts such as calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include basic salts such as N , N' -dibenzylethylenediamine, chloropropane, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) ≪ / RTI > amine. Examples of pharmaceutically unacceptable base addition salts include lithium salts and cyanate salts. Pharmaceutically unacceptable salts generally can not be used as medicines, but such salts may be useful in purification by recrystallization, for example as an intermediate in the synthesis of compounds of formula I. All of these salts can be prepared in a convenient manner from the corresponding compounds according to formula I, for example by reacting a compound of formula I with a suitable acid or base. The term "pharmaceutically acceptable salts" refers to inorganic or organic acid and / or base addition salts of non-toxic and, for example Lit et al., Salt Selection for Basic Drugs (1986), Int J. Pharm., 33, 201 -217, which is incorporated herein by reference in its entirety.

"Hydrate" is a compound that is present in a composition with water molecules. The composition may comprise water in stoichiometric amounts, such as monohydrate or dihydrate, or may comprise water at random levels. As used herein, the term " hydrate "is a solid form, i.e. the compound in the aqueous solution can be hydrated, but is not a hydrate as the term is used herein.

"Solvate" is a similar configuration except that the solvent except water is replaced by water. For example, methanol or ethanol may form an "alcoholate ", which may also be stoichiometric or non-stoichiometric. As used herein, the term "solvate" refers to a solid form, i.e. a solution of a compound in a solvent can be solvated, but is not a solvate as the term is used herein.

"Prodrug" is a substance that can be administered to a patient, as is well known in the art, wherein the patient is converted into a biochemical action within the body, e.g., by an enzyme, into a pharmaceutical component in which the substance is active. Examples of prodrugs include esters of carboxylic acid groups that can be hydrolyzed by an endogenous esterase found in the bloodstream of humans or other mammals.

Further, features or aspects of the present invention are described in terms of a Makush group, and those skilled in the art will recognize that the present invention is therefore described in terms of any individual member or subgroup of members of the Makushi family will be. For example, if X is described as being selected from the group consisting of Br, Cl, and I, then the claim that X is Br, and that X is Br and Cl are fully described. Further, features or aspects of the present invention are described in terms of the surface of a Makush group, and those skilled in the art will also appreciate that the present invention may also be described as a combination of individual members or a subgroup of members of a Makush family . Thus, for example, if X is selected as Br, Cl and I and Y is described as being selected from the group consisting of methyl, ethyl and propyl, the claims are fully described wherein X is Br and Y is methyl.

In various embodiments, the compounds or sets of compounds of the invention may be used as such, or as combinations thereof, and / or in combinations of sub-combinations of the various embodiments mentioned, as used in the practice of the methods of the invention And may be any one of them.

The conditions may apply to any of the categories or implementations described, where any one or more of the above-described implementations or classes may be excluded from such categories or implementations.

More specifically, the compounds of the present invention may be any of the specific examples shown below as exemplary compounds of the present invention.

Various embodiments of the present invention include compounds of formula (I) Or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, hydrate, or solvate thereof, wherein:

(I)

In the above formula (I)

The dotted line indicates that a single bond or a double bond may be present, provided that two double bonds and three single bonds are present in the ring including A ¹ , A ² , and A ³ ;

A ¹ , A ² , and A ³ are each independently C or O, or N (wherein N is bonded to one adjacent double ring atom with a double bond and a single bond) or NR When R is H or (C ₁ -C ₆ ) alkyl when bound to two adjacent ring atoms by a single bond, with the proviso that A ¹ , A ² , and A ³ At least one of A ¹ , A ² , and A ³ is N or NR, and only one of A ¹ , A ² , and A ³ is O;

L ¹ and L ² are independently a bond; (CHR ') _n (R' is H or (C ₁ -C ₆₎ alkyl, n is 1, 2 or 3); Or a heteroaryl selected from the group consisting of thiophenyl, phenyl, furanyl, or benzothiophenyl, said heteroaryl being substituted with 0-3 J;

J is independently selected from F, Cl, Br, I, OR ', OC (O) N (R') 2, CN, CF 3, OCF 3, CHF 2, NO 2, R ', O, S in each case , S (O), S (O), methylenedioxy, ethylenedioxy, N (R ') ₂ , N (R') CH ₂ CH ₂ OR ', SR', SOR ', SO ₂ R', SO _{2 N (R ') 2,} SO 3 R', C (O) R ', C (O) C (O) R', C (O) CH 2 C (O) R ', C (S) R' , C (O) OR ', OC (O) R', OC (O) OR ', C (O) N (R') 2, OC (O) N (R ') 2, C (S) N ( _{R ') 2, (CH 2} ) 0-2 NHC (O) R', (CH 2) 0-2 N (R ') 2, (CH 2) 0-2 N (R') N (R ') ₂ , N (R ') N (R') C (O) R ', N (R') N (R ') C ) ₂ , N (R ') SO ₂ R', N (R ') SO ₂ N (R') ₂ , N (R ') C , N (R ') N ( R'), N (R ') C (S) R', N (R ') C (O) N (R') 2, N (R ') C (S) N _{(R ') 2, N (} COR') COR ', N (oR') R ', C (= NH) N (R') 2, C (O) N (oR ') R', or C (= NOR ') R', wherein two of the J groups may together form a ring; Wherein R 'is independently in each occurrence hydrogen or alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein any alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with 0-3 Substituted or unsubstituted; Or two R 'groups In a 1 substituted with 0-3 of J with the nitrogen atoms or two adjacent nitrogen atom to which (C ₃ -C ₈₎ may form a heterocyclyl; Optionally further containing 1 to 3 additional heteroatoms selected from the group consisting of O, N, S, S (O) and S (O) ₂ ;

R < ⁵ > is monocyclic or bicyclic cycloalkyl, aryl, heterocyclyl, or heteroaryl; Each of which is substituted with 0-5 J, wherein any cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted by one or more additional cycloalkyl; Aryl; Heterocyclyl; Heteroaryl ring, fused with a heteroaryl ring, branched or spiral, wherein any of said one or more additional cycloalkyl, aryl, heterocyclic, heteroaryl rings may be monocyclic, bicyclic or polycyclic, saturated , Partially unsaturated, or aromatic and is substituted with 0-5 J;

R ⁶ is cycloalkyl, aryl, and heterocyclyl, or heteroaryl, wherein any cycloalkyl, aryl, heterocyclyl, or heteroaryl is independently J, (C ₁ -C ₆₎ alkyl, (C ₂ - C ₆₎ alkenyl, (C ₂ -C ₆₎ alkynyl, (C ₁ -C ₆₎ haloalkyl, hydroxyl, halo, (C ₁ -C ₆₎ haloalkoxy, cycloalkyl (C ₁ -C ₆₎ alkyl, heterocyclyl (C ₁ -C ₆₎ alkyl, aryl (C ₁ -C ₆₎ alkyl, heteroaryl (C ₁ -C ₆₎ alkyl, oR ³ (R ³ is H or (C ₁ -C ₆₎ including the alkyl) or NR ⁴ ₂ (each R ⁴ is independently H or (C ₁ -C ₆₎ include alkyl or; or two R ⁴ groups together with the nitrogen atom bonded thereto, optionally, N, O, (C ₃ -C ₈ ) heterocyclyl further comprising 1 to 3 heteroatoms selected from the group consisting of S, S (O) and S (O) ₂ , or R ⁴ is optionally substituted Cycloalkyl, optionally substituted aryl, optionally substituted < RTI ID = 0.0 > Heterocyclyl, or optionally substituted heteroaryl), either singly or multiply substituted;

Any alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, R ³ , R ⁴ , cycloalkyl, aryl, heterocyclyl, or heteroaryl may be further substituted by J;

Provided that (i), (ii), (iii) or (iv) applies:

(i) L ¹ is a bond or (CHR ') _n and R ⁵ is a bicyclic ring moiety optionally substituted with 0-5 J, wherein said bicyclic ring moiety is any one of ai to a- xxviii , The wavy line represents the point of attachment):

Provided that when R ⁵ is a-xvii or a-xix, L ² is a bond or (CHR ') _n ;

(ii) L ¹ And L < ² > are independently a bond or (CHR ') _n ; R ⁵ is a 6-immunogenic heteroaryl ring moiety optionally substituted with 0-3 of J ^1, wherein J ¹ is _{OR ', CF 3, Cl,} Br, F, CN, O (C 1 -C 6) alkoxy , O (C ₁ -C ₆ ) cycloalkoxy, alkyl, or N (R ') ₂ , The 6-membered heteroaryl ring moiety is any one of bi to b-xiii wherein the wavy line indicates the point of attachment:

;

(iii) L ¹ is a bond or (CHR ') _n and L ² is heteroaryl substituted with 0-3 J, wherein the heteroaryl is ci or c- ii wherein the wavy line indicates the point of attachment ;

;

or

(iv) L ¹ is a bond or (CHR ') _n , L ² is a bond or (CHR') _n or phenyl substituted with 0-5 J; And R ⁵ and R ⁶ are independently selected from phenyl or heteroaryl, each optionally substituted with 0-5 J; Provided that when L ² is a bond and R ⁵ and R ⁶ are both phenyl, R ⁵ is 4-CN, 3-alkyl-NHR ', 3-alkyl-OR' Alkyl and R < ⁶ > is substituted with at least 4-OR ';

Provided that in the case of (ii), (iii), or (iv), the compound of formula (I)

In various embodiments of the compounds according to the present invention, L < ² > is a bond.

In various embodiments of the compounds according to the invention, A ¹ and A ³ are N and A ² is O.

In various embodiments of the compounds according to the invention, A ² and A ³ are N and A ¹ is O, or A ¹ and A ² are N and A ³ is O.

In various embodiments of the compounds according to the invention, A ¹ and A ² are N and A ³ is NR.

In various embodiments of the compounds according to the invention, A ¹ is C, A ² is N and A ³ is O.

In various embodiments of the compounds according to the invention, A ¹ is O, A ² is N, A ³ is C,

In various embodiments of the compounds according to the invention, L ¹ and L ² are independently a bond or (CHR ') _n and R ⁵ or R ⁶ , or both, comprise a heteroaryl ring. For example, one or more heteroaryl rings of R ⁵ or R ⁶ are selected from the group consisting of pyridinyl or pyridinyl N-oxide, pyrazinyl, pyrrolyl, imidazolyl, benzimidazolyl, thiophenyl, benzothiophenyl, furyl, benzofuryl, Indolyl, indolinyl, piperidinyl, quinolyl, or isoquinolyl; Wherein any heteroaryl is substituted with 0-5 J; More specifically, any of the heteroaryl are 0-5 R ', F, Cl, Br, I, OR', CF _3, OCF _3, CHF ₂ or SO ₂ N (R ') ₂ .

In various embodiments of the compounds according to the present invention, L ¹ and L ² are independently a bond or (CHR ') _n and R ⁵ or R ⁶ , or both, comprise a bicyclic carbocyclic ring, The click ring is substituted with 0-5 J. More specifically, any bicyclic carbocyclic ring of 0-5 R ', F, Cl, Br, I, OR', CF _3, OCF _3, CHF ₂ or SO ₂ N (R ') ₂ .

For example, L < ¹ > may be a bond and R < ⁵ > may be a bicyclic ring moiety substituted with 0-5 J, wherein the bicyclic ring moiety is selected from the group consisting of ai to a- xxviii :

;

Any of the bicyclic ring moieties is substituted with 0-5 J.

For example, L ¹ And L < ² > may each be a bond; R ⁵ is a 6-membered heteroaryl ring moiety substituted with 0-3 J ¹ , wherein J ¹ is OR ', CF ₃ , Cl, Br, F, CN, O (C ₁ -C ₆ ) alkoxy, O a (C ₁ -C ₆₎ cycloalkoxy, alkyl, or an N (R ') _2, substituted with the R of the selective ⁵ The six-membered heteroaryl ring moiety is a bond in which the wavy line is the bond point bi to b- xiii : ≪ / RTI >

The 6-membered heteroaryl ring moiety is substituted with 0-3 J < ^{1 &} gt ;.

In various embodiments of the compounds according to the invention, L ¹ can be a bond, L ² can be ci or c-ii , and the wavy line is the point of attachment:

In the above, ci and c- ii are further substituted with 0-2 J.

In various embodiments of the compounds according to the present invention, L ¹ is a bond, L ² is a bond or phenyl substituted with 0-5 J; R ⁵ and R ⁶ are independently selected from phenyl or heteroaryl substituted with 0-5 J each; R ⁵ is 4-CN, 3-alkyl-N (R ') ₂ , 3-alkyl-OR', 4-alkyl-OR ', or a salt thereof, when L ² is a bond and R ⁵ and R ⁶ are both phenyl. 2,3-dialkyl, and R < ⁶ > is substituted with at least 4-OR '.

For example, an optionally substituted bicyclic ring moiety may be any one of ai - a - viii :

In the above, any moiety of the bicyclic ring moiety is substituted with 0-5 J atoms.

For example, the compounds of the present invention may have formula IB further substituted with 0-5 J:

For example, a compound of the present invention may have the formula IC further substituted with 0-5 J:

I-C

For example, the compounds of the present invention include Formula ID and may be further substituted with 0-5 J, wherein R ⁷ and R ⁸ are each independently H, OR ', OC (O) N (R' ₂ , N (R ') N (R') ₂ , N (R ') CH ₂ CH ₂ OR', CN, CHF ₂ , CF ₃ , OCF ₃ , NO ₂ , R ' (O), S (O), N (R ') ₂ , SR', SOR ', SO ₂ R', SO ₂ N (R ') ₂ , SO ₃ R' Or R ⁷ and R ⁸ together are ═O, ═NR ', or ═N (R') CH ₂ CH ₂ OR '

1-D .

For example, a compound of the present invention may have the formula IF :

I-F

Wherein R ⁷ and R ⁸ are each independently selected from H, OR ", N (R") ₂ and SR "and R" is hydrogen or alkyl, cycloalkyl, aryl, heterocyclyl , Or heteroaryl, and any such alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is substituted with 0-3 J; X is F, Cl, Br, I, CHF 2, CN, CF 3, NO 2 or OR '; Y is hydrogen or alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, and any such alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is substituted with 0-3 J;

In various embodiments, the compounds of the present invention may be any of the following compounds or any pharmaceutically acceptable salts, tautomers, stereoisomers, solvates, hydrates, or prodrugs thereof:

In various embodiments of the compounds according to the invention, said bicyclic ring moiety may be any one of a- ix to a- xv ,

In this formula, any bicyclic ring moiety may be substituted with 0-5 J.

More particularly, in various embodiments of the compounds according to the invention, the compounds are selected from any of the following compounds or any pharmaceutically acceptable salts, tautomers, stereoisomers, solvates, hydrates or prodrugs thereof Can:

In various embodiments of the compounds according to the invention, the optionally substituted bicyclic ring moiety may be any one of a- xvi to a- xxv ,

In the above, any bicyclic ring moiety is substituted with 0-5 J.

In various embodiments of the compounds according to the present invention, the compounds may be any of the following compounds or any pharmaceutically acceptable salts, tautomers, stereoisomers, solvates, hydrates or prodrugs thereof:

In various embodiments of the compounds according to the present invention, the optionally substituted 6-membered heteroaryl ring moiety of R < ⁵ > may be any of bi to bv :

Any of said 6-membered heteroaryl ring moieties is substituted with 0-3 J < ^{1 &} gt ;.

In various embodiments of the compounds according to the present invention, the compounds may be any of the following compounds or any pharmaceutically acceptable salts, tautomers, stereoisomers, solvates, hydrates or prodrugs thereof:

More particularly, in various embodiments of the compounds according to the invention, the compounds are selected from any of the following compounds or any pharmaceutically acceptable salts, tautomers, stereoisomers, solvates, hydrates or prodrugs thereof Can:

In various embodiments of the compounds according to the present invention, the compounds may be any of the following compounds or any pharmaceutically acceptable salts, tautomers, stereoisomers, solvates, hydrates or prodrugs thereof:

More particularly, in various embodiments of the compounds according to the invention, the compounds are selected from any of the following compounds or any pharmaceutically acceptable salts, tautomers, stereoisomers, solvates, hydrates or prodrugs thereof Can:

More particularly, in various embodiments of the compounds according to the invention, the compounds are selected from any of the following compounds or any pharmaceutically acceptable salts, tautomers, stereoisomers, solvates, hydrates or prodrugs thereof Can:

In various embodiments, the invention provides a pharmaceutical composition comprising a compound of the invention and a suitable excipient.

In various embodiments, the invention provides a pharmaceutical composition comprising a compound of the invention and a second agent. For example, the second agent may be medically prescribed for multiple sclerosis, transplant rejection, or adult respiratory distress syndrome.

Various embodiments of the present invention are directed to the use of a compound of formula (II) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament capable of treating a disorder or adverse symptom medically prescribed for the activation or inhibition of sphingosine- The invention provides the use of compounds, including pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, hydrates, or solvates thereof:

(II)

In the above formula (II)

The dotted line indicates that a single bond or a double bond may be present, provided that two double bonds and three single bonds are present in the ring including A ¹ , A ² , and A ³ ;

A ¹ , A ² , and A ³ are each independently C or O, or N (wherein N is bonded to one adjacent double ring atom with a double bond and a single bond) or NR When R is H or (C ₁ -C ₆ ) alkyl when bound to two adjacent ring atoms by a single bond, with the proviso that A ¹ , A ² , and A ³ At least one of A ¹ , A ² , and A ³ is N or NR, and only one of A ¹ , A ² , and A ³ is O;

L ¹ and L ² are independently a bond; (CHR ') _n (R' is H or (C ₁ -C ₆₎ alkyl, n is 1, 2 or 3); Or a heteroaryl selected from the group consisting of thiophenyl, phenyl, furanyl, or benzothiophenyl, said heteroaryl being substituted with 0-3 J;

J is independently selected from F, Cl, Br, I, OR ', OC (O) N (R') 2, CN, CF 3, OCF 3, CHF 2, NO 2, R ', O, S in each case , S (O), S (O), methylenedioxy, ethylenedioxy, N (R ') ₂ , N (R') CH ₂ CH ₂ OR ', SR', SOR ', SO ₂ R', SO _{2 N (R ') 2,} SO 3 R', C (O) R ', C (O) C (O) R', C (O) CH 2 C (O) R ', C (S) R' , C (O) OR ', OC (O) R', OC (O) OR ', C (O) N (R') 2, OC (O) N (R ') 2, C (S) N ( _{R ') 2, (CH 2} ) 0-2 NHC (O) R', (CH 2) 0-2 N (R ') 2, (CH 2) 0-2 N (R') N (R ') ₂ , N (R ') N (R') C (O) R ', N (R') N (R ') C ) ₂ , N (R ') SO ₂ R', N (R ') SO ₂ N (R') ₂ , N (R ') C , N (R ') N ( R'), N (R ') C (S) R', N (R ') C (O) N (R') 2, N (R ') C (S) N _{(R ') 2, N (} COR') COR ', N (oR') R ', C (= NH) N (R') 2, C (O) N (oR ') R', or C (= NOR ') R', wherein two of the J groups may together form a ring; Wherein R 'is independently in each occurrence hydrogen or alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein any alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with 0-3 Substituted or unsubstituted; Or two R 'groups In a 1 substituted with 0-3 of J with the nitrogen atoms or two adjacent nitrogen atom to which (C ₃ -C ₈₎ may form a heterocyclyl; Optionally further containing 1 to 3 additional heteroatoms selected from the group consisting of O, N, S, S (O) and S (O) ₂ ;

R < ⁵ > is monocyclic or bicyclic cycloalkyl, aryl, heterocyclyl, or heteroaryl; Each of which is substituted with 0-5 J, wherein any cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted by one or more additional cycloalkyl; Aryl; Heterocyclyl; Heteroaryl ring, fused with a heteroaryl ring, branched or spiral, wherein any of said one or more additional cycloalkyl, aryl, heterocyclic, heteroaryl rings may be monocyclic, bicyclic or polycyclic, saturated , Partially unsaturated, or aromatic and is substituted with 0-5 J;

R ⁶ is cycloalkyl, aryl, and heterocyclyl, or heteroaryl, wherein any cycloalkyl, aryl, heterocyclyl, or heteroaryl is independently J, (C ₁ -C ₆₎ alkyl, (C ₂ - C ₆₎ alkenyl, (C ₂ -C ₆₎ alkynyl, (C ₁ -C ₆₎ haloalkyl, hydroxyl, halo, (C ₁ -C ₆₎ haloalkoxy, cycloalkyl (C ₁ -C ₆₎ alkyl, heterocyclyl (C ₁ -C ₆₎ alkyl, aryl (C ₁ -C ₆₎ alkyl, heteroaryl (C ₁ -C ₆₎ alkyl, oR ³ (R ³ is H or (C ₁ -C ₆₎ including the alkyl) or NR ⁴ ₂ (each R ⁴ is independently H or (C ₁ -C ₆₎ include alkyl or; or two R ⁴ groups together with the nitrogen atom bonded thereto, optionally, N, O, (C ₃ -C ₈ ) heterocyclyl further comprising 1 to 3 heteroatoms selected from the group consisting of S, S (O) and S (O) ₂ , or R ⁴ is optionally substituted Cycloalkyl, optionally substituted aryl, optionally substituted < RTI ID = 0.0 > Heterocyclyl, or optionally substituted heteroaryl), either singly or multiply substituted;

Any alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, R ³ , R ⁴ , cycloalkyl, aryl, heterocyclyl, or heteroaryl may be further substituted by J;

Provided that (i), (ii), (iii) or (iv) applies:

(i) L ¹ is a bond or (CHR ') _n and R ⁵ is a bicyclic ring moiety optionally substituted with 0-5 J, wherein said bicyclic ring moiety is any one of ai to a- xxviii , The wavy line represents the point of attachment):

Provided that when R ⁵ is a-xvii or a-xix, L ² is a bond or (CHR ') _n ;

(ii) L ¹ And L < ² > are independently a bond or (CHR ') _n ; R ⁵ is a 6-immunogenic heteroaryl ring moiety optionally substituted with 0-3 of J ^1, wherein J ¹ is _{OR ', CF 3, Cl,} Br, F, CN, O (C 1 -C 6) alkoxy , O (C ₁ -C ₆ ) cycloalkoxy, alkyl, or N (R ') ₂ , The 6-membered heteroaryl ring moiety is any one of bi to b-xiii wherein the wavy line indicates the point of attachment:

(iii) L ¹ is a bond or (CHR ') _n and L ² is heteroaryl substituted with 0-3 J, wherein the heteroaryl is ci or c- ii wherein the wavy line indicates the point of attachment ;

;

or

(iv) L ¹ is a bond or (CHR ') _n , L ² is a bond or (CHR') _n or phenyl substituted with 0-5 J; And R ⁵ and R ⁶ are independently selected from phenyl or heteroaryl, each optionally substituted with 0-5 J; Provided that when L ² is a bond and R ⁵ and R ⁶ are both phenyl, R ⁵ is 4-CN, 3-alkyl-NHR ', 3-alkyl-OR' Alkyl and R < ⁶ > is substituted with at least 4-OR ';

Provided that in the case of (ii), (iii), or (iv), the compound of formula (I)

In various embodiments, the invention provides the use of compounds wherein L < ² > is a bond in the manufacture of a medicament.

In various embodiments, the present invention provides a compound of formula I, wherein A ¹ and A ³ are N and A ² is O, or A ² and A ³ are N and A ¹ is O, or A ¹ and A 3 ² is N and A < ³ > is O.

In various embodiments, the present invention provides a compound of formula I wherein A ¹ and A ² are N, A ³ is NR, A ¹ is C, A ² is N, A ³ is O, or A ¹ Is O, A < ² > is N and A < ³ >

In various embodiments, the present invention provides the use of a compound in the manufacture of a medicament wherein L ² is independently a bond or (CHR ') _n and R ⁵ or R ⁶ , or both, comprise a heteroaryl ring. do. For example, one or more heteroaryl rings of R ⁵ or R ⁶ are selected from the group consisting of pyridinyl or pyridinyl N-oxide, pyrazinyl, pyrrolyl, imidazolyl, benzimidazolyl, thiophenyl, benzothiophenyl, furyl, benzofuryl, Indolyl, indolinyl, piperidinyl, quinolyl, or isoquinolyl; Wherein any heteroaryl is substituted with 0-5 J; More specifically, the heteroaryl is substituted with 0-5 R ', F, Cl, Br, I, OR', CF ₃ , OCF ₃ , CHF ₂ or SO ₂ N (R ') ₂ .

In various embodiments, the present invention provides the use of a compound in the manufacture of a medicament wherein L ² is independently a bond or (CHR ') _n and R ⁵ or R ⁶ , or both, comprise a bicyclic carbocyclic ring Wherein the bicyclic carbocyclic ring is substituted with 0-5 J atoms. More specifically, any bicyclic carbocyclic ring of 0-5 R ', F, Cl, Br, I, OR', CF _3, OCF _3, CHF ₂ or SO ₂ N (R ') ₂ .

In various embodiments, the present invention provides the use of a compound in the manufacture of a medicament wherein L < ¹ > is a bond and R < ⁵ > is a bicyclic ring moiety substituted with 0-5 J, wherein the bicyclic ring moiety Is any one of ai to a- xxviii , and the following wavy line represents the point of attachment:

;

Any of the bicyclic ring moieties is substituted with 0-5 J.

In various embodiments, the present invention provides the use of a compound in the manufacture of a medicament, wherein, in said compound, L < ^{1 >} And L < ² > are each a bond; R ⁵ is a 6-membered heteroaryl ring moiety substituted with 0-3 J ¹ , wherein J ¹ is OR ', CF ₃ , Cl, Br, F, CN, O (C ₁ -C ₆ ) alkoxy, O (C ₁ -C ₆ ) cycloalkoxy, alkyl, or N (R ') ₂ ; The R ⁵ optionally substituted The 6-membered heteroaryl ring moiety is defined as bi to b- xiii : ≪ / RTI >

;

In the above, each 6-membered heteroaryl ring moiety is substituted with 0-3 J &^lt; ^{1 &} gt ;. More specifically, L ¹ = bond, L ² = ci or c- ii , and the wavy line is the bond point:

In the above formula, ci and c- ii are further substituted with 0-2 J.

In various embodiments, the invention provides the use of a compound in the manufacture of a medicament wherein L ¹ is a bond, L ² is a bond, or phenyl substituted with 0-5 J; R ⁵ and R ⁶ are independently selected from phenyl or heteroaryl substituted with 0-5 J each; R ⁵ is 4-CN, 3-alkyl-N (R ') ₂ , 3-alkyl-OR', 4-alkyl-OR ', or a salt thereof, when L ² is a bond and R ⁵ and R ⁶ are both phenyl. 2,3-dialkyl, and R < ⁶ > is substituted with at least 4-OR '. In various embodiments, the optionally substituted bicyclic ring moiety may be any one of ai - a - viii :

In this formula, any moiety of the bicyclic ring moiety is substituted with 0-5 J.

In various embodiments, the compound used in the manufacture of the medicament may have formula IB further substituted with 0-5 J:

IB .

In various embodiments, the compound used in the manufacture of a medicament may have a formula IC further substituted with 0-5 J:

IC .

In various embodiments, the compound used in the manufacture of a medicament comprises Formula ID and may be further substituted with 0-5 J, wherein R ⁷ and R ⁸ are each independently H, OR ', OC (O N (R ') ₂ , N (R') ₂ , N (R ') CH ₂ CH ₂ OR', CN, CHF ₂ , CF ₃ , OCF ₃ , NO ₂ , R ' O, S, C (O), S (O), N (R ') ₂ , SR', SOR ', SO ₂ R', SO ₂ N (R ') ₂ , SO ₃ R' O) R ', or R ⁷ and R ⁸ together are = O, = NR', or = N (R ') CH ₂ CH ₂ OR'

1-D .

In various embodiments, the compound used in the manufacture of a medicament may have the formula IF :

I-F

Wherein R ⁷ and R ⁸ are each independently selected from H, OR ", N (R") ₂ and SR "and R" is hydrogen or alkyl, cycloalkyl, aryl, heterocyclyl , Or heteroaryl, and any such alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is substituted with 0-3 J; X is F, Cl, Br, I, CHF 2, CN, CF 3, NO 2 Or OR '; Y is hydrogen or alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, and any such alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is substituted with 0-3 J;

In various embodiments, the invention provides the use of any of the following compounds in the manufacture of a medicament:

Various embodiments of the present invention are directed to a method of preparing a compound of formula (II) or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, hydrate or solvate thereof, Contacting, inhibiting, or antagonizing the sphingosine-1-phosphate receptor subtype 1, comprising the steps of:

In the above formula (II)

The dotted line indicates that a single bond or a double bond may be present, provided that two double bonds and three single bonds are present in the ring including A ¹ , A ² , and A ³ ;

A ¹ , A ² , and A ³ are each independently C or O, or N (wherein N is bonded to one adjacent double ring atom with a double bond and a single bond) or NR When R is H or (C ₁ -C ₆ ) alkyl when bound to two adjacent ring atoms by a single bond, with the proviso that A ¹ , A ² , and A ³ At least one of A ¹ , A ² , and A ³ is N or NR, and only one of A ¹ , A ² , and A ³ is O;

L ¹ and L ² are independently a bond; (CHR ') _n (R' is H or (C ₁ -C ₆₎ alkyl, n is 1, 2 or 3); Or a heteroaryl selected from the group consisting of thiophenyl, phenyl, furanyl, or benzothiophenyl, said heteroaryl being substituted with 0-3 J;

J is independently selected from F, Cl, Br, I, OR ', OC (O) N (R') 2, CN, CF 3, OCF 3, CHF 2, NO 2, R ', O, S in each case , S (O), S (O), methylenedioxy, ethylenedioxy, N (R ') ₂ , N (R') CH ₂ CH ₂ OR ', SR', SOR ', SO ₂ R', SO _{2 N (R ') 2,} SO 3 R', C (O) R ', C (O) C (O) R', C (O) CH 2 C (O) R ', C (S) R' , C (O) OR ', OC (O) R', OC (O) OR ', C (O) N (R') 2, OC (O) N (R ') 2, C (S) N ( _{R ') 2, (CH 2} ) 0-2 NHC (O) R', (CH 2) 0-2 N (R ') 2, (CH 2) 0-2 N (R') N (R ') ₂ , N (R ') N (R') C (O) R ', N (R') N (R ') C ) ₂ , N (R ') SO ₂ R', N (R ') SO ₂ N (R') ₂ , N (R ') C , N (R ') N ( R'), N (R ') C (S) R', N (R ') C (O) N (R') 2, N (R ') C (S) N _{(R ') 2, N (} COR') COR ', N (oR') R ', C (= NH) N (R') 2, C (O) N (oR ') R', or C (= NOR ') R', wherein two of the J groups may together form a ring; Wherein R 'is independently in each occurrence hydrogen or alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein any alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with 0-3 Substituted or unsubstituted; Or two R 'groups In a 1 substituted with 0-3 of J with the nitrogen atoms or two adjacent nitrogen atom to which (C ₃ -C ₈₎ may form a heterocyclyl; Optionally further containing 1 to 3 additional heteroatoms selected from the group consisting of O, N, S, S (O) and S (O) ₂ ;

R < ⁵ > is monocyclic or bicyclic cycloalkyl, aryl, heterocyclyl, or heteroaryl; Each of which is substituted with 0-5 J, wherein any cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted by one or more additional cycloalkyl; Aryl; Heterocyclyl; Heteroaryl ring, fused with a heteroaryl ring, branched or spiral, wherein any of said one or more additional cycloalkyl, aryl, heterocyclic, heteroaryl rings may be monocyclic, bicyclic or polycyclic, saturated , Partially unsaturated, or aromatic and is substituted with 0-5 J;

R ⁶ is cycloalkyl, aryl, and heterocyclyl, or heteroaryl, wherein any cycloalkyl, aryl, heterocyclyl, or heteroaryl is independently J, (C ₁ -C ₆₎ alkyl, (C ₂ - C ₆₎ alkenyl, (C ₂ -C ₆₎ alkynyl, (C ₁ -C ₆₎ haloalkyl, hydroxyl, halo, (C ₁ -C ₆₎ haloalkoxy, cycloalkyl (C ₁ -C ₆₎ alkyl, heterocyclyl (C ₁ -C ₆₎ alkyl, aryl (C ₁ -C ₆₎ alkyl, heteroaryl (C ₁ -C ₆₎ alkyl, oR ³ (R ³ is H or (C ₁ -C ₆₎ including the alkyl) or NR ⁴ ₂ (each R ⁴ is independently H or (C ₁ -C ₆₎ include alkyl or; or two R ⁴ groups together with the nitrogen atom bonded thereto, optionally, N, O, (C ₃ -C ₈ ) heterocyclyl further comprising 1 to 3 heteroatoms selected from the group consisting of S, S (O) and S (O) ₂ , or R ⁴ is optionally substituted Cycloalkyl, optionally substituted aryl, optionally substituted < RTI ID = 0.0 > Heterocyclyl, or optionally substituted heteroaryl), either singly or multiply substituted;

Any alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, R ³ , R ⁴ , cycloalkyl, aryl, heterocyclyl, or heteroaryl may be further substituted by J;

Provided that (i), (ii), (iii) or (iv) applies:

(i) L ¹ is a bond or (CHR ') _n and R ⁵ is a bicyclic ring moiety optionally substituted with 0-5 J, wherein said bicyclic ring moiety is any one of ai to a- xxviii , The wavy line represents the point of attachment):

Provided that when R ⁵ is a-xvii or a-xix, L ² is a bond or (CHR ') _n ;

(ii) L ¹ And L < ² > are independently a bond or (CHR ') _n ; R ⁵ is a 6-immunogenic heteroaryl ring moiety optionally substituted with 0-3 of J ^1, wherein J ¹ is _{OR ', CF 3, Cl,} Br, F, CN, O (C 1 -C 6) alkoxy , O (C ₁ -C ₆ ) cycloalkoxy, alkyl, or N (R ') ₂ , The 6-membered heteroaryl ring moiety is any one of bi to b-xiii wherein the wavy line indicates the point of attachment:

;

(iii) L ¹ is a bond or (CHR ') _n and L ² is heteroaryl substituted with 0-3 J, wherein the heteroaryl is ci or c- ii wherein the wavy line indicates the point of attachment ;

;

or

(iv) L ¹ is a bond or (CHR ') _n , L ² is a bond or (CHR') _n or phenyl substituted with 0-5 J; And R ⁵ and R ⁶ are independently selected from phenyl or heteroaryl, each optionally substituted with 0-5 J; Provided that when L ² is a bond and R ⁵ and R ⁶ are both phenyl, R ⁵ is 4-CN, 3-alkyl-NHR ', 3-alkyl-OR' Alkyl and R < ⁶ > is substituted with at least 4-OR ';

Provided that in the case of (ii), (iii), or (iv), the compound of formula (I)

In various embodiments, the methods of the present invention utilize compounds wherein L < ² > is a bond.

In various embodiments, the methods of the present invention are methods wherein A ¹ and A ³ are N and A ² is O, or A ² and A ³ are N and A ¹ is O, or A ¹ and A ² are N and A ³ is O or A ¹ and A ² are N and A ³ is NR.

In various embodiments, the methods of the present invention are those wherein A ¹ = C, A ² = N, A ³ = O; A compound wherein A ¹ = O, or A ² = N and A ³ = C, or L ¹ and L ² are independently a bond or (CHR ') _n and R ⁵ or R ⁶ or both form a heteroaryl ring ≪ / RTI > For example, one or more heteroaryl rings of R ⁵ or R ⁶ are selected from the group consisting of pyridinyl or pyridinyl N-oxide, pyrazinyl, pyrrolyl, imidazolyl, benzimidazolyl, thiophenyl, benzothiophenyl, furyl, benzofuryl, Indolyl, indolinyl, piperidinyl, quinolyl, or isoquinolyl; Wherein any heteroaryl is substituted with 0-5 J; More specifically, the optional heteroaryl is optionally substituted with 0-5 R ', F, Cl, Br, I, OR', CF ₃ , OCF ₃ , CHF ₂ or SO ₂ N (R ') ₂ .

In various embodiments, the methods of the present invention are directed to compounds of _formula (I) _wherein L ¹ and L ² are independently a bond or (CHR ') _n and R ⁵ or R ⁶ , or both comprise a bicyclic carbocyclic ring, Wherein the click ring is substituted with 0-5 J. For example, any bicyclic carbocyclic ring may contain 0-5 R ', F, Cl, Br, I, OR', CF ₃ , OCF ₃ , CHF ₂ or SO ₂ N (R ') ₂ .

In various embodiments, the methods of the invention are bicyclic ring moieties wherein L ¹ is a bond and R ⁵ is substituted with 0-5 J, wherein the bicyclic ring moiety is any one of ai to a-xxviii , The following wavy line represents a point of attachment:

;

In this formula, any of the bicyclic ring moieties is substituted with 0-5 J.

In various embodiments, the methods of the present invention comprise contacting L < ^{1 >} And L < ² > are each a bond; R ⁵ is a 6-membered heteroaryl ring moiety substituted with 0-3 J ¹ , wherein J ¹ is OR ', CF ₃ , Cl, Br, F, CN, O (C ₁ -C ₆ ) alkoxy, O (C ₁ -C ₆ ) cycloalkoxy, alkyl, or N (R ') ₂ ; The R ⁵ optionally substituted The 6-membered heteroaryl ring moiety is defined as bi to b- xiii Lt; RTI ID = 0.0 > of: < / RTI >

;

Wherein each 6-membered heteroaryl ring moiety may be substituted with 0-3 J &^lt; ^{1 &} gt ;, or L &^lt; ¹ > = bond, L < ^{2 &} gt ; = ci or c-

In the above formula, ci and c- ii are further substituted with 0-2 J.

In various embodiments, the methods of the invention are those wherein L ¹ is a bond, L ² is a bond, or 0-5 J; R ⁵ and R ⁶ are independently selected from phenyl or heteroaryl substituted with 0-5 J each; R ⁵ is 4-CN, 3-alkyl-N (R ') ₂ , 3-alkyl-OR', 4-alkyl-OR ', or a salt thereof, when L ² is a bond and R ⁵ and R ⁶ are both phenyl. Dialkyl, 2,3-dialkyl, and R ⁶ is substituted with at least 4-OR '.

In various embodiments, the optionally substituted bicyclic ring moiety may be any one of ai - a - viii :

In this formula, any moiety of the bicyclic ring moiety is substituted with 0-5 J.

In various embodiments, the methods of the invention comprise a compound of formula IB further substituted with 0-5 J; Lt; RTI ID = 0.0 > IC < / RTI > Expression that is further substituted with 0-5 J of ID (formula, R ⁷ and R ⁸ are each independently H, OR ', OC (O ) N (R') 2, N (R ') N (R') ₂ , N (R ') CH ₂ CH ₂ OR', CN, CHF ₂ , CF ₃ , OCF ₃ , NO ₂ , R ' (R ') ₂ , SO ₃ R', or C (O) R ', or R ⁷ and R ⁸ together are = O, = OR ₂ , SR', SOR ', SO ₂ R', SO ₂ N NR ', or = N (R') CH ₂ CH ₂ OR '); Or a group represented by the formula IF (formula, R ⁷ and R ⁸ are each independently H, OR '', N ( R '') 2, and SR '' is selected from, R '' is hydrogen or alkyl, cycloalkyl, aryl, Wherein X is selected from the group consisting of F, Cl, Br, I, CHF ₂ , CN, C ₁ -C 6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, CF ₃ , NO ₂ Or OR '; Y is hydrogen or alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, and any such alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is substituted with 0-3 J Lt; / RTI >

IB

IC ,

1-D ,

IF

In various embodiments, the methods of the present invention utilize any of the following compounds:

In various embodiments, the methods of the present invention utilize compounds that activate sphingosine-1-phosphate subtype 1 at a higher level than compounds that activate or effect other subtypes of sphingosine-1-phosphate receptors. For example, another subtype of the sphingosine-1-phosphate receptor is subtype 3. In various embodiments, the sphingosine-1-phosphate receptor subtype 1 may be placed within a living mammal.

In various embodiments, the present invention provides a method of treating an S1P1 receptor, comprising contacting the S1P1 receptor according to the methods of the invention by administering the compound to the patient for a frequency and duration sufficient to provide a beneficial effect to the patient, , Prophylactic, inhibiting, or antagonizing medically prescribed medicament. For example, selective activation or activation of the S1P subtype 1 receptor relative to other subtype S1P receptors is medically prescribed. More specifically, abnormal symptoms may include multiple sclerosis, transplant rejection, or adult respiratory distress syndrome. The method of the present invention may further comprise administering to the patient an effective amount of a second agent designed to treat multiple sclerosis, transplant rejection, or respiratory distress syndrome in an adult.

Composition and Combination Therapy

The S1P1 compound, a pharmaceutically acceptable salt thereof, or a hydrolysable ester of a compound of the present invention may be administered in combination with a pharmaceutically acceptable carrier to a mammalian species, more preferably to a human, A pharmaceutical composition useful for the treatment of disorders can be provided. The specific carrier used in such a pharmaceutical composition may vary depending on the desired dosage type (e.g., intravenous, oral, topical, suppository or parenteral).

Typical pharmaceutical magazines such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used when the compositions are prepared in oral liquid dosage forms (e.g., suspensions, elixirs and solutions). Likewise, when preparing solid oral dosage forms (e.g., powders, tablets and capsules), carriers such as starches, sugars, diluents, granulating agents, lubricants, binders and disintegrants may be used.

Another aspect of one embodiment of the present invention provides a composition comprising a compound of the invention, either alone or in combination with other S1P1 inhibitors or other types of therapeutic agents, or both. As described above, the compounds of the present invention include stereoisomers, tautomers, solvates, hydrates, salts such as pharmaceutically acceptable salts, and mixtures thereof. Compositions comprising the compounds of the present invention may be prepared by conventional techniques, for example, as described in Remington: The Science and Practice of Pharmacy , 19th Ed., 1995, which is incorporated herein by reference in its entirety. The compositions may take the usual forms such as capsules, tablets, aerosols, solutions, suspensions or topical applications.

Exemplary compositions include a compound of the present invention and a pharmaceutically acceptable excipient, which may be a carrier or diluent. For example, the active compound may be incorporated into the carrier, which may generally be in the form of an ampoule, capsule, sachet, paper or other container, mixed with or diluted with a carrier. When the active compound is mixed with a carrier, or when the carrier is used as a diluent, it may be a solid, semi-solid or liquid substance, which acts as a vehicle, excipient or medium for the active compound. The active compound may be adsorbed onto the granular solid carrier, for example, in a fog. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, Stearic acid or a lower alkyl ether of cellulose, pectin, acacia, cellulose, silic acid, fatty acid, fatty acid amine, fatty acid monoglyceride and diglyceride, pentaerythritol fatty acid ester , Polyoxyethylene, hydroxymethylcellulose, and polyvinylpyrrolidone. Likewise, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, either alone or in admixture with the wax.

The formulations may be mixed with adjuvants that do not react with the active compound in a deleterious manner. These additives may include wetting agents, emulsifying agents, suspending agents, salts affecting osmotic pressure, buffering agents and / or coloring matter preservative agents, sweetening agents or flavoring agents. In addition, the composition may be sterilized if appropriate.

The route of administration may be any route that effectively transports the active compounds of the present invention that inhibits the enzymatic activity of the facial adhesion kinase to a suitable or desired site of action such as oral, Transdermal or parenteral, such as rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic or ointment and oral route is preferred.

In parenteral administration, the carrier will typically comprise sterile water, but may also contain other ingredients that aid solubility or are used as preservatives. In addition, when a suitable liquid carrier, suspending agent or the like can be used, a suspension for injection can be prepared.

For topical administration, the compounds of the present invention may be formulated as ointments or creams using a mild moisturizing agent.

If the solid carrier is to be used for oral administration, the preparation may be tableted, in powdered or pelletized form in hard gelatin capsules, or in the form of a troche or rosogen. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or aseptic injection, in the form of an aqueous or nonaqueous liquid suspension or solution.

Injectable dosage forms generally include aqueous suspensions or oil suspensions which may be prepared using suitable dispersing or wetting agents or suspending agents. The injectable form may be in the form of a solution or suspension, prepared using a solvent or diluent. Acceptable solvents or vehicles include sterile water, Ringer's solution or isotonic aqueous salt solutions. In another example, sterile oils can be used as a solvent or as a suspending agent. Preferably, the oil or fatty acid is non-volatile and includes natural oils, synthetic oils, fatty acids, mono-, di- or tri-glycerides.

For injection, the formulation may also be a powder suitable for reconstitution using a suitable solution, as described above. Examples include, but are not limited to, lyophilized, spin-dried or spray-dried powders, amorphous powders, granules, precipitates or microparticles. For example, the formulations may optionally comprise stabilizers, pH modifiers, surfactants, bioavailability modifiers, and combinations thereof. The compounds may be formulated for parenteral administration by injection, such as by bolus injection or continuous infusion. The unit dosage form may be included in an ampoule or in a multi-dose container.

The formulations of the present invention can be designed to provide fast, sustained, delayed release of the active agent after administration to a patient by applying procedures well known in the art. Thus, also, the formulations may be formulated for slow release or for controlled release.

The compositions included in the present invention may comprise, for example, micelles or liposomes, or some other encapsulated form, or they may be administered in an extended release form to provide long-term storage and / or delivery effects . Thus, the formulation can be compressed into pellets or cylinders and transplanted intramuscularly or subcutaneously as a depot injection. Such implants may employ known inactive materials such as silicon and biodegradable polymers such as polylactide-polyglycolide. Examples of other biodegradable polymers include poly (orosoester) and poly (anhydride).

For nasal administration, the preparation may contain a compound of the present invention that inhibits the enzymatic activity of a lesion-associated kinase, dissolved or suspended in a liquid carrier, preferably an aqueous carrier, for aerosol application. The carrier may contain additives such as solubilizing agents such as an absorption enhancer such as propylene glycol, a surfactant, lecithin (polypytidylcholine) or cyclodextrin, or a preservative such as parabens.

For parenteral application, aqueous solutions with an active compound, especially dissolved in a injectable solution or suspension, preferably a polyhydroxylated castor oil, are suitable.

Tablets, dragees and capsules containing talc and / or carbohydrate carriers or binders are particularly suitable for oral use. Preferred carriers for tablets, dragees or capsules include lactose, corn starch and / or potato starch. If a sweet flavoring vehicle can be used, syrups or elixirs may be used.

Typical tablets which may be prepared by conventional tabletting techniques may include the following ingredients:

Core :

250 mg of the active compound (as the free compound or its salt)

^® 1.5 mg colloidal silicon dioxide (Aerosil)

Cellulose, microcrystalline (Avicel) ^® 70 mg

Modified cellulose gum ^{(Ac-di-Sol) ®} 7.5 mg

Magnesium stearate Ad.

Coating :

HPMC approx. 9 mg

* Mywacett 9-40 T approx. 0.9 mg

Acylated monoglycerides used as plasticizers for membrane coatings

A typical oral dosage capsule comprises a compound of the invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture is passed through a 60-mesh sieve and packed into gelatin capsule No. 1. A typical injectable preparation is prepared by aseptically placing 250 mg of the compound of the present invention in vials, aseptically lyophilized and then sealed. The contents of the vial are mixed with 2 ml of sterile physiological saline at the time of use to prepare a preparation for injection.

The compounds of the present invention may be administered to humans in need of treatment, prevention, elimination, relief, or improvement of abnormal symptoms mediated through S1P1 action, such as multiple sclerosis, transplant rejection and adult respiratory distress syndrome.

The pharmaceutical compositions and compounds of the present invention are generally administered at a dose of about 1 μg / kg (body weight) to about 1 g / kg (body weight), preferably about 5 μg / kg (body weight) to about 500 mg / , More preferably from about 10 μg / kg (body weight) to about 250 mg / kg (body weight), and most preferably from about 20 μg / kg (body weight) to about 100 mg / (E.g., tablets, capsules, etc.). One of ordinary skill in the art will recognize that the particular amount of the pharmaceutical composition and / or compound of the invention administered to a subject will be determined according to a number of factors including, but not limited to, the desired biological effect, But is not limited to these.

The compounds of the present invention are effective in a broad dosage range. For example, in the case of adult treatment, a dosage of about 0.05 to about 5000 mg, preferably about 1 to about 2000 mg, more preferably about 2 to about 2000 mg per day may be used. A typical dose is from about 10 mg to about 1000 mg per day. When choosing a therapy for a patient, it is often necessary to use high doses and when the symptoms are controlled, the dosage can be lowered. The actual dosage will depend on the activity of the compound, the mode of administration, the preferred therapy, the form to be administered, the weight of the subject being treated and the subject being treated, and the preference and experience of the physician or veterinarian. Castle S1P1 agonist life of the compounds of the present invention, as is well known in the art, may be determined using the in vitro assay system for determining the activation of S1P1, which may be represented by the EC ₅₀ value, of the present invention The inhibitor can be measured by the methods described in the Examples.

Generally, the compounds of the present invention are formulated in unit dosage forms, containing from about 0.05 mg to about 1000 mg of active ingredient per unit dose, and a pharmaceutically acceptable carrier.

In general, dosage forms suitable for oral, nasal, pulmonary or transdermal administration comprise from about 125 μg to about 1250 mg, preferably from about 250 μg to about 500 mg, more preferably from about 250 μg to about 500 mg, mixed with a pharmaceutically acceptable carrier or diluent Comprises from about 2.5 mg to about 250 mg of a compound.

Dosage forms may be administered daily, or two or more times a day, such as two or three times a day. In other instances, the dosage form may be administered at a lower frequency than once daily, such as once every two days or weekly, as determined by the prescribing physician.

Embodiments of the invention also include prodrugs of the compounds of the present invention that undergo chemical transformation upon administration by metabolic or other physiological processes prior to becoming active pharmacological agents. Conversion by metabolic or other physiological processes can be achieved by converting the prodrug into an active pharmacological agent, an enzymatic (e.g., specific, enzymatically catalyzed) and a non-enzymatic (such as a general or specific acid or base induced) But are not limited to, chemical conversion. In general, such prodrugs will be functional derivatives of the compounds of the present invention which are readily convertible in vivo with the compounds of the present invention. Conventional methods for selecting and preparing suitable prodrug derivatives are described, for example, in Design of Prodrugs , ed. H. Bundgaard, Elsevier, 1985.

In another embodiment, there is provided a method of making a composition of a compound described herein, such as formulating a compound of the present invention and a pharmaceutically acceptable carrier or diluent. In some embodiments, the pharmaceutically acceptable carrier or diluent is suitable for oral administration. In some such embodiments, the method may further comprise the step of formulating the composition as a tablet or capsule. In other embodiments, the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration. In some such embodiments, the method further comprises lyophilizing the composition into a lyophilized preparation.

The compounds of the present invention may be administered in combination with one or more other S1P1 inhibitors and / or ii) one or more other types of protein kinase inhibitors and / or one or more other types of therapeutic agents that can be administered orally, , By individual oral dosage forms (e. G., Sequentially or non-sequentially), or together or separately (e. G., Sequentially or non-sequentially).

That is, in another embodiment, the present invention provides a combination comprising:

a) a compound of the invention as described herein; And

b) i) the other compounds of the invention,

ii) one or more compounds comprising an agent for the treatment of abnormal symptoms in which the activation of S1P1 is medically prescribed, such as multiple sclerosis, transplant rejection, or an adult respiratory distress syndrome.

The combination of the present invention comprises a mixture of the compounds derived from (a) and (b) in a single formulation, and the compounds derived from (a) and (b) in separate formulations. Some combinations of the present invention may be packaged as separate formulations in a kit. In some embodiments, two or more compounds derived from (b) are formulated together, but the compounds of the invention are formulated separately.

When applied, the dosage and dosage forms for the other agents are used, Physicians' Desk Reference , which is incorporated herein by reference in its entirety.

Treatment method

In various embodiments, the invention provides a method of activating or effecting a sphingosine-1-phosphate receptor subtype, such as S1P1, using the compounds of the present invention (i.e., acting as an agonist so as to have an agonist effect) . The method includes contacting an appropriate concentration of a compound of the invention with the receptor to cause activation of the receptor. The contacting can be carried out in vitro, for example, by performing an assay to determine the S1P receptor activating activity of a compound of the invention undergoing an experiment involving the introduction of a regulatory approval.

Methods of activating S1P receptors such as S1P1 can be performed in vivo, i. E., In vivo in mammals such as human patients or test animals. The compounds of the present invention may be administered via one of the routes described above, for example, orally to a living organism, or may be provided locally in body tissue, for example, by injection of an internal organ tumor. In the presence of the compounds of the present invention, activation of the receptor is achieved and its effect can be studied.

An embodiment of the present invention provides a method of treating an abnormal condition in a patient, wherein the activation of the S1P receptor, such as S1P1, is medically prescribed, wherein the dose, frequency and duration of the The compound is administered to the patient. The compounds of the present invention may be administered by any suitable means, e. G. By the means described above.

Stably expressed S1P _One - GFP  Agonist-induced internalization in cells, receptor phosphorylation and receptor Polyubiquitination  Experimental procedure to study

Materials . S1P was purchased from Biomol. AFD-R, an S1P receptor agonist, I received a gift from Brickman (Novartis Pharma). The anti-GFP antibodies (ab-1218 and Ab-6556) were purchased from Abcam, anti-ubiquitin P4D1 antibody from Santa Cruz, 4-12% tris- glycine SDS- PAGE gel from Invitrogen, P ³² orthophosphate Were purchased from Perkin-Elmer. Fetal serum (FBS) and charcoal-stripped FBS were purchased from Hyclone, and other culture reagents were purchased from TSRI Supply Center (supplied by Invitrogen and Gibco BRL).

Cell culture. HEK-293 cells and 293-vector-GFP cells stably expressing the GFP-coupled human S1P ₁ receptor (S1P ₁ -GFP) were obtained from Dr Timothy Hla (Connecticut Health Science Center). Cells were maintained in high glucose-modified Eagles's medium containing GlutaMAX and supplemented with 10% FBS, 1% penicillin / streptomycin solution and screened using 500 ug / ml G418 (Gibco BRL).

Ligand  medium S1P _One - GFP  Microscopic image experiment for internalization

Using a gelatin S1P ₁ -GFP cells cultured in the coated coverslips, it was investigated ligand-induced internalization S1P ₁ -GFP. Cells were cultured overnight in charcoal-stripped FBS (cs-FBS) medium prior to the start of the experiment, after which all cultures were performed in cs-FBS medium containing 15 μg / ml cyclohexamide. The cells were incubated with the agonist (or vehicle control) for the indicated time, the medium was removed and then rinsed with PBS to terminate the reaction. In experiments with W146 antagonists, antagonist or vehicle was added to the cells for 30-45 minutes before incubation with the agonist. Cells were fixed in 3.7% paraformaldehyde for 10 minutes and placed on a cover slip using a GelMount mounting medium. Cells were scanned with an Olympus BX61 scanning confocal fluorescence microscope. To detect GFP, fluorescence was excited with an argon laser at 488 nm wavelength and absorbance was detected at 510-520 nm. To give the micrograph of a ligand for a vehicle with Metamorph software and, after ligand stimulation of most G protein-coupled confirmed the characteristics exhibited by the receptors ringdoe pattern of occurrence or absence of the in-house of S1P ₁ -GFP vesicles.

S1P _One - GFP  And In the ligand  Stimulated by S1P _One On polyubiquitination  About Immune sedimentation  And Immunoblotting

Polyethoxylated S1P ₁ -GFP formed receive stimulation by the agonist-ubiquitin chain formation effect, immunoprecipitated using anti -GFP antibody was analyzed by immune blotting experiments. The cells were inoculated into a 35 mm dish and cultured with ~ 95% confluence using a defined culture medium. The culture medium was replaced with cs-FBS medium, and the cells were cultured overnight. The drug or vehicle (both produced in cs-FBS medium) was incubated for a defined period of time. At the end of incubation, the monolayer was rinsed twice with ice-cold PBS and incubated with RIPA buffer (50 mM Tris-HCl, pH 7.5, 150 mM NaCl, 1 mM EDTA, 1% Nonidet P-40, 0.5% sodium deoxycholate, % SDS) + protease inhibitors (complete tablets, Roche), and 1mM NaVO _4, 1mM NaF and B- 0.5M glycerol-by incubation in a phosphate, to give a water hemolysis. Cell hemolyzed water was clarified by centrifugation (10,000xg, 15 min) and protein concentration in hemolyzed water supernatant was measured by BCA (Pierce) method. An equal volume of hemolyzed water (0.5-1 mg) was incubated overnight at 4 ° C with monoclonal GFP antibody (1 ug antibody / 400 ug protein) followed by protein-A sepharose beads (2 h, 4 캜). The beads were recovered by centrifugation (10,000xg, 1 min), washed with PBS (1: 1) without 3x RIPA buffer: protease inhibitor and washed twice with PBS. The beads were suspended in 2X Laemli buffer supplemented with 2-mercaptoethanol, boiled for 10 minutes, and protein bands were separated by SDS-PAGE using Novex, 4-12% tris-glycine gel. Then, the gel is moved to the PVDF membrane, the S1P ₁ -GFP GFP for detecting the expression of polyclonal antibody: P4D1 for detecting (1: 10,000) or poly-ubiquitination S1P ₁ -GFP- the conjugate (1: 200-1 : 800) overnight (4 < 0 > C). Western wasabi peroxidase-labeled antibodies were visualized by ECL chemiluminescence (Amersham Biosciences).

HEK293  Stimulated by agonists in cells S1P _One - GFP Polyphosphorylation

Cells stably expressing GFP-tagged human S1P ₁ were labeled with P ³² orthophosphate (80 μCi / ml, Perkin Elmer) for 2 hours and incubated at 37 ° C. for the indicated time with the indicated concentrations of agonist and incubation Respectively. The agonist was removed and the incubation was stopped by washing with PBS, and the receptor was immunoprecipitated with a GFP antibody derived from the same amount of protein as the cytolysate. Immunoprecipitated receptors were separated by SDS-PAGE and evaluated for P ³² incorporation on agonist-stimulated receptors by radiography (-80 ° C, 24 hr exposure).

S1P1 - GFP However, Ubiquitination  And phosphorylation

During the preceding optimization experiments, compounds SR-917, Compound 32 , and Compound 236 were evaluated for their impact on various biological studies. SR-917 is a well-known S1P1 receptor agonist and is indexed to the NIH Molecular Libraries Small Molecule Repository (MLMSR) with a compound ID of 976135. It is available from the ChemBridge Screening Library.

Stimulation by agonists of the S1P1 receptor is regulated by receptor degradation. Ligand stimulation leads to receptor phosphorylation, internalization, polyubiquitination and degradation (Gonzalez-Cabrera, Hla et al. 2007). S1P1-GFP internalization, protein phosphorylation and polyubiquitination are generated by stimulation with SR-917, a synthetic compound identified by high-performance screening, such as AFD-R and S1P. Please refer to Fig.

Compound 32 certainly induces both internalization and polyubiquitination with 5178, and this effect is blocked by the S1P1 antagonist W146R. See FIG.

Compound 236 induces S1P1 polyubiquitination by other compounds in the series. See FIG.

The S1P and S1P1 specific agonist SEW2897 was observed to cause lymphopenia (Wei, Rosen et al. 2005). SR-917 and Compound 32 did not induce lymphocytopenia when delivered to the gut. Compound 236 induced lymphocytopenia when administered at 10 mgpk with gavage delivery. See FIG. Compound 236 dissolves in water at 0.5 mg / mL, resulting in lymphocytopenia both intravenously and intraperitoneally (Sanna, Leaf).

Pharmacokinetics

In the early mouse efficacy experiment (Figure 5), plasma concentration at 23 hours of compound 236 was 395 / 87.6 Mean / SD. The intra-liver microbial stability of compound 236 was species-specific. In the case of human microspheres. The compounds were very stable and stable to medium levels in rats. All were NADPH dependent. In the presence of liver microsomes at 1.8 mg / ml, half-life (minute) was stable in humans, mouse was 50, and rat was 16.

The S1P1 polar amino acids essential for S1P mediated activation are not required for S1P1 receptor activation by compound 236. S1P requires several polar amino acids (R120, E121 and R292) lined with ligand-binding pockets for sufficient activation (Jo, Sanna et al. 2005). The S1P1 polar side chain of the R120, E121 and R29 residues forms a salt link with the phosphate of S1P1, and S1P can only activate at least the R120A, E121A and R292A mutations. On the other hand, wild-type S1P1 and R120A, E121A and R292A mutant S1P1 receptors are activated indiscriminately by compound 236 (FIG. 6).

Example

The following compounds were synthesized and evaluated by bioassay as described herein.

Synthetic process

Extraction solvent: ACS grade. Reaction solvent: Reagent grade. Reagents: Unless otherwise noted, Alfa Aesar, Fisher and Aldrich are among the best grades. TLC: silica gel 60 F ₂₅₄ aluminum plate, (whatman, type Al Sil G / UV, 250 mm laser); Visualization by UV absorption. Property chromatography was performed on silica gel 60 (0.40-0.63 mm, 230-440 mesh, EM Science). NMR: ¹ H: δ value, ppm (internal standard substance: TMS; ¹³ C: δ value, ppm (internal standard substance: TMS)

The reaction was monitored by LC / MS.

Aldehyde  General process of reduction:

To ethanol stirring suspension of aldehyde (1.0 eq., 0.4 M) and silica gel (catalytic) was added NaBH ₄ (1/3 equivalent) at 0 ° C. The reaction was warmed to room temperature and stirred for 2 hours. The solvent was removed under reduced pressure and the product purified in CC using hexane / EtOAc (7: 3).

synthesis To Amish Dignity  General process for:

A stirred suspension of hydroxylamine hydrochloride (1.1 eq.) And Na ₂ CO ₃ (1.1 equivalents) in ethanol, the corresponding benzonitrile (1 equiv) was added portionwise. The mixture was refluxed for 6 hours, then NH ₂ OH.HCl (1.1 eq) and Na ₂ CO ₃ (1.1 eq) were added and the reaction was refluxed for another 6 h. The suspension was cooled to room temperature and filtered. The solid was washed with ethanol and the organic phase was concentrated under reduced pressure. The amidic acid crude product was recrystallized from EtOAc / hexane and used without further purification.

synthesis Oxadiazole  General process for:

HOBt (1.3 equivalents) and EDCI (1.3 equivalents) were added sequentially to a stirred solution of 3,4-diethoxybenzoic acid (1 eq, 0.2 M) in DMF at room temperature. The reaction was stirred for 20 min and then the corresponding amidocin (1.3 eq., Prepared in the previous step) was added in one portion. The reaction was stirred at room temperature for another 30 minutes and then heated to 90-95 < 0 > C for 8-14 hours. The reaction was cooled to room temperature, diluted with saturated NaCl solution and then extracted with EtOAc (3X). The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The product was purified in CC using CH ₂ Cl ₂ : MeOH (9: 1) to give the diaryloxadiazole in intermediate yield.

Amine  General process for synthesis

To a stirred solution of benzyl alcohol (1 eq) and pyridine (1.1 eq) in CH ₂ Cl ₂ was added SOCl ₂ (1.1 eq.) At 0 ° C. The reaction was warmed to room temperature, stirred for another 1 hour and then concentrated under reduced pressure. To a stirred solution of the chloride in CH ₂ Cl ₂ at 0 ° C was added dropwise a solution of pyrrolidine (3 eq) in CH ₂ Cl ₂ . The reaction was warmed to room temperature and stirred for 2 hours. The organic phase was washed with water and then dried over Na ₂ SO ₄ anhydride. The crude product was concentrated under reduced pressure and purified by column chromatography using DCM / MeOH to give the pyrrolidine derivative in good yield.

Reduction of Indole Derivatives

To a stirred solution of indole-core (1 eq) in acetic acid was slowly added sodium cyanoborohydride (3 eq.) At 13 < 0 > C. The reaction was stirred for 2 hours at 13 < 0 > C and monitored by TLC. After completion of the reaction, the mixture was neutralized with 50% sodium hydroxide and the product was extracted with ethyl acetate. The organic layer was dried over Na ₂ CO ₃ and removal under reduced pressure. The indolin core was purified by column chromatography using CH ₂ Cl ₂ / MeOH (9: 1) and was obtained in quantitative yield.

Spectroscopic measurement of selected compounds Data

_{^{1 H NMR (500Hz, CDCl 3}} ) δ: 8.80 (s, 2H), 8.03 (d, J = 6.0Hz, 2H), 7.80 (dd, J = 8.5, 2.0Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 4.23-4.16 (m, 4H), 1.53-1.44 (m, 6H).

¹³ C NMR (125 Hz, CDCl ₃ )?: 176.47, 167.23, 152.99, 150.48, 148.88, 134.68, 122.16, 121.38, 120.31, 116.08, 112.50, 112.25, 64.82, 64.60, 14.68, MS. (M + 1) < / RTI >

^{1 H NMR (300 MHz, CDCl3} ) δ: 8.81 (brs, 2H), 8.06 (d, J = 6.0 Hz, 2H), 7.32 (s, 1H), 7.31 (s, 1H), 6.68 (t, J = 2.4 Hz, 1H), 4.10 (q, J = 6.9 Hz, 4H), 1.45 (t, J = 6.9 Hz, 6H); ¹³ C NMR (75 MHz, CDCl 3)?: 176.68, 167.33, 160.64, 150.24, 134.96, 125.12, 121.62, 121.59, 106.64, 106.41, 64.06, 14.79. MS (M + l) 312

_{^{1 H NMR (500Hz, CDCl 3}} ) δ: 8.80 (s, 2H), 8.05 (d, J = 5.0Hz, 2H), 7.65 (d, J = 3.0Hz, 1H), 7.11-7.09 (dd, J = 9.0, 3.0 Hz, 1H), 7.02 (d, J = 9.0 Hz, 1H), 4.18 (q, J = 7.0 Hz, 2H), 4.08 (q, J = 7.0Hz, 2H), 1.52 (t, J = 7.0 Hz, 3H), 1.44 (t, J = 7.0 Hz, 3H). ¹³ C NMR (125 Hz, CDCl ₃ ) δ: 175.92, 166.66, 152.78, 152.44, 150.48, 134.73, 121.53, 116.36, 115.86, 115.40, 113.89, 113.82, 113.69, 65.62, 64.30, 14.84, MS. (M + 1) < / RTI >

_{^{1 HNMR (300Hz, CDCl 3)}} δ: 8.81 (s, 2H), 8.04 (d, J = 4.5Hz, 2H), 7.82 (dd, J = 8.4, 2.0Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.00 (d , J = 8.4 Hz, 1H), 4.22 (q, J = 7.0 Hz, 2H), 3.97 (s, 3H), 1.53 (t, J = 7.0Hz). ¹³ C NMR (125 Hz, CDCl ₃ )?: 176.53, 167.28, 153.48, 150.41, 148.75, 134.89, 122.18, 116.30, 111.62, 111.36, 64.72, 56.20, 14.75. MS. (M + 1) < / RTI >

_{^{1 H NMR (500Hz, CDCl 3}} ) δ: 8.81 (s, 2H), 8.04 (d, J = 6.0Hz, 2H), 7.80 (d, J = 7.5Hz, 1H), 7.71-7.70 (m, 1H) , 7.47 (t, J = 8.5 Hz, 1H), 7.16 (d, J = 8.5 Hz, 1H), 4.16 (q, J = 7.0 Hz, 2H), 1.48 (t, J = 7.0 Hz, 3H). ¹³ C NMR (125 Hz, CDCl ₃ ) δ: 176.48, 167.38, 159.39, 150.53, 134.50, 130.32, 129.40, 124.82, 121.39, 120.46, 120.03, 115.92, 113.32, 63.88, MS. (M + 1) < / RTI >

_{^{1 H NMR (500Hz, CDCl 3}} ) δ: 8.81 (s, 2H), 8.05 (d, J = 4.5Hz, 2H), 7.73 (d, J = 8.0Hz, 1H), 7.60 (s, 1H), 7.31 (d, J = 7.5 Hz, 1H), 3.96 (s, 3H), 2.31 (s, 3H). ¹³ C NMR (125 Hz, CDCl ₃ )?: 176.71, 167.31, 158.13, 150.51, 134.60, 133.06, 131.24, 130.10, 122.33, 121.41, 120.56, 118.84, 108.90, 55.58, 16.62. MS. (M + 1) < / RTI >

_{^{1 H NMR (300MHz, CDCl 3}} ) δ: 8.84 (bs, 2H), 8.35 (d, J = 4.5Hz, 2H), 7.64 (s, 1H), 6.63 (s, 1H), 4.03 (s, 3H) , 4.01 (s, 3H), 3.96 (s, 3H). MS (M + 1) 314.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ: 8.80 (bs, 2H), 8.04 (bs, 2H), 7.78 (dd, J = 8.4, 2.1 Hz, 1H), 7.65 (d, J = 9.3, 1H), 6.97 (d, J = 5.1 Hz, 1H), 4.92-4.88 (m, 1H), 3.93 (s, 3H), 2.03-1.82 (m, 6H), 1.66-1.61 (m, 2H); ¹³ C NMR (75 MHz, CDCl ₃ )?: 176.31, 167.01, 153.95, 150.20, 147.79, 134.61, 121.75, 119.99, 115.94, 113.98, 113.96, 113.32, 111.35, 110.87, 80.91, 55.91, 32.59, 23.93. MS (M + 1) 338.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ: 8.83 (d, J = 5Hz, 2H), 8.24 (d, J = 5Hz, 2H), 8.15 (d, J = 8.7Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 3.91 (s, 3H). MS (M + 1) 254.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ: 8.86 (bs, 2H), 8.34 (bs, 2H), 7.82 (dd, J = 8.1, 1.7Hz, 1H), 7.63 (d, J = 1.7Hz, 1H) , 6.99 (d, J = 8.1 Hz, 1 H), 6.12 (s, 2H). MS (M + 1) 268.

4- (5- (3,4- Diethoxyphenyl )-4 H -1,2,4- Triazole Yl) pyridine

To a stirred solution of 3,4-diethoxybenzonitrile (7.84 mmol, 1.5 g) in anhydrous MeOH (23.53 mmol, 954 [mu] l) and anhydrous ether Lt; / RTI > The reaction was stirred at 0 < 0 > C for 1 hour and then in a refrigerator (0-5 [deg.] C) for 48 hours. The mixture was poured into N ₂ to remove HCl and concentrated under reduced pressure. Ether anhydrous was added to the crude product to precipitate methyl 3,4-diethoxybenzimidate in 63% yield (1.3 g) as a pale orange solid. The product was used without further purification.

The acetonitrile already Dean of the nitrile (0.5 mmol, 130 mg) (after extraction with freshly glass using a 1M Na ₂ CO ₃ solution, ether) was added, the pyridine-4-carbonyl hydrazide (0.55 mmol, 75.5mg) And the reaction was refluxed for 2 hours. The mixture was concentrated under reduced pressure and the crude product was heated to 180 < 0 > C for 2 hours. The product was purified by column chromatography using CH ₂ Cl ₂ : MeOH (9: 1) to give the product as a solid in 65% yield.

^{1 H NMR (400 MHz, CDCl} 3) δ: 8.71 (bs, 2H), 8.11 (d, J = 5.2 Hz, 2H), 7.60 (s, 1H), 7.57 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 8.4, 1H), 4.11 (q, J = 6.8 Hz, 2H), 4.07 (q, J = 6.8 Hz, 2H), 1.45 (t, J = 7.0Hz, 3H), 1.40 (t , J = 7.0 Hz, 3H). ¹³ C NMR (CDCl ₃ ): 157.73, 150.89, 149.42, 149.14, 139.66, 121.29, 120.56, 120.06, 119.68, 113.00, 111.53, 64.82, 64.72, 14.90, 14.86. MS (M + l) 311

2- (3,4- Diethoxyphenyl ) -5- (pyridin-4-yl) -1,3,4- Oxadiazole  (25)

To a stirred solution of 3,4-diethoxybenzoic acid (0.71 mmol, 150 mg) in CH ₂ Cl ₂ at room temperature was SOCl ₂ and the reaction was refluxed for 1.5 h. The mixture was concentrated under reduced pressure.

NMP (0.8 mL) of _{Na 2 CO 3 (1.42 mmol,} 150.52 mg) and pyridine-4-carbonyl hydrazide (0.71 mmol, 97 mg) to a stirred suspension of 3,4-diethoxy-benzoyl NMP (0.8 mL) Chloride (prepared as above) was added. The reaction was stirred at room temperature for 12 h, poured into 20 mL of cold H ₂ O and filtered. The precipitated intermediate product was dried under vacuum. Adding a solid to POCl ₃ (5 mL) and heated to 70-72 ℃ for 6 hours. This solution was poured into an ice water container and neutralized with NaOH (2M). The precipitated product was filtered and purified by column chromatography using CH ₂ Cl ₂ : MeOH (9: 1) to give the product in 67% yield (150 mg).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ: 8.84 (bs, 2H), 7.99 (d, J = 4.4Hz, 2H), 7.67 (dd, J = 2.0, 8.4 Hz, 1H), 7.64 (d, J = 2.0 Hz, 1H), 6.98 ( d, J = 8.4Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 4.18 (q, J = 7.2 Hz, 2H), 1.51 (t, J = 7.2Hz , 3H), 1.50 (t, J = 7.2 Hz, 3H). ¹³ C NMR (CDCl ₃ ) ?: 165.81, 162.46, 152.51, 150.84, 149.20, 131.52, 128.05, 120.97, 115.77, 112.78, 111.58, 65.05, 64.80, 14.92, 14.85. MS (M + l)

3- (3,4- Diethoxyphenyl ) -5- (pyridin-4-yl) -1,2,4- Oxadiazole

To a stirred solution of triethylamine (2 eq) and NH ₂ OH.HCl (2 eq) in ethanol 3,4-diethoxybenzonitrile (1 eq) was added and the reaction was refluxed overnight. The reaction was concentrated under reduced pressure. The crude product was dissolved in AcOEt and extracted with water. The organic phase was dried over Na ₂ SO ₄ anhydride and concentrated under reduced pressure. The crude product was used without further purification.

EDCI (1.3 eq.) And HOBt (1.3 eq.) Were added to a stirred solution of isonicotinic acid (1 eq) in DMF (microwave vial) and the reaction was stirred at room temperature for 5 min. 1.3 eq.). The reaction was stirred again for 10 min and then heated to 170 < 0 > C in the microwave for 5 min. The reaction was diluted with a saturated aqueous NaCl solution and extracted with EtOAc (3X). The organic phase was dried over Na ₂ SO ₄ anhydride and concentrated under reduced pressure. Which was purified by column chromatography using CH ₂ Cl ₂ : MeOH (9: 1) to give the oxadiazole% yield.

^{1 H NMR (300 MHz, CDCl3} ) δ: 8.85 (d, J = 5.4 Hz, 2H), 8.02 (d, J = 6.0 Hz, 2H), 7.71 (dd, J = 8.1, 1.8 Hz, 1H), 7.62 (d, J = 2.1 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 4.19 (q, J = 6.9 Hz, 2H), 4.14 (q, J = 6.9 Hz, 2H), 1.50 (t , J = 3.0 Hz, 3H), 1.46 (t, J = 3.3 Hz, 3H); ¹³ C NMR (75 MHz, CDCl 3) δ: 173.54, 16928, 151.64, 151.07, 148.91, 131.37, 121.48, 121.15, 118.75, 112.74, 111.82, 64.78, 64.59, 14.87, 14.81; MS (M + l) 312.

_{^{1 H NMR (500Hz, CDCl 3}} ) δ: 8.63-8.61 (m, 1H), 7.99 (d, J = 5Hz, 1H), 7.80 (dd, J = 8.5, 2.0Hz, 1H), 7.67 (d, J = 1.5 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 4.23-4.17 (m, 4H), 2.68 (s, 3H), 1.52-1.49 (m, 6H). ¹³ C NMR (125 Hz, CDCl ₃ ) ?: 175.43, 167.82, 152.93, 152.24, 148.88, 147.62, 133.73, 132.32, 123.10, 122.14, 116.13, 112.52, 112.29, 64.81, 64.60, 19.00, 14.69, 14.61. MS. (M + 1) < / RTI >

_{^{1 H NMR (500Hz, CDCl 3}} ) δ: 8.84 (dt, J = 3.0, 1.0Hz, 1H), 8.76 (dd, J = 7.5, 1.0Hz, 1H), 7.85-7.84 (m, 1H), 7.75 ( d, J = 2.0Hz, 1H) , 7.45-7.42 (m, 1H), 6.98 (d, J = 8.5Hz, 1H), 4.22-4.16 (m, 4H), 1.51 (t, J = 7.0Hz, 6H ). ¹³ CNMR (125Hz)?: 176.50, 168.61, 152.79, 150.35, 148.80, 146.62, 136.99, 125.36, 123.20, 122.21, 116.33, 112.40, 64.81, 64.55, 14.70, 14.60. MS. (M + 1) < / RTI >

_{^{1 H NMR (500Hz, CDCl 3}} ) δ: 9.40 (s, 1H), 8.76 (d, J = 3.0Hz, 1H), 8.45 (d, J = 8.0Hz, 1H), 7.82 (dd, J = 8.5, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.47-7.44 (m, 1H), 7.00 (d, J = 8.5 Hz, 1H), 4.24-4.17 1.50 (m, 6 H). ¹³ CNMR (125 Hz, CDCl ₃ )?: 176.19, 166.82, 152.92, 151.68, 148.89, 148.56, 134.90, 122.67, 122.15, 120.32, 116.23, 112.52, 112.29, 64.84, 64.61, 14.70, 14.62. MS. (M + 1) < / RTI >

_{^{1 H NMR (500Hz, CDCl 3}} ) δ: 8.22 (d, J = 4.5Hz, 2H), 7.79 (dd, J = 8.5, 2.0Hz, 1H), 7.66 (d, J = 2.0Hz, 1H), 7.37 (d, J = 5.0 Hz, 1H), 7.26 (s, 1H), 6.99 (d, J = 8.5 Hz, 1H), 4.77-4.71 (m, 2H), 4.23-4.17 1.49 (m, 6H). ¹³ C NMR (125 Hz, CDCl ₃ )?: 176.20, 167.51, 158.85, 152.90, 148.86, 148.78, 136.32, 122.11, 116.22, 112.50, 112.25, 111.76, 106.58, 64.82, 64.61, MS. (M + 1) < / RTI >

_{^{1 H NMR (300Hz, CDCl 3}} ) δ: 8.18- 8.15 (m, 2H), 7.80 (dd, J 1 = 1.8 Hz, J 2 = 8.4 Hz, 1H), 7.69 (d, J = 3.1 Hz, 1H) , 7.53-7.48 (m, 3H), 6.99 (d, J = 8.4 Hz, 1H), 4.23 (q, J = 7.2 Hz, 2H), 4.19 (q, J = 4.8 Hz, 2H), 1.53 (t, J = 2.7 Hz, 3H), 1.49 (t, J = 4.2 Hz, 3H); MS (M + 1) 311.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ: 8.06 (dd, J = 2.1, 8.7 Hz, 1H), 7.81 (dd, J = 1.8, 8.4 Hz, 1H), 7.70 (d, J = 2.1 Hz, 1H) , 7.43-7.30 (m, 3H), 6.69 (d, J = 8.7 Hz), 4.21 (q, J = 6.9 Hz, 2H), 4.19 (q, J = 6.9 Hz, 2H), 2.67 (s, 3H) , 1.51 (t, J = 7.2 Hz, 6H); ¹³ C NMR (75 MHz, CDCl 3) δ: 174.76, 169.45, 152.59, 148.80, 138.22, 131.33, 130.53, 130.49, 130.12, 126.45, 125.98, 122.01, 116.69, 112.48, 112.25, 64.79, 64.09, 22.08, 14.75; MS 325 (M + l)

¹ H NMR (300 MHz, CDCl ₃ )?: 8.82 (bs, 2H), 8.02 (d, J = 2.7, 2H), 7.93 (q, J = 1.5 Hz, 1H), 7.47 (s, 5H); ¹³ C NMR (75 MHz, CDCl ₃ )?: 171.12, 167.81, 150.86, 145.70, 135.09, 134.12, 133.14, 123.32, 129.04, 126.35, 126.33, 121.67, 120.21, 105.04; MS 374 (M + 1).

_{^{1 H NMR (300MHz, CDCl 3}} ) δ: 8.63 (brs, 2H), 7.95 (d, J = 5.1 Hz, 1H), 7.912 (t, J = 1.5, 1H), 7.462 (s, 5H), 2.67 ( s, 3H); ¹³ C NMR (75 MHz, CDCl ₃ )?: 170.06, 168.32, 152.51, 147.88, 145.63, 145.60, 134.93, 133.13, 132.69, 129.26, 128.85, 126.40, 120.18, 105.01, 19.38; MS 388 (M + l)

_{^{H 1 NMR (400MHz, CDCl 3}} ) δ: 7.83 (d, J = 7.6Hz, 1H), 7.79 (dd, J = 2, 8.4 Hz, 1H), 7.68 (d, J = 2Hz, 1H), 7.32 ( (t, J = 8 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 4.78 (s, 2H) 4.18 (q, J = 7.2 Hz, 4H) , 6.8 Hz, 6H). ¹³ C NMR (CDCl ₃ ) ?: 175.2, 169.8, 152.9, 149.0, 140.2, 136.3, 130.0, 129.9, 127.6, 126.1, 122.2, 116.7, 112.7, 112.4, 65.0, 64.8, 63.8, 16.4, 14.9. MI (M + 1)

_{^{1 H NMR (500MHz, CDCl 3}} ) δ: 8.05 (d, J = 7.5Hz, 1H), 7.80 (dd, J = 8.0Hz, 2.0Hz, 1H), 7.68 (d, J = 2.0Hz, 1H), 2H), 6.99 (d, J = 8.5 Hz, 1H), 4.73 (s, 2H), 4.21-4.18 (m, 4H) 7.0 Hz, 1 Hz, 6H). ¹³ C NMR (125 MHz, CDCl ₃ ) ?: 174.70, 169.17, 152.59, 148.78, 143.23, 138.45, 130.34, 129.57, 125.56, 124.18, 121.18, 121.99, 116.60, 112.51, 112.32, 64.78, 64.57, 22.07, 14.69, . MS. (M + 1) < / RTI >

_{^{1 H NMR (500MHz, CDCl 3}} ) δ: 7.968-7.94 (m, 2H), 7.79 (dd, J = 8.5Hz, 1.5Hz, 1H), 7.68 (d, J = 2.0Hz, 1H), 7.50 (d J = 8.0 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 4.75 (s, 2H), 4.23-4.16 (m, 4H), 2.40 7.0 Hz, 1 Hz, 6H). ¹³ C NMR (125 MHz, CDCl ₃ )?: 175.62, 168.61, 164.61, 152.61, 148.77, 141.82, 136.39, 129.06, 127.47, 126.14, 125.20, 122.0, 116.59, 112.47, 112.28, 64.78, 64.56, 63.05, 18.57, 14.69 , 14.61. MS. (M + 1) < / RTI >

_{1H NMR (300MHz, CDCl 3)} δ: 8.06 (d, J = 8.1 Hz, 2H), 7.76 (dd, J = 1.5, 9.9 Hz, 1H), 7.66 (d, J = 1.8 Hz, 1H), 7.34 ( d, J = 8.1 Hz, 2H ), 6.96 (d, J = 8.4 Hz, 1H), 4.21 (q, J = 7.2 Hz, 2H), 4.16 (q, J = 6.9 Hz, 2H), 3.88 (t, J = 6.6 Hz, 2H), 2.91 (t, J = 6.6 Hz, 2H), 1.51 (t, J = 1.5, 3H), 1.48 (t, J = 1.2 Hz, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) ?: 175.54, 168.52, 152.49, 148.64, 141.98, 132.14, 129.72, 127.59, 125.17, 121.93, 116.46, 112.31, 112.07, 64.68, 64.47, 63.25, 39.07, 14.64. MS 355 (M + l)

_{^{H 1 NMR (400MHz, CDCl 3}} ) δ: 8.11 (s, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.79 (dd, J = 2.0, 8.4 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.46 ( t, J = 7.6 Hz, 1H), 6.98 (d, J = 8.4Hz, 1H), 4.22 (q, J = 7.2Hz, 2H), 4.18 (q, J = 7.2 Hz 2H), 3.74 (s, 2H), 2.60 (s, 4H), 1.82 (s, 4H), 1.52 (t, J = 7.0Hz, 3H), 1.50 (t, J = 7.0Hz, 3H). ¹³ C NMR (CDCl ₃ ) ?: 175.87, 169.02, 152.80, 148.98, 132.02, 129.09, 128.21, 127.27, 126.51, 122.20, 116.85, 112.64, 112.44, 64.99, 64.77, 60.47, 54.31, 23.69, 14.93, 14.85. MI (M + 1) < / RTI > 394.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ: 8.07 (d, J = 8.4Hz, 2H), 7.74 (dd, J = 1.6, 8.4Hz, 1H), 1.64 (d, J = 1.6Hz, 1H), 7.44 (d, J = 8.0Hz, 2H ), 6.92 (d, J = 8.4Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 4.12 (q, J = 7.2Hz, 2H), 3.68 (s , 2H), 2.54 (s, 4H), 1.77 (s, 4H), 1.47 (t, J = 7.0 Hz, 3H), 1.45 (t, J = 7.0 Hz, 3H). ¹³ C NMR (CDCl ₃ ) ?: 175.68, 168.72, 152.65, 148.82, 142.13, 129.42, 127.54, 125.95, 122.05, 116.67, 112.50, 112.27, 64.82, 64.61, 60.31, 54.14, 23.51, 14.79, 14.71. MI (M + 1) < / RTI > 394.

_{^{H 1 NMR (400MHz, CDCl 3}} ) δ: 7.79 (dd, J = 2.0, 8.4 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.50 (d, J = 7.6Hz, 1H), 7.28 (t, = J 7.6Hz, 1H), 6.98 (d, = J 8.4Hz, 1H), 4.20 (q, = J 7.0Hz, 2H), 4.19 (q , J = 7.0Hz, 2H), 3.72 (s, 2H), 2.59 (s, 4H), 1.80 (s, 4H), 1.50 (t, J = 7.0Hz, 6H). ¹³ C NMR (CDCl ₃ ) ?: 175.06, 170.12, 152.77, 148.98, 137.18, 131.98, 129.40, 127.50, 125.75, 122.17, 116.84, 112.66, 112.40, 64.95, 64.77, 58.51, 54.42, 23.74, 16.80, 14.91, 14.84 .

_{^{1 H NMR (500Hz, CDCl 3}} ) δ: 8.01 (d, J = 7.5Hz, 1H), 7.81 (dd, J = 8.5Hz, 2Hz, 1H), 7.69 (d, J = 2Hz, 1H), 7.32- 2H), 6.99 (d, J = 8.5 Hz, 1H), 4.23-4.17 (m, 4H), 3.67 (s, 2H) -1.80 (m, 4H), 1.52-1. 49 (m, 6H). ¹³ C NMR (125 Hz, CDCl ₃ )?: 174.63, 169.33, 152.56, 148.80, 138.15, 131.78, 131.07, 126.46, 125.11, 121.96, 116.72, 112.54, 112.35, 64.78, 64.7, 60.32, 54.17, 23.46, , 14.63. MS. (M + 1) < / RTI >

_{^{1 H NMR (500MHz, CDCl 3}} ) δ: 7.94-7.93 (m, 2H), 7.80 (dd, J = 8.5Hz, 2.0Hz, 1H), 7.69 (d, J = 2.0Hz, 1H), 7.47 (d 2H), 2.56-2.54 (m, 4H), 2.44 (s, 2H) 3H), 1.80-1.78 (m, 4H), 1.52 (q, J = 7.0 Hz, 6H). ¹³ C NMR (125 MHz, CDCl ₃ ) ?: 175.49, 168.80, 152.54, 148.76, 140.88, 137.34, 129.51, 128.95, 125.39, 124.82, 121.94, 116.71, 112.46, 112.29, 64.76, 64.53, 57.82, 54.29, 23.55, , 14.68, 14.60. MS. (M + 1) < / RTI >

^{1 H NMR (300MHz, CDCl3)} δ: 8.06 (d, J = 8.0 Hz, 2H), 7.72 (dd, J = 8.4, 2.0, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.33 (d J = 8.4, 2H), 6.92 (d, J = 8.4,1H), 4.16 (q, J = 6.8,2H), 4.11 (q, J = 6.8,2H), 3.30-3.22 (M, 2H), 2.02 (m, 2H), 1.47 (t, J = 10 Hz, 3H), 1.43 (t, J = 3.6, 3H); 2.74-2.69 (m, 2H). MS 408 (M + 1).

_{^{H 1 NMR (400MHz, CDCl 3}} ) δ: 8.01 (d, J = 7.2Hz, 1H), 7.81 (dd, J = 8.4, 2.0 Hz, 1H), 7.52 (s, 1H), 7.52 (d, J = J = 8.0 Hz, 1 H), 7.23 (s, 1 H), 6.96 (d, J = 8.4 Hz, 1 H), 4.18 (q, J = 6.8 Hz, 2H), 4.16 (q, J = 6.8 Hz, 2H), 1.47 (t, J = 6.8 Hz, 3H), 1.46 (t, J = 6.8 Hz, 3H). _{^{13 C NMR (CDCl 3) δ}} : 175.0, 169.5, 152.6, 148.9 (2), 125.7, 122.2, 121.8, 121.7, 121.3, 121.2, 117.0, 114.4, 114.3, 112.7, 112.5; MI (M + 1) < / RTI > 350.

^{1 H NMR (300MHz, CDCl3)} δ: 7.78 (dd, J = 8.4, 2.1 Hz, 1H), 7.68 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.16 ( t, J = 7.5 Hz, 1H ), 6.97 (d, J = 7.5 Hz, 1H), 6.76 (d, J = 7.5 Hz, 1H), 4.21 (q, J = 6.9 Hz, 2H), 4.16 (q, J = 6.9 Hz, 2H), 3.65 (brs, 2H), 3.46 (t, J = 8.1 Hz, 2H), 1.52 (t, J = 3.1 Hz, 3H), 1.48 (t, J = 3.3 Hz, 3H) ; ¹³ C NMR (75 MHz, CDCl 3)?: 175.05, 169.06, 152.62, 148.84, 127.84, 123.67, 122.09, 118.90, 116.83, 112.53, 112.32, 111.60, 64.86, 64.67, 47.29, 31.41, 14.85, 14.78. MS 352 (M + l)

_{^{1 H NMR (500MHz, CDCl 3}} ) δ: 7.80 (dd, J = 8.5, 2Hz, 1H), 7.69 (d, J = 2.0Hz, 1H), 7.45 (d, J = 7.5Hz, 1H), 7.14 ( d, J = 8.0Hz, 2H) , 6.97 (d, J = 8.0Hz, 1H), 4.24-4.15 (m, 4H), 3.98-3.95 (m, 1H), 3.43 (t, J = 8.5Hz, 2H ), 3.01 (t, J = 8.5 Hz, 2H), 1.52 (q, J = 7.0 Hz, 6H), 1.20 (d, J = 6.5 Hz, 6H). ¹³ C NMR (125 MHz, CDCl ₃ ) ?: 175.24, 169.48, 152.4, 148.74, 133.96, 126.11, 124.39, 121.93, 116.92, 112.46, 112.35, 105.03, 64.77, 64.52, 4.42, 28.42, 28.10, 18.18, 14.69, . MS. (M + 1) < / RTI >

_{^{1 H NMR (500MHz, CDCl 3}} ) δ: 8.56 (s, 1H), 8.51 (s, 1H), 8.01 (dd, J = 8.5Hz, 1.5Hz, 1H), 7.83 (dd, J = 8.5Hz, 2.0 Hz, 1H), 7.73 (d , J = 1.5Hz, 1H), 7.45 (d, J = 8.5Hz, 1H), 7.27-7.26 (m, 1H), 7.00 (d, J = 8.5Hz, 1H), 6.66-6.65 (m, 1H), 4.24-4.17 (m, 4H), 1.52-1.48 (m, 6H). ¹³ C NMR (125 MHz, CDCl ₃ )?: 175.26, 169.79, 152.44, 148.75, 137.33, 127.93, 125.27, 121.94, 121.27, 120.94, 118.77, 116.96, 112.51, 112.34, 111.43, 103.56, 64.78, 64.56, . MS. (M + 1) < / RTI >

_{^{1 H NMR (500MHz, CDCl 3}} ) δ: 7.86-7.82 (m, 2H), 7.78 (dd, J = 8.0Hz, 2Hz, 1H), 7.68 (d, J = 2.0Hz, 1H), 6.98 (d, J = 8.5Hz, 1H), 6.69 (d, J = 8.0Hz, 1H), 4.23-4.16 (m, 5H), 3.67 (t, J = 8.5Hz, 2H), 3.18 (t, J = 8.0Hz, 2H), 1.52-1.48 (m, 6H). ¹³ C NMR (125 MHz, CDCl ₃ ) ?: 175.00, 169.08, 154.04, 152.40, 148.73, 129.62, 127.89, 123.85, 121.87, 117.04, 116.98, 112.48, 112.32, 105.92, 64.76, 64.54, 47.28, 29.23, 14.71, 14.63 .

MS. (M + 1) 352

^{1 H NMR (300MHz, CDCl3)} δ: 7.78 (dd, J = 8.4, 2.1 Hz, 1H), 7.68 (d, J = 2.1, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.20 (t , J = 9.6 Hz, 1H) , 6.96 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 7.8 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 4.17 (q, J = 7.2 Hz, 2H), 3.55 (t, J = 1.8 Hz, 2H), 3.40 (t, J = 7.2 Hz, 2H), 3.29 (t, J = 7.2 Hz, 2H), 2.73 (t, J = 7.8 Hz, 2H), 2.60 (q , J = 7.2 Hz, 4H), 1.51 (t, J = 2.1 Hz, 3H), 1.49 (t, J = 1.8 Hz, 3H), 1.09 (t, J = 7.2 Hz, 6H). ¹³ C NMR (CDCl 3) ?: 174.30, 168.39, 152.52, 151.93, 148.17, 129.32, 127.33, 122.70, 121.40, 116.75, 116.21, 111.87, 107.94, 104.24, 64.15, 52.82, 49.53, 46.92, 29.54, 14.15, 11.03; MS 451 (M + 1).

^{1 H NMR (300MHz, CDCl3)} δ: 8.95 (d, J = 8.4 Hz, 1H), 8.33 (d, J = 7.2 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.74 (s, 1H), 7.65-7.54 (m, 3H), 7.0 (d, J = 8.4 Hz, 1H), 4.23 ( q, J = 6.9 Hz, 2H), 4.20 (q, J = 7.2 Hz, 2H), 1.52 (t, J = 7.2 Hz, 6H); ¹³ C NMR (75 MHz, CDCl 3)?: 174.23, 168.57, 152.00, 148.15, 133.22, 131.00, 130.08, 128.65, 127.94, 126.82, 125.64, 124.44. 123.51, 121.44, 115.92, 111.81, 111.61, 64.13, 14.07. MS (M + 23) 383.

_{^{1 H NMR (500MHz, CDCl 3}} ) δ: 9.03 (d, J = 8.5Hz, 1H), 8.80 (d, J = 5.5Hz, 1H), 7.94-7.90 (m, 2H), 7.84-7.71 (m, 4H), 7.01 (d, J = 8.5 Hz, 1H), 4.23-4.17 (m, 4H), 1.52-1.49 (m, 6H).

¹³ C NMR (125 Hz, CDCl ₃ ) δ: 175.95, 168.38, 152.91, 148.84, 146.36, 142.37, 136.93, 130.70, 128.68, 127.20, 127.08, 123.04, 122.38, 122.37, 116.22, 112.62, 112.45, 64.86, 64.58, , 14.62. MS. (M + 1) 362.

_{^{1 H NMR (500MHz, CDCl 3}} ) δ: 7.83 (d, J = 7.5Hz, 1H), 7.80 (dd, J = 8.5Hz, 2.0Hz, 1H), 7.68 (d, J = 2.0Hz, 1H), 7.50 (d, J = 7.0 Hz, 1 H), 7.33 (t, J = 7.5 Hz, 1 H), 6.99 (d, J = 8.5 Hz, 1 H), 4.22-4.17 ), 3.73-3.70 (m, 2H), 2.92-2.90 (m, 2H), 2.60 (s, 3H), 2.47 (s, 2H), 1.52-1.49 (m, 6H). ¹³ C NMR (125 MHz, CDCl ₃ ) ?: 174.95, 169.69, 152.68, 148.84, 137.99, 136.65, 132.75, 131.30, 129.76, 127.70, 125.93, 122.02, 116.58, 112.32, 64.80, 64.59, 60.51, 51.27, 50.68, , 14.63. MS. (M + 1) < / RTI > 398.

_{^{1 H NMR (500MHz, CDCl 3}} ) δ: 8.05 (d, J = 8.0Hz, 1H), 7.80 (dd, J = 5.0Hz, 2.0Hz, 1H), 7.68 (d, J = 2.0Hz, 1H), 2H), 6.99 (d, J = 8.5 Hz, 1H), 4.28-4.17 (m, 4H), 3.89-3.84 (m, 2H), 3.72-3.69 s, 2H), 2.66 (s, 3H), 2.54-2.48 (m, 3H), 1.52 (dt, J = 7.0Hz, 1Hz, 6H). ¹³ C NMR (125 MHz, CDCl ₃ ) δ: 174.72, 169.16, 152.63, 148.82, 138.52, 132.63, 131.27, 130.41, 129.78, 125.85, 125.61, 121.99, 116.65, 112.56, 112.37, 64.80, 64.59, 22.06, 14.71, 14.63 . MS. (M + 1) < / RTI > 398.

One- Hydroxy -2,3- Dihydro -One H - Inden -4- Carbonitrile

1-oxo-2,3-dihydro -1 H in ethanol-inden-4-carbonitrile (1.0 eq., 0.4M) and the stirred suspension of silica gel (catalytic) at 0 ℃ NaBH ₄ (1/3 eq. ). The reaction was warmed to room temperature and stirred for 2 hours. To remove the solvent under reduced pressure and product hexanes / EtOAc (5: 5) using purified by column chromatography to give 1-hydroxy-2,3-dihydro -1 H - 80% of indene-4-carbonitrile ≪ / RTI >

_{^{1 H NMR (400MHz, CDCl 3}} ) δ: 8.10 (d, J = 7.6, 1H), 7.78 (dd, J = 1.6, 8 Hz, 1H), 7.67 (d, J = 1.6Hz, 1H), 7.56 ( d, J = 7.6Hz, 1H) , 7.39 (t, J = 7.6, 1H), 6.97 (d, J = 8.0 Hz, 1H), 5.29 (t, J = 6.4 Hz, 1H), 4.19 (q, J 2H), 4.18 (q, J = 7.2, 2H), 3.51-4.43 (m, 1H), 3.22-3.14 (m, 1H), 2.59-2.51 1H), 1.5 (t, J = 7.2, 3H), 1.49 (t, J = 7.2, 3H): 13 C NMR (CDCl 3) δ: 175.2, 168.9, 152.8, 148.9, 146.6, 143.3, 128.9, 127.4, (M + 1) 367 (M + 1) < SEP > 377 < SEP >

4- (5- (3,4- Diethoxyphenyl ) -1,2,4- Oxadiazole Yl) -2,3- Dihydro -One H - Inden -1-one

To a suspension of PCC (1.5 eq.) In dry CH ₂ Cl ₂ and powdered molecular sieves (3 Å, 1/3 wt. PCC) suspension was added benzyl alcohol (1 eq. Prepared in the above step) at 0 ° C. The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. To the residue was added Et ₂ O-EtOAc (1: 1), the slurry was stirred and then filtered through a celite pad. The residue was rinsed 4 times with Et ₂ O-EtOAc (1: 1). The filtrate was concentrated under reduced pressure and the product was purified by column chromatography to obtain a ketone in 70% yield.

_{^{1 H NMR (500MHz, CDCl 3}} ) δ: 8.48 (dd, J = 8.0Hz, 1.5Hz, 1H), 7.91 (d, J = 7.5Hz, 1H), 7.81 (dd, J = 8.5Hz, 2.0Hz, 1H), 7.68 (d, J = 2.0Hz, 1H), 7.56 (t, J = 7.5Hz, 1H), 6.99 (d, J = 8.5Hz, 1H), 4.24-4.17 (m, 4H), 3.55- 3.53 (m, 2H), 2.79-2.77 (m, 2H), 1.53-1. 49 (m, 6H). ¹³ C NMR (125 MHz, CDCl ₃ ) δ: 206.62, 175.32, 167.79, 154.40, 152.86, 148.86, 138.22, 134.63, 127.72, 126.00, 125.55, 122.10, 116.32, 112.55, 112.36, 64.82, 64.60, 36.25, 27.61, , 14.61. MS. (M + 1) 365.

Amination  fair

From 0 ℃, it was treated with a solution of CH ₂ Cl ₂ in an alcohol solution SOCl ₂ (1.1 eq.) And pyridine (1.1 equiv.) In (1 equivalent). The reaction was stirred at room temperature for 2 hours. The reaction was diluted with CH ₂ Cl ₂ and rinsed with NaHCO ₃ (2X). The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude product was dissolved in DMF and treated with the corresponding amine (2 eq) and DIPEA (2.0 eq). The reaction was stirred at 50 < 0 > C for 48 hours. The reaction was diluted with H ₂ O and the product was extracted with EtOAc (3X). The product was purified by column chromatography using CH ₂ Cl ₂ / MeOH (9: 1) to give the amino-diaryloxadiazole in some yield.

_{^{1 H NMR (500MHz, CDCl 3}} ) δ: 8.12 (d, J = 7.5Hz, 1H), 7.79 (dd, J = 8.5, 2.0Hz, 1H), 7.68 (d, J = 2.0Hz, 1H), 7.63 (d, J = 7.5 Hz, IH), 7.40-7.37 (m, IH), 4.49-4.47 (m, IH), 4.23-4.16 (m, 4H), 3.78-3.70 (m, 1H), 3.29-3.22 (m, 1H), 2.96-2.94 (m, 4H), 2.56-2.50 . ¹³ C NMR (125 Hz): 175.03, 168.66, 152.71, 148.87, 143.76, 128.71, 127.11, 123.89, 122.04, 116.67, 112.63, 112.49, 64.84, 64.61, 62.70, 60.34, 47.98, 31.90, 29.69, 14.72, 14.64. MS. (M + 1) < / RTI >

_{^{1 H NMR (400MHz, CDCl 3}} ) δ: 8.10 (d, J = 7.6Hz, 1H), 7.79 (dd, J = 8.5, 2.0Hz, 1H), 7.69 (d, J = 2.0Hz, 1H), 7.55 (d, J = 7.6Hz, 1H ), 7.38 (t, J = 7.6 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 4.44 (t, J = 6.8 Hz, 1H), 4.24-4.16 (m, 4H), 3.42-3.34 (m, 1H), 3.27-3.19 (m, 1H), 3.28 (s, 6H), 2.19-2.12 (m, 4H), 1.53-1. ¹³ C NMR (75 MHz, CDCl ₃ ): 174.09, 168.87, 152.58, 148.77, 143.88, 128.27,127.91,126.79,123.47,121.98,116.67,114.84,121.49,121.31,69.67,64.77,64.56,40.66,32.40,23.05, 14.70, 14.62. MS. (M + 1) < / RTI > 394.

2- (3,4- Diethoxyphenyl ) -5- (pyridin-4-yl) -1,3,4- Oxadiazole

SOCl ₂ was added to a stirred solution of 3,4-diethoxybenzoic acid (0.71 mmol, 150 mg) in CH ₂ Cl ₂ at room temperature and the reaction was refluxed for 1.5 hours and then concentrated under reduced pressure to give 3,4- Benzoyl chloride was quantitatively obtained. 3, 4-diethoxy in NMP (0.8 mL) of _{Na 2 CO 3 (1.42 mmol,} 150.52 mg) and pyridine-4-carbonyl hydrazide To a stirred suspension of (0.71 mmol, 97 mg), NMP (0.8 mL) A benzoyl chloride solution was added and the reaction was stirred at room temperature for 12 hours. The mixture was poured into 20 mL of cold H ₂ O and filtered. The precipitated intermediate product was dried in vacuo. Was added to the solids in POCl ₃ (5 mL), it was heated to 70-72 ℃ for 6 hours. The solution was poured into an ice water container and neutralized with NaOH (2M) solution. The precipitated product was filtered and purified by column chromatography using CH ₂ Cl ₂ : MeOH (9: 1) to give the product as a white solid in 67% yield (150 mg). ^{1 H NMR (400 MHz, CDCl} 3): δ 8.84 (bs, 2H), 7.99 (d, J = 4.4 Hz, 2H), 7.67 (dd, J1 = 2.0, J2 = 8.4 Hz, 1H), 7.64 (d, J = 2.0 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 4.18 (q J = 7.2 Hz, 2H), 1.51 (t, J = 7.2 Hz, 3H), 1.50 (t, J = 7.2 Hz, 3H); ^{13 C NMR (100 MHz, CDCl} 3): δ 165.81, 162.46, 152.51, 150.84, 149.20, 131.52, 128.05, 120.97, 115.77, 112.78, 111.58, 65.05, 64.80, 14.92, 14.85. MS (EI) m / z: 312 (M +), HRMS (EI): C 17 H 17 N 3 O 3 (M +): calcd 312.1343, found 312.1350.

4- (5- (3,4- Diethoxyphenyl )-4 H -1,2,4- Triazole Yl) pyridine

A cold 4M HCl in dioxane (31.5 mmol, 8.87 mL) was added to a stirred solution of 3,4-diethoxybenzonitrile (7.84 mmol, 1.5 g) in anhydrous MeOH (23.53 mmol, 954 uL) and anhydrous ether Solution. The reaction was stirred at 0 < 0 > C for 1 hour and then placed in a refrigerator (0-5 [deg.] C) for 48 hours. The mixture was purged with H ₂ by injection of N ₂ . And concentrated under reduced pressure. Anhydrous ether was added to the crude product and the methyl 3,4-diethoxybenzimidate salt precipitated as a pale orange solid in 63% yield (1.3 g). This product was used without further purification. To a stirred solution of imidine (0.5 mmol, 130 mg) in acetonitrile (freshly liberated from the imidate salt using ₁ M Na ₂ CO ₃ solution and extracted with ether) was added pyridine-4-carbohydrazide (0.55 mmol, mg) was added and the reaction was refluxed for 12 hours. The mixture was concentrated under reduced pressure and the crude product was heated to 180 < 0 > C for 2 hours. The product was purified by column chromatography using CH ₂ Cl ₂ : MeOH (9: 1) to give the product as a white solid in 65% yield (100 mg, 0.32 mmol). ^{1 H NMR (400 MHz, CDCl} 3): δ 8.71 (bs, 2H), 8.11 (d, J = 5.2 Hz, 2H), 7.60 (s, 1H), 7.57 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 8.4, 1H), 4.11 (q, J = 6.8 Hz, 2H), 4.07 (q, J = 6.8 Hz, 2H), 1.45 (t, J = 7.0 Hz, 3H), 1.40 (t , ≪ / RTI > J = 7.0 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 157.73, 150.89, 149.42, 149.14, 139.66, 121.29, 120.56, 120.06, 119.68, 113.00, 111.53, 64.82, 64.72, 14.90, 14.86. MS (EI) m / z: 311 (M +), HRMS (EI): C 17 H 18 N 4 O 2 (M +): calcd 311.1502, found 311.1506.

4- [5- (4- Phenyl -5- Trifluoromethyl - thiophen-2-yl) - [l, 2,4] Oxadiazole -3-yl] -pyridine

In a round bottom flask, a stirred solution of 3,4-diethoxybenzoic acid (100 mg, 0.3673 mmol) in DMF (1.8 mL) was treated sequentially with HOBt (64 mg, 0.48 mmol) and EDCI (91 mg, 0.48 mmol) . The reaction was stirred for 20 minutes and then N ' -hydroxy isonicotine imidamide (66 mg, 0.48 mmol) was added in one portion. The reaction was stirred again at room temperature for 30 minutes and then heated to 90-95 < 0 > C for 10 hours. The reaction was cooled to room temperature, diluted with a saturated aqueous NaCl solution and then extracted with EtOAc (3 x 50 mL). The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The product was purified by column chromatography using CH ₂ Cl ₂ : MeOH (9: 1) to give the product as a pale yellow solid in 56% yield (78 mg). ^{1 H NMR (300 MHz, CDCl} 3): δ 8.82 (bs, 2H), 8.02 (d, J = 2.7, 2H), 7.93 (q, J = 1.5 Hz, 1H), 7.47 (s, 5H); ^{13 C NMR (75 MHz, CDCl} 3): δ 171.12, 167.81, 150.86, 145.70, 135.09, 134.12, 133.14, 123.32, 129.04, 126.35, 126.33, 121.67, 120.21, 105.04. MS (EI) m / z: 374 (M +), HRMS (EI): C 18 H 10 F 3 N 3 SO (M +): calcd 374.0569, found 374.0579.

6- (5- (3,4- Diethoxyphenyl ) -1,2,4- Oxadiazole -3 days) Indolin -2-one

Hydroxylamine hydrochloride (286 mg, 4.11 mmol) and potassium bicarbonate (411 mg, 4.11 mmol) were carefully added to an ethanol solution of 2-oxoindoline-4-carbonitrile (500 mg, 3.16 mmol). The reaction mixture was refluxed under a nitrogen atmosphere for 20 hours. The mixture was cooled to room temperature and the solid was filtered. The organic solvent was concentrated under reduced pressure and N ' -hydroxyimidamide was used in the next step without further purification.

EDCI (87 mg, 0.45 mmol) and HOBt (62 mg, 0.45 mmol) were added to a stirred solution of 3,4-diethoxybenzoic acid (73 mg, 0.35 mmol) in 1,4-dioxane and the reaction was stirred at 20 Lt; / RTI > To the reaction was added N ' -hydroxy imidamide (87 mg, 0.45 mmol) and the mixture was stirred at room temperature for 30 minutes and then at 16O < 0 > C for 16 hours. The reaction was concentrated under reduced pressure, diluted with EtOAc (80 mL) and then rinsed with brine (2X30 mL). The organic layer was dried on Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by column chromatography using CH ₂ Cl ₂ : MeOH (9: 1) to give the product as a pale yellow solid in 50% yield (64 mg, 0.175 mmol). MS (EI) m / z : 366 (M ^< ^{+ &} gt ^; ).

5- (3,4- Diethoxyphenyl ) -3- (lH-pyrrolo [2,3-b] pyridin-4-yl) Oxadiazole

Hydroxylamine hydrochloride (632 mg, 9.1 mmol) and sodium carbonate (964 mg, 9.1 mmol) were carefully added to a solution of 4-cyano, -7-azaindole (1 g, 7 mmol) in methanol (30 mL) Respectively. The reaction mixture was refluxed under a nitrogen atmosphere for 6 hours, and hydroxylamine hydrochloride (632 mg, 9.1 mmol) and sodium carbonate (964 mg, 9.1 mmol) were added. The reaction was refluxed for another 14 hours. The mixture was cooled to room temperature and the solid was filtered. The organic solvent was concentrated under reduced pressure, and the crude product was recrystallized from ethanol to obtain 200 mg of N' -hydroxyimidamide.

EDCI (59 mg, 0.31 mmol) and HOBt (41 mg, 0.31 mmol) were added to a stirred solution of 3,4-diethoxybenzoic acid (50 mg, 0.24 mmol) in DMF and the reaction was stirred at room temperature for 20 minutes. To this reaction was added N ' -hydroxyimidamide (54 mg, 0.31 mmol) and the mixture was stirred at room temperature for 30 minutes and then at 16O < 0 > C for 16 hours. The reaction was concentrated under reduced pressure, diluted with EtOAc (80 ml), and then rinsed with a saturated aqueous NaHCO ₃ solution (2 × 30 ml) and brine (50 ml). The organic phase was dried over Na ₂ SO _4, and concentrated under reduced pressure. The crude product was purified by column chromatography using CH ₂ Cl ₂ : MeOH (9: 1) to give the product as a brown solid in 5% yield (4 mg, 0.01 mmol). MS (EI) m / z : 351 (M ^< ^{+ &} gt ^; ).

3- (lH-Indol-5-yl) -5- (4- Phenyl -5- ( Trifluoromethyl ) Thiophen-2-yl) -1,2,4- Oxadiazole

To a solution of 1 H -indole e-5-carbonitrile (2 g, 14.06 mmol) in ethanol under reflux was added hydroxylamine hydrochloride (4.88 g, 70.3 mmol) and potassium bicarbonate (7.04 g, 70.3 mmol) mmol) were added and the reaction was refluxed for 16 hours. The mixture was cooled to room temperature and the solid was filtered. The organic solvent was concentrated under reduced pressure and N ' -hydroxyimidamide was used in the next step without further purification.

EDCI (125 mg, 0.65 mmol) and HOBt (88 mg, 0.65 mmol) were added to a solution of phenyl-5- (trifluoromethyl) -2-thiophenecarboxylic acid in 1,4-dioxane under a nitrogen atmosphere. The reaction was stirred at room temperature for 30 minutes and then N' -hydroxyimidamide (114 mg, 0.65 mmol) was added and the reaction was stirred at room temperature for 30 minutes and then at 16O < 0 > C for 15 hours. The reaction was concentrated under reduced pressure. The crude product was diluted with EtOAc (80 mL) and rinsed with NaHCO ₃ (2X50 mL). The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The product was purified by column chromatography using CH ₂ Cl ₂ : MeOH (9: 1) to give 91 mg (46.7%) of the product. MS (EI) m / z : 412 (M ^< ^{+ &} gt ^; ).

3- ( Indolin -5-yl) -5- (4- Phenyl -5- ( Trifluoromethyl ) Thiophen-2-yl) -1,2,4- Oxadiazole

(4-phenyl-5- (trifluoromethyl) thiophen-2-yl) -1,2,4-oxa To a stirred solution of the diazole (40 mg, 0.097 mmol) was slowly added sodium cyano, borohydride (19 mg, 0.29 mmol). After the addition, the reaction was warmed to 18-20 ° C and then stirred for 2 hours. After the reaction was completed, the mixture was neutralized with 50% sodium hydroxide and extracted with ethyl acetate (50 ml X2). The organic layers were combined, dried over Na ₂ SO ₄ and then removed under reduced pressure. The crude indolinoline compound was purified by column chromatography using CH ₂ Cl ₂ / MeOH (9: 1) to give the product in 84.3% yield (33.8 mg, 0.082 mmol). MS (EI) m / z : 414 (M ^< ^{+ &} gt ^; ).

3- (3- Methyl pyridine Yl) -5- (4- Phenyl -5- ( Trifluoromethyl ) Thiophen-2-yl) -1,2,4- Oxadiazole

Hydroxylamine hydrochloride (23.53 g, 339 mmol) was dissolved in water (120 ml) and potassium bicarbonate (33.9 g, 3339 mmol) was carefully added. The mixture was stirred slowly until it was completely dissolved. The mixture was added to a solution of 3-methylisonicotinonitrile (2 g, 16.9 mmol) in THF (30 mL) at -25 ° C (cold methanol bath) and the reaction stirred at room temperature for 16 hours. The reaction mixture was extracted with EtOAc (3 x 100 mL) and the combined organic phases were rinsed with brine (80 mL). The organic phase was dried over Na ₂ SO _4, and concentrated under reduced pressure. The product was purified by column chromatography using hexane / EtOAc (1: 1) to give N' -hydroxyimidamide in 47% yield (1.2 g).

To a solution of 4-phenyl-5- (trifluoromethyl) -2-thiophenecarboxylic acid (200 mg, 0.735 mmol) in DMF was added EDCI (183 mg, 0.95 mmol) and HOBt (129 mg, 0.95 mmol) Respectively. The reaction was stirred at room temperature for 30 minutes, then N' -hydroxyimidamide (143 mg, 0.95 mmol) was added and the reaction was stirred at room temperature for 30 minutes and then at 16O < 0 > C for 16 hours. The reaction was concentrated under reduced pressure. Diluting the crude product in EtOAc (80mL), and rinsed with NaHCO ₃ (2X50ml) saturated solution. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The product was purified by column chromatography using CH ₂ Cl ₂ : MeOH (9: 1) to give 161 mg (56.6%) of product. MS (EI) m / z : 412 (M ^< ^{+ &} gt ^; ).

4- (5- (3,4- Diethoxyphenyl ) -1,2,4- Oxadiazole Yl) -2,3- Dihydro -1H- Inden -1-ol

From 0 ℃, ethanol (30mL) solution of l-oxo-2,3-dihydro -1 H - inden-4-carbonitrile To a stirred suspension of (5g, 31.8mmol) and silica gel _{(100mg), NaBH 4 (400mg} , 10.6 mmol). The reaction was warmed to room temperature and stirred for 2 hours. To remove the solvent under reduced pressure, and product hexanes / EtOAc (5: 5) was purified by column chromatography using, as a white solid, 1-hydroxy-2,3-dihydro -1 H - inden-4-carbonitrile The nitrile was obtained in 80% yield (4.04 g, 25.4 mmol). ^{1 H NMR (300 MHz, CDCl} 3): δ 7.62 (d, J = 7.5 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 5.28 ( t, J = 6.3 Hz, 1H), 3.28-3.18 (m, 1H), 3.02-2.92 (m, 1H), 2.63-2.52 (m, 1H), 2.06-1.99 (m, 1H).

Ethanol (100 mL) of 1-hydroxy-2,3-dihydro -1 H - inden-4-carbonitrile (3g, 18.86 mmol) hydroxylamine hydrochloride To a stirred solution, under reflux slowly over 16 hours ( 6.55 g, 94.3 mmol) and potassium carbonate (13.03 g, 94.3 mmol) were added in equal amounts. The mixture was cooled to room temperature and the solid was filtered. The organic solvent was concentrated under reduced pressure and the crude product was recrystallized from ethanol to give 2.5 g (69%) amidoxime.

In a microwave vial, HOBt (168 mg, 1.24 mmol) and EDCI (237 mg, 1.24 mmol) were treated at room temperature to a stirred solution of 3,4-diethoxybenzoic acid (200 mg, 0.95 mmol) in DMF. The reaction was stirred for 20 min and amidocin (238 mg, 1.24 mmol) was added in one portion. The reaction was stirred at room temperature for another 30 minutes and then heated at 130 占 폚 for 35 minutes in an open period. The reaction was diluted with a saturated aqueous NaCl solution and extracted with EtOAc (3 x 80 mL). The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The product was purified by column chromatography using CH ₂ Cl ₂ : MeOH (9: 1) to give the product as a white solid in 69% yield (208 mg). ^{1 H NMR (400 MHz, CDCl} 3): δ 8.10 (d, J = 7.6, 1H), 7.78 (dd, J1 = 1.6 Hz, J2 = 8 Hz , 1H), 7.67 (d, J = 1.6 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 6.97 ( d, J = 8.0 Hz, 1H ), 5.29 (t, J = 6.4 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H), 4.18 (q, J = 7.2 Hz, 2H), 3.51-4.43 ( J = 7.2 Hz, 3H), 1.49 (t, J = 7.6 Hz, 1H) 7.2, 3H); ^{13 C NMR (100 MHz, CDCl} 3): δ 175.2, 168.9, 152.8, 148.9, 146.6, 143.3, 128.9, 127.4, 127.0, 123.8, 122.2, 116.7, 112.7, 112.4, 76.2, 64.9, 64.8, 35.7, 31.5, 14.9, 14.8. MS (EI) m / z 367 (M ⁺ ), HRMS (EI): C ₂₁ H ₂₂ N ₂ O ₄ (M ⁺ ): calculated 367.1652, found 367.1653.

N1 - ((4- (5- (3,4- Diethoxyphenyl ) -1,2,4- Oxadiazole Yl) pyridin-2-yl) methyl ) - N2 , N2 - Diethylethane -1,2- Diamine

To a stirred suspension of 2- (hydroxymethyl) isonicotinonitrile (570 mg, 4.25 mmol) in ethanol (40 mL) was added carefully hydroxylamine hydrochloride (1.37 g, 21.25 mmol) and sodium carbonate (2.25 g, 21.25 mmol) was added in an equal amount. The mixture was cooled to room temperature and the solid was filtered. The organic solvent was concentrated under reduced pressure, and the crude product was recrystallized from ethanol to obtain 600 mg (3.59 mmol, 84%) of amidoxime.

In a microwave vial, a stirred solution of 3,4-diethoxybenzoic acid (300 mg, 1.43 mmol) in DMF was treated with HOBt (250 mg, 1.85 mmol) and EDCI (354 mg, 1.85 mmol) at room temperature. The reaction was stirred for 20 min and then amidocin (309 mg, 1.85 mmol) was added in one portion. The reaction was stirred at room temperature for another 30 minutes and then heated to 130 < 0 > C for 35 minutes in the open phase. The reaction was diluted with a saturated aqueous NaCl solution and then extracted with EtOAc (3 x 80 mL). The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The product was purified by column chromatography using CH ₂ Cl ₂ : MeOH (9: 1) to give (4- (5- (3,4-diethoxyphenyl) -1,2,4- oxadiazole Yl) pyridin-2-yl) methanol was obtained in 71% yield (350 mg). ^{1 H NMR (400 MHz, CDCl} 3): δ 8.65 (d, J = 4.8 Hz, 1H), 8.00 (s, 1H), 7.86 (d, J = 4.8 Hz, 1H), 7.70 (dd, J1 = 2.0 Hz, J2 = 8.8 Hz, 1H ), 7.59 (d, J = 2.0, 1H), 6.91 (d, J = 8.8 Hz, 1H), 4.85 (s, 2H), 4.16 (q, J = 7.2 Hz, 2H ), 4.13 (q, J = 7.2 Hz, 2H), 1.49 (t, J = 6.8 Hz, 3H), 1.46 (t, J = 6.8 Hz, 3H); ¹³ C NMR (100 MHz CDCl ₃ ): δ 176.54, 167.22, 153.03, 149.36, 148.91, 135.50, 122.23, 120.11, 118.48, 116.05, 112.48, 112.17, 64.90, 64.50, 14.82, 14.73. MS (EI) m / z: 342 (M +), HRMS (EI): C 18 H 19 N 3 O4

To a stirred solution of pyridine (20 mg, 0.059 mmol) in DMSO (1 ml) was added N, N'-dicyclohexylcarbodiimide (36.3 mg, 0.176 mmol) and 1.0 M anhydrous H ₃ PO ₄ in DMSO , 0.03 mmol) sequentially, and the reaction mixture was stirred at room temperature for 2 hours. Precipitated dicyclohexylurea was separated by filtration and rinsed with ether (10 ml) and water (10 ml). The aqueous layer was extracted with ether (3 x 20 ml) and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography using CH ₂ Cl ₂ : MeOH (95: 5) to give 15 mg (75%) of pyridine carboxaldehyde. MS (EI) m / z 340 (M ^< ^{+ &} gt ^; ).

Dichloroethane in pyridine carboxaldehyde (15mg, 0.044mmol) was added to, N ^1, N ¹ - diethyl ethane-1,2-diamine (19㎕, 0.13mmol) and sodium triazole hydride (11mg in setok time signal, 0.05 mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours. The mixture was poured into silica gel and purified by column chromatography using CH ₂ Cl ₂ : MeOH: Et ₃ N (90: 9.8: 0.2) to give 8 mg (42%) of the product as a brown solid. MS (EI) m / z 440 (M ^< ^{+ &} gt ^; ).

2- (4- (5- (3,4- Diethoxyphenyl ) -1,2,4- Oxadiazole -3 days) Indolin -1-yl) ethanol

HOBt (330 mg, 2.5 mmol) and EDCI (474 mg, 2.5 mmol) were successively added to a stirred solution of 3,4-diethoxybenzoic acid (400 mg, 1.9 mmol) in DMF at room temperature. The reaction was stirred for 20 minutes and then, N '- hydroxy -1 H - indole-4-carboxamide, imidazole imide (666mg, 3.8mmol) was added in one portion. The reaction was stirred again at room temperature for 30 minutes and then heated to 90-95 [deg.] C for 14 hours. Reaction was cooled to room temperature and then diluted with, Na ₂ CO ₃ saturated aqueous solution and extracted with EtOAc (100ml X3). The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The product was purified by column chromatography using CH ₂ Cl ₂ : MeOH (9: 1) to give compound 110 in 50% yield (331 mg). ^{H 1 NMR (400 MHz, CDCl} 3): δ 8.01 (d, J = 7.2 Hz, 1H), 7.81 (dd, J1 = 2.0 Hz, J2 = 8.4 Hz, 1H), 7.52 (s, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.34 (s, 1H), 7.28 (t, J = 8.0 Hz, 1H), 7.23 (s, 1H ), 6.96 (d, J = 8.4 Hz, 1H), 4.18 (q, J = 6.8 Hz, 2H), 4.16 (q, J = 6.8 Hz, 2H), 1.47 (t, J = 6.8 Hz, 3H), 1.46 (t, J = 6.8 Hz, 3 H); ^{13 C NMR (100 MHz, CDCl} 3): δ 175.0, 169.5, 152.6, 148.9 (2), 125.7, 122.2, 121.8, 121.7, 121.3, 121.2, 117.0, 114.4, 114.3, 112.7, 112.5, 64.97, 64.76, 14.86 , 14.78. MS (EI) m / z 350 (M +), HRMS (EI): C 20 H 19 N 3 0 3 (M ^< ⁺ & gt ^; ): calculated 350.1499, found 350.1504.

To a stirred solution of the previous stage product 110 (260 mg, 0.74 mmol) in acetic acid was slowly added sodium cyanoborohydride (140 mg, 2.25 mmol) at 10-15 < 0 > C. The reaction was warmed to 18-20 < 0 > C and then stirred for 2 hours. After the reaction was completed, the mixture was neutralized with 50% sodium hydroxide and then extracted with ethyl acetate (100 ml X2). By combining the organic layer was removed under reduced pressure and then dried over Na ₂ SO _4. The crude indolinone compound was purified by column chromatography using CH ₂ Cl ₂ / MeOH (9: 1) to give the dihydro compound in 80.5% yield (211 mg, 0.60 mmol). ^{1 H NMR (300 MHz, CDCl} 3): δ 7.78 (dd, J1 = 2.1 Hz, J2 = 8.4 Hz, 1H), 7.68 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 6.97 (d, J = 7.5 Hz, 1H), 6.76 (d, J = 7.5 Hz, 1H), 4.21 (q, J = 6.9 Hz, 2H) , 4.16 (q, J = 6.9 Hz, 2H), 3.65 (bs, 2H), 3.46 (t, J = 8.1 Hz, 2H), 1.52 (t, J = 3.1 Hz, 3H), 1.48 (t, J = 3.3 Hz, 3H); ^{13 C NMR (75 MHz, CDCl} 3): δ 175.05, 169.06, 152.62, 148.84, 127.84, 123.67, 122.09, 118.90, 116.83, 112.53, 112.32, 111.60, 64.86, 64.67, 47.29, 31.41, 14.85, 14.78. MS (EI) m / z 352 (M +), HRMS (EI): C 20 H 21 N 3 O 3 (M +): calcd 352.1656, found 352.1660.

Potassium carbonate (118 mg, 0.85 mmol) and 2-bromoethanol (20 [mu] l, 0.28 mmol) were added to a stirred solution of the dihydro product prepared in the previous step in DMF (3 ml) (50 mg, 0.14 mmol). The reaction was stirred at 60 占 폚 for 48 hours. At the end of the reaction, the solution was poured into water (50ml) and the mixture was extracted with EtOAc (3x50ml). The organic phases were combined, rinsed with water, then dried over sodium sulfate and concentrated under reduced pressure. The product was purified by column chromatography using CH ₂ Cl ₂ : MeOH (9: 1) to give 35 mg (63%) of the product as a brown solid. ^{1 H NMR (300 MHz, CDCl} 3) δ: 7.74 (dd, J1 = 1.8 Hz, J2 = 8.4 Hz, 1H), 7.61 (d, J = 2.1 Hz, 1H), 7.33 (dd, J1 = 0.6 Hz, J2 = 7.8 Hz, 1H), 7.20 (t, J = 5.1 Hz, 1H), 7.17 (d, J = 1.8 Hz, 1H), 6.70 (d, J = 8.1 Hz, 1H), 4.14 (q, J = 7.2 Hz, 4H), 3.62 ( t, J = 6.0 Hz, 2H), 3.55 (t, J = 8.7 Hz, 2H), 3.28 (t, J = 8.1 Hz, 2H), 3.21 (t, J = 6.0 Hz , 2H), 1.39 (t, J = 1.8 Hz, 3H), 1.35 (t, J = 1.5 Hz, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ):? 168.67, 158.97,158.46,153.35,152.73,148.72,129.76,128.39,122.19,117.36,115.89,113.54,113.38,119.94,64.48,64.43,58.90,53.20,51.46, 29.99, 15.00, 14.90. MS (EI) m / z 396 (M +), HRMS (EI): C 22 H 25 N 3 O 4 (M +): calcd 396.1918, found 396.1918.

2- (4- (5- (3,4- Diethoxyphenyl ) -1,2,4- Oxadiazole Yl) -2,3- Dihydro -1H- Inden -One- Amino )ethanol

To a stirred solution of 215 (400 mg, 1.09 mmol) in CH ₂ Cl ₂ was added pyridine (89 μl, 1.1 mmol) and thionyl chloride (81 μl, 1.1 mmol) at 0 ° C., The mixture was stirred under reduced pressure. The crude product was diluted in DMF (10 ml), potassium carbonate (290 mg, 2.1 mmol) and ethanolamine (128 [mu] l, 2.1 mmol) were added and the reaction was stirred at 60 [deg.] C overnight. The reaction mixture was poured into water (100ml) and extracted with EtOAc (100ml X3). The organic phase was dried over Na ₂ SO _4, and concentrated under reduced pressure. The crude product was purified by column chromatography using CH ₂ Cl ₂ : MeOH (9: 1) to give 312 mg (70% yield) of the product as a white solid. ^{1 H NMR (500 MHz, CDCl} 3): δ 8.12 (d, J = 7.5 Hz, 1H), 7.79 (dd, J1 = 2.0 Hz J2 = 8.5 Hz, 1 H), 7.68 (d, J = 2.0 Hz, 1 H), 7.63 (d, J = 7.5 Hz, 1 H), 7.40-7.37 4H), 2.56-2.50 (m, 4H), 3.78-3.70 (m, 1H), 3.53-3.46 1H), 2.09-2.03 (m, 1H), 1.52-1.49 (m, 6H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 175.03, 168.66, 152.71, 148.87, 143.76, 128.71, 127.11, 123.89, 122.04, 116.67, 112.63, 112.49, 104.66, 64.84, 64.61, 62.70, 60.34, 47.98, 29.69, 14.72, 14.64. MS (EI) m / z 410 (M ⁺ ), HRMS (EI): C ₂₃ H ₂₇ N ₃ O ₄ (M ⁺ ): calculated 410.2074, found 410.2077.

N1 - (4- (5- (3,4- Diethoxyphenyl ) -1,2,4- Oxadiazole Yl) -2,3- Dihydro -1H- Inden -1-yl) -N2, N2-di on Lt; RTI ID = 0.0 & Diamine

To a stirred solution of 215 (40 mg, 0.109 mmol) in CH ₂ Cl ₂ was added pyridine (9 μl, 1.1 mmol) and thionyl chloride (8 μl, 1.1 mmol) at 0 ° C. and the reaction was stirred at room temperature for 1 hour And concentrated under reduced pressure. The crude product was diluted in DMF (1 ml) and potassium carbonate (29 mg, 0.21 mmol) and N, N-diethylethylenediamine (30 [mu] l, 0.21 mmol) were added. The reaction was stirred at 60 < 0 > C overnight. The reaction mixture was poured into water (100ml) and extracted with EtOAc (20ml X3). The organic phase was dried over Na ₂ CO _3, and concentrated under reduced pressure. The crude product was purified by column chromatography using CH ₂ Cl ₂ : MeOH (9: 1) to give 65% (33 mg) of the product as a brown solid. MS (EI) m / z 465 (M ^< ^{+ &} gt ^; ).

3- (1H- Benzo [d] imidazole -5-yl) -5- (4- Phenyl -5- ( Trifluoromethyl ) Thiophen-2-yl) -1,2,4- Oxadiazole

In a microwave vial, HOBt (64 mg, 0.48 mmol) and EDCI (92 mg, 0.48 mmol) were treated at room temperature to a stirred solution of 3,4-diethoxybenzoic acid (100 mg, 0.367 mmol) in DMF. The reaction was stirred for 20 minutes and then N'-hydroxy-1H-benzo [d] imidazole-4-carboximidamide (68 mg, 0.367 mmol) was added in one portion. The reaction was stirred at room temperature for 30 minutes and then heated to 130 < 0 > C for 35 minutes in the open phase. The reaction was diluted with a saturated aqueous NaHCO ₃ solution and extracted with EtOAc (3 x 80 mL). The organic phase was dried in 0Na ₂ SO ₄ anhydride and concentrated under reduced pressure. The crude product was purified by column chromatography using CH ₂ Cl ₂ : MeOH (9: 1) to give the product of 40% yield (61 mg) as a brown solid. MS (EI) m / z 413 (M ^< ^{+ &} gt ^; ).

3- (3,4- Diethoxyphenyl ) -5- (pyridin-4-yl) -1,2,4- Oxadiazole

In a microwave vial, HOBt (319 mg, 2.43 mmol) and EDCI (467 mg, 2.43 mmol) were added at room temperature to a stirred solution of isonicotinic acid (200 mg, 1.62 mmol) in DMF. The reaction was stirred for 20 minutes and ( Z ) -3,4-diethoxy- N ' -hydroxybenzimidamide (436 mg, 1.94 mmol) was added in one go. The reaction was stirred at room temperature for 30 minutes and then heated to 130 < 0 > C for 35 minutes at initiation. The reaction was diluted with aqueous NaHCO ₃ solution and extracted with EtOAc (80 mL X3). The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The product was purified by column chromatography using CH ₂ Cl ₂ : MeOH (95: 5) to give the product as a light brown solid in 26% yield (131 mg). ^{1 H NMR (300 MHz, CDCl} 3): δ 8.85 (d, J = 5.4 Hz , 2H), 8.02 (d, J = 6.0 Hz, 2H), 7.71 (dd, J1 = 1.8 Hz, J2 = 8.1 Hz, 1H), 7.62 (d, J = 2.1 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 4.19 (q, J = 6.9 Hz, 2H), 4.14 (q, J = 6.9 Hz, 2H), 1.50 (t, J = 3.0 Hz, 3H), 1.46 (t, J = 3.3 Hz, 3H); ^{13 C NMR (75 MHz, CDCl} 3): δ 173.54, 16928, 151.64, 151.07, 148.91, 131.37, 121.48, 121.15, 118.75, 112.74, 111.82, 64.78, 64.59, 14.87, 14.81. MS (EI) m / z: 312 (M +), HRMS (EI): C 17 H 17 N 3 O 3 (M +): calcd 312.1343, found 312.1348.

2- (3,4- Diethoxyphenyl ) -4- (pyridin-4-yl) Oxazole

(134mg, 0.478mmol) and 3,4-diethoxybenzamide (100mg, 0.478mmol) in DMF (5ml) were added to a solution of 2- And the reaction was heated to 170 < 0 > C for 40 minutes. The reaction mixture was poured into a saturated aqueous NaHCO ₃ solution and extracted with EtOAc (50 mL X3). The organic phases were combined, rinsed with a saturated aqueous solution of NaCl (2 * 30 ml) and concentrated under reduced pressure. The product was purified by column chromatography using CH ₂ Cl ₂ : MeOH (95: 5) to give 4 mg (2.7%) of the product. MS (EI) m / z : 311 (M ^< ^{+ &} gt ^; ).

2- (3,4- Diethoxyphenyl )-4- Phenyloxazole

After dissolving 2-bromo-1-phenylethanone (95 mg, 0.478 mmol) and 3,4-diethoxybenzamide (100 mg, 0.478 mmol) in DMF (5 ml) in a microwave vial, Gt; 170 C < / RTI > The reaction mixture was poured into a saturated aqueous NaHCO ₃ solution and extracted with EtOAc (50 mL X3). The organic phases were combined, rinsed with a saturated aqueous solution of NaCl (30 ml X 2) and concentrated under reduced pressure. The product was purified by column chromatography using CH ₂ Cl ₂ : MeOH (95: 5) to give the product in a yield of 25 mg (17%). MS (EI) m / z : 310 (M < ^{+ &} gt ^; ).

4- (5- (4- Isopropoxy -3- ( Trifluoromethyl ) Phenyl ) -1,2,4- Oxadiazole Yl) -2,3- Dihydro -1H- Inden -1-ol

In a microwave vial, HOBt (495 mg, 3.67 mmol) and EDCI (702 mg, 3.67 mmol) were added to a stirred solution of 4-isopropoxy-3- (trifluoromethyl) benzoic acid (700 mg, 2.82 mmol) in DMF Was added at room temperature. The reaction was stirred for 20 minutes and then, at a time N ', 1- dihydroxy-2,3-dihydro -1 H - inden-4-carboxamide, the already imide (650mg, 3.38mmol) was added. The reaction was stirred again at room temperature for 30 minutes and then heated to 130 < 0 > C for 35 minutes at initiation. The reaction was diluted with a saturated aqueous NaCl solution and extracted with EtOAc (100 mL X3). The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The product was purified by column chromatography using CH ₂ Cl ₂ : MeOH (9: 1) to give the product as a white solid in 68% yield (780 mg). ^{1 H NMR (300 MHz, CDCl} 3 -CH 3 OD): δ 8.38 (d, J = 1.8 Hz , 1H), 8.28 (dd, J1 = 2.4 Hz, J2 = 8.7 Hz, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 7.5 1H) , 7.7.37 (t, J = 7.5 Hz, 1H), 7.11 (dd, J1 = 2.4 Hz, J2 = 9.0 Hz, 1H), 5.24 (t, J = 6.3 Hz, 1H), 4.20 (q, J = 6.9 Hz, 1H), 3.48-3.40 ( m, 1H), 3.19-3.09 (m, 1H), 2.57-2.46 (m, 1H), 2.04-1.92 (m, 1H), 1.46 (t, J = 6.9 Hz , ≪ / RTI > 3H), 1.39 (d, J = 6.0 Hz, 3H); ¹³ C NMR (75 MHz, CDCl ₃ -CH ₃ OD): δ 169.05, 158.85, 146.82, 143.33, 133.55, 128.79, 127.41, 127.22, 116.23, 113.38, 104.88, 65.27, 35.55, 31.44, 21.87, 14.55. MS (EI) m / z 405 (M +), HRMS (EI): C 21 H 19 N 2 O 3 (M +): calcd 405.1420, found 405.1424.

4- (5- (4- Ethoxy -3- ( Trifluoromethyl ) Phenyl ) -1,2,4- Oxadiazole Yl) -2,3- Dihydro -1H-inden-l-ol

HOBt (151 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were added to a stirred solution of 4-ethoxy-3- (trifluoromethyl) benzoic acid (200 mg, 0.85 mmol) in DMF . The reaction was stirred for 20 minutes and then, at a time N ', 1- dihydroxy-2,3-dihydro -1 H - inden-4-carboxamide, the already imide (213mg, 1.11mmol) was added. The reaction was stirred again at room temperature for 30 minutes and then heated to 130 < 0 > C for 35 minutes at initiation. The reaction was diluted with a saturated aqueous NaCl solution and extracted with EtOAc (80 mLX3). The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The product was purified by column chromatography using CH ₂ Cl ₂ : MeOH (9: 1) to give the product as a white solid in 51% yield (200 mg).

^{1 H NMR (300 MHz, CDCl} 3 -CH 3 OD): δ 8.27 (d, J = 1.8 Hz , 1H), 8.21 (dd, J1 = 2.1 Hz, J2 = 8.7 Hz, 1H), 7.94 (d, J = 7.5 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.26 (q, J = 9.9 Hz, 1H), 7.05 (d, J = 8.7 Hz, 1H), 5.13 (t, J = 6.3 Hz, 1H), 4.11 (q, J = 6.9 Hz, 2H) , 3.38-3.28 (m, 1H), 3.08-2.97 (m, 1H), 2.44-2.34 (m, 1H), 1.91-1.84 (m, 1H), 1.35 (t, J = 6.9 Hz, 3H); ^{13 C NMR (75 MHz, CDCl} 3 -CH 3 OD): δ 150.90, 147.26, 143.96, 137.60, 137.59, 132.62, 132.59, 131.31, 131.27, 131.24, 127.21, 120.11, 117.48, 104.99, 79.55, 69.27, 39.27, 35.35, 18.39. MS (EI) m / z 391 (M ⁺ ), HRMS (EI): C ₂₀ H ₁₇ F ₃ N ₂ O ₃ (M ⁺ ): calculated 391.1264, found 391.1261.

4- (5- (4- Isopropoxy -3- ( Trifluoromethyl ) Phenyl ) -1,2,4- Oxadiazole Yl) -2,3- Dihydro -1H- Inden -1-ol

HOBt (172 mg, 1.26 mmol) and EDCI (242 mg, 1.26 mmol) were added to a stirred solution of 4-ethoxy-3- (trifluoromethyl) benzoic acid (200 mg, 0.97 mmol) in DMF Respectively. The reaction was stirred for 20 minutes and then, at a time N ', 1- dihydroxy-2,3-dihydro -1 H - inden-4-carboxamide, the already imide (243mg, 1.26mmol) was added. The reaction was stirred again at room temperature for 30 minutes and then heated at 130 < 0 > C for 35 minutes in the open phase. The reaction was diluted with a saturated aqueous NaCl solution and extracted with EtOAc (80 mL X3). The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The product was purified by column chromatography using CH ₂ Cl ₂ : MeOH (9: 1) to give the product as a pale yellow solid in 63% yield (229 mg).

^{1 H NMR (300 MHz, CDCl} 3 -CH 3 OD): δ 8.36 (d, J = 2.1 Hz, 1H), 8.29 (dd, J1 = 2.4 Hz, J2 = 9.0 Hz, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 7.5 Hz, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1H), 5.26 (t, J = 6.3 1H), 2.04-1.95 (m, 1 H), 3.48-3.38 (m, 1.45 (d, J = 6.3 Hz, 6 H); ^{13 C NMR (75 MHz, CDCl} 3 -CH 3 OD): δ 173.11, 168.95, 162.82, 146.70, 143.26, 134.15, 134.041, 128.27, 127.30, 127.18, 123.18, 116.85, 115.41, 113.66, 103.86, 72.85, 35.57, 31.42, 21.82. MS (EI) m / z 362 (M +), HRMS (EI): C 21 H 19 N 3 O 3 (M +): calcd 362.1499, found 362.1494.

2- Ethoxy -5- (3- (1- Hydroxy -2,3- Dihydro -1H- Inden Yl) -1,2,4- Oxadiazole -5 days) Benzonitrile

In a microwave vial, HOBt (185 mg, 1.36 mmol) and EDCI (260 mg, 1.36 mmol) were treated at room temperature to a stirred solution of 3-cyano-4-ethoxybenzoic acid (200 mg, 1.05 mmol) in DMF. The reaction was stirred for 20 minutes and then, at a time N ', 1- dihydroxy-2,3-dihydro -1 H - inden-4-carboxamide, the already imide (261mg, 1.36mmol) was added. The reaction was stirred again at room temperature for 30 minutes and then heated to 130 < 0 > C for 35 minutes at initiation. The reaction was diluted with a saturated aqueous NaCl solution and extracted with EtOAc (80 mL X3). The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The product was purified by column chromatography using CH ₂ Cl ₂ : MeOH (9: 1) to give the product as a pale yellow solid in 79% yield (274 mg).

^{1 H NMR (300 MHz, CDCl} 3 -CH 3 OD): δ J = 7.5 Hz, 1H), 7.46 (d, J = 7.5 Hz, 1H), 8.31 (d, J = 2.1 Hz, 1H), 8.25 (dd, J1 = 2.1 Hz, J2 = 8.7 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.06 (d, J = 9.0 Hz, 1H), 5.16 (t, J = 6.0 Hz, 1H), 4.18 (q, J = 6.9 Hz, 2H) , 3.40-3.30 (m, 1H), 3.10-2.93 (m, 1H), 2.46-2.39 (m, 1H), 1.94-1.87 (m, 1H), 1.43 (t, J = 6.9 Hz, 3H); ^{13 C NMR (75 MHz, CDCl} 3 -CH 3 OD): δ 172.91, 167.05, 161.92, 145.72, 142.08, 133.24, 132.83, 127.38, 126.16, 126.10, 121.85, 115.98, 111.76, 101.85, 74.36, 64.55, 34.08, 30.18, 13.20. MS (EI) m / z 348 (M ⁺ ), HRMS (EI): C ₂₃ H ₂₇ N ₃ O ₃ (M ⁺ ): calculated 348.1343, found 348.1345.

2- (4- (5- (4- Isopropoxy -3- ( Trifluoromethyl ) Phenyl ) -1,2,4- Oxadiazole Yl) -2,3- Dihydro -1H- Inden -One- Amino )ethanol

To a stirred solution of 259 (75 mg, 0.185 mmol) in CH ₂ Cl ₂ was added pyridine (15 μL, 0.195 mmol) and thionyl chloride (14 μL, 0.195 mmol) at 0 ° C. The reaction was quenched at room temperature for 1 hour Stirred, and concentrated under reduced pressure. The crude product was diluted with DMF (1 ml) and DIPEA (161 [mu] l, 0.927 mmol) and ethanolamine (56 [mu] l, 0.927 mmol) were added at 0 [deg.] C. The reaction was stirred at 60 < 0 > C overnight. The reaction mixture was poured into water (100ml) and extracted with ethyl acetate (20ml X3). The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography using CH ₂ Cl ₂ : MeOH (9: 1) to give the product as a brown solid in 40% (18 mg) yield.

^{1 H NMR (300 MHz, CDCl} 3 -CH 3 OD): δ 8.37 (s, 1H), 8.28-8.24 (m, 1H), 8.06 (t, J = 4.8 Hz, 1H), 7.51 (d, J = 6.9 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H ), 7.11 (d, J = 8.4 Hz, 1H), 4.36-4.32 (m, 1H), 4.19 (d, J = 6.9 Hz, 1H), 3.67-3.59 (m, 3H), 3.39-3.34 (m, 2H), 3.23-3.12 (m, 1H ), 2.49-2.43 (m, 1H), 1.97-1.90 (m, 1H), 1.45 (t, J = 6.9 Hz, 3H), 1.38 (d, J = 4.2 Hz , 3H); ^{13 C NMR (75 MHz, CDCl} 3 -CH 3 OD): δ 169.63, 146.26, 144.53, 134.30, 128.97, 127.76, 127.64, 124.09, 116.72, 115.25, 114.30, 103.98, 72.86, 65.91, 63.32, 61.30, 32.74, 32.59, 22.08, 14.76. MS (EI) m / z 448 (M +), HRMS (EI): C 23 H 24 F 3 N 3 O 3 (M +): calcd 448.1842, found 448.1849.

2- (4- (5- (4- Ethoxy -3- ( Trifluoromethyl ) Phenyl ) -1,2,4- Oxadiazole Yl) -2,3-dihydro-1H- Inden -One- Amino )ethanol

To a stirred solution of 260 (154 mg, 0.394 mmol) in CH ₂ Cl ₂ was added pyridine (33 μL, 0.414 mmol) and thionyl chloride (30 μL, 0.414 mmol) at 0 ° C., , And concentrated under reduced pressure. The crude product was diluted in DMF (2 ml) and DIPEA (360 [mu] l, 2.07 mmol) and ethanolamine (125 [mu] l, 2.07 mmol) were added at 0 [deg.] C. The reaction was stirred at 60 < 0 > C. The reaction mixture was poured into water (100ml) and extracted with ethyl acetate (20ml X3). The organic phase was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography using CH ₂ Cl ₂ : MeOH (9: 1) to give the product as a brown solid in 18% yield (31 mg).

^{1 H NMR (300 MHz, CDCl} 3 -CH 3 OD): δ 8.31 (s, 1H), 8.23 (d, J = 8.7 Hz, 1H), 7.99 (d, J = 7.5 Hz, 1H), 7.48 (d, J = 7.2 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.07 (d , J = 8.7 Hz, 1H), 4.33 (t, J = 6.0 Hz, 1H), 4.15 (q, J = 6.9 Hz, 3H), 3.64 (t, J = 4.5 Hz, 2H), 3.41-3.33 (m, 1H), 3.19-3.08 (m, 1H), 2.78 (t, J = 4.8 Hz, 2H) 1.96-1.87 (m, 1H), 1.40 (t, J = 7.2 Hz, 3H); ¹³ C NMR (75 MHz, CDCl ₃ -CH ₃ OD): δ 168.45, 159.91, 144.62, 143.36, 133.04, 128.04, 127.17, 126.73, 126.57, 122.99, 119.63, 115.59, 112.89, 100.08, 64.73, 62.19, 60.09, 48.89, 48.32, 31.63, 31.46, 13.93. MS (EI) m / z 434 (M +), HRMS (EI): C 22 H 22 F 3 N 3 O 3 (M +): calcd 434.1686, found 434.1692.

5- (3- (1- (2- Hydroxyethylamino ) -2,3- Dihydro -1H- Inden Yl) -1,2,4- Oxadiazole -5-yl) -2- Isopropoxybenzonitrile

To a stirred solution of 261 (130 mg, 0.360 mmol) in CH ₂ Cl ₂ was added pyridine (30 μL, 0.378 mmol) and thionyl chloride (27 μL, 0.378 mmol) at 0 ° C. and the reaction was stirred at room temperature Stirred and then concentrated under reduced pressure. The crude product was diluted in DMF (2 mL) and DIPEA (328 L, 1.889 mmol) and ethanolamine (114 L, 1.889 mmol) were added at 0 < 0 > C. The reaction was stirred at 60 < 0 > C overnight. The reaction mixture was poured into water (100ml) and extracted with ethyl acetate (20ml X3). The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography using CH ₂ Cl ₂ : MeOH (9: 1) to give the product as a light brown solid in yield 23% (34 mg).

^{1 H NMR (300 MHz, CDCl} 3 -CH 3 OD): δ 8.33 (d, J = 2.1 Hz, 1 H), 8.26 (dd, J1 = 2.4 Hz, J2 = 9.0 Hz, 1H), 7.99 (d, J = 7.5 (d, J = 7.5 Hz, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.33 (t, J = 7.5 Hz, 1H), 7.07 (d , J = 9.0 Hz, 1H), 4.74 (t, J = 6.0 Hz, 1H), 4.27 (t, J = 6.6 Hz, 1H), 3.62 (q, J = 6.0 Hz, 2H), 3.37-3.32 (m, IH), 3.18-3.10 (m, IH), 2.79 (t, 5.1 Hz, 2H), 2.48-2.37 (d, J = 6.0 Hz, 6H); 13 C NMR (75 MHz, CDCl 3 -CH 3 OD): δ 172.73, 168.58, 162.49, 145.45, 143.33, 133.74, 133.71, 127.85, 126.69, 126.58, 122.81, 116.40, 115.00, 113.31, 103.33, 72.46, 62.30, 60.54, 32.15, 31.51, 21.35. MS (EI) m / z 405 (M +), HRMS (EI): C 23 H 24 N 4 O 3 (M +): calcd 405.1921, found 405.1920.

4- (5- (4- Ethoxy -3-nitro Phenyl ) -1,2,4- Oxadiazole Yl) -2,3- Dihydro -1H- Inden -1-ol

In a microwave vial, HOBt (167 mg, 1.231 mmol) and EDCI (236 mg, 1.231 mmol) were treated at room temperature to a stirred solution of 4-ethoxy-3-nitrobenzoic acid (200 mg, 0.947 mmol) in DMF. The reaction was stirred for 20 minutes and then, at a time N ', 1- dihydroxy-2,3-dihydro -1 H - inden-4-carboxamide, the already imide (200mg, 1.04mmol) was added. The reaction was stirred again at room temperature for 30 minutes and then heated to 130 < 0 > C for 35 minutes at initiation. The reaction was diluted with a saturated aqueous NaCl solution and extracted with EtOAc (80 mL X3). The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The product was purified by column chromatography using CH ₂ Cl ₂ : MeOH (9: 1) to give the product as a pale brown solid in 40% yield (150 mg).

^{1 H NMR (300 MHz, CDCl} 3 -CH 3 OD): δ 8.03 (d, J = 1.2 Hz , 1H), 7.73 (dd, J1 = 1.5 Hz, J2 = 8.7 Hz, 1H), 7.46 (d, J = 7.5 Hz, 1H), 6.97 (d, J = 7.2 Hz, 1H), 6.79 (t, J = 7.5 Hz, 1H), 6.67 (d, J = 8.7 Hz, 1H), 4.65 (t, J = 6.0 Hz, 1H), 3.70 (q, J = 6.9 Hz, 2H) , 2.87-2.79 (m, 1H), 2.60-2.49 (m, 1H), 1.96-1.90 (m, 1H), 1.43-1.36 (m, 1H), 0.91 (t, J = 6.9 Hz, 3H); ^{13 C NMR (75 MHz, CDCl} 3 -CH 3 OD): δ 177.85, 168.55, 156.35, 154.87, 146.33, 142.70, 139.50, 133.09, 128.02, 126.86, 125.14, 122.43, 115.87, 114.54, 74.97, 65.63, 34.68, 30.80, 13.82. MS (EI) m / z 368 (M +), HRMS (EI): C 19 H 17 N 3 O 5 (M +): calcd 368.1241, found 368.1242.

Additional exemplary compounds shown as specific examples of compound No. 1-271 were prepared and evaluated as follows.

Biological data of selected compounds Compound No. tPSA ClogP Ec ₅₀ (S1P ₁ Ag) (nM) _{Ec 50 (S1P 3 Ag) (} nM) One 55.5 3.99 466 [mu] M NA 2 46.3 3.17 6.5 μM NA 3 68.7 1.59 5.9 [mu] M NA 4 58.7 1.86 7.8 [mu] M NA 5 46.3 2.82 4.1 [mu] M 5100 6 46.3 3.35 4.1 [mu] M NA 7 46.3 3.92 270 nM 782 8 55.5 2.33 73 μM NA 9 55.5 3.78 68.4 [mu] M NA 10 55.5 3.10 246 nM 3330 11 74 1.50 6500 NA 12 64.8 2.34 NA NA 14 94.1 5.72 12.3 [mu] M NA 15 115.7 2.13 19.7 [mu] M NA 16 94.1 4.39 3.3 1201 18 132.5 0.42 397 NA 19 115.7 1.47 12 μM NA 20 118.8 -0.65 NA NA 21 106.5 0.84 NA NA 22 106.5 2.13 1028 NA 23 51.1 6.06 3300 3500 24 55.5 2.82 1800 NA 25 71.9 1.24 NA NA 26 96 3.03 NA NA 27 55.5 2.47 NA NA 28 55.5 4.07 477 NA 29 55.5 3.58 576 NA 30 64.8 4.30 1390 NA 31 55.2 3.21 NA NA 32 64.8 3.29 0.15 397 33 64.8 3.30 116 NA 34 64.8 3.09 8.8 5370 35 64.8 3.09 3.7 661 36 90.8 2.85 1.7 387 37 64.8 2.88 NA NA 38 55.5 2.86 938 NA 39 55.5 2.86 418 NA 40 64.8 3.64 621 NA 41 67.9 1.51 7700 NA 42 55.5 2.47 909 NA 43 55.5 3.01 1180 NA 44 55.5 2.83 731 NA 45 55.5 4.30 1480 NA 46 66.9 4.31 544 NA 47 43.2 298.34 31.8 [mu] M NA 48 58.8 3.44 295 NA 49 46.3 3.67 487 NA 50 64.8 2.57 64 2700 51 46.3 4.37 847 NA 52 75.8 2.17 NA NA 53 46.3 5.94 156 327 54 64.8 3.51 71.6 322 55 46.3 4.61 113 448 56 46.3 4.91 83.4 NA 57 61.9 1.49 290 NA 58 64.8 3.59 11.7 3400 59 46.3 5.06 10.8 5600 60 46.3 5.26 One 803 61 72.3 4.82 0.78 1319 62 46.3 5.56 5.0 24 μM 63 46.3 5.06 129 NA 64 55.5 3.05 228 NA 65 81.6 2.61 319 NA 66 55.5 3.35 1990 NA 67 55.5 2.86 95.5 μM NA 68 46.3 3.87 37.7 NA 69 72.3 3.43 197 NA 70 46.3 4.17 7.08 μM NA 71 46.3 3.67 491.8 NA 72 55.5 3.02 84.8 NA 73 81.6 2.58 249 NA 74 55.5 3.32 601 NA 75 55.5 2.83 274 NA 76 46.3 6.49 77 55.6 4.97 450 NA 78 55.6 4.33 45.2 NA 79 93.9 4.60 14.9 NA 80 55.6 4.97 86.5 NA 81 55.6 4.33 123 NA 82 37.2 6.94 48 NA 86 63.5 6.27 NA NA 87 37.2 4.79 NA NA 88 55.6 2.65 NA NA 89 64.8 3.09 224 NA 93 67.6 2.71 2800 NA 100 58.9 4.05 86.3 NA 103 64.8 2.39 4400 NA 104 46.3 4.05 264 3500 105 46.3 2.26 8400 NA 106 46.3 4.03 63 8000 109 46.3 3.18 1500 NA 110 64.4 4.48 0.52 823 121 52.4 5.56 639 NA 122 76.2 4.14 5.0 NA 123 64.4 4.39 0.2 529 124 64.4 4.49 3.0 NA 125 55.6 5.16 171 NA 128 55.6 4.53 19.1 NA 129 55.6 4.48 4.1 5200 150 64.4 4.39 4.2 NA 151 55.6 5.06 5.9 2400 152 55.6 5.11 6.0 2100 153 64.4 4.49 6.9 2000 154 64.4 4.39 3.1 1800 155 81.5 3.28 1.7 NA 165 78.4 3.66 29.4 NA 166 52.4 5.14 12.5 NA 167 76.8 3.62 2.2 2200 177 72.6 3.61 0.8 774 181 76.8 5.0 733 NA 184 52.4 5.45 11.7 2000 185 52.4 5.86 245 NA 186 72.6 3.46 4.2 606 187 72.6 3.46 7 1500 191 55.6 5.27 53.8 NA 192 72.6 3.69 1.1 691 200 72.6 3.66 104 NA 201 72.6 3.66 0.5 716 202 55.6 5.41 35.8 NA 203 55.6 4.78 12.2 10 μM 204 79.7 5.29 32.2 NA 205 61.6 5.65 10 μM NA 206 67.7 4.96 > 5000 NA 208 64.8 4.48 153.7 NA 209 85 2.0 0.14 938 210 96.2 3.44 163.6 NA 211 52.4 5.67 27.2 13.5 [mu] M 212 52.4 5.67 341 NA 213 96.7 3.97 636 NA 214 85 2.06 15.9 13.5 [mu] M 215 72.6 4.6 0.1 NA 216 84.7 4.40 91.5 NA 217 55.6 4.75 24.6 13.5 218 97.0 2.58 132 NA 219 64.8 4.48 13 NA 220 91.1 3.17 28 NA 221 87.9 3.80 1400 NA 222 79.7 4.23 284 NA 223 67.7 4.99 10 μM NA 224 79.7 5.29 485 NA 225 85 2.05 24.5 NA 226 80.0 3.90 2.7 NA 227 69.5 4.14 21.3 NA 228 75.9 4.03 17.8 2900 229 96.7 3.26 648 NA 230 87.9 3.70 300 NA 231 87.9 3.70 120 NA 232 58.9 6.24 93.9 NA 233 76.5 3.85 581 NA 234 75.9 4.24 <0.5 NA 235 88.2 2.3 82.1 NA 236 84.7 3.7 1.1 NA 237 87.9 3.70 1200 NA 238 79.7 5.29 686 NA 239 96.7 3.26 867 NA 240 87.9 3.80 3100 NA 241 102.1 3.65 95.6 NA 242 114.1 2.36 26.5 NA 243 67.7 5.72 0.7 NA 248 76.8 3.92 1.5 2300 250 75.9 4.03 6.1 NA 251 84.7 3.42 3.4 692 252 84.7 3.42 10.1 NA 253 61.6 5.05 26.6 NA 254 76.8 5.15 15.4 NA 257 64.8 3.09 7.3 258 75.9 4.55 One NA 259 63.4 4.96 <0.5 NA 260 63.4 4.69 <0.5 NA 261 87.2 3.63 <0.5 NA 262 87.2 3.32 <0.5 NA 263 75.4 4.81 10 NA 264 75.4 4.50 8 NA 265 99.2 3.44 <0.5 NA 266 64.8 2.33 224 NA 267 67.6 2.86 2800 NA 268 52.4 3.42 10.7 NA 269 53.4 3.77 112 NA 270 74.8 3.95 2.5 NA 271 86.9 3.77 <0.5 NA

Using the synthetic process provided herein, any compound of the present invention is prepared within the ordinary skill. Using the above referenced references and methods for assessing S1P1 inhibitory viability in combination with the knowledge of those skilled in the art, those skilled in the art will be able to determine the efficacy against S1P1 inhibition, the selective potency of S1P1 in the presence of other receptor subtypes such as S1P3 For efficacy in biological assays using cells exhibiting inhibition, and in vivo S1P1 inhibition, any compounds thus prepared can be assessed. That is, the full scope of the claims set forth below may be enabled by the teachings herein.

Claims (87)

The compound of formula (I) Or a pharmaceutically acceptable salt, a tautomer, a stereoisomer, a hydrate, or a solvate thereof:

In the above formula (I)
The dotted line indicates that a single bond or a double bond may be present, provided that two double bonds and three single bonds are present in the ring including A ¹ , A ² , and A ³ ;
A ¹ and A ³ are N and A ² is O;
L ¹ and L ² are independently a bond; Or (CHR ') _n (R' is H or (C ₁ -C ₆₎ alkyl, n is 1, 2 or 3);
J is in each occurrence independently F, Cl, Br, I, OR ', OC (O) N (R') ₂ , CN, CF ₃ , OCF ₃ , CHF ₂ , NO ₂ , O, S (O), methylene dioxy, ethylene dioxy, N (R ') ₂ , N (R') CH ₂ CH ₂ OR ', SR', SOR ', SO ₂ R', SO ₂ N _{R ') 2, SO 3 R} ', C (O) R ', C (O) C (O) R', C (O) CH 2 C (O) R ', C (S) R', OC ( O) R ', OC (O ) OR', C (O) N (R ') 2, OC (O) N (R') 2, C (S) N (R ') 2, (CH 2) 0 _{-2 NHC (O) R ',} (CH 2) 0-2 N (R') 2, (CH 2) 0-2 N (R ') N (R') 2, N (R ') N (R N (R ') ₂ , N (R') SO ₂ (R ') C (O) R' R ', N (R') SO 2 N (R ') 2, N (R') C (O) OR ', N (R') C (O) R ', N (R') N (R ' ), N (R ') C (S) R', N (R ') C (O) N (R') 2, N (R ') C (S) N (R') 2, N (COR ' ) COR ', N (oR' a) R ', C (= NH ) N (R') 2, C (O) N (oR ') R', or C (= NOR ') R' , wherein J groups Two of which may form a ring together; Wherein R 'is independently in each occurrence hydrogen or alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein any alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with 0-3 Substituted;
R ⁵ is an ai group substituted with 0-5 J, wherein the wavy line represents the point of attachment

;
R ⁶ is cycloalkyl, aryl, and heterocyclyl, or heteroaryl, wherein any cycloalkyl, aryl, heterocyclyl, or heteroaryl is independently by J, singly or multiply substituted. ^2. A compound according to claim 1, wherein L &lt; ² &gt; is a bond. 2. A compound according to claim 1, which is a compound of formula IC further substituted with 0-5 J atoms.

here,
J is F, Cl, Br, I, OR ', OC (O) N (R') 2, CN, CF 3, OCF 3, CHF 2, NO 2, O, S, C (O) in each case , S (O), methylenedioxy, ethylene dioxy, N (R ') ₂ , N (R') CH ₂ CH ₂ OR ', SR', SOR ', SO ₂ R', SO ₂ N _{) 2, SO 3 R ',} C (O) R', C (O) C (O) R ', C (O) CH 2 C (O) R', C (S) R ', OC (O) R ', OC (O) OR ', C (O) N (R ') 2, OC (O) N (R') 2, C (S) N (R ') 2, (CH 2) 0-2 NHC (O) R ', ( CH 2) 0-2 N (R') 2, (CH 2) 0-2 N (R ') N (R') 2, N (R ') N (R') C (O) R ', N (R') N (R ') C (O) OR', N (R ') N (R') CON (R ') 2, N (R') SO 2 R ' _{, N (R ') SO 2} N (R') 2, N (R ') C (O) OR', N (R ') C (O) R', N (R ') N (R'), N (R ') ₂ , N (COR') COR (O) N (R ') ₂ , N (R') C C (= NOR ') R', C (= NH) N (R ') ₂ , C Together form a ring; Wherein R 'is independently in each occurrence hydrogen or alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein any alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with 0-3 . The method of claim 1, wherein as the compound of formula ID further substituted with 0-5 of J,
R ⁷ and R ⁸ are each independently H, OR ', OC (O ) N (R') 2, N (R ') N (R') 2, N (R ') CH 2 CH 2 OR', CN O, S, C (O), S (O), N (R ') ₂ , SR', SOR ', SO ₂ R', SO ₂ R ', CHF ₂ , CF ₃ , OCF ₃ , NO ₂ , SO ₂ N (R ') compounds wherein the _2, SO ₃ R' or C (O) R ':

Here, J is independently in each case F, Cl, Br, I, OR ', OC (O) N (R') 2, CN, CF 3, OCF 3, CHF 2, NO 2, O, S, C (O), S (O), methylenedioxy, ethylenedioxy, N (R ') ₂ , N (R') CH ₂ CH ₂ OR ', SR', SOR ', SO ₂ R', SO ₂ N _{(R ') 2, SO 3} R', C (O) R ', C (O) C (O) R', C (O) CH 2 C (O) R ', C (S) R', OC (O) R ', OC ( O) OR', C (O) N (R ') 2, OC (O) N (R') 2, C (S) N (R ') 2, (CH 2) _{0-2 NHC (O) R ',} (CH 2) 0-2 N (R') 2, (CH 2) 0-2 N (R ') N (R') 2, N (R ') N ( N (R ') ₂ , N (R') SO (R ') C (O) R' _{2 R ', N (R'} ) SO 2 N (R ') 2, N (R') C (O) OR ', N (R') C (O) R ', N (R') N (R '), N (R') C (S) R ', N (R') C (O) N (R ') 2, N (R') C (S) N (R ') 2, N (COR (R ') ₂ , C (O) N (OR') R ', or C (= NOR') R ' Two of which may form a ring together; Wherein R 'is independently in each occurrence hydrogen or alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein any alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with 0-3 . A compound according to claim 1, wherein said compound is of formula IF ;

In this formula,
R ⁷ and R ⁸ are each independently selected from H, OR ", N (R") ₂ , and SR ";
R "is hydrogen or alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, and any such alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is substituted with 0-3 J;
X is F, Cl, Br, I, CHF 2, CN, CF 3, NO 2 , or OR ';
Y is hydrogen or alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, and any such alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is substituted with 0-3 J; The compound of claim 1, wherein said compound is any of the following compounds or any pharmaceutically acceptable salts, tautomers, or stereoisomers thereof:

A pharmaceutical composition for the treatment of multiple sclerosis, transplant rejection, or respiratory distress syndrome in an adult comprising the compound of claim 1 and an excipient. A pharmaceutical combination comprising a compound of claim 1 and a medicament for the treatment of multiple sclerosis, transplant rejection, or respiratory distress syndrome in an adult. 9. The combination of claim 8 wherein the medicament is medically prescribed for the treatment of multiple sclerosis, transplant rejection, or respiratory distress syndrome in an adult. 7. A compound according to any one of claims 1 to 6 for use in the treatment of multiple sclerosis, transplant rejection, or respiratory distress syndrome in an adult. 7. A method according to any one of claims 1 to 6 for the treatment of symptoms medically indicated by agonism, inhibition or antagonism of the sphingosine-1-phosphate receptor subtype of the sphingosine-1-phosphate receptor subtype &Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof. The compound according to claim 1, wherein said compound is

&Lt; / RTI &gt; or a pharmaceutically acceptable salt or stereoisomer thereof. 2. A compound according to claim 1, wherein the compound of formula (I)

&Lt; / RTI &gt; or a pharmaceutically acceptable salt or stereoisomer thereof. 2. A compound according to claim 1, wherein the compound of formula (I)

&Lt; / RTI &gt; or a pharmaceutically acceptable salt or stereoisomer thereof. 2. A compound according to claim 1, wherein the compound of formula (I)

&Lt; / RTI &gt; or a pharmaceutically acceptable salt or stereoisomer thereof. 2. A compound according to claim 1, wherein the compound of formula (I)

&Lt; / RTI &gt; or a pharmaceutically acceptable salt or stereoisomer thereof. 2. A compound according to claim 1, wherein the compound of formula (I)

&Lt; / RTI &gt; or a pharmaceutically acceptable salt or stereoisomer thereof. 2. A compound according to claim 1, wherein the compound of formula (I)

&Lt; / RTI &gt; or a pharmaceutically acceptable salt or stereoisomer thereof. 2. A compound according to claim 1, wherein the compound of formula (I)

&Lt; / RTI &gt; or a pharmaceutically acceptable salt or stereoisomer thereof. 2. A compound according to claim 1, wherein the compound of formula (I)

&Lt; / RTI &gt; or a pharmaceutically acceptable salt or stereoisomer thereof. 2. A compound according to claim 1, wherein the compound of formula (I)

&Lt; / RTI &gt; or a pharmaceutically acceptable salt or stereoisomer thereof. 2. A compound according to claim 1, wherein the compound of formula (I)

&Lt; / RTI &gt; or a pharmaceutically acceptable salt or stereoisomer thereof. 2. A compound according to claim 1, wherein the compound of formula (I)

&Lt; / RTI &gt; or a pharmaceutically acceptable salt or stereoisomer thereof. 2. A compound according to claim 1, wherein the compound of formula (I)

&Lt; / RTI &gt; or a pharmaceutically acceptable salt or stereoisomer thereof. 25. A compound according to any one of claims 12 to 24, for use in the treatment of transplant rejection. 25. Compounds according to any of claims 12 to 24, for use in the treatment of multiple sclerosis. 25. A compound according to any one of claims 12 to 24 for use in the treatment of respiratory distress syndrome in an adult. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete

Images