KR20130040284A - Chromane derivatives as trpv3 modulators - Google Patents

Abstract

PURPOSE: A chromane derivative as a TRPV 3(transient receptor potential vanilloid 3) regulator is provided to prevent or treat diseases, symptoms, and/or disorders by TRPV3. CONSTITUTION: A compound is denoted by chemical formula I. A pharmaceutical composition contains a free base or a pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient is a carrier or a diluent. The pain is chronic pain, acute pain, and postoperative pain. The compound of chemical formula I is prepared by binding a compound of chemical formula 1 and a compound of chemical formula 2 in a solvent.

Description

CHROMANE DERIVATIVES AS TRPV3 MODULATORS}

This patent application is issued by Indian Patent Application No. 2481 / MUM / 2007, filed December 18, 2007, Indian Patent Application No. 647 / MUM / 2008, filed March 26, 2008, January 9, 2008. US Patent Provisional Application No. 61 / 019,995, filed April 10, 2008, filed with US Patent Provisional Application No. 61 / 043,931, all of which are incorporated herein by reference.

Technical field

The present patent application relates to Chromaman derivatives having Transient Receptor Potential Vanilloid 3 (TRPV3) activity.

background

The movement of ions across the cell membrane is performed by specialized proteins. TRP channels are one large group of non-selective cation channels that function to help regulate ion flux and membrane potential. TRP channels are divided into six subgroups, including the TRPV group. TRPV3 is a member of the TRPV class of the TRP channel.

TRPV3 is a calcium permeable channel, in particular a calcium permeable non-selective cation channel. In addition to calcium ions, the TRPV3 channel is permeable to other cations such as sodium. Thus, the TRPV3 channel modulates membrane potential by regulating the flux of cations such as calcium and sodium ions. TRPV3 receptors are completely different in mechanism from voltage-gated calcium channels. In general, voltage-gated calcium channels allow the influx of calcium from extracellular media to respond and open to membrane depolarization resulting in increased intracellular calcium levels or concentrations. On the other hand, TRP channels, which are non-selective cation channels, are generally ligand-gated (eg, 2-aminoethoxydiphenyl borate [2-APB], heat, and vanilloids), are long-lasting, and allow for prolonged ion concentration changes. Cause This mechanism difference is accompanied by structural differences between voltage-switching and TRP channels. Thus, it is important to recognize the significant structural, functional, and mechanism differences between different ion channel classes, although different channels act in response to numerous stimuli to modulate ion flux and membrane potential in different cell types. .

TRPV3 protein is derived from skin cells (Peier et. al . Science (2002), 296 , 2046-2049) and dorsal root ganglia, trigeminal ganglia, spinal cord and brain (Xu et al . Nature (2002), 418 , 181-185; Smith et al. Nature (2002), 418 , 186-188). TRPV3 is also very much expressed in the skin. In keratinocyte cell lines, stimulation of TRPV3 results in the release of inflammatory mediators including interleukin-1. Thus TRPV3 may also play an important role in controlling inflammation and pain resulting from the release of inflammatory stimuli. TRPV3 proteins that can be used in certain screening tests as described herein to identify compounds that modulate the function of TRPV3 include, but are not limited to, human TRPV3, mouse TRPV3, rat TRPV3, and Drosophila TRPV3. US 2004/0009537 (filed '537) discloses sequences corresponding to human, mouse, and Drosophila TRPV3. For example, SEQ ID Nos 106 and 107 of the '537 application correspond to human nucleic acid and amino acid sequences, respectively. SEQ ID Nos 108 and 109 of the '537 application correspond to mouse nucleic acid and amino acid sequences, respectively.

TRPV3 function is primarily involved in the acceptance and transformation of pain. Thus, it would be desirable to identify and prepare compounds capable of modulating one or more functions of TRPV3.

WO 2007/056124 and WO 2006/017995 disclose TRPV3 modulators, in particular antagonists, for the treatment of various TRPV3 mediated diseases.

WO 2006/065686 and WO 2007/042906 disclose benzopyran derivatives.

In an effort to find better analgesics, there is still a need for therapeutic treatment of diseases, conditions and / or disorders controlled by TRPV3.

summary

The present patent application relates to Chromman compounds having TRP channel regulatory activity, in particular TRPV3 regulatory activity. This patent application relates to compounds of formula (I)

here,

R ¹ is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted cycloalkyl; Wherein the aryl, heteroaryl and heterocyclic rings are mono, bi or tricyclic; Completely or partially aromatic;

Wherein the substituents on aryl, heteroaryl, heterocyclic ring and cycloalkyl are halogen, hydroxy, nitro, cyano, substituted or unsubstituted amino, substituted or unsubstituted alkyl, linear or branched chain alkyl, linear or branched Chain alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkyl, fully or partially substituted haloalkyl, substituted or unsubstituted haloalkyloxy, completely or partially substituted Haloalkyloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted Not aryloxy, substituted or Unsubstituted arylalkyl, substituted or unsubstituted arylalkoxy, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heteroaryl, -S (O) _p R ^a , -NHS (O) _p R ^a , -O (CH ₂ ) _m NR ^a R ^b , -C (O) -R ^a or -C (O) NR ^a R ^b independently;

R ² is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted hetero Is selected from the group consisting of cyclic groups;

In each case R ^a , R ^b , R ^c and R ^d are hydrogen, nitro, cyano, halogen, -OR ^e , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl , Optionally substituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group;

R ^e is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted hetero Is selected from the group consisting of cyclic groups;

R ³ and R ⁴ are hydrogen, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, linear or branched chain alkyl, linear or branched chain alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted Unsubstituted alkoxy, substituted or unsubstituted haloalkyl, fully or partially substituted haloalkyl, substituted or unsubstituted haloalkyloxy, fully or partially substituted haloalkyloxy, substituted or unsubstituted cycloalkyl, substituted or substituted Independently selected from unsubstituted cycloalkoxy, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkylalkoxy, substituted or unsubstituted aryl;

'm' is an integer selected from 1 to 4;

'n' is an integer selected from 0 to 3;

'p' is an integer selected from 0 to 2;

Provided that R ^b is not a group selected from -OR ^e , -NR ^a R ^b or C (O) NR ^a R ^b .

It is to be understood that Formula (I) structurally includes all stereoisomers, enantiomers and diastereomers and pharmaceutically acceptable salts that may be considered from chemical structures of the kind described herein.

According to one embodiment of the invention, 'n' is an integer of 1.

According to another embodiment of the invention, 'n' is an integer 2.

According to another embodiment of the invention, 'n' is an integer 3.

According to another embodiment of the invention, R ¹ is substituted or unsubstituted monocyclic aryl, preferably phenyl. In this embodiment, one or more substituents are halogen (eg F, Cl or Br), hydroxyl, alkyl (eg methyl), alkoxy (eg methoxy, ethoxy, n-propoxy , n-butoxy iso- propoxy), cycloalkyloxy (eg cyclopentyloxy) and 'm' is 1, 2 or 3, preferably 2.

According to another embodiment of the invention, R ^b is halogen (eg F, Cl or Br).

According to another embodiment of the invention, R ^a , R ^c and R ^d are independently selected from hydrogen or hydroxy.

According to another embodiment of the invention, R ³ and R ⁴ are hydrogen.

Another preferred embodiment of the invention is a compound of formula (II),

here,

R ¹ is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted cycloalkyl; Wherein the aryl, heteroaryl and heterocyclic rings are mono, bi or tricyclic; Completely or partially aromatic;

Wherein the substituents on aryl, heteroaryl, heterocyclic ring and cycloalkyl are halogen, hydroxyl, nitro, cyano, amino, substituted or unsubstituted alkyl, linear or branched chain alkyl, linear or branched chain alkoxy, substitution Or unsubstituted alkenyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkyl, fully or partially substituted haloalkyl, substituted or unsubstituted haloalkyloxy, fully or partially substituted haloalkyloxy, Substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted Arylalkyl, unsubstituted or substituted, Ring or unsubstituted arylalkoxy, substituted or unsubstituted heterocyclic group, substituted or unsubstituted ^{_{heteroaryl, -S (O) p R a}} , -NHS (O) p R a, -O (CH 2) _m NR ^a R ^b , -C (O) -R ^a or -C (O) NR ^a R ^b independently;

In each case R ^a , R ^b , R ^c and R ^d are hydrogen, nitro, cyano, halogen, -OR ^e , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl , Optionally substituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group;

R ^e is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted hetero Is selected from the group consisting of cyclic groups;

R ³ and R ⁴ are hydrogen, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, linear or branched chain alkyl, linear or branched chain alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted Unsubstituted alkoxy, substituted or unsubstituted haloalkyl, fully or partially substituted haloalkyl, substituted or unsubstituted haloalkyloxy, fully or partially substituted haloalkyloxy, substituted or unsubstituted cycloalkyl, substituted or substituted Independently selected from unsubstituted cycloalkoxy, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkylalkoxy, substituted or unsubstituted aryl;

'm' is an integer selected from 1 to 4;

'n' is an integer selected from 0 to 3;

'p' is an integer selected from 0 to 2;

Provided that R ^b is not a group selected from -OR ^e , -NR ^a R ^b or C (O) NR ^a R ^b .

It is to be understood that formula (II) structurally includes all stereoisomers, enantiomers, diastereomers and pharmaceutically acceptable salts that may be considered from the chemical structures of the kind described herein.

According to one embodiment of the invention, 'n' is an integer of 1.

According to one embodiment of the invention, R ¹ is substituted or unsubstituted aryl, wherein aryl is a monocyclic, bicyclic or tricyclic ring system, preferably a mono or bicyclic ring. In this embodiment, 'm' is 1, 2 or 3.

According to another embodiment of the invention, R ¹ is substituted or unsubstituted monocyclic aryl, preferably phenyl. In this embodiment, one or more substituents are halogen (eg F, Cl or Br), hydroxyl, alkyl (eg methyl), alkoxy (eg methoxy, ethoxy, n-propoxy , n-butoxy iso- propoxy), cycloalkyloxy (eg cyclopentyloxy), cycloalkylalkoxy (eg cyclopropylmethoxy), alkyl sulfonyl amino (eg -NHS ( O) ₂ CH _{3 ,} -NHS (O) ₂ CH (CH ₃ ) ₂ ), alkylaminoalkoxy (eg, -OCH ₂ CH ₂ N (CH ₃ ) ₂ ) _, arylalkyloxy (eg benzyl Oxy) or heteroaryl (eg, pyridine or pyrimidine); 'm' is 1, 2 or 3.

According to another embodiment of the invention, R ¹ is substituted or unsubstituted bicyclic aryl, preferably naphthyl. In this embodiment, the one or more substituents are independently selected from alkoxy (eg methoxy, ethoxy, or iso- propoxy) or fully or partially substituted haloalkoxy (OCHF ₂ ); 'm' is 1, 2 or 3.

According to another embodiment of the invention, R ¹ is substituted or unsubstituted bicyclic aryl. In this embodiment, aryl is partly an aromatic ring, preferably tetrahydronaphthalene; 'm' is 1, 2 or 3.

According to another embodiment of the invention, R ¹ is a substituted or unsubstituted heterocyclic group, wherein the heterocyclic group is a mono, bi or tricyclic system and is wholly or partially aromatic.

According to another embodiment of the invention, R ¹ is substituted or unsubstituted heteroaryl, wherein the heteroaryl is a monocyclic, bicyclic or tricyclic ring system. In this embodiment, 'm' is 1, 2 or 3.

According to another embodiment of the invention, R ¹ is substituted or unsubstituted monocyclic heteroaryl, preferably pyridine. In this embodiment, 'm' is 1, 2 or 3.

According to another embodiment of the invention, R ¹ is substituted or unsubstituted bicyclic heteroaryl, preferably indole, bezodioxol, benzisoxazole, benzofuran, quinoline or benzodioxin. In this embodiment one or more substituents are halogen (eg F, Cl or Br), alkyl (eg methyl) or alkoxy (eg methoxy, ethoxy, n-propoxy, n-part Methoxy iso- propoxy); 'm' is 1, 2 or 3.

According to another embodiment of the invention, R ¹ is substituted or unsubstituted tricyclic heteroaryl, preferably dibenzofuran. In this embodiment 'm' is 1, 2 or 3.

According to another embodiment of the invention, R ^b is selected from hydrogen or halogen (eg fluorine, chlorine or bromine).

According to another embodiment of the invention, R ^a , R ^c and R ^d are hydrogen, halogen (eg fluorine, chlorine or bromine), substituted or unsubstituted alkyl (eg methyl) Selected independently.

According to another embodiment of the invention, R ^a , R ^c and R ^d are independently selected from hydrogen or -OR ^e , wherein R ^e is hydrogen, substituted or unsubstituted alkyl (eg methyl) or Substituted or unsubstituted aryl (eg phenyl) or substituted or unsubstituted arylalkyl (eg benzyl).

According to another embodiment of the invention, R ³ and R ⁴ are independently hydrogen, hydroxyl or alkyl (methyl). In this embodiment, 'm' is 1, 2 or 3.

The following are representative compounds, which are merely exemplary in nature and are not intended to limit the scope of the invention.

N- (8-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2-phenylacetamide (Compound No. 1),

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (2-methoxyphenyl) acetamide (Compound No. 2),

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclopropane] -4-yl) -2- {2-[(methylsulfonyl) amino] phenyl} acetamide ( Compound No. 3),

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (2- (cyclopentyloxy) -3-methoxyphenyl) acet Amide (Compound No. 4),

N - [(4 R) -8- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -2- (2-cyclopentyloxy-3-methoxy Phenylacetamide (Compound No. 5),

N - [(4 S) -8- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -2- (2-cyclopentyloxy-3-methoxy Phenylacetamide (Compound No. 6),

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (3,4-dimethoxyphenyl) acetamide (Compound No. 7 ),

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2-pyridin-2-ylacetamide (Compound No. 8),

N- (3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (1-naphthyl) acetamide (Compound No. 9),

N- (6-Fluoro- (3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (1-naphthyl) acetamide (Compound No. 10) ,

N - [(4 R) with 6, 8-difluoro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -2- (1-naphthyl) acetamide Amide (Compound No. 11),

N - [(4 R) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -2- (1-naphthyl) acetamide (Compound No 12),

N - [(4 S) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -2- (1-naphthyl) acetamide (Compound No 13),

N- (7-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (1-naphthyl) acetamide (Compound No. 14),

N - [(4 R) -8- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -2- (1-naphthyl) acetamide (Compound No 15),

N - [(4 S) -8- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -2- (1-naphthyl) acetamide (Compound No 16),

N- (5-hydroxy-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (1-naphthyl) acetamide (Compound No. 17),

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (2-naphthyl) acetamide (Compound No. 18),

N - [(4 R) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -2- (6-methoxy-2-naphthyl) Propanamide (Compound No. 19),

N - [(4 S) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -2- (6-methoxy-2-naphthyl) Propanamide (Compound No. 20),

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (1,2,3,4-tetrahydronaphthalen-1-yl Acetamide (Compound No. 21),

N -[(6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl)]-2- (1,2,3,4-tetrahydronaphthalene-2 -Yl) acetamide (Compound No. 22),

2- (1,3-benzodioxol-5-yl) - N - (6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) acetamide ( Compound No. 23),

N- (6-fluoro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (5-fluoro-3-methyl-1 H -indole- 2-yl) acetamide (Compound No. 24),

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (5-methoxy-2-methyl-1 H -indole-3 -Yl) acetamide (Compound No. 25),

2- (1,2-benzisoxazol-3-yl) - N - [(R 4) - (6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4 -Yl) acetamide (Compound No. 26),

2- (1,2-benzisoxazol-3-yl) - N - [(4 S ) - (6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4 -Yl) acetamide (Compound No. 27),

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-cyclopentyloxyphenyl) propanamide (Compound No. 28) ,

N - [(4 R) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -3- (2-cyclopentyloxy) phenyl-propanamide ( Compound No. 29),

N - [(4 S) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -3- (2-cyclopentyloxy) phenyl-propanamide ( Compound No. 30),

N - [(4 S) - (8- Chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (4-methoxyphenyl) -1-naphthyl Tilpropanamide (Compound No. 31),

N - [(4 S) -8- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane-4-yl] -2- [2- (cyclopentyloxy) phenyl propanamide ( Compound No. 32),

7-benzyloxy- N- (3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-cyclopentyloxyphenyl) propanamide (Compound No. 33 ),

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- {2-[(isopropylsulfonyl) amino] phenyl} propanamide (Compound No. 34),

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-pyridin-2-ylphenyl) propanamide (Compound No. 35),

N- (6,8-dichloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-pyridin-3-ylphenyl) propanamide (compound No. 36),

N- (3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-cyclopentyloxy-3-methoxy) phenylpropanamide (Compound No. 37 ),

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2,3-dimethoxy) phenylpropanamide (Compound No. 38 ),

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-isopropoxy-3-methoxy) phenylpropanamide ( Compound No. 39),

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (3-chloro-4-methoxy) phenylpropanamide (Compound No 40),

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-cyclopropylmethoxy-3-methoxy) phenylpropanamide (Compound No. 41),

N - [(4 R) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl)] - 3- (2-cyclopentyloxy-3-methoxy Methoxy) phenylpropanamide (Compound No. 42),

N - [(4 S) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl)] - 3- (2-cyclopentyloxy-3-methoxy Methoxy) phenylpropanamide (Compound No. 43),

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-cyclopentyloxy-3-ethoxy) phenylpropanamide ( Compound No. 44),

N- (7-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-cyclopentyloxy-3-methoxy) phenylpropanamide ( Compound No. 45),

N- (8-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-ethoxy-3-methoxy) phenylpropanamide (compound No. 46),

N - [(4 R) -8- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl)] - 3- (2-cyclopentyloxy-3-methoxy Methoxy) phenylpropanamide (Compound No. 47),

N - [(4 S) - (8- Chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (2-cyclopentyloxy-3-methoxy Methoxy) phenylpropanamide (Compound No. 48),

N- (6-chloro-7-methyl-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-cyclopentyloxy-3-methoxy) Phenylpropanamide (Compound No. 49),

N- (5-benzyloxy-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-cyclopentyloxy-3-methoxy) phenylpropanamide (Compound No. 50),

N- (5-hydroxy-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-cyclopentyloxy-3-methoxy) phenylpropanamide (Compound No. 51),

N- (3,4-dihydrospiro [chromen-2,1'-cyclobutane] -5-methoxy-4-yl) -3- (2-cyclopentyloxy-3-methoxy) phenylpropanamide (Compound No. 52),

(4 R) -6- chloro - N - (3,4- dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (2-cyclopentyloxy-3-methyl) Phenylpropanamide (Compound No. 53),

(4 S) -6- chloro - N - (3,4- dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (2-cyclopentyloxy-3-methyl) Phenylpropanamide (Compound No. 54),

N -6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl-3- (2-hydroxy-3-methoxyphenyl) propanamide (Compound No. 55),

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-benzyloxy-3-methoxy) phenylpropanamide (compound No. 56),

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- {2-isopropoxy-3-[(methylsulfonyl) amino ] Phenyl} propanamide (Compound No. 57),

N- (8-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- {2-isopropoxy-3-[(methylsulfonyl) amino ] Phenyl} propanamide (Compound No. 58),

N- (6,8-dichloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-cyclopentyloxy-3-methoxy) phenylpropane Amide (Compound No. 59),

N- (6,8-dichloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2-{[2- (dimethylamino) ethoxy-3-meth Methoxy] phenyl} propanamide (Compound No. 60),

N- (6,8-dichloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- {2-propoxy-3-[(methylsulfonyl) Amino] phenyl} propanamide (Compound No. 61),

N- (6,8-dichloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- {2-isopropoxy-5-[(methylsulfonyl ) Amino] phenyl} propanamide (Compound No. 62),

N- (6,8-dichloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- {2-butoxy-3-[(methylsulfonyl) Amino] phenyl} propanamide (Compound No. 63),

N- (6,8-dichloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- {2- (cyclopropylmethoxy) -3-[( Methylsulfonyl) amino] phenyl} propanamide (Compound No. 64),

N- (6,8-dichloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- {2-isopropoxy-3-[(methylsulfonyl ) Amino] phenyl} propanamide (Compound No. 65),

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (1-naphthyl) propanamide (Compound No. 66),

N- [4 ( S )-(6-Chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (4-methoxy) -1-naph Tilpropanamide (Compound No. 67),

N - [4 R - (6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (4-methoxyphenyl) propan-1-naphthyl Amide (Compound No. 68),

N - [(4 R) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (4-methoxyphenyl) -1-naphthyl Propanamide (Compound No. 69),

N - [(4 S) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (4-methoxyphenyl) -1-naphthyl Propanamide (Compound No. 70),

(4 R) -6- chloro - N - (3,4- dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (4-difluoromethoxy-1-naphthyl Thi) propanamide (Compound No. 71),

(4 S) -6- chloro - N - (3,4- dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (4-difluoromethoxy-1-naphthyl Ethyl) propanamide (Compound No. 72),

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (1-naphthyl) propanamide (Compound No. 73),

N - [4 R - (6-chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (6-methoxy-2-naphthyl) propane Amide (Compound No. 74),

N - [4 S - (6-chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (6-methoxy-2-naphthyl) propane Amide (Compound No. 75),

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (quinolin-2-yl) propanamide (Compound No. 76),

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- ( 1H -indol-3-yl) propanamide (Compound No. 77),

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (2-methyl-1-benzofuran-4-yl) propanamide (Compound No. 78),

N - [(4 R) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -3- (7-methoxy-2-methyl-1 -Benzofuran-5-yl) propanamide (Compound No. 79),

N - [(4 S) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -3- (7-methoxy-2-methyl-1 -Benzofuran-5-yl) propanamide (Compound No. 80),

3- (1,4-benzo dioxin-6-yl) - N - (6-fluoro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) propanamide (Compound No. 81),

3- (1,3-benzodioxol-4-yl) - N - [6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] propanamide ( Compound No. 82),

3- (1,3-benzodioxol-4-yl) - N - (8- Chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) propanamide ( Compound No. 83),

3- (1,4-benzo dioxin-5-yl) - N - (6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) propanamide ( Compound No. 84),

3-dibenzo [b, d] furan-2-yl - N - [(4 R) -6- chloro-3,4-dihydro -2 H - chromen-4-yl] acetamide (Compound No. 85),

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclopentan] -4-yl) -3- (2-cyclopentyloxy-3-methoxy) propanamide (compound No. 86),

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclohexane] -4-yl) -3- (2-cyclopentyloxy-3-methoxy) phenylpropanamide ( Compound No. 87),

N- (2,2-dimethyl-3,4-dihydro- 2H -chromen-4-yl) -3- (2-cyclopentyloxy-3-methoxy) phenylpropanamide (Compound No. 88) ,

N- (6-chloro-3,4-dihydro-2 H -thiochromen-4-yl) -4- (2-cyclopentyloxy-3-methoxyphenyl) propanamide (Compound No. 89),

N- (6-chloro-3,4-dihydro- 2H -thiochromen-4-yl) -3- (2-methoxy-1-naphthyl) propanamide (Compound No. 90),

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -4- (2-cyclopentyloxyphenyl) butanamide (Compound No. 91) ,

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -4- [2- (cyclopentyloxy) -3-methoxyphenyl] butane Amide (Compound No. 92),

N - (4 R) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl-4- (2-cyclopentyloxy-3-methoxyphenyl) Butanamide (Compound No. 93),

N - {(4 S) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl} -4 - [(2- (cyclopentyloxy) -3 -Methoxyphenyl] butanamide (Compound No. 94),

(4 R) - N - ( 8- Chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -4- (2-cyclopentyloxy-3-methoxy Phenyl) butanamide (Compound No. 95),

(4 S) - N - ( 8- Chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -4- (2-cyclopentyloxy-3-methoxy Phenyl) butanamide (Compound No. 96),

N- (8-chloro-6-fluoro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -4- (2-cyclopentyloxy-3-methoxy Phenyl) butanamide (Compound No. 97),

N- (6,8-dichloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -4- (2-cyclopentyloxy-3-methoxyphenyl) butane Amide (Compound No. 98),

N- (7-benzyloxy-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -4- (2-cyclopentyloxy-3-methoxyphenyl) butanamide (Compound No. 99),

N- (7-hydroxy-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -4- (2-cyclopentyloxy-3-methoxyphenyl) butanamide (Compound No. 100),

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -4-oxo-4- (4-methoxynaphthyl) butanamide (compound No. 101),

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -4-hydroxy-4- (4-methoxynaphthyl) butanamide ( Compound No. 102),

N- (6-chloro-2,2-dimethyl-3,4-dihydro- 2H -chromen-4-yl) -4- (2-cyclopentyloxy-3-methoxy) phenylbutanamide (compound No. 103),

N- (6-chloro-3,4-dihydro- 2H -thiochromen-4-yl) -4- (2-cyclopentyloxy-3-methoxyphenyl) butanamide (Compound No. 104) and

Stereoisomers, enantiomers, diastereomers and pharmaceutically acceptable salts of compounds 1 to 104 are also contemplated.

The patent application also provides a pharmaceutical composition comprising at least one compound as described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein. The compounds of the present invention may be bound to pharmaceutically acceptable excipients (such as carriers or diluents), may be diluted by the carrier, or may be placed in a carrier which may be in the form of capsules, parcels, paper or other containers. .

The compounds and pharmaceutical compositions described herein are useful for the treatment of diseases, conditions and / or disorders controlled by the TRPV3 receptor.

The present invention further provides a method of treating a disease, condition and / or disorder modulated by a TRPV3 receptor in a subject in need thereof by administering to the subject an amount of one or more compounds described herein in an amount effective to cause inhibition of the TRPV3 receptor. To provide.

Also provided are processes for preparing the compounds described herein.

details

This patent application provides Chromaman derivatives that can be used as TRPV3 modulators, and processes for synthesizing such compounds. Also provided are pharmaceutically acceptable salts, enantiomers, diastereomers of such compounds that may have the same type of activity. Further provided are pharmaceutical compositions comprising a pharmaceutically acceptable carrier, excipient or diluent together with the described compounds that can be used for the treatment of diseases, conditions and / or disorders mediated by TRPV3.

The following definitions apply to the terminology used herein:

The term "halogen" or "halo" includes fluorine, chlorine, bromine, or iodine.

The term "alkyl" refers to a linear or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms, containing no unsaturation, and having from 1 to 8 carbon atoms, which is attached to the rest of the molecule by a single bond, For example methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl). The term "C _{1 -6} alkyl" refers to an alkyl chain having 1 to 6 carbon atoms.

The term "alkenyl" refers to an aliphatic hydrocarbon group comprising a carbon-carbon double bond, and has a linear or branched chain having 2 to about 10 carbon atoms, for example ethenyl, 1-propenyl, 2-prop Phenyl (allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl.

The term "alkynyl" refers to a linear or branched chain hydrocarbyl radical having at least one carbon-carbon triple bond and having from 2 to about 12 carbon atoms (preferably a radical having from 2 to about 10 carbon atoms) And ethynyl, propynyl, and butynyl.

The term "alkoxy" refers to an alkyl group attached to the remainder of the molecule via an oxygen bond. Representative examples of those groups are -OCH _3, and -OC ₂ H _5.

The term "cycloalkyl" refers to a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronaphthyl, adamantyl and norbornyl groups, crosslinked cyclic groups or spirobicyclic groups, for example, spiro (4,4) It is non-2-day.

The term “cycloalkylalkyl” refers to a cyclic ring-bearing radical having 3 to about 8 carbon atoms attached directly to an alkyl group. Cycloalkylalkyl groups can be attached to the main structure at any carbon atom of the alkyl group, which results in the formation of a stable structure. Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.

The term “cycloalkenyl” refers to a cyclic ring-bearing radical that contains at least one carbon-carbon double bond and has 3 to about 8 carbon atoms, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl .

The term "aryl" refers to an aromatic radical having 6 to 14 carbon atoms, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl.

The term "arylalkyl" refers to an aryl group as defined above directly connected to an alkyl group as defined above, for example -CH ₂ C ₆ H ₅ and -C ₂ H ₅ C ₆ H ₅ .

The terms "heterocyclyl" and "heterocyclic ring" refer to stable 3- to 15-membered ring radicals composed of carbon atoms and 1 to 5 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. For the purposes of the present invention, heterocyclic ring radicals may comprise fused, crosslinked or spiro ring systems, wherein nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radicals are optionally in various oxidation states. It may be a monocyclic, bicyclic or tricyclic ring system that can be oxidized. Moreover, nitrogen atoms can be optionally quaternized; Ring radicals may be partially or fully saturated (ie, heterocyclic or heteroaryl). Examples of such heterocyclic ring radicals include azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolinyl, naphthyridinyl, Perhydroazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pterridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazolyl , Imidazolyl, tetrahydroisoquinolinyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazinyl, azepi Neil, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl, isoxazolidi Nil, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazole Dinyl, indolyl, isoindolinyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolinyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzo Pyranyl, benzothiazolyl, benzooxazolyl, furyl, tetrahydrofuranyl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxa Phospholanil, oxadiazolyl, chromanyl, and isochromenyl. Heterocyclic ring radicals may be attached to the main structure at any heteroatom or carbon atom, which results in the formation of a stable structure.

The term “heterocyclylalkyl” refers to a heterocyclic ring radical bonded directly to an alkyl group. Heterocyclylalkyl radicals may be attached to the main structure at any carbon atom of the alkyl group, which results in the formation of a stable structure.

The term "heteroaryl" refers to an aromatic heterocyclic ring radical. Heteroaryl ring radicals may be attached to the main structure at any heteroatom or carbon atom, which results in the formation of a stable structure.

The term "heteroarylalkyl" refers to a heteroaryl ring radical bonded directly to an alkyl group. Heteroarylalkyl radicals may be attached to the main structure at any carbon atom of the alkyl group, which results in the formation of a stable structure.

Unless otherwise specified, the term "substituted" as used herein refers to hydroxy, halogen, carboxyl, cyano, nitro, oxo (= O), thio (= S), substituted or unsubstituted alkyl, substituted or Unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cyclo Alkenylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted Unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or substituted Are ^{guanidine, -COOR x, -C (O)} R x, -C (S) R x, -C (O) NR x R y, -C (O) ONR x R y, -NR x CONR y R z , -N (R ^x ) SOR ^y , -N (R ^x ) SO ₂ R ^y ,-(= NN (R ^x ) R ^y ), -NR ^x C (O) OR ^y , -NR ^x R ^y ,- NR ^x C (O) R ^y , -NR ^x C (S) R ^y , -NR ^x C (S) NR ^y R ^z , -SONR ^x R ^y , -SO ₂ NR ^x R ^y , -OR ^x ,- OR ^x C (O) NR ^y R ^z , -OR ^x C (O) OR ^y , -OC (O) R ^x , -OC (O) NR ^x R ^y , -R ^x NR ^y C (O) R ^z , -R ^x OR ^y , -R ^x C (O) OR ^y , -R ^x C (O) NR ^y R ^z , -R ^x C (O) R ^y , -R ^x OC (O) R ^y ,- Refers to one or more of substituents consisting of SR ^x , -SOR ^x , -SO ₂ R ^x , and -ONO ₂ , wherein R ^x , R ^y and R ^z are hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted Unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl , Substituted or Independently from unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted heterocyclic ring Is selected. Substituents in the aforementioned "substituted" groups may not be further substituted. For example, when the substituent on "substituted alkyl" is "substituted aryl", the substituent on "substituted aryl" may not be "substituted alkenyl".

The term "treating or treatment" of a term, condition, disorder or condition includes:

(1) A condition, disorder or condition of a condition, disorder or condition that has not yet experienced or exhibited clinical or subclinical symptoms of the condition, disorder or condition, but which has suffered or may be suffering from the condition, disorder or condition. Inhibiting or delaying the appearance of clinical symptoms;

(2) inhibiting a condition, disorder or condition, ie, stopping or reducing the progression of the disease or at least one clinical or subclinical symptom thereof; or

(3) alleviating the disease, ie causing regression of at least one of the condition, disorder or condition or clinical or subclinical symptoms thereof.

The benefit to the subject to be treated is statistically significant or at least recognized by the patient or physician.

The term "subject" includes mammals (especially humans) and other animals such as domestic animals (eg, domestic pets, including cats and dogs), and non-livestock (such as wild animals).

A "therapeutically effective amount" means an amount of a compound that, when administered to a subject to treat a condition, disorder, or condition, is sufficient to effect such treatment. A "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, health condition and responsiveness of the subject being treated.

The compounds described in this patent application may form salts. Non-limiting examples of pharmaceutically acceptable salts that form part of this patent application include salts derived from inorganic bases, salts of organic bases, salts of chiral bases, salts of natural amino acids and salts of non-natural amino acids. Certain compounds of the present patent application may exist in stereoisomeric forms (eg diastereomers and enantiomers). For the entire compound described by formula (I), the present patent application extends to these stereoisomeric forms and mixtures thereof. To the extent that the prior art teaches the synthesis or separation of certain stereoisomers, different stereoisomeric forms of the present patent application may be separated from one another by methods known in the art, or given isomers may be stereospecific or asymmetrical synthesis. It can be obtained by. Tautomeric forms and mixtures of the compounds described herein are also contemplated.

Pharmaceutical composition

The pharmaceutical compositions provided herein comprise at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably the pharmaceutical composition contemplated comprises the compound (s) described herein in an amount sufficient to inhibit the TRPV3 receptor in the subject.

Subjects contemplated include, for example, mammals, including living cells and humans. The compounds of the present invention may be bound to pharmaceutically acceptable excipients (such as carriers or diluents), may be diluted by the carrier, or may be placed in a carrier which may be in the form of capsules, parcels, paper or other containers. .

Examples of suitable carriers include water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, white clay, sucrose, dextrin, magnesium carbonate, sugars, cyclodextrins, amylose Lower alkyl ethers, silicic acids, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or cellulose Hydroxymethylcellulose and polyvinylpyrrolidone.

The carrier or diluent may comprise a sustained release material, such as glyceryl monostearate or glyceryl distearate, alone or in admixture with wax.

The pharmaceutical composition may also include one or more pharmaceutically acceptable adjuvants, wetting agents, emulsifiers, suspending agents, preservatives, salts for affecting osmotic pressure, buffers, sweeteners, flavoring agents, coloring agents, or any combination thereof. have. The pharmaceutical compositions of the present invention may be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a subject using procedures known in the art.

The pharmaceutical compositions described herein can be prepared by conventional techniques, such as those described in Remington: The Science and Practice of Pharmacy, 20 ^th Ed., 2003 (Lippincott Williams & Wilkins). For example, the active compound may be mixed with the carrier, diluted by the carrier, or placed in a carrier that may be in the form of an ampoule, capsule, parcel, paper, or other container. If the carrier acts as a diluent, it may be a solid, semisolid, or liquid substance that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed to granular solid containers, for example in vesicles.

The pharmaceutical composition may be in conventional form, for example capsules, tablets, aerosols, solutions, suspensions or products for topical application.

The route of administration can be any route that effectively delivers the active compound of the invention to an appropriate or desired site of action. Suitable routes of administration include oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, spleen, rectal, depot, subcutaneous, intravenous, urethra, intramuscular, intranasal, ocular (such as ophthalmic solution) or topical (Such as as topical ointment), but not limited to. Oral route is preferred.

Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (including active ingredients in powder or pellet form), oral tablets, and lozenges. Tablets, dragees, or capsules with talc and / or carbohydrate carriers or binders and the like are particularly suitable for oral application. Suitable carriers for tablets, dragees, or capsules include lactose, cornstarch, and / or potato starch. Syrups or elixirs may be used where sweet vehicles can be used.

Typical tablets that can be prepared by conventional tableting techniques may include: (1) Core: active compound (as a free compound or salt thereof), 250 mg colloidal silicon dioxide (Aerosil?), 1.5 mg fine Crystalline cellulose (Avicel®), 70 mg modified cellulose gum (Ac-Di-Sol®), and 7.5 mg magnesium stearate; (2) Coating: HPMC, about 9 mg Mywacett 9-40 T and about 0.9 mg acylated monoglycerides

Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids such as aqueous or non-aqueous liquid suspensions or solutions.

In nasal tract applications, aqueous solutions comprising the active compound dissolved in an injectable solution or suspension, preferably polyhydroxylated castor oil, are particularly suitable.

How to treat

The present invention provides compounds and pharmaceutical formulations thereof useful for the treatment of diseases, conditions and / or disorders regulated by TRPV3. The relationship between therapeutic effect and inhibition of TRPV3 is described, for example, in WO2007 / 056124; Wissenbach, U. et al , Biology of the cell (2004), 96 , 47-54; Nilius, B. et al ., Physiol Rev (2007), 87 , 165-217; Okuhara, DY et al , Expert Opinion on Therapeutic Targets (2007), 11 , 391-401; Hu, HZ et al , Journal of Cellular Physiology , (2006), 208 , 201-212 and their cited references, all of which are incorporated herein by reference in their entirety and for the purposes presented.

The present patent application also provides a method of administering to a subject a therapeutically effective amount of a compound or pharmaceutical composition of the invention to treat a disease, condition and / or disorder regulated by TRPV3 in a subject in need thereof.

Diseases, conditions, and / or disorders controlled by TRPV3 include heart pain, acute pain, chronic pain, neuropathic pain, post-operative pain, pain due to neuralgia (eg, migraine, joint pain, ischemic myocardium) Neuralgia or trigeminal neuralgia after shingles), pain due to diabetic neuropathy, toothache and cancer pain, inflammatory pain conditions (eg arthritis and osteoarthritis) are believed to be.

In addition, diseases, conditions, and / or disorders controlled by TRPV3 include pain, nociceptive pain, toothache, heart pain arising from ischemic myocardium, pain from migraine, arthralgia, neuropathy, neurodegeneration, retinopathy, neurotic skin Disorders, stroke, bladder hypersensitivity, urinary incontinence, female vulvar pain, gastrointestinal disorders such as susceptible bowel syndrome, gastro-esophageal reflux disease, enterocolitis, ileitis, gastric-duodenal ulcer, inflammatory bowel disease, Crohn's disease, celiac disease, pancreatitis and Respiratory disorders such as inflammatory diseases, allergic and non-allergic rhinitis, asthma or obstructive pulmonary disease, irritation of the skin, eyes or mucous membranes, pruritic conditions such as dermatitis, urethral pruritus, fever, muscle spasms, vomiting, dyskinesia Syndrome, depression, Huntington's disease, memory disorders, limited brain function, amyotrophic lateral sclerosis (ALS), dementia, arthritis, osteoarthritis, diabetes, obesity, urticaria, actinic keratosis, keratosis Including tumors, alopecia, Meniere's disease, tinnitus, hearing, irritability, anxiety and benign prostatic hyperplasia but it is believed not limited to:

General Manufacturing Method

Compounds described herein, including compounds of Formulas (I) and (II) and specific examples, are prepared using techniques known to those skilled in the art. The compounds described herein are prepared via reaction sequences as shown in Schemes 1 and 2. All possible stereoisomers are also envisioned within the scope of the present invention.

Starting materials for the following reaction schemes are commercially available and may be prepared by following methods known to those skilled in the art or by the methods described herein. In general, the compounds according to the invention can be prepared in the above reaction scheme as follows, where all symbols are as defined above.

Compounds of formula (I) wherein R ¹ , R ³ , R ⁴ R ^a , R ^b , R ^c , R ^d , n, m are as defined above and R ² is H can be prepared according to Synthesis Scheme 1. . Thus, the spirocyclic amine of formula (1) is combined with the aryl substituted carboxylic acid of formula (2) to form the amide of formula (I). Amide bond formation is dicyclohexylcarbodiimide (DCC) or 1- (3-dimethylaminopropyl) -3-ethylcarbide in the presence of an activator such as 1-hydroxybenzotriazole (HOBt) and a base in a suitable solvent. It can be carried out according to known reaction conditions using a suitable binder such as bodyimide hydrochloride (EDCI).

Synthetic Scheme 1

Alternatively, compounds of general formula (I) wherein R ¹ , R ³ , R ⁴ R ^a , R ^b , R ^c , R ^d , n, m are as defined above and R ² is H are suitable such as tetrahydrofuran. In the presence of a suitable base such as triethylamine in a solvent, a spirocyclic amine of formula (1) and an acyl halide of formula (3) wherein X is halogen may be prepared to provide a compound of formula (I).

Synthetic Scheme 2

The starting material 3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-one is commercially available or commercially available, or is available from Kabbe, HJ. meat al . Angewandte Prepared by reaction of an appropriately substituted 2-hydroxy acetophenone with cyclic ketones in the presence of a base as described in Chemie (1982), 94 , 254-262. Ram, P. et al . Indian J. Chem . All unsubstituted and substituted 3,4-dihydrospiro [chromen-2,1'-cyclobutane] -4-amines are 3,4-di as described in Sec B , (1981), 12 , 1063-1067. It was prepared through its oxime intermediate in two steps from hydrospiro [chromen-2,1′-cyclobutan] -4-one. Optically pure or enriched isomers of 3,4-dihydrospiro [chromen-2,1'-cyclobutane] -4-amines are prepared by cleavage of the corresponding amines using the appropriate chiral acid as the splitting agent. It became. The best results were obtained when optically pure N -tosylproline was used as the splitting agent. Two enantiomers of N -tosyl proline are Izumiya, N. et. al . Bull . Chem . Soc . Japan . (1953), 26 , 53-56.

Some of the phenylacetic acid derivatives used in the study were commercially available. Derivatives that are not commercially available and commercially available have been prepared by homologation of the appropriate benzaldehydes. Tetrahydronaphthalene acetic acid was prepared from the corresponding tetralone by Wittig-Horner reaction followed by catalytic hydrogenation and ester hydrolysis. Fox, SS et al ., J. Am . Chem . Soc . (1951), 73 , 756-2758 and Jackson et al ., Canadian J. Res . As described in Sec. B , (1935), 13 , 170-172, it was prepared by Fischer indole synthesis from indole-3-acetic acid substituted phenyl hydrazine and g-ketoic acid. Casini, G. et al . Benzisoxazole acetic acid was prepared from 4-hydroxy coumarin as described in J. Heterocyclic Chemistry , (1969), 6 , 279-283.

Rubenstein et al . J. Chem . Soc . As described in (1926), 650, aryl propanoic acid was prepared from aromatic aldehydes and malonic acid using the Knoevenagel condensation reaction as a key reaction. Biaryl propanoic acid was prepared by Suzuki binding reaction of 2-formyl boronic acid and aryl halide followed by homologization of the resulting aldehyde through malonic acid condensation.

All aryl butanoic acids were prepared from aryl aldehydes by a continuous Wittig homologization approach. Thus, substituted benzaldehydes provided the corresponding phenyl acetaldehyde derivatives on the first carbon homolog with methoxymethylene (triphenyl) phosphorane chloride, which was obtained with methyl (triphenylphosphoranilidene) acetate. Further second carbon homologation provided a substituted methyl phenyl butenoate. This gave the desired aryl butanoic acid derivatives upon hydrolysis following catalytic hydrogenation.

Experimental procedure

3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-one:

All starting spirochromen-4-ones required for the synthesis of 3,4-dihydropyrrochromen-4-amine are commercially available in the presence of excess triethylamine (2-3 equivalents) in reflux methanol. Prepared by the reaction of hydroxy acetophenone (1 equiv) and cycloalkanone (1 equiv).

3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-amine:

3,4-Dihydrospiro [chromen-2,1'-cyclobutane] -4 ( 3H ) -one (1.0 equiv) mixed with ethanol (10 V) is hydroxyl in the presence of aqueous NaOH (3 equiv) amine hydrochloride (1.5 eq) and the reaction (4 E) -6- chloro-spiro [chromene -2,1'- cyclobutane] -4 (3 H) - provided the oxime in good yield. The oxime intermediate (1.0 equiv) was reduced with zinc dust (2-3 equiv) mixed with glacial acetic acid (10 vol) to give the free amine. All 4-amino chromene intermediates prepared by this method (Table 1) were characterized by spectral and analytical methods.

Siting Amine  General procedure for manufacturing:

A stirred solution of (±) 3,4-dihydrospiro [chromen-2,1'-cyclobutane] -4-amine derivative (1.0 eq.) Mixed with isopropanol (10-12 ml) was refluxed for 10 min. To yield a clear solution. Then L -proline tosylate (0.5 eq.) Mixed in isopropanol (10 ml) was added over 15 min and further stirred for 30 min at the same temperature. The mixture was cooled to room temperature and the precipitated diastereomeric salt was collected by filtration. The precipitate was dissolved in isopropanol (10 vol) under reflux and slowly cooled to room temperature. The mixture was further stirred for 18 h. Precipitated salts were collected by filtration. A suspension of the salt mixed with water was basified to pH 8.0 by addition of an aqueous K ₂ CO ₃ solution. The solution was extracted with ethyl acetate (3 x 50 ml). The combined organic extracts were dried over K ₂ CO ₃ and evaporated in vacuo to afford 30-38% pure enantiomers. The enantiomeric purity of the material was analyzed by a 250 × 4.6 mm CHIRALPAK-I A column using n-hexane: isopropanol: diethylamine (98: 2: 0.1) as the mobile phase.

Priority Amine  General Procedure for Manufacturing

Of (±) 3,4-dihydrospiro [chromen-2,1'-cyclobutane] -4-amine derivative (1.0 eq.) Using D -proline tosylate (0.5 eq.) As described above Optical cleavage provided the preferential amine in 30-38% separation yield. Enantiomeric purity of the material was determined by a 250 × 4.6 mm CHIRALPAK-I A column using n-hexane: isopropanol: diethylamine (98: 2: 0.1) as the mobile phase.

All intermediates prepared were characterized by spectral and analytical methods prior to use for the preparation of the compounds of the present invention. Structural details and selected physicochemical details of 3,4-dihydrospiro [chromen-2,1'-cyclobutane] -4-amine are given in Table 1.

Table 1 : 3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-amine

Sr . No . rescue Chirality Molecular formula
[α] _D  ( MeOH )
Intermediate 1

Racemic C ₁₂ H ₁₄ ClNO - Intermediate 2

Racemic C ₁₂ H ₁₄ ClNO - Intermediate 3

R-isomer C ₁₂ H ₁₄ ClNO -6.63 ° Intermediate 4

S-isomer C ₁₂ H ₁₄ ClNO + 6.30 ° Intermediate 5

Racemic C ₁₂ H ₁₅ NO Intermediate 6

Racemic C ₁₂ H ₁₄ FNO - Intermediate 7

Racemic C ₁₂ H ₁₃ F ₂ NO - Intermediate 8

R-isomer C ₁₂ H ₁₄ ClNO + 8.64 ° Intermediate 9

S-isomer C ₁₂ H ₁₄ ClNO -8.19 ° Intermediate 10

Racemic C ₁₂ H ₁₄ ClNO - Intermediate 11

Racemic C ₁₉ H ₂₁ NO ₂ - Intermediate 12

Racemic C ₁₉ H ₂₁ NO ₂ - Intermediate 13

Racemic C ₁₂ H ₁₃ Cl ₂ NO - Intermediate 14

Racemic C ₁₃ H ₁₆ ClNO - Intermediate 15

Racemic C ₁₃ H ₁₇ NO ₂ - Intermediate 16

Racemic C ₁₃ H ₁₆ ClNO - Intermediate 17

Racemic C ₁₄ H ₁₈ ClNO - Intermediate 18

Racemic C ₁₁ H ₁₅ NO - Intermediate 19

Racemic C ₉ H ₁₀ ClNS - Intermediate 20

Racemic C ₁₂ H ₁₃ ClFNO - Intermediate 21

Racemic C ₁₁ H ₁₄ ClNO -

Spectral and analytical data selected for 3,4-dihydrospiro [chromen-2,1'-cyclobutane] -4-amine are given below.

Intermediate 1

8-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-amine:

Check if the structure is required for all intermediates

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.68-1.77 (m, 4H), 1.74-1.82 (m, 1H), 1.88-1.93 (m, 3H), 2.35-2.57 (m, 2H), 3.99-4.04 (m, 1H), 6.69 (d, J = 7.2 Hz, 1H), 7.04 (dd J = 2.4, 6.3 Hz, 1H), 7.36 (s, 1H).

Intermediate 2

6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-amine:

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.68-1.77 (m, 4H), 1.85-1.94 (m, 1H), 2.10-2.20 (m, 3H), 2.35-2.45 (m, 2H), 3.93-3.99 (m, 1H), 6.69 (d, J = 7.5 Hz, 1H), 7.04 (dd J = 2.4, 6.9 Hz, 1H), 7.36 (s, 1H).

Intermediate 3

(4 R) -8- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-amine:

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.68-1.77 (m, 2H), 1.74-1.82 (m, 2H), 1.88-1.93 (m, 2H), 1.97-2.05 (m, 1H), 2.10-2.19 (m, 1H), 2.23-2.39 (m, 1H), 2.35-2.57 (m, 1H), 3.99-4.04 (m, 1H), 6.80 (t, J = 7.2 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H); HPLC: retention time for main enantiomer: 26.23 min; ee = 96.06%; Specific lightness: [a] _D =-6.63 °, c = 1% in methanol.

Intermediate 4

(4 S) -8- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-amine:

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.68-1.77 (m, 2H), 1.74-1.82 (m, 2H), 1.88-1.93 (m, 2H), 1.97-2.05 (m, 1H), 2.10-2.19 (m, 1H), 2.23-2.39 (m, 1H), 2.35-2.57 (m, 1H), 3.99-4.04 (m, 1H), 6.80 (t, J = 7.2 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H); HPLC: retention time of main enantiomer: 30.57 min; ee = 97.14%; Specific lightness: [a] _D = + 6.30 °, c = 1% in methanol.

Intermediate 5

3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-amine:

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.65-1.75 (m, 3H), 1.90-2.00 (m, 3H), 2.30-2.36 (m, 2H), 3.94-4.05 (m, 1H), 5.60-5.66 (m, 2H), 6.80-6.90 (m, 2H), 7.08-7.25 (m, 2H).

Intermediate 6

6-fluoro-3,4-dihydrospiro [chromen-2,1'-cyclobutane] -4-amine:

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.67-1.76 (m, 2H), 1.90-2.00 (m, 2H), 2.10-2.20 (m, 2H), 2.28-2.39 (m, 2H), 3.90-4.00 (m, 1H), 5.70-5.76 (m, 1H), 6.70-6.99 (m, 3H), 7.08 (dd, J = 2.4, 9.0 Hz, 1H).

Intermediate 7

6,8-difluoro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-amine:

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.69-1.82 (m, 5H), 2.05-2.22 (m, 3H), 2.36-2.55 (m, 2H), 3.99-4.06 (m, 1H), 6.69-6.76 (m, 1 H), 6.96 (d, J = 9.0 Hz, 1 H).

Intermediate 8

(4 R) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-amine:

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.68-1.77 (m, 4H), 1.74-1.82 (m, 1H), 1.88-1.93 (m, 3H), 2.35-2.57 (m, 2H), 3.99-4.04 (m, 1 H), 6.69 (d, J = 7.2 Hz, 1 H), 7.04 (dd J = 2.4, 6.3 Hz, 1 H), 7.36 (s, 1 H); HPLC: retention time of main enantiomer: 26.57 min; ee = 98.03%; Specific lightness: [a] _D = + 8.64 °, c = 1% in methanol.

Intermediate 9

(4 S) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-amine:

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.68-1.77 (m, 4H), 1.74-1.82 (m, 1H), 1.88-1.93 (m, 3H), 2.35-2.57 (m, 2H), 3.99-4.04 (m, 1 H), 6.69 (d, J = 7.2 Hz, 1 H), 7.04 (dd J = 2.4, 6.3 Hz, 1 H), 7.36 (s, 1 H); HPLC: retention time for main enantiomer: 27.26 min; ee = 99.88%; Specific lightness: [a] _D =-8.19 °, c = 1% in methanol.

Intermediate 10

7-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-amine:

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.59-1.78 (m, 2H), 1.85-1.95 (m, 2H), 2.00-2.10 (m, 2H), 2.16-2.26 (m, 2H), 2.33-2.40 (m, 1H), 2.47-2.57 (m, 1H), 3.99-4.05 (m, 1H), 6.80 (t, J = 7.8 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H), 7.28 ( d, J = 7.8 Hz, 1H).

Intermediate 11

5-benzyloxy-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-amine:

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.00-2.14 (m, 6H), 2.25-2.40 (m, 2H), 3.73 (br s, 2H), 4.29 (t, J = 6.9 Hz, 1H), 5.03 -5.12 (m, 2H), 6.50 (dd, J = 2.4, 8.4 Hz, 2H), 7.07 (t, J = 8.4 Hz, 1H), 7.33-7.40 (m, 5H).

Intermediate 12

7- (benzyloxy) -3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-amine:

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.64-1.71 (m, 1H), 1.84-1.91 (m, 3H), 2.10-2.18 (m, 2H), 2.26-2.34 (m, 1H), 4.45 (br s, 1H), 5.07 (s, 2H), 6.45 (s, 1H), 6.62 (d, J = 7.8 Hz, 1H), 7.09 (s, 1H), 7.26-7.37 (m, 5H), 8.69 (br s, 3H).

Intermediate 13

(6,8-dichloro) -3,4-dihydrospiro [chromen-2,1'-cyclobutane] -4-amine:

IR (KBr) 3426, 2920, 1519, 1458, 1243, 1153, 865 cm ⁻¹ ; ¹ H NMR (300 MHz, CD ₃ OD) δ 1.74-1.90 (m, 3H), 2.14-2.30 (m, 3H), 2.50-2.57 (m, 2H), 2.62-2.69 (m, 1H), 4.65- 4.71 (m, 1 H), 6.90-6.96 (m, 1 H), 7.43 (s, 2 H); ESI-MS ( m / z ) 258.20 (M + H) ⁺ .

Intermediate 14

(6-Chloro-7-methyl) -3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-amine:

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.85-1.93 (m, 4H), 2.05-2.19 (m, 4H), 2.72 (s, 3H), 4.15-4.22 (m, 1H), 4.76 (br s, 2H, interchangeable with D ₂ O ), 6.67 (s, 1H), 7.45 (s, 1H).

Intermediate 15

5-methoxy-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-amine:

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.65-1.80 (m, 1H), 1.90-2.08 (m, 3H), 2.20-2.30 (m, 4H), 2.36 (br s, 2H, D ₂ O Available), 3.83 (s, 3H), 4.15 (t, J = 6.3 Hz, 1H), 6.41 (d, J = 8.1 Hz, 1H), 6.47 (d, J = 8.1 Hz, 1H), 7.06 (t, J = 8.4 Hz, 1H).

Intermediate 16

6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclopentane] -4-amine:

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.30-1.45 (m, 4H), 1.68-1.78 (m, 4H), 2.05-2.12 (m, 2H), 3.90-4.01 (m, 1H), 6.76 (d , J = 8.4 Hz, 1H), 7.02 (dd, J = 2.4, 8.4 Hz, 1H), 7.35 (s, 1H).

Intermediate 17

6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclohexane] -4-amine:

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.35-1.55 (m, 7H), 1.70-1.78 (m, 3H), 2.07-2.17 (m, 2H), 3.93-3.98 (s, 1H), 6.71 (d , J = 8.7 Hz, 1H), 7.04 (dd, J = 2.4, 8.7 Hz, 1H), 7.38 (s, 1H).

Intermediate 18

2,2-dimethylchroman-4-amine:

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.23 (s, 3H), 1.34 (s, 3H), 1.48-1.56 (m, 1H), 1.97-2.03 (m, 3H), 3.80-3.86 (m , 1H), 6.64 (d, J = 6.9 Hz, 1H), 6.83 (t, J = 7.5 Hz, 1H), 7.05 (t, J = 6.9 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H ).

Intermediate 19

6-chlorothiochroman-4-amine:

¹ H NMR (300 MHz, CD ₃ OD) δ 2.20-2.26 (m, 1H), 2.32-2.40 (m, 1H), 3.00-3.10 (m, 2H), 4.51 (br s, 1H), 7.07 (d , J = 8.4 Hz, 1H), 7.17 (dd, J = 2.4, 9.0 Hz, 1H), 7.34 (s, 1H).

Intermediate 20

(8-chloro-6-fluoro) -3,4-dihydrospiro [chromen-2,1'-cyclobutane] -4-amine:

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.74-1.86 (m, 1H), 1.92-2.05 (m, 2H), 2.15-2.29 (m, 3H), 2.45-2.55 (m, 1H), 2.63-2.69 (m, 1 H), 4.66-4.72 (m, 1 H), 7.17-7.26 (m, 2 H).

Intermediate 21

(6-chloro) -2,2-dimethylchroman-4-amine:

IR (KBr) 2977, 2924, 1522, 1482, 1223, 1150, 815 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.29 (s, 3H), 1.48 (s, 3H), 1.84-1.92 (m, 1H), 2.31-2.37 (m, 1H), 4.57-4.64 (m, 1H ), 6.82 (d, J = 8.7 Hz, 1H), 7.23 (dd J = 2.1, 8.4 Hz, 1H), 7.47 (s, 1H).

Example

The invention is further illustrated by the following examples, which are in no way to be construed as limiting the scope of the disclosure, but are intended to be illustrative only.

Example  One

N- (8-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2-phenylacetamide:

To a well stirred solution of intermediate 1 (200 mg, 0.898 mmol) in dichloromethane (10 ml) was added EDCI.HCl (258 mg, 1.348 mmol), HOBt (206 mg, 1.348 mmol), phenylacetic acid (183 mg, 1.348 mmol) and triethylamine (375 μl, 2.696 mmol) were added at room temperature. The reaction mixture was stirred at room temperature under nitrogen for 16 h. The reaction mixture was diluted with water (10 ml) and the layers separated. The aqueous layer was extracted with chloroform (2 × 10 ml) and the combined organic layers were washed with water (2 × 30 ml), brine (30 ml) and dried over Na ₂ SO ₄ . The crude product obtained after evaporation of the solvent under reduced pressure was purified by silica gel column chromatography using 10% acetone in petroleum ether to give 210 mg of the product as an off-white solid; IR (KBr) 3294, 2943, 1647, 1448, 1243, 704 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.63-1.77 (m, 2H), 1.88-1.92 (m, 1H), 2.01-2.08 (m, 1H), 2.17-2.28 (m, 2H), 2.34-2.41 (m, 2H), 3.64 (s, 2H), 5.26 (q, J = 9.3 Hz, 1H), 5.48 (d, J = 9.0 Hz, 1H), 6.72 (t, J = 7.8 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 7.27-7.35 (m, 6H); ESI-MS ( m / z ) 342.50 (M + H) ⁺ .

Example  2

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (2-methoxyphenyl) -acetamide:

The title compound was present in EDCI.HCl (219 mg, 1.148 mmol), HOBt (175 mg, 1.148 mmol) and triethylamine (318 μL, 2.289 mmol) in dichloromethane (10 ml) as described in Example 1. Prepared under intermediate 2 (200 mg, 0.763 mmol) and 2-methoxyphenylacetic acid (190 mg, 1.148 mmol) for 6 h to give 206 mg of the product as a white solid; IR (KBr) 3272, 2979, 1634, 1475, 1248, 753 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.65-1.74 (m, 2H), 1.85-2.04 (m, 2H), 2.12-2.20 (m, 2H), 2.24-2.38 (m, 2H), 3.62 (q , J = 14.7 Hz, 2H), 3.85 (s, 3H), 5.19 (q, J = 9.3 Hz, 1H), 5.78 (d, J = 8.4 Hz, 1H), 6.67 (d, J = 8.7 Hz, 1H ), 6.87-6.94 (m, 3H), 7.02 (d, J = 8.4 Hz, 1H), 7.26-7.30 (m, 2H); ESI-MS ( m / z ) 372.50 (M + H) ⁺ .

Example  3

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclopropane] -4-yl) -2- {2-[(methylsulfonyl) -amino] phenyl} acetamide :

Step 1 : N- (6-Chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (2-nitrophenyl) acetamide: in Example 1 This compound was diluted with dichloromethane (10 ml) in the presence of EDCI.HCl (191 mg, 1.789 mmol), HOBt (153 mg, 1.789 mmol) and triethylamine (802 [mu] L, 2.289 mmol). 500 mg, 1.923 mmol) and 2-nitrophenylacetic acid (348 mg, 1.923 mmol) for 6 h to give 550 mg of the product as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.67-1.84 (m, 5H), 2.10-2.18 (m, 2H), 2.32-2.43 (m, 2H), 3.91 (s, 2H), 5.19-5.27 (m , 1H), 5.92-5.98 (m, 1H), 6.71 (d, J = 9.3 Hz, 1H), 7.00-7.08 (m, 1H), 7.45-7.53 (m, 2H), 7.64 (d, J = 7.5 Hz, 1H), 8.05 (d, J = 8.9 Hz, 1H).

Step 2: 2- (2-aminophenyl) - N - (6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) acetamide: ethanol (5 ml To a well stirred solution of step 1 intermediate (200 mg, 0.512 mmol) mixed with) was added NH ₄ Cl (276 mg, 5.102 mmol) mixed with water (3 ml) at room temperature. The reaction mixture was stirred at the same temperature for 15 min and then heated to 80 ° C for 15 min. Iron (86 mg, 1.552 mmol) was added at the same temperature. The reaction mixture was further refluxed for 2 h. The residue obtained after evaporation of the solvent was extracted with chloroform (2 x 50 ml). This chloroform layer was passed through celite. The layers were separated. The organic layer was washed with water (2 x 30 ml), brine (30 ml) and dried over Na ₂ S0 ₄ . The solvent was evaporated to give 150 mg of product.

Step 3 : N- (6-Chloro-3,4-dihydrospiro [chromen-2,1'-cyclopropane] -4-yl) -2- {2-[(methyl-sulfonyl) amino] phenyl } Acetamide: To a well stirred solution of step 2 intermediate (150 mg, 0.420 mmol) mixed in dichloromethane (5 ml) pyridine (1 ml) was added at 0 ° C. Methanesulfonyl chloride (52 mg, 0.462 mmol) was added dropwise at the same temperature. The reaction mixture was stirred overnight at room temperature under nitrogen. The reaction mixture was diluted with water (20 ml) and the layers separated. The aqueous layer was extracted with chloroform (2 x 20 ml) and the combined organic layers were washed with water (2 x 30 ml), brine (30 ml) and dried over Na ₂ S0 ₄ . The crude product obtained after evaporation of the solvent under reduced pressure was purified by silica gel column chromatography using 10% acetone in petroleum ether to give 210 mg of the product as an off-white solid; IR (KBr) 3348, 3299, 2937, 1646, 1477, 1153, 976 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.67-1.79 (m, 3H), 2.10-2.18 (m, 3H), 2.34-2.40 (m, 2H), 3.10 (s, 3H), 3.66 (d, J = 6.0 Hz, 2H), 5.16 (q, J = 6.9 Hz, 1H), 6.10 (d, J = 9.0 Hz, 1H), 6.72 (d, J = 8.7 Hz, 1H), 6.97 (s, 1H), 7.06 (d, J = 9.0 Hz, 1H), 7.17 (d, J = 7.5 Hz, 1H), 7.20 (s, 1H), 7.31 (t, J = 6.6 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 9.09 (s, 1H); ESI-MS ( m / z ) 433.38 (M ⁻ H) ⁻ .

Example  4

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (2- (cyclopentyloxy) -3-methoxyphenyl) acet amides:

The title compound was diluted with dichloromethane (10 ml) in the presence of EDCI.HCl (221 mg, 1.153 mmol), HOBt (178 mg, 1.153 mmol) and triethylamine (321 μL, 2.307 mmol) as described in Example 1. Prepared from Intermediate 2 (200 mg, 0.763 mmol) and [2- (cyclopentyloxy) -3-methoxyphenyl] acetic acid (283 mg, 1.153 mmol) mixed in to give 236 mg of the product as a white solid; IR (KBr) 3311, 2963, 1653, 1529, 1476, 1266, 813 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.58-1.64 (m, 6H), 1.70-1.80 (m, 6H), 1.97-2.04 (m, 1H), 2.13 (t, J = 7.8 Hz, 2H), 2.26-2.33 (m, 2H), 3.58 (q, J = 14.4 Hz, 2H), 3.81 (s, 3H), 4.99 (br s, 1H), 5.09-5.17 (m, 1H), 6.31 (d, J = 8.1 Hz, 1H), 6.66 (t, J = 8.4 Hz, 1H), 6.81-7.02 (m, 4H).

Example  5

N - [(4 R) -8- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -2- (2-cyclopentyloxy-3-methoxy Phenylacetamide:

The title compound was present in EDCI.HCl (192 mg, 1.047 mmol), HOBt (154 mg, 1.047 mmol) and triethylamine (275 μl, 2.008 mmol) in dichloromethane (10 ml) as described in Example 1. Prepared from intermediate 3 (150 mg, 0.675 mmol) and 2- (2-cyclopentyloxy-3-methoxyphenyl) acetic acid (167 mg, 0.675 mmol) for 5 h under to give 181 mg of the product as a white solid. ; IR (KBr) 3309, 2934, 1654, 1451, 1074, 968 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.60-1.74 (m, 11H), 1.84-1.95 (m, 1H), 2.04-2.10 (m, 1H), 2.16-2.24 (m, 2H), 2.31-2.44 (m, 2H), 3.62 (d, J = 7.8 Hz, 2H), 3.80 (s, 3H), 4.96 (br s, 1H), 5.18 (d, J = 8.7 Hz, 1H), 6.28 (d, J = 8.7 Hz, 1H), 6.68 (t, J = 7.8 Hz, 1H), 6.79-6.88 (m, 2H), 6.96 (t, J = 7.8 Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H ); APCI-MS ( m / z ) 454.72 (M ⁻ H) ⁻ .

Example  6

N - [(4 S) -8- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -2- (2-cyclopentyl-oxy-3-methoxy Methoxy) phenylacetamide:

The title compound was present in EDchloro.HCl (192 mg, 1.047 mmol), HOBt (154 mg, 1.047 mmol) and triethylamine (275 μl, 2.008 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 4 (150 mg, 0.675 mmol) and 2- (2-cyclopentyloxy-3-methoxyphenyl) acetic acid (167 mg, 0.675 mmol) to give 200 mg of the product as a white solid; IR (KBr) 3308, 2934, 1654, 1527, 1451, 1074, 968 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.60-1.74 (m, 11H), 1.83-1.93 (m, 1H), 2.00-2.10 (m, 1H), 2.16-2.24 (m, 2H), 2.31-2.44 (m, 2H), 3.62 (d, J = 7.8 Hz, 2H), 3.79 (s, 3H), 4.96 (br s, 1H), 5.18 (d, J = 8.7 Hz, 1H), 6.28 (d, J = 8.7 Hz, 1H), 6.68 (t, J = 7.8 Hz, 1H), 6.79-6.88 (m, 2H), 6.97 (t, J = 7.8 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H ); APCI-MS ( m / z ) 454.72 (M ⁻ H) ⁻ .

Example  7

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (3,4-dimethoxyphenyl) acetamide:

The title compound was present in EDCI.HCl (219 mg, 1.145 mmol), HOBt (175 mg, 1.145 mmol) and triethylamine (425 μL, 3.053 mmol) in dichloromethane (10 ml) as described in Example 1. Prepared from intermediate 2 (200 mg, 0.763 mmol) and 3,4-dimethoxyphenylacetic acid (224 mg, 1.145 mmol) to give 217 mg of the product as a white solid; IR (KBr) 3232, 2938, 1634, 1478, 1241, 813 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.62-1.70 (m, 2H), 1.87-1.90 (m, 2H), 1.99-2.15 (m, 2H), 2.18-2.37 (m, 2H), 3.60 (q , J = 16.2 Hz, 2H), 3.85 (s, 6H), 5.23 (q, J = 9.6 Hz, 1H), 5.48 (d, J = 9.0 Hz, 1H), 6.68 (d, J = 9.0 Hz, 1H ), 6.77-6.84 (m, 3H), 6.96 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H); ESI-MS ( m / z ) 401.27 (100%).

Example  8

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2-pyridin-2-ylacetamide:

The title compound was present in EDCI.HCl (258 mg, 1.348 mmol), HOBt (206 mg, 1.348 mmol) and triethylamine (375 μl, 2.696 mmol) in dichloromethane (10 ml) as described in Example 1. Prepared from intermediate 2 (200 mg, 0.898 mmol) and 2-pyridylacetic acid (234 mg, 1.348 mmol) to give 151 mg of the product as a white solid; IR (KBr) 3272, 2936, 1644, 1477, 1265, 812 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.65-1.88 (m, 3H), 2.02-2.20 (m, 3H), 2.25-2.35 (m, 2H), 3.71 (q, J = 12.0 Hz, 2H ), 5.00-5.15 (m, 1H), 6.73 (t, J = 7.8 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 7.10-7.20 (m, 2H), 7.22-7.30 (m, 1H), 7.70-7.80 (m, 1H), 8.49 (s, 1H), 8.62 (d, J = 8.4 Hz, 1H); ESI-MS ( m / z ) 343.21 (M + H) ⁺ .

Example  9

N- (3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (1-naphthyl) acetamide:

The title compound was present in EDCI.HCl (230 mg, 1.209 mmol), HOBt (185 mg, 1.209 mmol) and triethylamine (336 μl, 2.418 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 3 (150 mg, 0.806 mmol) and 1-naphthylacetic acid (150 mg, 0.806 mmol) for 3 h to give 151 mg of the product as a white solid; IR (KBr) 3278, 2932, 1635, 1551, 1229, 771 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.50-1.60 (m, 2H), 1.70-1.80 (m, 2H), 2.05-2.13 (m, 3H), 2.25 (dd, J = 5.7, 13.5 Hz, 1H ), 4.10 (s, 2H), 5.18-5.24 (m, 1H), 5.35-5.42 (m, 1H), 6.58-6.70 (s, 3H), 7.00 (t, J = 7.8 Hz, 1H), 7.30- 7.39 (m, 2H), 7.48-7.59 (m, 2H), 7.70-7.77 (m, 1H), 7.84 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H); APCI-MS ( m / z ) 358.36 (M + H) ⁺ .

Example  10

N- (6-Fluoro- (3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (1-naphthyl) acetamide:

The title compound was present in EDCI.HCl (463 mg, 2.455 mmol), HOBt (246 mg, 1.611 mmol) and triethylamine (926 μl, 4.835 mmol) in dichloromethane (10 ml) as described in Example 1. Prepared from intermediate 6 (300 mg, 1.611 mmol) and 1-naphthylacetic acid (400 mg, 1.933 mmol) to afford 310 mg of the product as a white solid; IR (KBr) 3280, 2933, 1643, 1485, 1202, 795 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.44-1.54 (m, 2H), 1.75-1.80 (m, 2H), 2.02-2.10 (m, 3H), 2.13-2.26 (m, 1H), 4.11 (q , J = 16.5 Hz, 2H), 5.19 (q, J = 9.0 Hz, 1H), 5.32 (d, J = 8.4 Hz, 1H), 6.42 (dd, J = 3.0, 6.3 Hz, 1H), 6.60-6.68 (m, 1H), 6.69-6.73 (m, 1H), 7.39-7.50 (m, 2H), 7.52-7.61 (m, 2H), 7.77-7.87 (m, 2H), 7.99 (d, J = 8.1 Hz , 1H); ESI-MS ( m / z ) 376.32 (M + H) ⁺ .

Example  11

N - [(4 R) with 6, 8-difluoro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -2- (1-naphthyl) acetamide amides:

The title compound was present in EDCI.HCl (121 mg, 0.632 mmol), HOBt (96 mg, 0.632 mmol) and triethylamine (176 μl, 1.265 mmol) in dichloromethane (10 ml) as described in Example 1. Prepared from intermediate 7 (95 mg, 0.421 mmol) and 1-naphthylacetic acid (117 mg, 0.632 mmol) under to give 91 mg of the product as an off-white solid; IR (KBr) 3272, 2936, 1645, 1565, 1484, 1226, 794 cm ^-1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.59-1.61 (m, 2H), 1.77-1.87 (m, 2H), 2.10-2.18 (m, 2H), 2.24-2.30 (m, 2H), 4.12 (q , J = 16.5 Hz, 2H), 5.16-5.24 (m, 1H), 5.30-5.36 (m, 1H), 6.22 (d, J = 8.7 Hz, 1H), 6.55-6.62 (m, 1H), 7.39- 7.44 (m, 2H), 7.54-7.61 (m, 2H), 7.79 (d, J = 6.9 Hz, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H ); ESI-MS ( m / z ) 409.19 (M) ⁺ .

Example  12

N - [(4 R) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -2- (1-naphthyl) acetamide:

The title compound was present in EDCI.HCl (193 mg, 1.011 mmol), HOBt (154 mg, 1.011 mmol) and triethylamine (281 μl, 2.022 mmol) in dichloromethane (10 ml) as described in Example 1. Prepared from intermediate 8 (150 mg, 0.674 mmol) and 1-naphthylacetic acid (188 mg, 1.011 mmol) under 123 mg of the product as a white solid; IR (KBr) 3277, 2952, 1640, 1478, 1236, 751 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.46-1.53 (m, 2H), 1.75-1.81 (m, 2H), 2.07-2.16 (m, 3H), 2.22-2.39 (m, 1H), 4.12 (q , J = 16.5 Hz, 2H), 5.19 (q, J = 9.6 Hz, 1H), 5.33 (d, J = 8.4 Hz, 1H), 6.58 (d, J = 8.7 Hz, 1H), 6.66 (s, 1H ), 6.93 (d, J = 7.2 Hz, 1H), 7.23-7.42 (m, 2H), 7.54 (t, J = 14.1 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H), 7.82 (dd , J = 8.4, 10.2 Hz, 2H), 7.99 (d, J = 8.7 Hz, 1H); ESI-MS ( m / z ) 392.49 (M + H) ⁺ .

Example  13

N - [(4 S) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -2- (1-naphthyl) -acetamide:

The title compound was present in EDCI.HCl (257 mg, 1.345 mmol), HOBt (206 mg, 1.341 mmol) and triethylamine (374 μl, 2.692 mmol) in dichloromethane (10 ml) as described in Example 1. Prepared from intermediate 9 (200 mg, 0.896 mmol) and 1-naphthylacetic acid (200 mg, 1.076 mmol) under 169 mg of the product as a white solid; IR (KBr) 3272, 2942, 1642, 1473, 1266, 776 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.45-1.53 (m, 2H), 1.74-1.82 (m, 2H), 2.06-2.12 (m, 3H), 2.14-2.28 (m, 1H), 4.11 (q , J = 16.5 Hz, 2H), 5.19 (q, J = 9.6 Hz, 1H), 5.33 (d, J = 9.0 Hz, 1H), 6.57 (d, J = 8.7 Hz, 1H), 6.66 (s, 1H ), 6.93 (d, J = 6.3 Hz, 1H), 7.39-7.43 (m, 2H), 7.51 (t, J = 6.9 Hz, 1H), 7.61 (t, J = 6.9 Hz, 1H), 7.70 (dd , J = 1.8, 5.1 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H); ESI-MS ( m / z ) 392.45 (M + H) ⁺ .

Example  14

N- (7-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (1-naphthyl) acetamide:

The title compound was prepared in the presence of EDCI.HCl (221 mg, 1.141 mmol), HOBt (176 mg, 1.141 mmol) and triethylamine (317 μL, 2.283 mmol) in THF (5 ml) as described in Example 1. Prepared from intermediate 10 (200 mg, 0.761 mmol) and 1-naphthylacetic acid (171 mg, 0.913 mmol) to give 250 mg of the product as a white solid; IR (KBr) 3236, 2945, 1638, 1412, 1223, 788 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.47-1.55 (m, 2H), 1.72-1.78 (m, 2H), 2.09 (t, J = 7.8 Hz, 3H), 2.16-2.26 (m, 1H), 4.09 (q, J = 6.9 Hz, 2H), 5.11-5.19 (m, 1H), 5.29 (d, J = 8.4 Hz, 1H), 6.55 (s, 2H), 6.66 (s, 1H), 7.35-7.42 (m, 2H), 7.49-7.59 (m, 2H), 7.77 (d, J = 7.2 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H) ; APCI-MS ( m / z ) 392.12 (M + H) ⁺ .

Example  15

N - [(4 R) -8- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -2- (1-naphthyl) -acetamide:

The title compound was present in EDCI.HCl (128 mg, 0.672 mmol), HOBt (102 mg, 0.672 mmol) and triethylamine (185 μl, 2.022 mmol) in dichloromethane (10 ml) as described in Example 1. Prepared from intermediate 3 (100 mg, 0.448 mmol) and 1-naphthylacetic acid (99 mg, 0.531 mmol) to give 100 mg of the product as a white solid; IR (KBr) 3271, 2938, 1636, 1449, 1244, 778 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.62-1.78 (m, 5H), 2.11-2.30 (m, 3H), 4.09 (q, J = 16.8 Hz, 2H), 5.23 (q, J = 9.3 Hz, 1H), 5.46 (d, J = 7.8 Hz, 1H), 6.52 (t, J = 7.2 Hz, 1H), 6.60 (d, J = 7.2 Hz, 1H), 7.07 (d, J = 7.8 Hz, 1H) , 7.37-7.42 (m, 2H), 7.48-7.59 (m, 2H), 7.77 (t, J = 6.3 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H); ESI-MS ( m / z ) 392.59 (M + H) ⁺ .

Example  16

N - [(4 S) -8- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -2- (1-naphthyl) -acetamide:

The title compound was present in EDCI.HCl (193 mg, 1.008 mmol), HOBt (154 mg, 1.008 mmol) and triethylamine (279 μl, 2.004 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 4 (150 mg, 0.668 mmol) and 1-naphthylacetic acid (149 mg, 0.801 mmol) to give 150 mg of the product as an off-white solid; IR (KBr) 3275, 2939, 1636, 1244, 778 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.61-1.79 (m, 5H), 2.10-2.30 (m, 3H), 4.08 (q, J = 16.5 Hz, 2H), 5.22 (q, J = 8.7 Hz, 1H), 5.43 (d, J = 8.1 Hz, 1H), 6.52 (t, J = 7.2 Hz, 1H), 6.60 (d, J = 7.2 Hz, 1H), 7.07 (d, J = 7.8 Hz, 1H) , 7.35-7.42 (m, 2H), 7.48-7.60 (m, 2H), 7.77 (t, J = 6.3 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H); ESI-MS ( m / z ) 392.63 (M + H) ⁺ .

Example  17

N- (5-hydroxy-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (1-naphthyl)-acetamide:

Step 1 : N- (5-benzyloxy-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (1-naphthyl) acetamide: Intermediate 11 in the presence of EDCI.HCl (772 mg, 4.027 mmol), HOBt (411 mg, 2.685 mmol) and triethylamine (1.123 ml, 2.274 mmol) in dichloromethane (10 ml) as described in Example 1 Prepared from (872 mg, 2.954 mmol) and 1-naphthylacetic acid (500 mg, 2.685 mmol) to give 420 mg of the product as a white solid; IR (KBr) 3293, 2929, 1638, 1466, 1120, 778 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.25-1.35 (m, 2H), 1.45-1.52 (m, 1H), 1.58-1.64 (m, 1H), 1.94-2.00 (m, 2H), 2.15-2.25 (m, 2H), 3.64-3.70 (m, 1H), 3.98-4.04 (m, 1H), 4.87-5.02 (m, 2H), 5.23-5.30 (m, 2H), 6.34-6.40 (m, 2H) , 7.00-7.07 (m, 3H), 7.28-7.39 (m, 7H), 7.67-7.75 (m, 2H), 7.85-7.91 (m, 1H); APCI-MS ( m / z ) 464.5 (M + H) ⁺ .

Step 2 : N- (5-hydroxy-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (1-naphthyl) acetamide: step 1 intermediate Deprotection of (400 mg, 0.863 mmol) was performed using 50% Pd / C (80 mg) mixed in methanol (70 ml) in a Paar apparatus for 8 h at 65 psi pressure. The reaction mixture was filtered through a celite bed. The filtrate was concentrated under reduced pressure to give a crude residue which was purified by silica gel column chromatography to give 115 mg of product as a white solid; IR (KBr) 3293, 2972, 1608, 1469, 1120, 775 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.26-1.35 (m, 1H), 1.89-1.96 (m, 2H), 2.12-2.22 (m, 2H), 3.64-3.70 (m, 1H), 3.98-4.04 (m, 1H), 4.85-4.91 (m, 1H), 5.00-5.08 (m, 1H), 5.20-2.30 (m, 2H), 6.33-6.42 (m, 2H), 6.99-7.07 (m, 2H) , 7.28-7.42 (m, 5H), 7.68 (d, J = 7.5 Hz, 1H), 7.75-7.86 (m, 1H), 10.02 (br s 1H); ESI-MS ( m / z ) 374.37 (M + H) ⁺ .

Example  18

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (2-naphthyl) acetamide:

The title compound was present in EDCI.HCl (213 mg, 1.145 mmol), HOBt (176 mg, 1.145 mmol) and triethylamine (425 μL, 3.052 mmol) in dichloromethane (10 ml) as described in Example 1. Prepared from intermediate 2 (200 mg, 0.764 mmol) and 2-naphthylacetic acid (213 mg, 1.141 mmol) to give 193 mg of the product as a white solid; IR (KBr) 3262, 2933, 1643, 1474, 1230, 816 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.63-1.77 (m, 2H), 1.84-1.92 (m, 2H), 1.95-2.02 (m, 2H), 2.16-2.36 (m, 2H), 3.82 (s , 2H), 5.24 (q, J = 9.6 Hz, 1H), 5.50 (d, J = 8.7 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 9.3 Hz, 2H ), 7.39 (d, J = 8.4 Hz, 1H), 7.45-7.50 (m, 2H), 7.73 (s, 1H), 7.78-7.86 (m, 3H); ESI-MS ( m / z ) 392.58 (M + H) ⁺ .

Example  19

N - [(4 R) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -2- (6-methoxy-2-naphthyl) Propanamide:

The title compound was present in EDCI.HCl (221 mg, 1.153 mmol), HOBt (176 mg, 1.153 mmol) and triethylamine (321 μL, 2.307 mmol) in dichloromethane (10 ml) as described in Example 1. under prepared from intermediate 8 (200 mg, 0.769 mmol) and (2 S) -2- (6- methoxy-2-naphthyl) propanoic acid (213 mg, 0.923 mmol) to give the product in 112 mg of a white solid did; IR (KBr) 3351, 2938, 1652, 1518, 1482, 1261, 857 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.64 (s, 3H), 1.66 (s, 2H), 1.80-1.90 (m, 2H), 2.08-2.14 (m, 3H), 2.21-2.27 (m, 1H ), 3.76 (q, J = 6.9 Hz, 1H), 3.89 (s, 3H), 5.16-5.24 (m, 1H), 5.47 (d, J = 8.4 Hz, 1H), 6.60-6.67 (m, 1H) , 6.94-7.02 (m, 1H), 7.10-7.16 (m, 3H), 7.36 (dd, J = 1.5 Hz, 1.5 Hz, 1H), 7.64-7.72 (m, 3H); APCI-MS ( m / z ) 436.29 (M + H) ⁺ .

Example  20

N - [(4 S) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -2- (6-methoxy-2-naphthyl) Propanamide:

The title compound was present in EDCI.HCl (221 mg, 1.153 mmol), HOBt (176 mg, 1.153 mmol) and triethylamine (321 μL, 2.307 mmol) in dichloromethane (10 ml) as described in Example 1. under prepared from intermediate 9 (200 mg, 0.769 mmol) and (2 S) -2- (6- methoxy-2-naphthyl) propanoic acid (213 mg, 0.923 mmol) to give the product in 103 mg of a white solid did; IR (KBr) 3267, 2932, 1638, 1477, 1263, 814 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.65 (s, 3H), 1.68-1.74 (m, 2H), 1.84-1.90 (m, 1H), 2.13 (t, J = 7.8 Hz, 3H), 2.27-2.37 (m, 2H), 3.74 (q, J = 6.9 Hz, 1H), 3.89 (s, 3H), 5.22 (d, J = 9.9 Hz, 1H), 5.50 (d, J = 8.4 Hz, 1H ), 6.60 (d, J = 9.0 Hz, 1H), 6.70-6.76 (m, 1H), 6.94 (dd, J = 1.8, 2.1 Hz, 1H), 7.10-7.16 (m, 2H), 7.39 (d, J = 8.7 Hz, 1 H), 7.67-7.76 (m, 3 H); APCI-MS ( m / z ) 436.37 (M + H) ⁺ .

Example  21

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (1,2,3,4-tetrahydro naphthalen-1-yl Acetamide:

The title compound was present in EDCI.HCl (227 mg, 1.663 mmol), HOBt (121 mg, 0.791 mmol) and triethylamine (330 μL, 2.371 mmol) in dichloromethane (10 ml) as described in Example 1. Prepared from intermediate 2 (212 mg, 0.951 mmol) and 5,6,7,8-tetrahydronaphthalen-1-ylacetic acid (150 mg, 0.791 mmol) to give 154 mg of the product as a white solid; IR (KBr) 3278, 2935, 1637, 1474, 1263, 818 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.70-1.87 (m, 6H), 2.03-2.18 (m, 3H), 2.20-2.46 (m, 3H), 2.60-2.70 (m, 1H), 2.77 (br s, 2H), 3.47 (br s, 2H), 5.27 (q, J = 9.3 Hz, 1H), 5.45 (d, J = 7.8 Hz, 1H), 6.70 (d, J = 8.7 Hz, 1H), 7.05 -7.18 (m, 6 H); ESI-MS ( m / z ) 394.76 (M ⁻ H) ⁻ .

Example  22

N -[(6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl)]-2- (1,2,3,4-tetrahydro naphthalene-2 Acylamide:

The title compound was present in EDCI.HCl (302 mg, 1.585 mmol), HOBt (241 mg, 1.585 mmol) and triethylamine (439 μl, 3.165 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 2 (218 mg, 1.053 mmol) and 1,2,3,4-tetrahydronaphthalen-2-ylacetic acid (200 mg, 1.053 mmol) to give 40 mg of the product as a white solid; IR (KBr) 3250, 2931, 2343, 1635, 1474, 1232, 738 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.67-1.82 (m, 3H), 1.83-1.95 (m, 2H), 2.21-2.29 (m, 3H), 2.30-2.39 (m, 4H), 2.48-2.59 (m, 1H), 2.85-2.96 (m, 3H), 5.32 (q, J = 7.8 Hz, 1H), 5.59 (d, J = 7.8 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H) , 6.73 (d, J = 8.4 Hz, 1H), 7.08-7.14 (m, 6H); ESI-MS ( m / z ) 396.95 (M + H) ⁺ .

Example  23

2- (1,3-benzodioxol-5-yl) - N - (6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) acetamide:

The title compound was present in EDCI.HCl (256 mg, 1.343 mmol), HOBt (205 mg, 1.343 mmol) and triethylamine (366 μl, 2.683 mmol) in dichloromethane (10 ml) as described in Example 1. Prepared from intermediate 2 (200 mg, 0.892 mmol) and 1,3-benzodioxol-4-ylacetic acid (161 mg, 0.881 mmol) to give 125 mg of the product as a white solid; IR (KBr) 3059, 2941, 1634, 1488, 1243, 1045 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.63-1.72 (m, 2H), 1.83-1.89 (m, 1H), 2.00-2.07 (m, 1H), 2.12-2.18 (m, 2H), 2.25-2.38 (m, 2H), 3.55 (d, J = 2.4 Hz, 2H), 5.21 (q, J = 9.9 Hz, 1H), 5.49 (d, J = 8.1 Hz, 1H), 5.94 (s, 2H), 6.68 -6.76 (m, 4H), 6.93 (s, 1H), 7.04 (dd, J = 2.4, 6.3 Hz, 1H); ESI-MS ( m / z ) 384.16 (M ⁻ H) ⁻ .

Example  24

N- (6-fluoro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (5-fluoro-3-methyl-1 H -indole- 2-yl) acetamide:

The title compound was present in EDCI.HCl (276 mg, 1.145 mmol), HOBt (221 mg, 1.145 mmol) and triethylamine (401 μL, 3.003 mmol) in dichloromethane (10 ml) as described in Example 1. Prepared from intermediate 6 (200 mg, 0.963 mmol) and (5-fluoro-2-methyl-1 H -indol-3-yl) acetic acid (200 mg, 0.963 mmol) under to give 18 mg of the product as a white solid. did; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.52-1.74 (m, 4H), 1.88-1.95 (m, 2H), 2.08-2.25 (m, 2H), 2.40 (s, 3H), 3.70 (s , 2H), 5.23 (q, J = 8.7 Hz, 1H), 5.68 (d, J = 9.0 Hz, 1H), 6.61-6.66 (m, 2H), 6.72-6.89 (m, 2H), 7.07-7.18 ( m, 2H), 8.01 (s, 1 H); ESI-MS ( m / z ) 397.33 (M + H) ⁺ .

Example  25

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (5-methoxy-2-methyl-1 H -indole-3 Acylamide:

The title compound was present in EDCI.HCl (256 mg, 1.345 mmol), HOBt (205 mg, 1.345 mmol) and triethylamine (374 μL, 3.003 mmol) in dichloromethane (10 ml) as described in Example 1. Prepared from intermediate 2 (200 mg, 0.896 mmol) and (5-methoxy-2-methyl-1 H -indol-3-yl) acetic acid (195 mg, 0.896 mmol) under to give 35 mg of the product as a white solid did; IR (KBr) 3383, 2934, 2343, 1648, 1475, 1217, 820 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.50-1.65 (m, 5H), 1.83-1.95 (m, 3H), 2.40 (s, 3H), 3.73 (s, 3H), 3.82 (s, 2H), 5.23 (q, J = 9.6 Hz, 1H), 5.76 (d, J = 8.7 Hz, 1H), 6.62 (d, J = 8.4 Hz, 1H), 6.77 (dd, J = 2.4, 6.6 Hz, 1H), 6.82-6.89 (m, 2H), 6.98 (dd, J = 2.1, 6.3 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.84 (s, 1H); ESI-MS ( m / z ) 423.58 (M ⁻ H) ⁻ .

Example  26

2- (1,2-benzisoxazol-3-yl) - N - [(4 R ) - (6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4 Acylamide:

The title compound was present in EDCI.HCl (219 mg, 1.145 mmol), HOBt (175 mg, 1.145 mmol) and triethylamine (425 μL, 3.053 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 8 (200 mg, 0.763 mmol) and 1,2-benzisoxazol-3-ylacetic acid (148 mg, 0.839 mmol) to give 176 mg of the product as a white solid; IR (KBr) 3314, 2940, 1654, 1533, 1235, 749 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.61-1.68 (m, 1H), 1.77-1.87 (m, 2H), 2.03-2.14 (m, 3H), 2.29-2.38 (m, 2H), 4.06 (s , 2H), 5.24 (q, J = 7.2 Hz, 1H), 6.34 (d, J = 8.7 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 6.92 (s, 1H), 7.02 (d , J = 9.0 Hz, 1H), 7.28-7.38 (m, 1H), 7.57 (s, 2H), 7.80 (d, J = 7.8 Hz, 1H); ESI-MS ( m / z ) 383.50 (M + H) ⁺ .

Example  27

2- (1,2-benzisoxazol-3-yl) - N - [(4 S ) - (6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4 Acylamide:

The title compound was present in EDCI.HCl (219 mg, 1.145 mmol), HOBt (175 mg, 1.145 mmol) and triethylamine (425 μL, 3.053 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 9 (200 mg, 0.763 mmol) and 1,2-benzisoxazol-3-ylacetic acid (148 mg, 0.839 mmol) to give 176 mg of the product as a white solid; IR (KBr) 3314, 2940, 1654, 1533, 1235, 749 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.60-1.67 (m, 1H), 1.79-1.87 (m, 2H), 2.05-2.18 (m, 3H), 2.29-2.38 (m, 2H), 4.05 (s , 2H), 5.24 (q, J = 7.2 Hz, 1H), 6.34 (d, J = 8.7 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 6.92 (s, 1H), 7.02 (d , J = 9.0 Hz, 1H), 7.28-7.38 (m, 1H), 7.57 (s, 2H), 7.80 (d, J = 7.8 Hz, 1H); ESI-MS ( m / z ) 383.50 (M + H) ⁺ .

Example  28

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-cyclopentyloxy phenyl) propanamide:

The title compound was present in EDCI.HCl (222 mg, 1.152 mmol), HOBt (177 mg, 1.152 mmol) and triethylamine (427 μl, 3.116 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 2 (200 mg, 0.779 mmol) and 3-[(2-cyclopentyloxyphenyl) propanoic acid (181 mg, 0.779 mmol) to give 150 mg of the product as a white solid; IR (KBr) 3316, 2952, 1651, 1488, 749 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.58-1.65 (m, 3H), 1.72-1.87 (m, 8H), 2.02-2.12 (m, 3H), 2.26-2.36 (m, 2H), 2.56 (t , J = 6.9 Hz, 2H), 2.95 (t, J = 7.5 Hz, 2H), 4.72 (br s, 1H), 5.15 (q, J = 8.7 Hz, 1H), 5.59 (d, J = 7.8 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 6.80-6.88 (m, 3H), 7.04 (dd, J = 2.4, 5.7 Hz, 1H), 7.14 (d, J = 7.5 Hz, 2H); ESI-MS ( m / z ) 440.34 (M) ⁺ .

Example  29

N - [(4 R) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -3- (2-Cyclopentyl-phenoxy) phenyl-propanamide :

The title compound was present in EDCI.HCl (128 mg, 0.672 mmol), HOBt (102 mg, 0.672 mmol) and triethylamine (187 μl, 1.344 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 8 (100 mg, 0.448 mmol) and 3-[(3-cyclopentyloxyphenyl) propanoic acid (105 mg, 0.448 mmol) to give 105 mg of the product as a white solid; IR (KBr) 3019, 2400, 2973, 1663, 1215, 761 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.64-1.70 (m, 4H), 1.80-1.88 (m, 7H), 2.00-2.08 (m, 1H), 2.15 (t, J = 8.1 Hz, 2H), 2.25-2.32 (m, 2H), 2.55 (q, J = 6.9 Hz, 2H), 2.97 (t, J = 6.6 Hz, 2H), 4.72 (br s, 1H), 5.17 (q, J = 4.2 Hz, 1H), 5.40 (d, J = 7.8 Hz, 1H), 6.68-6.78 (m, 4H), 6.93 (s, 1H), 7.05 (d, J = 6.6 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H); ESI-MS ( m / z ) 440.54 (M + H) ⁺ .

Example  30

N - [(4 S) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -3- (2-cyclopentyloxy) phenyl-propanamide:

The title compound was present in EDCI.HCl (128 mg, 0.672 mmol), HOBt (102 mg, 0.672 mmol) and triethylamine (186 μl, 1.344 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 9 (104 mg, 0.444 mmol) and 3-[(2-cyclopentyloxyphenyl) propanoic acid (100 mg, 0.444 mmol) to give 100 mg of the product as a white solid; IR (KBr) 3293, 2934, 1694, 1532, 1216, 756 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.62-1.70 (m, 6H), 1.78-1.85 (m, 5H), 2.04-2.16 (m, 3H), 2.28-2.32 (m, 2H), 2.54 (d , J = 6.9 Hz, 2H), 2.90-2.99 (m, 2H), 4.72 (br s, 1H), 5.18 (q, J = 5.7 Hz, 1H), 5.37 (d, J = 7.5 Hz, 1H), 6.71-6.77 (m, 3H), 6.92 (s, 1H), 7.04 (d, J = 7.8 Hz, 1H), 7.10-7.18 (m, 2H); ESI-MS ( m / z ) 440.55 (M + H) ⁺ .

Example  31

N - [(4 S) - (8- Chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (4-methoxyphenyl) -1-naphthyl Tyl Propanamide:

The title compound was present in EDCI.HCl (128 mg, 0.672 mmol), HOBt (102 mg, 0.672 mmol) and triethylamine (186 μl, 1.344 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 3 (100 mg, 0.448 mmol) and 3-[(2-cyclopentyloxyphenyl) propanoic acid (125 mg, 0.536 mmol) to give 142 mg of the product as a white solid; IR (KBr) 3321, 2950, 1646, 1453, 1239, 989 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.68-1.75 (m, 11H), 2.05-2.17 (m, 3H), 2.36-2.46 (m, 2H), 2.56 (t, J = 7.2 Hz, 2H), 2.96 (t, J = 6.6 Hz, 2H), 4.72 (br s, 1H), 5.22 (q, J = 8.7 Hz, 1H), 5.55 (d, J = 8.7 Hz, 1H), 6.69 (s, 2H) , 6.78-6.88 (m, 2 H), 7.14-7.19 (m, 3 H); ESI-MS ( m / z ) 440.34 (M + H) ⁺ .

Example  32

N - [(4 S) -8- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane-4-yl] -2- [2- (2-cyclopentyloxy-phenyl) propanamide:

The title compound was present in EDCI.HCl (129 mg, 0.674 mmol), HOBt (103 mg, 0.674 mmol) and triethylamine (187 μl, 1.348 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 4 (100 mg, 0.448 mmol) and 3-[(2-cyclopentyloxyphenyl) propanoic acid (115 mg, 0.494 mmol) to give 211 mg of the product as a white solid; IR (KBr) 3321, 2950, 1646, 1453, 1239, 989 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.68-1.75 (m, 11H), 2.05-2.17 (m, 3H), 2.36-2.46 (m, 2H), 2.56 (t, J = 7.2 Hz, 2H), 2.96 (t, J = 6.6 Hz, 2H), 4.72 (br s, 1H), 5.22 (q, J = 8.7 Hz, 1H), 5.55 (d, J = 8.7 Hz, 1H), 6.69 (s, 2H) , 6.78-6.88 (m, 2 H), 7.14-7.19 (m, 3 H); ESI-MS ( m / z ) 440.34 (M + H) ⁺ .

Example  33

7-benzyloxy- N- (3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-cyclopentyloxy phenyl) propanamide:

The title compound was present in EDCI.HCl (173 mg, 0.904 mmol), HOBt (138 mg, 0.904 mmol) and triethylamine (335 μl, 2.413 mmol) in dichloromethane (10 ml) as described in Example 1. Prepared from intermediate 12 (200 mg, 0.603 mmol) and 3- (2-cyclopentyloxyphenyl) propanoic acid (169 mg, 0.723 mmol) to give 163 mg of the product as a white solid; IR (KBr) 3324, 2954, 1647, 1239, 1171, 745 cm ^-1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.66-1.79 (m, 11H), 2.04-2.12 (m, 4H), 2.25-2.32 (m, 2H), 2.52 (t, J = 7.2 Hz, 2H), 2.94 (t, J = 7.5 Hz, 2H), 4.69 (br s, 1H), 4.98 (s, 2H), 5.17 (q, J = 5.7 Hz, 1H), 5.48 (d, J = 9.3 Hz, 1H) , 6.39-6.46 (m, 2H), 6.67 (d, J = 8.7 Hz, 1H), 6.75-6.85 (m, 2H), 7.10-7.16 (m, 2H), 7.29-7.37 (m, 4H); ESI-MS ( m / z ) 510.34 (M + H) ⁺ .

Example  34

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- {2-[(isopropyl sulfonyl) amino] phenyl} propanamide :

Step 1: (2 E) - N - (6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- {2 - [(isopropylsulfonyl Ponyl) amino] phenyl} acrylamide: This compound was prepared in EDCI.HCl (165 mg, 0.865 mmol), HOBt (132 mg, 0.865 mmol) and triethylamine in dichloromethane (10 ml) as described in Example 1. from acrylic acid (186 mg, 0.692 mmol) - intermediate 2 (150 mg, 0.576 mmol) and (2 E) -3- in the presence of (240 ㎕, 1.732 mmol) { [( isopropylsulfonyl) amino] phenyl} 2 To give 125 mg of the product as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.82-0.90 (m, 2H), 1.20-1.26 (m, 4H), 1.74-1.85 (m, 3H), 2.10-2.20 (m, 3H), 2.46-2.52 (m, 2H), 3.29 (t, J = 6.3 Hz, 1H), 3.34-3.40 (m, 1H), 6.00-6.06 (m, 1H), 6.40 (d, J = 15.6 Hz, 1H), 6.72 ( (d, J = 8.4 Hz, 1H), 7.05-7.18 (m, 3H), 7.33 (d, J = 7.8 Hz, 2H), 7.49 (d, J = 7.5 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 8.08 (d, J = 15.9 Hz, 1H).

Step 2 : N- (6-Chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- {2-[(isopropyl-sulfonyl) amino] Phenyl} propanamide: Step 1 intermediate (110 mg, 0.232 mmol) was reduced using 5% Pd / C (30 mg) mixed with ethyl acetate in a Paar apparatus for 1.5 h at 30 psi pressure. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to afford crude compound which was purified by silica gel column chromatography using 13% acetone in petroleum ether to give 51 mg of product as a white solid. ; IR (Neat) 3343, 2936, 1651, 1537, 1475, 1320, 1102, 756 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.40-1.50 (m, 5H), 1.56-1.62 (m, 2H), 1.65-1.71 (m, 2H), 1.85-1.91 (m, 1H), 2.10-2.20 (m, 3H), 2.27-2.33 (m, 2H), 2.60-2.68 (m, 2H), 3.04-3.12 (m, 2H), 3.32-3.38 (m, 1H), 5.15 (br s, 1H), 5.60 (br s, 1H), 6.66-6.72 (m, 2H), 7.03 (d, J = 6.9 Hz, 1H), 7.12-7.20 (m, 2H), 7.47 (d, J = 7.8 Hz, 1H), 8.22 (s, 1 H); ESI-MS ( m / z ) 477.95 (M) ⁺ .

Example  35

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-pyridin-2-ylphenyl) propanamide:

Step 1: (2 E) - N - (6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (2-pyridin-2-yl Phenyl) acrylamide: This compound was diluted in dichloromethane (10 ml) as described in Example 1, EDCI.HCl (332 mg, 1.730 mmol), HOBt (177 mg, 1.153 mmol) and triethylamine (402 μl, intermediate in the presence of 2.884 mmol) 2 (300 mg, 1.153 mmol) and (2 E) -3- (2- pyridin-2-yl-phenyl) acrylic acid (260 mg, prepared from 1.153 mmol) of the product of white 400 mg Provided as a solid; IR (Neat) 3228, 2935, 1651, 1540, 1475, 1264, 759 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.80-1.90 (m, 2H), 2.08-2.20 (m, 4H), 2.35-2.49 (m, 2H), 3.46 (q, J = 7.2 Hz, 1H), 5.34 (q, J = 9.3 Hz, 1H), 5.84 (d, J = 8.7 Hz, 1H), 6.37 (d, J = 15.0 Hz, 1H), 6.73 (d, J = 8.1 Hz, 1H), 7.08 ( d, J = 8.4 Hz, 1H), 7.14 (s, 1H), 7.33-7.43 (m, 4H), 7.61-7.70 (m, 3H), 8.55-8.61 (m, 2H); ESI-MS ( m / z ) 431.24 (M + H) ⁺ .

Step 2 : N- (6-Chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-pyridin-2-ylphenyl) propanamide: Step 1 Intermediate (300 mg, 0.696) was reduced using Pd / C (50 mg) mixed with methanol in a Paar apparatus for 3 h at 40 psi pressure. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to afford crude compound which was purified by silica gel column chromatography using 25% ethyl acetate in petroleum ether to give 231 mg of product as a white solid. did; IR (KBr) 3270, 2972, 1674, 1635, 1449, 775 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.65-1.71 (m, 2H), 1.81-1.89 (m, 1H), 1.92-2.04 (m, 3H), 2.07-2.14 (m, 4H), 3.01 (q , J = 4.2 Hz, 2H), 5.13 (q, J = 9.3 Hz, 1H), 5.39 (d, J = 7.8 Hz, 1H), 6.70 (d, J = 8.7 Hz, 1H), 6.85 (s, 1H ), 7.05 (d, J = 9.0 Hz, 1H), 7.20 (d, J = 7.2 Hz, 1H), 7.30-7.37 (m, 4H), 7.67 (d, J = 7.8 Hz, 1H), 8.55 (s , 2H); ESI-MS ( m / z ) 433.48 (M + H) ⁺ .

Example  36

N- (6,8-dichloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-pyridin-3-yl-phenyl) propanamide:

The title compound was present in EDCI.HCl (97 mg, 0.509 mmol), HOBt (78 mg, 0.511 mmol) and triethylamine (142 μl, 2.884 mmol) in dichloromethane (5 ml) as described in Example 1. Under intermediate 13 (100 mg, 0.340 mmol) and 3- (2-pyridin-2-ylphenyl) propanoic acid (85 mg, 0.374 mmol) to give 59 mg of the product as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.71-1.79 (m, 4H), 1.98-2.07 (m, 2H), 2.22-2.39 (m, 4H), 2.76-2.84 (m, 2H), 4.90-5.05 (m, 1H), 6.83 (br s, 1H), 7.29-7.49 (m, 5H), 7.78 (d, J = 7.2 Hz, 1H), 8.28 (s, 2H), 8.50-8.58 (m, 2H) .

Example  37

N- (3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-cyclopentyloxy-3-methoxy) phenylpropanamide:

The title compound was present in EDCI.HCl (172 mg, 0.906 mmol), HOBt (137 mg, 0.906 mmol) and triethylamine (249 μl, 1.835 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 5 (113 mg, 0.604 mmol) and 3- [2- (cyclopentyloxy-3-methoxy) phenyl] propanoic acid (150 mg, 0.604 mmol) to give 125 mg of the product as a white solid. ; IR (KBr) 3282, 2949, 1640, 1454, 1232, 753 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.68-1.78 (m, 11H), 2.05-2.15 (m, 3H), 2.28-2.39 (m, 2H), 2.55 (t, J = 6.6 Hz, 2H), 2.98 (t, J = 6.6 Hz, 2H), 3.79 (s, 3H), 4.85 (br s, 1H), 5.19 (q, J = 6.9 Hz, 1H), 5.64 (d, J = 7.8 Hz, 1H) , 6.73-6.80 (m, 5H), 6.95 (t, J = 7.8 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H); ESI-MS ( m / z ) 433.30 (M ⁻ H) ⁻ .

Example  38

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2,3-dimethoxy) -phenylpropanamide:

The title compound was present in EDCI.HCl (258 mg, 1.348 mmol), HOBt (206 mg, 1.348 mmol) and triethylamine (372 μL, 2.695 mmol) in dichloromethane (10 ml) as described in Example 1. Prepared from intermediate 2 (200 mg, 0.898 mmol) and 3- (2,3-dimethoxyphenyl) propanoic acid (207 mg, 0.988 mmol) to give 246 mg of the product as a white solid; IR (KBr) 3051, 2942, 1642, 1475, 1263, 750 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.62-1.69 (m, 2H), 1.82-1.89 (m, 1H), 2.09-2.17 (m, 3H), 2.25-2.36 (m, 2H), 2.57 (t , J = 6.9 Hz, 2H), 3.00 (t, J = 6.9 Hz, 2H), 3.81 (s, 6H), 5.16 (q, J = 8.7 Hz, 1H), 5.62 (d, J = 7.8 Hz, 1H ), 6.68 (d, J = 9.0 Hz, 1H), 6.79-6.86 (m, 3H), 7.00 (q, J = 7.2 Hz, 2H); ESI-MS ( m / z ) 416.16 (M + H) ⁺ .

Example  39

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-isopropoxy-3-methoxy) phenylpropanamide:

The title compound was present in EDCI.HCl (258 mg, 1.348 mmol), HOBt (206 mg, 1.348 mmol) and triethylamine (372 μL, 2.695 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 2 (200 mg, 0.898 mmol) and 3- (2-isopropoxy-3-methoxyphenyl) propanoic acid (235 mg, 0.988 mmol) to give 157 mg of the product as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.23 (s, 6H), 1.87 (br s, 2H), 2.13-2.26 (m, 6H), 2.58 (br s, 2H), 3.01 (br s, 2H) , 3.79 (s, 3H), 4.49 (br s, 1H), 5.15 (br s, 1H), 5.84 (br s, 1H), 6.67 (d, J = 7.8 Hz, 1H), 6.79-6.86 (m, 3H), 6.97-7.04 (m, 2H).

Example  40

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (3-chloro-4-methoxy) phenylpropanamide:

The title compound was present in EDCI.HCl (221 mg, 1.153 mmol), HOBt (175 mg, 1.153 mmol) and triethylamine (321 μL, 2.307 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 2 (200 mg, 0.763 mmol) and 3- (3-chloro-4-methoxyphenyl) propanoic acid (198 mg, 0.923 mmol) to give 136 mg of the product as a white solid; IR (KBr) 3272, 2972, 1645, 1484, 1226, 794 cm ^-1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.60-1.73 (m, 1H), 1.85-1.91 (m, 1H), 2.03-2.17 (m, 3H), 2.22-2.32 (m, 2H), 2.44-2.56 (m, 2H), 2.91-2.96 (m, 2H), 3.86 (s, 3H), 5.22 (q, J = 8.4 Hz, 1H), 5.49 (d, J = 8.4 Hz, 1H), 6.69 (d, J = 8.7 Hz, 1H), 6.83-6.90 (m, 2H), 7.05 (t, J = 7.8 Hz, 2H), 7.21 (s, 1H); ESI-MS ( m / z ) 456.38 (M + H) ⁺ .

Example  41

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-cyclopropylmethoxy-3-methoxy) phenylpropanamide :

The title compound was present in EDCI.HCl (221 mg, 1.153 mmol), HOBt (176 mg, 1.153 mmol) and triethylamine (321 μL, 2.307 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 2 (200 mg, 0.769 mmol) and 3- (2-cyclopropylmethoxy-3-methoxyphenyl) propanoic acid (232 mg, 0.923 mmol) to give 134 mg of the product as a white solid; IR (KBr) 3262, 2938, 1641, 1476, 1263, 1082, 820 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.26 (d, J = 4.8 Hz, 2H), 0.51-0.57 (m, 2H), 1.16-1.23 (m, 1H), 1.63-1.71 (m, 4H), 1.85-1.89 (m, 1H), 2.01-2.16 (m, 1H), 2.23-2.36 (m, 2H), 2.61 (t, J = 7.2 Hz, 2H), 3.03 (t, J = 7.5 Hz, 2H) , 3.76 (s, 3H), 3.80 (s, 2H), 5.15 (q, J = 12.0 Hz, 1H), 5.77 (d, J = 8.7 Hz, 1H), 6.67 (d, J = 8.7 Hz, 1H) , 6.77-6.83 (m, 3 H), 6.95-7.04 (m, 2 H); ESI-MS ( m / z ) 456.38 (M + H) ⁺ .

Example  42

N - [(4 R) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl)] - 3- (2-cyclopentyl-oxy-3 Methoxy) phenylpropanamide:

The title compound was present in EDCI.HCl (193 mg, 1.011 mmol), HOBt (154 mg, 1.011 mmol) and triethylamine (281 μl, 2.021 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 8 (150 mg, 0.674 mmol) and 3- (2-cyclopentyloxy-3-methoxyphenyl) propanoic acid (213 mg, 0.674 mmol) to give 167 mg of the product as a white solid; IR (KBr) 3274, 2956, 1643, 1475, 1263, 1079 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.71-1.78 (m, 8H), 2.04-2.16 (m, 6H), 2.22-2.39 (m, 2H), 2.54-2.59 (m, 2H), 2.97 (t , J = 6.6 Hz, 2H), 3.79 (s, 3H), 4.85 (br s, 1H), 5.14 (q, J = 8.7 Hz, 1H), 5.78 (d, J = 8.4 Hz, 1H), 6.67 ( d, J = 8.4 Hz, 1H), 6.77-6.84 (m, 3H), 6.94-7.00 (m, 2H); ESI-MS ( m / z ) 392.35 (M + H) ⁺ .

Example  43

N - [(4 S) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl)] - 3- (2-cyclopentyl-oxy-3 Methoxy) phenylpropanamide:

The title compound was present in EDCI.HCl (193 mg, 1.011 mmol), HOBt (154 mg, 1.011 mmol) and triethylamine (281 μl, 2.022 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 9 (150 mg, 0.674 mmol) and 3- (2-cyclopentyloxy-3-methoxyphenyl) propanoic acid (195 mg, 0.741 mmol) to give 113 mg of the product as a white solid; IR (KBr) 3316, 2955, 1650, 1477, 1264, 1078 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.68-1.72 (m, 8H), 1.74-1.82 (m, 6H), 2.22-2.39 (m, 2H), 2.54-2.59 (m, 2H), 2.97 (t , J = 7.5 Hz, 2H), 3.80 (s, 3H), 4.85 (br s, 1H), 5.14 (q, J = 6.3 Hz, 1H), 5.76 (d, J = 8.4 Hz, 1H), 6.67 ( d, J = 8.4 Hz, 1H), 6.77-6.84 (m, 3H), 6.94-7.00 (m, 2H); ESI-MS ( m / z ) 470.42 (M) ⁺ .

Example  44

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-cyclopentyloxy-3-ethoxy) phenylpropanamide:

The title compound was present in EDCI.HCl (166 mg, 0.863 mmol), HOBt (133 mg, 0.863 mmol) and triethylamine (241 μl, 1.734 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 2 (150 mg, 0.571 mmol) and 3- (2-cyclopentyloxy-3-ethoxyphenyl) propanoic acid (177 mg, 0.631 mmol) to give 180 mg of the product as a white solid; IR (KBr) 3327, 2953, 1646, 1476, 1263, 1071 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.39-1.46 (m, 4H), 1.64-1.81 (m, 10H), 2.06-2.16 (m, 3H), 2.22-2.32 (m, 2H), 2.57 (t , J = 7.2 Hz, 2H), 2.97 (t, J = 7.5 Hz, 2H), 3.99 (q, J = 6.3 Hz, 2H), 4.84 (br s, 1H), 5.14 (q, J = 5.4 Hz, 1H), 5.76 (d, J = 9.3 Hz, 1H), 6.66-6.91 (m, 4H), 7.01 (d, J = 8.4 Hz, 2H); ESI-MS ( m / z ) 484.28 (M) ⁺ .

Example  45

N- (7-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-cyclopentyloxy-3-methoxy) phenylpropanamide:

The title compound was present in EDCI.HCl (221 mg, 1.543 mmol), HOBt (176 mg, 1.543 mmol) and triethylamine (321 μL, 2.307 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 10 (200 mg, 0.769 mmol) and 3- (2-cyclopentyloxy-3-methoxyphenyl)) propanoic acid (243 mg, 0.923 mmol) to give 121 mg of the product as a white solid; IR (KBr) 3263, 2938, 1641, 1480, 1270, 1081, 966 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.59-1.77 (m, 10H), 2.13-2.27 (m, 5H), 2.57 (br s, 2H), 2.97 (br s, 2H), 3.47 (s, 1H ), 3.79 (s, 3H), 4.85 (br s, 1H), 5.12-5.19 (m, 1H), 5.69-5.77 (m, 1H), 6.60-6.66 (m, 2H), 6.74-6.79 (m, 3H), 6.89-6.95 (m, 1H); ESI-MS ( m / z ) 470.23 (M) ⁺ .

Example  46

N- (8-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-ethoxy-3-methoxy) phenylpropanamide:

The title compound was present in EDCI.HCl (257 mg, 1.346 mmol), HOBt (205 mg, 1.346 mmol) and triethylamine (497 μl, 3.563 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 1 (200 mg, 0.893 mmol) and 3- (2-ethoxy-3-methoxyphenyl) propanoic acid (240 mg, 1.074 mmol) to give 132 mg of the product as a white solid; IR (KBr) 3263, 2936, 1649, 1451, 1243, 749 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.33 (t, J = 6.9 Hz, 3H), 1.63-1.74 (m, 2H), 1.85-1.91 (m, 1H), 2.03-2.17 (m, 3H), 2.22-2.32 (m, 2H), 2.40-2.50 (m, 2H), 3.00 (t, J = 6.6 Hz, 2H), 3.80 (s, 3H), 4.00 (q, J = 6.9 Hz, 2H), 5.21 (q, J = 8.7 Hz, 1H), 5.65 (d, J = 8.1 Hz, 1H), 6.63-6.70 (m, 2H), 6.77-6.84 (m, 2H), 6.88-6.97 (m, 1H), 6.99-7.17 (m, 1 H); ESI-MS ( m / z ) 430.31 (M + H) ⁺ .

Example  47

N - [(4 R) -8- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl)] - 3- (2-cyclopentyl-oxy-3 Methoxy) phenylpropanamide:

The title compound was prepared in the presence of EDCI.HCl (193 mg, 1.511 mmol), HOBt (154 mg, 1.511 mmol) and triethylamine (279 μl, 2.001 mmol) in THF (10 ml) as described in Example 1. Prepared from intermediate 3 (150 mg, 0.674 mmol) and 3- (2-cyclopentyloxy-3-methoxyphenyl)) propanoic acid (213 mg, 0.824 mmol) to give 207 mg of the product as a white solid; IR (KBr) 3247, 2960, 1634, 1450, 1276, 1084, 746 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.22-1.27 (m, 1H), 1.68-1.91 (m, 9H), 2.08-2.31 (m, 4H), 2.40-2.48 (m, 2H), 2.57 (t , J = 6.9 Hz, 2H), 2.95 (t, J = 6.9 Hz, 2H), 3.79 (s, 3H), 4.85 (br s, 1H), 5.20-5.30 (m, 1H), 5.72 (d, J = 8.1 Hz, 1H), 6.62-6.70 (m, 2H), 6.78-6.85 (m, 2H), 6.95 (t, J = 7.8 Hz, 1H), 7.16 (d, J = 6.3 Hz, 1H); ESI-MS ( m / z ) 470.58 (M) ⁺ .

Example  48

N - [(4 S) - (8- Chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (2-cyclopentyloxy-3-methoxy Methoxy) phenylpropanamide:

The title compound was present in EDCI.HCl (193 mg, 1.013 mmol), HOBt (154 mg, 1.013 mmol) and triethylamine (203 μL, 2.107 mmol) in dichloromethane (10 ml) as described in Example 1. Prepared from intermediate 4 (150 mg, 0.676 mmol) and 3- (2-cyclopentyloxy-3-methoxyphenyl)) propanoic acid (212 mg, 0.892 mmol) to give 141 mg of the product as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.22-1.27 (m, 1H), 1.68-1.91 (m, 9H), 2.08-2.31 (m, 4H), 2.40-2.48 (m, 2H), 2.57 (t , J = 6.9 Hz, 2H), 2.95 (t, J = 6.9 Hz, 2H), 3.79 (s, 3H), 4.85 (br s, 1H), 5.20-5.30 (m, 1H), 5.72 (d, J = 8.1 Hz, 1H), 6.62-6.70 (m, 2H), 6.78-6.85 (m, 2H), 6.95 (t, J = 7.8 Hz, 1H), 7.16 (d, J = 6.3 Hz, 1H); ESI-MS ( m / z ) 470.68 (M) ⁺ .

Example  49

N- (6-chloro-7-methyl-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-cyclo-pentyloxy-3-methoxy Phenylpropanamide:

The title compound was present in EDCI.HCl (242 mg, 1.262 mmol), HOBt (129 mg, 0.841 mmol) and triethylamine (351 μL, 2.524 mmol) in dichloromethane (10 ml) as described in Example 1. Prepared from intermediate 14 (200 mg, 0.841 mmol) and 3- (2-cyclopentyloxy-3-methoxyphenyl)) propanoic acid (222 mg, 0.841 mmol) to give 72 mg of the product as a white solid; IR (KBr) 3060, 2939, 1643, 1475, 1158, 1080, 882 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.63-1.78 (m, 12H), 2.03-2.25 (m, 3H), 2.20-2.25 (m, 4H), 2.55 (t, J = 7.2 Hz, 2H ), 2.97 (t, J = 7.5 Hz, 2H), 3.79 (s, 3H), 4.85 (br s, 1H), 5.14 (q, J = 9.3 Hz, 1H), 5.70 (d, J = 8.4 Hz, 1H), 6.63 (s, 1H), 6.78 (d, J = 7.8 Hz, 2H), 6.85 (s, 1H), 6.96 (d, J = 7.8 Hz, 1H); ESI-MS ( m / z ) 484.61 (M) ⁺ .

Example  50

N- (5-benzyloxy-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-cyclopentyloxy-3-methoxy) phenylpropanamide :

The title compound was present in EDCI.HCl (218 mg, 1.137 mmol), HOBt (116 mg, 0.756 mmol) and triethylamine (316 μl, 2.274 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 11 (246 mg, 0.833 mmol) and 3- (2-cyclopentyloxy-3-methoxyphenyl)) propanoic acid (200 mg, 0.758 mmol) to give 170 mg of the product as a white solid; IR (KBr) 3293, 2956, 1631, 1465, 1120, 776 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.59-1.70 (m, 4H), 1.88-1.92 (m, 5H), 2.00-2.06 (m, 5H), 2.23-2.36 (m, 4H), 2.78-2.84 (m, 2H), 3.75 (s, 3H), 4.77 (br s, 1H), 4.99 (s, 2H), 5.20 (q, J = 3.0 Hz, 1H), 5.63 (d, J = 6.0 Hz, 1H ), 6.43-6.50 (m, 2H), 6.67 (d, J = 7.8 Hz, 2H), 6.83-6.89 (m, 1H), 7.07-7.13 (m, 2H), 7.25-7.31 (m, 4H); ESI-MS ( m / z ) 542.38 (M + H) ⁺ .

Example  51

N- (5-hydroxy-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-cyclopentyloxy-3-methoxy) phenylpropanamide :

Example 50 (140 mg, 0.258 mmol) was deprotected using Pd / C (28 mg) mixed with methanol in a Paar apparatus under nitrogen at 45 psi pressure for 4 h. The reaction mixture was filtered through a celite bed. The filtrate was concentrated under reduced pressure to afford a crude compound which was purified by silica gel column chromatography using 25% ethyl acetate in petroleum ether to give 51 mg of product as a white solid; IR (KBr) 3275, 2955, 1638, 1463, 1117, 783 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.20-1.30 (m, 4H), 1.76-1.88 (m, 5H), 2.05-2.17 (m, 5H), 2.50-2.56 (m, 4H), 2.92 (t , J = 6.6 Hz, 2H), 3.80 (s, 3H), 4.87 (br s, 1H), 5.02-5.10 (m, 1H), 5.96 (d, J = 8.7 Hz, 1H), 6.33 (d, J = 7.8 Hz, 1H), 6.41 (d, J = 8.4 Hz, 1H), 6.68-6.74 (m, 2H), 6.86 (t, J = 7.8 Hz, 1H), 7.00 (t, J = 8.4 Hz, 1H ), 10.02 (br s, 1 H, exchangeable with D ₂ O ); ESI-MS ( m / z ) 452.51 (M + H) ⁺ .

Example  52

N- (3,4-dihydrospiro [chromen-2,1'-cyclobutane] -5-methoxy-4-yl) -3- (2-cyclopentyloxy-3-methoxy) phenylpropanamide :

The title compound was present in EDCI.HCl (218 mg, 1.137 mmol), HOBt (116 mg, 0.757 mmol) and triethylamine (317 μL, 2.273 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 15 (165 mg, 0.757 mmol) and 3- (2-cyclopentyloxy-3-methoxyphenyl)) propanoic acid (200 mg, 0.757 mmol) to give 80 mg of the product as a white solid; IR (KBr) 3286, 2957, 1632, 1471, 1122, 775 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.64-1.89 (m, 8H), 1.98-2.09 (m, 6H), 2.22-2.32 (m, 2H), 2.41-2.46 (m, 2H), 2.93 (t, J = 7.8 Hz, 2H), 3.70 (s, 3H), 3.78 (s, 3H), 4.81 (br s, 1H), 5.14 (q, J = 3.6 Hz, 1H), 5.54 (d, J = 6.3 Hz, 1H), 6.36 (d, J = 7.8 Hz, 1H), 6.46 (d, J = 8.1 Hz, 1H), 6.70-6.80 (m, 2H), 6.91 (t, J = 7.8 Hz, 1H ), 7.11 (t, J = 8.4 Hz, 1H); ESI-MS ( m / z ) 466.17 (M + H) ⁺ .

Example  53

(4 R) -6- chloro - N - (3,4- dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (2-cyclopentyloxy-3-methyl) Phenylpropanamide:

The title compound was present in EDCI.HCl (129 mg, 0.675 mmol), HOBt (103 mg, 0.673 mmol) and triethylamine (187 μl, 1.346 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 8 (100 mg, 0.449 mmol) and 3- (2-cyclopentyloxy-3-methylphenyl) propanoic acid (122 mg, 0.491 mmol) to give 126 mg of the product as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.70-1.81 (m, 8H), 2.06-2.33 (m, 11H), 2.64 (d, J = 6.0 Hz, 2H), 3.03 (t, J = 6.3 Hz, 2H), 4.74 (br s, 1H), 5.18 (q, J = 6.0 Hz, 1H), 5.99 (d, J = 7.8 Hz, 1H), 6.72 (d, J = 8.7 Hz, 1H), 6.87 (s , 1H), 6.97-7.05 (m, 4H).

Example  54

(4 S ) -6-Chloro- N- (3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-cyclopentyl oxy-3-methyl) Phenylpropanamide:

The title compound was present in EDCI.HCl (129 mg, 0.675 mmol), HOBt (103 mg, 0.673 mmol) and triethylamine (187 μl, 1.346 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 9 (100 mg, 0.449 mmol) and 3- (2-cyclopentyloxy-3-methylphenyl) propanoic acid (122 mg, 0.491 mmol) to give 89 mg of the product as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.70-1.81 (m, 8H), 2.06-2.33 (m, 11H), 2.64 (d, J = 6.0 Hz, 2H), 3.03 (t, J = 6.3 Hz, 2H), 4.74 (br s, 1H), 5.18 (q, J = 6.0 Hz, 1H), 5.99 (d, J = 7.8 Hz, 1H), 6.72 (d, J = 8.7 Hz, 1H), 6.87 (s , 1H), 6.97-7.05 (m, 4H).

Example  55

N -6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutane] -4-yl-3- (2-hydroxy-3-methoxy phenyl) propanamide:

Step 1: (2 E) - N - (6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (2-benzyloxy-3 Methoxyphenyl) acrylamide: This compound was diluted in dichloromethane (15 ml) as described in Example 1, EDCI.HCl (555 mg, 2.897 mmol), HOBt (443 mg, 2.897 mmol) and triethylamine (806). ㎕, prepared in the presence of from 5.791 mmol), intermediate 2 (500 mg, 1.938 mmol) and (2 E) -3- [2- (benzyloxy) -3-methoxyphenyl] acrylic acid (575 mg, 2.023 mmol) 633 mg of the product was provided as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.70-1.84 (m, 3H), 2.11-2.22 (m, 3H), 2.35-2.47 (m, 2H), 3.89 (s, 3H), 5.02 (q, J = 11.4 Hz, 2H), 5.34 (q, J = 9.9 Hz, 1H), 5.44 (d, J = 8.4 Hz, 1H), 6.59 (d, J = 15.6 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.92-6.96 (m, 1H), 7.04-7.10 (m, 4H), 7.19-7.29 (m, 3H), 7.41 (d, J = 6.6 Hz, 2H), 7.69 (d, J = 16.2 Hz, 1H).

Step 2 : N -6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl-3- (2-hydroxy-3-methoxyphenyl) propanamide: Step 1 Intermediate (200 mg, 0.408 mmol) was deprotected and reduced using 5% Pd / C (50 mg) mixed with ethyl acetate (20 ml) in a Paar apparatus under nitrogen at 45 psi pressure for 4 h. The reaction mixture was filtered through a celite bed. The filtrate was concentrated under reduced pressure to afford a crude compound which was purified by silica gel column chromatography using 1% methanol in chloroform to give 121 mg of product as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.57-1.69 (m, 2H), 1.83-1.88 (m, 1H), 2.11-2.17 (m, 3H), 2.26-2.36 (m, 2H), 2.62 (t , J = 6.9 Hz, 2H), 3.02 (t, J = 6.6 Hz, 2H), 3.85 (s, 3H), 5.17 (q, J = 9.9 Hz, 1H), 5.60 (d, J = 7.8 Hz, 1H ), 6.07 (s, 1 H), 6.67-6.76 (m, 4 H), 6.82-6.86 (m, 1 H), 7.04 (dd, J = 6.3, 1.8 Hz, 1 H).

Example  56

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-benzyloxy-3-methoxy) phenylpropanamide:

Example 55 N -6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl-3- (2-hydroxy-) mixed with dimethyl formamide (5 ml) To a stirred solution of 3-methoxyphenyl) propanamide (150 mg, 0.371 mmol) was added dropwise K ₂ CO ₃ and benzyl bromide (70 mg, 0.411 mmol) at room temperature and stirred overnight at the same temperature. . The reaction mixture was filtered and the filtrate was extracted with ethyl acetate. The ethyl acetate layer was washed with water (2 x 20 ml), brine (20 ml), dried over Na ₂ S0 ₄ and concentrated. The crude product obtained was purified by silica gel column chromatography using 10% acetone in petroleum ether to give 130 mg of the product as a white solid; IR (KBr) 3283, 2939, 1644, 1476, 1263, 1082, 820 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.63-1.86 (m, 2H), 2.02 (br s, 1H), 2.11-2.36 (m, 5H), 2.41 (t, J = 7.2 Hz, 2H), 2.88 (t, J = 7.8 Hz, 2H), 3.86 (s, 3H), 4.99 (s, 2H), 5.06 (q, J = 6.0 Hz, 1H), 5.40 (d, J = 7.8 Hz, 1H), 6.67 -6.83 (m, 4H), 6.95-7.04 (m, 2H), 7.21-7.30 (m, 3H), 7.35 (d, J = 7.2 Hz, 2H); ESI-MS ( m / z ) 492.14 (M) ⁺ .

Example  57

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- {2-isopropoxy-3-[(methylsulfonyl) amino ] Phenyl} propanamide:

The title compound was present in EDCI.HCl (111 mg, 0.576 mmol), HOBt (59 mg, 0.384 mmol) and triethylamine (134 μl, 0.961 mmol) in dichloromethane (5 ml) as described in Example 1. Prepared from intermediate 2 (100 mg, 0.384 mmol) and 3- {2-isopropoxy-3-[(methylsulfonyl) amino] phenyl} propanoic acid (116 mg, 0.384 mmol) under Provided as a solid; IR (KBr) 3331, 2950, 1645, 1473, 1140, 984 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.35 (d, J = 4.8 Hz, 6H), 1.65-1.72 (m, 2H), 1.89-1.95 (m, 1H), 2.10-2.18 (m, 3H), 2.31-2.38 (m, 2H), 2.59 (t, J = 7.5 Hz, 2H), 3.00 (s, 5H), 4.22-4.28 (m, 1H), 5.21 (q, J = 6.3 Hz, 1H), 5.60 (d, J = 8.7 Hz, 1H), 6.71 (d, J = 9.0 Hz, 1H), 6.86 (s, 1H), 6.95 (d, J = 9.3 Hz, 2H), 7.01-7.08 (m, 2H) , 7.37 (d, J = 7.2 Hz, 1H); ESI-MS ( m / z ) 507.39 (M + H) ⁺ .

Example  58

N- (8-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- {2-isopropoxy-3-[(methylsulfonyl) amino ] Phenyl} propanamide:

The title compound was present in EDCI.HCl (111 mg, 0.576 mmol), HOBt (59 mg, 0.384 mmol) and triethylamine (134 μl, 0.961 mmol) in dichloromethane (5 ml) as described in Example 1. 121 mg of the product was prepared from intermediate 1 (100 mg, 0.384 mmol) and 3- {2-isopropoxy-3-[(methylsulfonyl) amino] phenyl} propanoic acid (116 mg, 0.384 mmol) under white Provided as a solid; IR (KBr) 3302, 2937, 1643, 1449, 1151, 978 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.34 (d, J = 3.9 Hz, 6H), 1.68-1.79 (m, 2H), 1.89-1.95 (m, 1H), 2.18-2.25 (m, 3H), 2.36-2.46 (m, 2H), 2.58 (t, J = 7.2 Hz, 2H), 2.99 (s, 5H), 4.23-4.29 (m, 1H), 5.25 (q, J = 6.9 Hz, 1H), 5.58 (d, J = 9.0 Hz, 1H), 6.72-6.78 (m, 2H), 6.85 (s, 1H), 6.96 (d, J = 6.6 Hz, 1H), 7.04 (t, J = 8.1 Hz, 1H) , 7.19 (s, 1 H), 7.37 (d, J = 7.8 Hz, 1 H); ESI-MS ( m / z ) 507.46 (M + H) ⁺ .

Example  59

N- (6,8-dichloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-cyclopentyloxy-3-methoxy) phenylpropane amides:

The title compound was present in EDCI.HCl (147 mg, 0.766 mmol), HOBt (78 mg, 0.511 mmol) and triethylamine (249 μl, 1.788 mmol) in dichloromethane (10 ml) as described in Example 1. Prepared from intermediate 13 (150 mg, 0.511 mmol) and 3- [2- (cyclopentyloxy-3-methoxy) phenyl] propanoic acid (127 mg, 0.511 mmol) to give 85 mg of the product as a white solid. ; IR (KBr) 3277, 2956, 1644, 1451, 1246, 1080, 970 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.62-1.68 (m, 3H), 1.74-1.88 (m, 8H), 2.04-2.27 (m, 4H), 2.58-2.61 (m, 3H), 2.96 (d , J = 6.9 Hz, 2H), 3.79 (s, 3H), 4.85 (br s, 1H), 5.17 (q, J = 9.3 Hz, 1H), 5.81 (d, J = 8.1 Hz, 1H), 6.77 ( d, J = 8.4 Hz, 3H), 6.96 (t, J = 7.8 Hz, 1H), 7.17 (s, 1H); ESI-MS ( m / z ) 504.16 (M) ⁺ .

Example  60

N- (6,8-dichloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2-{[2- (dimethyl-amino) ethoxy-3- Methoxy] phenyl} propanamide:

The title compound was present in EDCI.HCl (97 mg, 0.509 mmol), HOBt (78 mg, 0.509 mmol) and triethylamine (141 μl, 1.017 mmol) in dichloromethane (10 ml) as described in Example 1 57 mg of product was prepared from Intermediate 13 (100 mg, 0.339 mmol) and 3- {2- [2- (dimethylamino) ethoxy] -3-methoxyphenyl} propanoic acid (102 mg, 0.407 mmol) under Provided as a white solid; IR (KBr) 3273, 2938, 1651, 1539, 1454, 1268, 1247, 1081, 957 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.17-1.25 (m, 3H), 1.63-1.74 (m, 2H), 1.91 (br s, 1H), 2.14-2.22 (m, 2H), 2.27 (s, 6H), 2.30-2.36 (m, 2H), 2.44-2.51 (m, 1H), 2.60-2.71 (m, 4H), 2.95-3.02 (m, 2H), 3.81 (s, 1H), 4.05-4.11 ( m, 2H), 5.17-5.26 (m, 1H), 6.63 (d, J = 7.8 Hz, 1H), 6.79 (d, J = 7.5 Hz, 2H), 6.97 (t, J = 7.8 Hz, 1H), 7.16 (s, 1 H); APCI-MS ( m / z ) 507.81 (M + H) ⁺ .

Example  61

N- (6,8-dichloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- {2-propoxy-3-[(methylsulfonyl) Amino] phenyl} propanamide:

The title compound was present in EDCI.HCl (98 mg, 0.509 mmol), HOBt (52 mg, 0.339 mmol) and triethylamine (119 μl, 0.848 mmol) in dichloromethane (10 ml) as described in Example 1. 119 mg of the product was prepared from intermediate 13 (100 mg, 0.339 mmol) and 3- {3-[(methylsulfonyl) amino] -2-propoxyphenyl} propanoic acid (103 mg, 0.339 mmol) under white solid. Provided by; IR (KBr) 3305, 2937, 1644, 1451, 1141, 986 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.08 (t, J = 7.5 Hz, 3H), 1.68-1.75 (m, 2H), 1.82-1.89 (m, 3H), 2.14-2.20 (m, 3H), 2.32-2.38 (m, 1H), 2.42-2.50 (m, 1H), 2.60 (t, J = 7.5 Hz, 2H), 3.04 (s, 5H), 3.81 (t, J = 6.9 Hz, 2H), 5.24 (q, J = 6.3 Hz, 1H), 5.62 (d, J = 8.7 Hz, 1H), 6.81 (s, 1H), 6.86 (s, 1H), 6.97 (d, J = 7.8 Hz, 1H), 7.07 (t, J = 7.8 Hz, 1H), 7.20 (s, 1H), 7.38 (d, J = 7.5 Hz, 1H); ESI-MS ( m / z ) 541.67 (M) ⁺ .

Example  62

N- (6,8-dichloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- {2-isopropoxy-5-[(methylsulfonyl ) Amino] phenyl} propanamide:

The title compound was present in EDCI.HCl (98 mg, 0.509 mmol), HOBt (78 mg, 0.509 mmol) and triethylamine (142 μl, 1.017 mmol) in dichloromethane (5 ml) as described in Example 1 90 mg of the product was prepared from intermediate 13 (100 mg, 0.339 mmol) and 3- {2-isopropoxy-5-[(methylsulfonyl) amino] phenyl} propanoic acid (112 mg, 0.372 mmol) under white Provided as a solid; IR (KBr) 3275, 2935, 1648, 1497, 1152, 960 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.30 (s, 6H), 1.58-1.64 (m, 2H), 1.70-1.76 (m, 2H), 2.10-2.17 (m, 2H), 2.38-2.45 (m , 2H), 2.58-2.65 (m, 2H), 2.90-3.02 (m, 4H), 4.49 (br s, 1H), 5.21 (br s, 1H), 5.74 (br s, 1H), 6.50-6.55 ( m, 1H), 6.73-6.79 (m, 2H), 6.98-7.08 (m, 2H), 7.22 (d, J = 15.6 Hz, 2H); APCI-MS ( m / z ) 541.60 (M + H) ⁺ .

Example  63

N- (6,8-dichloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- {2-butoxy-3-[(methylsulfonyl) Amino] phenyl} propanamide:

The title compound was present in EDCI.HCl (98 mg, 0.509 mmol), HOBt (52 mg, 0.339 mmol) and triethylamine (119 μl, 0.848 mmol) in dichloromethane (10 ml) as described in Example 1. 107 mg of the product prepared from intermediate 13 (100 mg, 0.339 mmol) and 3- {2-butoxy-3-[(methylsulfonyl) amino] phenyl} propanoic acid (107 mg, 0.339 mmol) for 3 h under Provided as a white solid; IR (KBr) 3289, 2935, 1647, 1451, 1156, 979 cm ^-1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.99 (t, J = 7.2 Hz, 3H), 1.47-1.54 (m, 2H), 1.68-1.80 (m, 4H), 1.83-1.98 (m, 1H), 2.04-2.16 (m, 3H), 2.32-2.45 (m, 2H), 2.60 (t, J = 6.9 Hz, 2H), 3.04 (s, 4H), 3.84 (t, J = 6.3 Hz, 2H), 5.24 (q, J = 6.6 Hz, 1H), 5.62 (d, J = 9.3 Hz, 1H), 6.80 (s, 1H), 6.85 (s, 1H), 6.97 (d, J = 7.8 Hz, 1H), 7.07 (t, J = 7.8 Hz, 1H), 7.20 (s, 1H), 7.37 (d, J = 7.8 Hz, 1H); ESI-MS ( m / z ) 555.32 (M) ⁺ .

Example  64

N- (6,8-dichloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- {2- (cyclopropyl methoxy) -3-[( Methylsulfonyl) amino] phenyl} propanamide:

The title compound was present in EDCI.HCl (98 mg, 0.509 mmol), HOBt (52 mg, 0.339 mmol) and triethylamine (119 μl, 0.848 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 13 (100 mg, 0.339 mmol) and 3- {2- (cyclopropylmethoxy) -3-[(methylsulfonyl) amino] phenyl} propanoic acid (107 mg, 0.339 mmol) for 3 h 140 mg of the product was provided as a white solid; IR (KBr) 3303, 2934, 1644, 1451, 1140, 982 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.35 (d, J = 6.9 Hz, 2H), 0.69 (d, J = 5.4 Hz, 2H), 1.22-1.26 (m, 2H), 1.68-1.80 (m, 2H), 1.83-1.98 (m, 1H), 2.12-2.20 (m, 3H), 2.32-2.45 (m, 2H), 2.60 (t, J = 7.2 Hz, 2H), 3.03 (s, 4H), 3.73 (d, J = 6.9 Hz, 2H), 5.24 (q, J = 5.7 Hz, 1H), 5.62 (d, J = 8.4 Hz, 1H), 6.87 (s, 1H), 6.97-7.07 (m, 3H) , 7.20 (s, 1 H), 7.37 (d, J = 7.2 Hz, 1 H); ESI-MS ( m / z ) 553.60 (M) ⁺ .

Example  65

N- (6,8-dichloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- {2-isopropoxy-3-[(methylsulfonyl ) Amino] phenyl} propanamide:

The title compound was present in EDCI.HCl (98 mg, 0.509 mmol), HOBt (52 mg, 0.339 mmol) and triethylamine (119 μl, 0.848 mmol) in dichloromethane (10 ml) as described in Example 1. Prepared from intermediate 13 (100 mg, 0.339 mmol) and 3- {2-isopropoxy-3-[(methylsulfonyl) amino] phenyl} propanoic acid (103 mg, 0.339 mmol) for 3 h under 85 mg of The product was provided as a white solid; IR (KBr) 3292, 2935, 1648, 1451, 1155, 979 cm ^-1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.35 (d, J = 5.7 Hz, 6H), 1.71 (t, J = 3.4 Hz, 2H), 1.82-1.90 (m, 1H), 2.12-2.20 (m, 3H), 2.32-2.39 (m, 1H), 2.40-2.48 (m, 1H), 2.60 (t, J = 7.5 Hz, 2H), 3.01 (s, 5H), 4.22-4.28 (m, 1H), 5.19 (q, J = 9.0 Hz, 1H), 5.61 (d, J = 9.0 Hz, 1H), 6.86 (s, 2H), 6.96 (d, J = 7.8 Hz, 1H), 7.06 (t, J = 8.4 Hz , 1H), 7.20 (s, 1H), 7.36 (d, J = 8.1 Hz, 1H); ESI-MS ( m / z ) 540.86 (M) ⁺ .

Example  66

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (1-naphthyl) propanamide:

The title compound was present in EDCI.HCl (256 mg, 1.345 mmol), HOBt (205 mg, 1.345 mmol) and triethylamine (371 μl, 2.690 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 2 (200 mg, 0.896 mmol) and 1-naphthylpropanoic acid (178 mg, 0.896 mmol) to give 160 mg of the product as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.43-1.51 (m, 1H), 1.63-1.69 (m, 1H), 1.81-1.97 (m, 2H), 2.09-2.26 (m, 4H), 2.64-2.70 (m, 2H), 3.50 (t, J = 7.2 Hz, 2H), 5.14 (q, J = 9.9 Hz, 1H), 5.26 (d, J = 8.4 Hz, 1H), 6.65 (d, J = 8.7 Hz , 1H), 6.82 (s, 1H), 7.01 (dd, J = 2.4, 8.7 Hz, 1H), 7.35-7.54 (m, 4H), 7.73 (d, J = 6.9 Hz, 1H), 7.84 (d, J = 7.5 Hz, 1H), 8.04 (d, J = 8.1 Hz, 1H); ESI-MS ( m / z ) 406.34 (M + H) ⁺ .

Example  67

N - [4 R - (6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (4-methoxyphenyl) propan-1-naphthyl amides:

The title compound was present in EDCI.HCl (129 mg, 0.677 mmol), HOBt (103 mg, 0.677 mmol) and triethylamine (187 μl, 1.348 mmol) in dichloromethane (10 ml) as described in Example 1. Prepared from intermediate 8 (100 mg, 0.449 mmol) and 3- (2-methoxy-1-naphthyl) propanoic acid (113 mg, 0.494 mmol) to give 91 mg of the product as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.38-1.50 (m, 1H), 1.62-1.69 (m, 1H), 1.89-2.10 (m, 5H), 2.20-2.30 (m, 1H), 2.65 (t , J = 7.2 Hz, 2H), 3.43-3.49 (m, 2H), 3.83 (s, 3H), 5.08 (q, J = 9.3 Hz, 1H), 5.76 (d, J = 8.1 Hz, 1H), 6.67 (d, J = 8.7 Hz, 1H), 6.83 (s, 1H), 7.03 (dd, J = 2.4, 6.3 Hz, 1H), 7.30 (s, 1H), 7.33-7.37 (m, 1H), 7.47- 7.52 (m, 1 H), 7.76 (t, J = 8.4 Hz, 2H), 7.98 (d, J = 8.4 Hz, 1H).

Example  68

N- [4 ( S )-(6-Chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (4-methoxy) -1-naph Tilpropanamide:

The title compound was present in EDCI.HCl (129 mg, 0.677 mmol), HOBt (103 mg, 0.677 mmol) and triethylamine (187 μl, 1.348 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 9 (100 mg, 0.449 mmol) and 3- (2-methoxy-1-naphthyl) propanoic acid (113 mg, 0.494 mmol) to give 117 mg of the product as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.38-1.50 (m, 1H), 1.62-1.69 (m, 1H), 1.89-2.10 (m, 5H), 2.20-2.30 (m, 1H), 2.65 (t , J = 7.2 Hz, 2H), 3.43-3.49 (m, 2H), 3.83 (s, 3H), 5.08 (q, J = 9.3 Hz, 1H), 5.76 (d, J = 8.1 Hz, 1H), 6.67 (d, J = 8.7 Hz, 1H), 6.83 (s, 1H), 7.03 (dd, J = 2.4, 6.3 Hz, 1H), 7.30 (s, 1H), 7.33-7.37 (m, 1H), 7.47- 7.52 (m, 1 H), 7.76 (t, J = 8.4 Hz, 2H), 7.98 (d, J = 8.4 Hz, 1H).

Example  69

N - [(4 R) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (4-methoxyphenyl) -1-naphthyl Propanamide:

The title compound was present in EDCI.HCl (129 mg, 0.677 mmol), HOBt (103 mg, 0.677 mmol) and triethylamine (187 μl, 1.348 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 4 (100 mg, 0.449 mmol) and 3- (4-methoxy-1-naphthyl) propanoic acid (102 mg, 0.449 mmol) for 4 h to give 110 mg of the product as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.62-1.69 (m, 1H), 1.89-1.95 (m, 2H), 2.09-2.26 (m, 5H), 2.64 (t, J = 5.4 Hz, 2H), 3.41 (t, J = 7.5 Hz, 2H), 3.96 (s, 3H), 5.14 (q, J = 8.1 Hz, 1H), 5.26 (d, J = 8.7 Hz, 1H), 6.65 (d, J = 8.7 Hz, 1H), 6.73 (d, J = 7.8 Hz, 1H), 6.84 (s, 1H), 7.00 (d, J = 9.0 Hz, 1H), 7.26-7.30 (m, 1H), 7.43-7.55 (m , 2H), 7.95 (d, J = 8.1 Hz, 1H), 8.28 (d, J = 8.1 Hz, 1H).

Example  70

N - [(4 S) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (4-methoxyphenyl) -1-naphthyl Propanamide:

The title compound was present in EDCI.HCl (129 mg, 0.677 mmol), HOBt (103 mg, 0.677 mmol) and triethylamine (187 μl, 1.348 mmol) in dichloromethane (10 ml) as described in Example 1. Prepared from intermediate 9 (100 mg, 0.449 mmol) and 3- (4-methoxy-1-naphthyl) propanoic acid (102 mg, 0.449 mmol) to give 100 mg of the product as a white solid for 4 h; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.62-1.69 (m, 1H), 1.89-1.95 (m, 2H), 2.09-2.26 (m, 5H), 2.64 (t, J = 5.4 Hz, 2H), 3.41 (t, J = 7.5 Hz, 2H), 3.96 (s, 3H), 5.14 (q, J = 8.1 Hz, 1H), 5.26 (d, J = 8.7 Hz, 1H), 6.65 (d, J = 8.7 Hz, 1H), 6.73 (d, J = 7.8 Hz, 1H), 6.84 (s, 1H), 7.00 (d, J = 9.0 Hz, 1H), 7.26-7.30 (m, 1H), 7.43-7.55 (m , 2H), 7.95 (d, J = 8.1 Hz, 1H), 8.28 (d, J = 8.1 Hz, 1H).

Example  71

(4 R) -6- chloro-N - (3,4- dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (4-fluoro-methoxy-l -Naphthyl) propanamide:

The title compound was present in EDCI.HCl (128 mg, 0.671 mmol), HOBt (102 mg, 0.671 mmol) and triethylamine (124 μl, 0.894 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 8 (100 mg, 0.447 mmol) and 3- (4-difluoromethoxy-1-naphthyl) propanoic acid (142 mg, 0.536 mmol) to give 89 mg of the product as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.53-1.64 (m, 2H), 1.88-1.97 (m, 2H), 2.13-2.25 (m, 5H), 2.63-2.69 (m, 2H), 3.47 (t , J = 7.5 Hz, 2H), 5.17 (q, J = 5.7 Hz, 1H), 5.32 (d, J = 6.3 Hz, 1H), 6.65 (t, J = 8.7 Hz, 1H), 6.86 (d, J = 6.6 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 7.2 Hz, 1H), 7.55-7.60 (m, 2H ), 8.03 (d, J = 7.5 Hz, 1H), 8.21 (d, J = 7.5 Hz, 1H).

Example  72

(4 S) -6- chloro - N - (3,4- dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (4-fluoro-methoxy-1 Naphthyl) propanamide:

The title compound was present in EDCI.HCl (128 mg, 0.671 mmol), HOBt (102 mg, 0.671 mmol) and triethylamine (124 μl, 0.894 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 9 (100 mg, 0.449 mmol) and 3- (4-difluoromethoxy-1-naphthyl) propanoic acid (142 mg, 0.536 mmol) to give 62 mg of the product as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.53-1.64 (m, 2H), 1.88-1.97 (m, 2H), 2.13-2.25 (m, 5H), 2.63-2.69 (m, 2H), 3.47 (t , J = 7.5 Hz, 2H), 5.17 (q, J = 5.7 Hz, 1H), 5.32 (d, J = 6.3 Hz, 1H), 6.65 (t, J = 8.7 Hz, 1H), 6.86 (d, J = 6.6 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 7.2 Hz, 1H), 7.55-7.60 (m, 2H ), 8.03 (d, J = 7.5 Hz, 1H), 8.21 (d, J = 7.5 Hz, 1H).

Example  73

N- (6-Chloro-3,4-dihydrospiro [chromen-2,1′-cyclobutan] -4-yl) -3- (1-naphthyl) -propanamide:

The title compound was present in EDCI.HCl (143 mg, 0.751 mmol), HOBt (114 mg, 0.751 mmol) and triethylamine (209 μl, 1.518 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 3 (100 mg, 0.506 mmol) and 3- (2-naphthyl) propanoic acid (103 mg, 0.506 mmol) for 3 h to give 101 mg of the product as a white solid; IR (KBr) 3287, 2937, 1645, 1475, 1234, 817 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.41-1.48 (m, 1H), 1.80-1.86 (m, 2H), 2.06-2.26 (m, 4H), 2.56-2.68 (m, 2H), 3.19 (t , J = 7.2 Hz, 2H), 3.47 (s, 1H), 5.17 (q, J = 9.0 Hz, 1H), 5.35 (d, J = 7.8 Hz, 1H), 6.65 (d, J = 8.7 Hz, 1H ), 6.91 (s, 1H), 7.01 (d, J = 8.4 Hz, 1H), 7.33-7.42 (m, 3H), 7.65 (s, 1H), 7.77 (d, J = 8.1 Hz, 3H); ESI-MS ( m / z ) 406.56 (M + H) ⁺ .

Example  74

N - [4 R - (6-chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (6-methoxy-2-naphthyl) propane amides:

The title compound was present in EDCI.HCl (193 mg, 1.017 mmol), HOBt (154 mg, 1.011 mmol) and triethylamine (281 μl, 2.022 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 8 (150 mg, 0.674 mmol) and 3- (4-methoxy-2-naphthyl) propanoic acid (170 mg, 0.741 mmol) to give 190 mg of product as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.42-1.50 (m, 1H), 1.80-1.86 (m, 2H), 2.06-2.20 (m, 4H), 2.54-2.68 (m, 2H), 3.15 (t , J = 6.6 Hz, 2H), 3.89 (s, 3H), 5.15 (q, J = 6.0 Hz, 1H), 5.35 (d, J = 7.8 Hz, 1H), 6.65 (d, J = 7.8 Hz, 1H ), 6.89 (s, 1H), 7.05 (d, J = 7.8 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 1H), 7.57 (s, 1H ), 7.65 (d, J = 7.8 Hz, 2H).

Example  75

N - [4 S - (6-chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (6-methoxy-2-naphthyl) propane amides:

The title compound was present in EDCI.HCl (193 mg, 1.017 mmol), HOBt (154 mg, 1.011 mmol) and triethylamine (281 μl, 2.022 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 9 (150 mg, 0.674 mmol) and 3- (4-methoxy-2-naphthyl) propanoic acid (170 mg, 0.741 mmol) to give 127 mg of the product as a white solid; IR (KBr) 3293, 2956, 1631, 1465, 1120, 776 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.42-1.50 (m, 1H), 1.80-1.86 (m, 2H), 2.06-2.20 (m, 4H), 2.54-2.68 (m, 2H), 3.15 (t , J = 6.6 Hz, 2H), 3.89 (s, 3H), 5.15 (q, J = 6.0 Hz, 1H), 5.35 (d, J = 7.8 Hz, 1H), 6.65 (d, J = 7.8 Hz, 1H ), 6.89 (s, 1H), 7.05 (d, J = 7.8 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 1H), 7.57 (s, 1H ), 7.65 (d, J = 7.8 Hz, 2H); ESI-MS ( m / z ) 542.38 (M + H) ⁺ .

Example  76:

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (quinolin-2-yl) propanamide:

Step 1: (2 E) - N - (6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3-quinolin-2-yl acrylamide: This compound was prepared in the presence of EDCI.HCl (257 mg, 1.342 mmol), HOBt (205 mg, 1.342 mmol) and triethylamine (248 μl, 2.684 mmol) in dichloromethane (10 ml) as described in Example 1. under it prepared from intermediate 2 (200 mg, 0.894 mmol) and (2 E) -3- 2-yl acrylic acid (213 mg, 1.073 mmol) provided 167 mg of product as a white solid; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.69-1.92 (m, 3H), 2.04-2.16 (m, 3H), 2.27-2.41 (m, 2H), 5.20 (q, J = 10.2 Hz, 1H ), 6.81 (d, J = 9.0 Hz, 1H), 7.10-7.20 (m, 2H), 7.27 (d, J = 15.6 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.73-7.77 (m, 2H), 7.92-7.99 (m, 2H), 8.29 (s, 1H), 8.40 (d, J = 8.1 Hz, 1H), 8.88 (d, J = 8.4 Hz, 1H).

Step 2 : N- (6-Chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (quinolin-2-yl)

Propanamide: Step 1 intermediate (150 mg, 0.388 mmol) was reduced using 10% Pd / C (50 mg) mixed in ethyl acetate (25 ml) in a Paar apparatus under nitrogen for 2 h at 50 psi pressure. The reaction mixture was filtered through a celite bed and the filtrate was concentrated under reduced pressure to afford crude compound, which was purified by silica gel column chromatography using 1% methanol in chloroform to give 121 mg of product as a white solid. did; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.64-1.77 (m, 3H), 2.00-2.07 (m, 3H), 2.19-2.28 (m, 2H), 2.67-2.82 (m, 2H), 3.17 -3.26 (m, 2H), 5.02 (br s, 1H), 6.72 (d, J = 9.0 Hz, 1H), 6.94 (s, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.44-7.54 (m, 2H), 7.69 (t, J = 7.5 Hz, 1H), 7.91 (d, J = 7.2 Hz, 2H), 8.25 (d, J = 8.1 Hz, 1H), 8.40 (d, J = 8.4 Hz , 1H).

Example  77

N- (6-Chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- ( 1H -indol-3-yl) -propanamide:

The title compound was present in EDCI.HCl (258 mg, 1.345 mmol), HOBt (206 mg, 1.345 mmol) and triethylamine (375 μL, 2.684 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 2 (200 mg, 0.894 mmol) and 3- ( 1H -indol-3-yl) propanoic acid (187 mg, 0.988 mmol) to give 121 mg of the product as a white solid; IR (KBr) 3395, 2926, 1642, 1474, 1234, 748 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.78-1.96 (m, 2H), 2.09-2.26 (m, 6H), 2.63 (t, J = 6.3 Hz, 2H), 3.17-3.21 (m, 2H), 5.15 (q, J = 9.6 Hz, 1H), 5.34 (d, J = 8.4 Hz, 1H), 6.65 (d, J = 8.7 Hz, 1H), 6.77 (s, 1H), 6.99-7.14 (m, 4H ), 7.35 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H), 8.05 (s, 1H); ESI-MS ( m / z ) 395.63 (M + H) ⁺ .

Example  78

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (2-methyl-1-benzofuran-4-yl) propanamide :

The title compound was present in EDCI.HCl (256 mg, 1.345 mmol), HOBt (205 mg, 1.345 mmol) and triethylamine (371 μl, 2.690 mmol) in dichloromethane (10 ml) as described in Example 1. Prepared from intermediate 2 (200 mg, 0.896 mmol) and 3- (2-methyl-1-benzofuran-4-yl) propanoic acid (209 mg, 0.896 mmol) for 4 h under 60 mg of the product as a white solid. Provided; IR (KBr) 3395, 2972, 1642, 1515, 1423, 1235, 775 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.41-1.61 (m, 4H), 1.90-1.98 (m, 4H), 2.46 (s, 3H), 2.55-2.62 (m, 2H), 3.96 (s, 3H ), 5.10-5.16 (m, 1H), 5.26 (d, J = 8.4 Hz, 2H), 6.40-6.46 (m, 1H), 6.60-6.70 (m, 3H), 6.83 (s, 1H), 6.91 ( d, J = 7.8 Hz, 1H), 7.02 (d, J = 7.5 Hz, 1H); ESI-MS ( m / z ) 395.63 (M + H) ⁺ .

Example  79

N - [(4 R) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -3- (7-methoxy-2-methyl-1 -Benzofuran-5-yl) propanamide:

The title compound was present in EDCI.HCl (258 mg, 1.345 mmol), HOBt (206 mg, 1.345 mmol) and triethylamine (375 μL, 2.684 mmol) in dichloromethane (10 ml) as described in Example 1. 231 mg of the product was prepared from intermediate 8 (200 mg, 0.894 mmol) and 3- (7-methoxy-2-methyl-1-benzofuran-4-yl) propanoic acid (252 mg, 1.078 mmol) under white Provided as a solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.47-1.55 (m, 1H), 1.63-1.74 (m, 2H), 1.84-1.99 (m, 5H), 2.09-2.18 (s, 3H), 2.52-2.57 (m, 2H), 3.11-3.16 (m, 2H), 3.95 (s, 3H), 5.14 (q, J = 9.3 Hz, 1H), 5.30 (d, J = 7.8 Hz, 1H), 6.42 (s, 1H), 6.64-6.68 (m, 2H), 6.83 (s, 1H), 6.91 (d, J = 7.8 Hz, 1H), 7.02 (dd, J = 2.4, 6.9 Hz, 1H).

Example  80

N - [(4 S) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -3- (7-methoxy-2-methyl-1 -Benzofuran-5-yl) propanamide:

The title compound was present in EDCI.HCl (258 mg, 1.347 mmol), HOBt (206 mg, 1.347 mmol) and triethylamine (375 μL, 2.698 mmol) in dichloromethane (10 ml) as described in Example 1. 199 mg of the product was prepared from intermediate 9 (200 mg, 0.898 mmol) and 3- (7-methoxy-2-methyl-1-benzofuran-5-yl) propanoic acid (252 mg, 1.078 mmol) under Provided as a solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.47-1.55 (m, 1H), 1.63-1.74 (m, 2H), 1.84-1.99 (m, 5H), 2.09-2.18 (s, 3H), 2.52-2.57 (m, 2H), 3.11-3.16 (m, 2H), 3.95 (s, 3H), 5.14 (q, J = 9.3 Hz, 1H), 5.30 (d, J = 7.8 Hz, 1H), 6.42 (s, 1H), 6.64-6.68 (m, 2H), 6.83 (s, 1H), 6.91 (d, J = 7.8 Hz, 1H), 7.02 (dd, J = 2.4, 6.9 Hz, 1H).

Example  81

3- (1,4-benzo dioxin-6-yl) - N - (6-fluoro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) propanamide :

The title compound was present in EDCI.HCl (276 mg, 1.441 mmol), HOBt (221 mg, 1.441 mmol) and triethylamine (403 μl, 2.891 mmol) in dichloromethane (10 ml) as described in Example 1. 16 mg of product was prepared from Intermediate 6 (200 mg, 0.963 mmol) and 3- (2,3-dihydro-1,4-benzodioxin-6-yl) propanoic acid (187 mg, 0.963 mmol) under Provided as a white solid; IR (KBr) 3307, 2951, 1869, 1643, 1508, 1257, 1071, 817 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.13-1.23 (m, 1H), 1.66-1.78 (m, 3H), 2.04-2.13 (m, 3H), 2.18-2.27 (m, 2H), 2.42 -2.49 (m, 1H), 2.72-2.79 (m, 2H), 4.17 (s, 4H), 5.01 (br s, 1H), 6.54 (d, J = 11.1 Hz, 1H), 6.38-6.74 (m, 4H), 6.93 (t, J = 8.1 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H); ESI-MS ( m / z ) 396.66 (M ⁻ H) ⁻ .

Example  82

3- (1,3-benzodioxol-4-yl) - N - [6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] propanamide:

The title compound was present in EDCI.HCl (192 mg, 1.005 mmol), HOBt (154 mg, 1.005 mmol) and triethylamine (135 μl, 1.341 mmol) in dichloromethane (10 ml) as described in Example 1. Prepared from Intermediate 2 (150 mg, 0.679 mmol) and 3- (1,3-benzodioxol-4-yl) propanoic acid (169 mg, 0.892 mmol) to give 137 mg of the product as a white solid; IR (KBr) 3314, 2940, 1640, 1456, 1243, 1064 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.63-1.72 (m, 2H), 1.85-1.89 (m, 1H), 2.04-2.17 (m, 3H), 2.27-2.37 (m, 2H), 2.58 (t , J = 6.9 Hz, 2H), 2.96-3.02 (m, 2H), 5.20 (q, J = 9.3 Hz, 1H), 5.54 (d, J = 8.7 Hz, 1H), 5.87 (d, J = 8.7 Hz , 2H), 6.69-6.80 (m, 4H), 6.92 (s, 1H), 7.05 (d, J = 8.7 Hz, 1H).

Example  83

3- (1,3-benzodioxol-4-yl) - N - (8- Chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) propanamide:

The title compound was present in EDCI.HCl (192 mg, 1.005 mmol), HOBt (154 mg, 1.005 mmol) and triethylamine (135 μl, 1.341 mmol) in dichloromethane (10 ml) as described in Example 1. Prepared from intermediate 1 (150 mg, 0.679 mmol) and 3- (1,3-benzodioxol-4-yl) propanoic acid (169 mg, 0.892 mmol) to give 56 mg of the product as a white solid; IR (KBr) 3371, 2940, 1651, 1461, 1245, 1064, 934 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.67-1.77 (m, 2H), 1.90-1.95 (m, 1H), 2.06-2.20 (m, 3H), 2.32-2.47 (m, 2H), 2.58 (t , J = 7.5 Hz, 2H), 2.96-3.02 (m, 2H), 5.26 (q, J = 9.3 Hz, 1H), 5.55 (d, J = 8.7 Hz, 1H), 5.85 (d, J = 13.8 Hz , 2H), 6.66-6.80 (m, 5H), 7.18 (d, J = 6.9 Hz, 1H); ESI-MS ( m / z ) 400.58 (M + H) ⁺ .

Example  84

3- (1,4-benzo dioxin-5-yl) - N - (6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) propanamide:

The title compound was present in EDCI.HCl (221 mg, 1.153 mmol), HOBt (176 mg, 1.153 mmol) and triethylamine (321 μL, 2.307 mmol) in dichloromethane (10 ml) as described in Example 1. 141 mg of the product prepared from Intermediate 2 (200 mg, 0.769 mmol) and 3- (2,3-dihydro-1,4-benzodioxin-5-yl) propanoic acid (191 mg, 0.923 mmol) under Provided as a white solid; IR (KBr) 3276, 2935, 1639, 1474, 1262, 1094 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.63-1.71 (m, 3H), 1.89 (br s, 1H), 2.13-2.27 (m, 2H), 2.33-2.37 (m, 2H), 2.57 (t, J = 7.5 Hz, 2H), 2.96 (t, J = 6.9 Hz, 2H), 4.19 (d, J = 6.3 Hz, 4H), 5.19 (q, J = 8.7 Hz, 1H), 5.62 (d, J = 8.1 Hz, 1H), 6.69-6.74 (m, 4H), 6.95 (s, 1H), 7.05 (d, J = 8.1 Hz, 1H); ESI-MS ( m / z ) 414.47 (M + H) ⁺ .

Example  85

3-dibenzo [b, d] furan-2-yl - N - [(4 R) -6- chloro-3,4-dihydro -2 H - chromen-4-yl] acetamide:

The title compound was present in EDCI.HCl (256 mg, 1.345 mmol), HOBt (205 mg, 1.345 mmol) and triethylamine (371 μl, 2.690 mmol) in dichloromethane (10 ml) as described in Example 1. Prepared from intermediate 2 (200 mg, 0.896 mmol) and 3-dibenzo [ b , d ] furan-4-ylpropanoic acid (214 mg, 0.896 mmol) for 4 h to give 215 mg of the product as a white solid. ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.81-1.91 (m, 3H), 2.08-2.13 (m, 3H), 2.17-2.26 (m, 2H), 2.72-2.79 (m, 2H), 3.35-3.41 (m, 2H), 5.16 (q, J = 9.3 Hz, 1H), 5.44 (d, J = 8.7 Hz, 1H), 6.63 (d, J = 8.7 Hz, 1H), 6.82 (s, 1H), 6.99 (dd, J = 6.3, 1.8 Hz, 1H), 7.28-7.33 (m, 3H), 7.42 (t, J = 6.9 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.82 (d, J = 6.3 Hz, 1H), 7.91 (d, J = 8.7 Hz, 1H); ESI-MS ( m / z ) 446.29 (M + H) ⁺ .

Example  86

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclopentan] -4-yl) -3- (2-cyclopentyloxy-3-methoxy) propanamide:

The title compound was present in EDCI.HCl (241 mg, 1.261 mmol), HOBt (193 mg, 1.261 mmol) and triethylamine (351 μl, 2.504 mmol) in dichloromethane (10 ml) as described in Example 1. Prepared from intermediate 16 (200 mg, 0.841 mmol) and 3- (2-cyclopentyloxy-3-methoxyphenyl) propanoic acid (266 mg, 1.009 mmol) to give 197 mg of the product as a white solid; IR (Neat) 3276, 2959, 1642, 1475, 1262, 1082 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.74-2.05 (m, 18H), 2.56 (t, J = 6.3 Hz, 2H), 2.96 (t, J = 6.3 Hz, 2H), 3.79 (s, 3H) , 4.58 (br s, 1H), 5.14 (q, J = 9.0 Hz, 1H), 5.73 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 8.7 Hz, 1H), 6.77 (d, J = 7.8 Hz, 2H), 6.95-7.00 (m, 3H); ESI-MS ( m / z ) 484.64 (M) ⁺ .

Example  87

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclohexane] -4-yl) -3- (2-cyclopentyloxy-3-methoxy) phenylpropanamide:

The title compound was present in EDCI.HCl (116 mg, 0.756 mmol), HOBt (218 mg, 1.137 mmol) and triethylamine (316 μl, 2.274 mmol) in dichloromethane (10 ml) as described in Example 1 Under intermediate 17 (209 mg, 0.833 mmol) and 3- (2-cyclopentyloxy-3-methoxyphenyl) propanoic acid (200 mg, 0.758 mmol) to give 250 mg of the product as a white solid; IR (KBr) 3269, 2935, 1644, 1475, 1261, 1080, 970 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.29-1.51 (m, 5H), 1.70-1.78 (m, 8H), 2.02-2.08 (m, 5H), 2.56-2.62 (m, 4H), 2.96 (t , J = 6.0 Hz, 2H), 3.79 (s, 3H), 4.85 (br s, 1H), 5.14 (q, J = 9.9 Hz, 1H), 5.71 (d, J = 9.0 Hz, 1H), 6.69 ( d, J = 8.7 Hz, 1H), 6.77 (d, J = 7.8 Hz, 2H), 6.93-7.04 (m, 3H); ESI-MS ( m / z ) 498.06 (M) ⁺ .

Example  88

N- (2,2-dimethyl-3,4-dihydro-2 H -chromen-4-yl) -3- (2-cyclopentyloxy-3-methoxy) phenylpropanamide:

The title compound was present in EDCI.HCl (324 mg, 1.671 mmol), HOBt (259 mg, 1.671 mmol) and triethylamine (471 μl, 3.383 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 18 (200 mg, 1.129 mmol) and 3- (2-cyclopentyloxy-2-methoxyphenyl) propanoic acid (328 mg, 1.242 mmol) to give 187 mg of the product as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.27 (s, 3H), 1.36 (s, 3H), 1.48-1.79 (m, 8H), 2.02-2.10 (m, 1H), 2.55 (t, J = 7.5 Hz, 2H), 2.92-2.99 (s, 2H), 3.80 (s, 3H), 4.80 (br s, 1H), 5.18 (q, J = 9.9 Hz, 1H), 5.67 (d, J = 8.7 Hz, 1H), 6.70-6.80 (m, 5H), 6.94 (t, J = 8.1 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H).

Example  89

N- (6-Chloro-3,4-dihydro-2 H -thiochromen-4-yl) -4- (2-cyclopentyloxy-3-methoxyphenyl) -propanamide:

The title compound was present in EDCI.HCl (121 mg, 0.635 mmol), HOBt (97 mg, 0.635 mmol) and triethylamine (176 μl, 1.270 mmol) in dichloromethane (10 ml) as described in Example 1. Prepared from intermediate 19 (100 mg, 0.423 mmol) and 3- [2- (cyclopentyloxy) -3-methoxyphenyl] propanoic acid (134 mg, 0.508 mmol) to give 113 mg of the product as a white solid. ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.57-1.80 (m, 8H), 1.90-1.96 (m, 1H), 2.12-2.18 (m, 1H), 2.50-2.56 (m, 2H), 2.75-2.85 (m, 2H), 2.90-2.98 (m, 2H), 3.79 (s, 3H), 4.82 (br s, 1H), 5.02 (br s, 1H), 5.92 (br s, 1H), 6.72-6.80 ( m, 2H), 6.91-6.98 (m, 3H), 7.03-7.10 (m, 1H).

Example  90

N- (6-chloro-3,4-dihydro-2 H -thiochromen-4-yl) -3- (2-methoxy-1-naphthyl) propanamide:

The title compound was present in EDCI.HCl (121 mg, 0.635 mmol), HOBt (97 mg, 0.635 mmol) and triethylamine (176 μl, 1.270 mmol) in dichloromethane (10 ml) as described in Example 1. Prepared from intermediate 19 (100 mg, 0.423 mmol) and 3- (2-methoxy-1-naphthyl) propanoic acid (146 mg, 0.508 mmol) to give 67 mg of the product as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.79-1.87 (m, 1H), 2.07-2.14 (m, 1H), 2.52-2.70 (m, 4H), 3.38-3.45 (m, 2H), 3.80 (s , 3H), 4.97 (br s, 1H), 5.95 (d, J = 6.9 Hz, 1H), 6.92-6.98 (m, 2H), 7.04-7.10 (m, 1H), 7.16-7.21 (m, 1H) , 7.33 (t, J = 7.5 Hz, 1H), 7.48 (t, J = 8.4 Hz, 1H), 7.75 (t, J = 9.3 Hz, 2H), 7.95 (d, J = 8.4 Hz, 1H).

Example  91

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -4- (2-cyclopentyloxy-phenyl) butanamide:

The title compound was present in EDCI.HCl (166 mg, 0.863 mmol), HOBt (133 mg, 0.863 mmol) and triethylamine (241 μl, 2.043 mmol) in dichloromethane (5 ml) as described in Example 1. Under intermediate 2 (150 mg, 0.579 mmol) and 4- (2-cyclopentyloxyphenyl) butanoic acid (158 mg, 0.639 mmol) to give 153 mg of the product as a white solid; IR (KBr) 3300, 2943, 1646, 1474, 1238, 749 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.70-2.00 (m, 12H), 2.24-2.41 (m, 7H), 2.64-2.70 (m, 2H), 3.47 (s, 1H), 4.75 (br s, 1H), 5.25 (d, J = 6.0 Hz, 1H), 5.50 (d, J = 6.9 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.79-6.85 (m, 2H), 7.05- 7.12 (m, 4 H); ESI-MS ( m / z ) 454.30 (M) ⁺ .

Example  92

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -4- [2- (cyclopentyloxy) -3-methoxyphenyl] butane amides:

The title compound was present in EDCI.HCl (222 mg, 1.158 mmol), HOBt (118 mg, 0.772 mmol) and triethylamine (273 μl, 2.702 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 2 (200 mg, 0.772 mmol) and 4- (2-cyclopentyloxy-3-methoxyphenyl) butanoic acid (214 mg, 0.772 mmol) to give 210 mg of the product as a white solid; IR (KBr) 3019, 2970, 1665, 1475, 1215, 769 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.70-1.80 (m, 11H), 1.97-2.04 (m, 2H), 2.14-2.20 (m, 5H), 2.30-2.42 (m, 2H), 2.71 (t , J = 6.9 Hz, 2H), 3.81 (s, 3H), 4.80 (br s, 1H), 5.24 (br s, 1H), 5.55 (d, J = 8.7 Hz, 1H), 6.70-6.77 (m, 3H), 6.94 (t, J = 7.2 Hz, 1H), 7.06 (d, J = 9.9 Hz, 2H); ESI-MS ( m / z ) 482.44 (M ⁻ H) ⁻ .

Example  93

N - (4 R) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl-4- (2-cyclopentyloxy-3-methoxyphenyl) Butanamide:

The title compound was present in EDCI.HCl (129 mg, 0.672 mmol), HOBt (69 mg, 0.450 mmol) and triethylamine (157 μl, 1.123 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 8 (100 mg, 0.449 mmol) and 4- (2-cyclopentyloxy-3-methoxyphenyl) butanoic acid (124 mg, 0.449 mmol) to give 105 mg of the product as a white solid; IR (KBr) 3019, 2970, 1665, 1475, 1215, 769 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.70-1.80 (m, 11H), 1.97-2.04 (m, 2H), 2.14-2.20 (m, 5H), 2.30-2.42 (m, 2H), 2.71 (t , J = 6.9 Hz, 2H), 3.81 (s, 3H), 4.80 (br s, 1H), 5.24 (br s, 1H), 5.55 (d, J = 8.7 Hz, 1H), 6.70-6.77 (m, 3H), 6.94 (t, J = 7.2 Hz, 1H), 7.06 (d, J = 9.9 Hz, 2H); ESI-MS ( m / z ) 482.44 (M ⁻ H) ⁻ .

Example  94

N - {(4 S) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl} -4 - [(2- (cyclopentyl-oxy) - 3-methoxyphenyl] butanamide:

The title compound was present in EDCI.HCl (129 mg, 0.672 mmol), HOBt (69 mg, 0.450 mmol) and triethylamine (157 μl, 1.123 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 9 (100 mg, 0.449 mmol) and 4- (2-cyclopentyloxy-3-methoxyphenyl) butanoic acid (132 mg, 0.474 mmol) to give 140 mg of the product as a white solid; IR (KBr) 3019, 2970, 1665, 1475, 1215, 769 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.70-1.80 (m, 11H), 1.97-2.04 (m, 2H), 2.14-2.20 (m, 5H), 2.30-2.42 (m, 2H), 2.71 (t , J = 6.9 Hz, 2H), 3.81 (s, 3H), 4.80 (br s, 1H), 5.24 (br s, 1H), 5.55 (d, J = 8.7 Hz, 1H), 6.70-6.77 (m, 3H), 6.94 (t, J = 7.2 Hz, 1H), 7.06 (d, J = 9.9 Hz, 2H); ESI-MS ( m / z ) 482.44 (M ⁻ H) ⁻ .

Example  95

(4 R) - N - ( 8- Chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -4- (2-cyclopentyloxy-3-methoxy Phenyl) butanamide:

The title compound was present in EDCI.HCl (193 mg, 1.012 mmol), HOBt (154 mg, 1.012 mmol) and triethylamine (279 μl, 2.043 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 3 (150 mg, 0.619 mmol) and 4- (2-cyclopentyloxy-3-methoxyphenyl) butanoic acid (205 mg, 0.739 mmol) to give 149 mg of the product as a white solid; IR (KBr) 3315, 2945, 1642, 1438, 1244, 1040 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.57-1.70 (m, 10H), 1.97-2.04 (m, 4H), 2.14-2.20 (m, 4H), 2.40-2.47 (m, 2H), 2.66-2.72 (m, 2H), 3.80 (s, 3H), 4.79 (br s, 1H), 5.28 (d, J = 6.3 Hz, 1H), 5.56 (d, J = 8.4 Hz, 1H), 6.66-6.77 (m , 3H), 6.90-7.04 (m, 2H), 7.14-7.20 (m, 1H); ESI-MS ( m / z ) 484.26 (M) ⁺ .

Example  96

(4 S) - N - ( 8- Chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -4- (2-cyclopentyloxy-3-methoxy Phenyl) butanamide:

The title compound was present in EDCI.HCl (193 mg, 1.012 mmol), HOBt (154 mg, 1.012 mmol) and triethylamine (279 μl, 2.043 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 4 (150 mg, 0.619 mmol) and 4- (2-cyclopentyloxy-3-methoxyphenyl) butanoic acid (205 mg, 0.739 mmol) to give 153 mg of the product as a white solid; IR (KBr) 3316, 2946, 1642, 1538, 1451, 1084 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.70-1.80 (m, 10H), 1.97-2.04 (m, 4H), 2.05-2.12 (m, 4H), 2.39-2.49 (m, 2H), 2.70 (t , J = 7.2 Hz, 2H), 3.81 (s, 3H), 4.80 (br s, 1H), 5.29 (q, J = 6.3 Hz, 1H), 5.55 (d, J = 7.5 Hz, 1H), 6.76- 6.79 (m, 3 H), 6.91-7.05 (m, 4 H), 7.20 (s, 1 H); ESI-MS ( m / z ) 484.21 (M) ⁺ .

Example  97

N- (8-chloro-6-fluoro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -4- (2-cyclopentyl oxy-3-methoxy Phenyl) butanamide:

The title compound was present in EDCI.HCl (207 mg, 1.079 mmol), HOBt (110 mg, 0.719 mmol) and triethylamine (250 μl, 1.798 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 20 (200 mg, 0.719 mmol) and 4- (2-cyclopentyloxy-3-methoxyphenyl) butanoic acid (200 mg, 0.719 mmol) to give 105 mg of the product as a white solid; IR (KBr) 3313, 2956, 1645, 1463, 1214, 1083, 742 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.65-1.79 (m, 9H), 1.99-2.05 (m, 4H), 2.08-2.18 (m, 5H), 2.38-2.43 (m, 2H), 2.71 (t , J = 6.3 Hz, 2H), 3.81 (s, 3H), 4.80 (br s, 1H), 5.27 (q, J = 6.6 Hz, 1H), 5.54 (d, J = 7.8 Hz, 1H), 6.66- 6.75 (m, 3 H), 6.91-6.96 (m, 2H); ESI-MS ( m / z ) 500.38 (M ⁻ H) ⁻ .

Example  98

N- (6,8-dichloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -4- (2-cyclopentyloxy-3-methoxyphenyl) butane amides:

The title compound was present in EDCI.HCl (147 mg, 0.766 mmol), HOBt (78 mg, 0.511 mmol) and triethylamine (178 μl, 1.277 mmol) in dichloromethane (10 ml) as described in Example 1. Under intermediate 13 (150 mg, 0.511 mmol) and 4- (2-cyclopentyloxy-3-methoxyphenyl) butanoic acid (142 mg, 0.511 mmol) to give 105 mg of the product as a white solid; IR (KBr) 3283, 2954, 1644, 1451, 1220, 1083 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.72-1.82 (m, 10H), 1.97-2.01 (m, 3H), 2.12-2.20 (m, 5H), 2.36-2.42 (m, 2H), 2.71 (t , J = 6.6 Hz, 2H), 3.80 (s, 3H), 4.80 (br s, 1H), 5.24 (q, J = 6.3 Hz, 1H), 5.53 (d, J = 7.8 Hz, 1H), 6.72- 6.78 (m, 2 H), 6.91-6.96 (m, 1 H), 7.01 (s, 1 H), 7.20 (s, 1 H); ESI-MS ( m / z ) 518.17 (M) ⁺ .

Example  99

N- (7-benzyloxy-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -4- (2-cyclopentyloxy-3-methoxyphenyl) butanamide :

The title compound was present in EDCI.HCl (173 mg, 0.904 mmol), HOBt (138 mg, 0.904 mmol) and triethylamine (335 μl, 2.413 mmol) in dichloromethane (10 ml) as described in Example 1. From Intermediate 12 (200 mg, 0.603 mmol) and 3- (2-cyclopentyloxy-3-methoxyphenyl) butanoic acid (167 mg, 0.603 mmol) to give 156 mg of the product as a white solid; IR (KBr) 3254, 2960, 1639, 1269, 1134, 1019 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.68-1.81 (m, 11H), 1.97-2.02 (m, 4H), 2.18-2.25 (m, 4H), 2.32-2.37 (m, 2H), 2.69 (t , J = 7.2 Hz, 2H), 3.81 (s, 3H), 4.79 (br s, 1H), 4.99 (s, 2H), 5.17 (q, J = 6.0 Hz, 1H), 5.49 (d, J = 8.1 Hz, 1H), 6.41 (s, 1H), 6.50 (d, J = 8.7 Hz, 1H), 6.62-6.74 (m, 2H), 6.96-7.04 (m, 2H), 7.29-7.37 (m, 4H) ; ESI-MS ( m / z ) 554.40 (M ⁻ H) ⁻ .

Example  100

N- (7-hydroxy-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -4- (2-cyclopentyloxy-3-methoxyphenyl) butanamide :

Example 99 (100 mg, 0.181) performed by 10% Pd / C (30 mg) mixed with methanol (10 ml) under nitrogen for 2 h at 50 psi pressure as described in Example 17, step 2 debenzylation of mmol) gave 53 mg of the product as a white solid; IR (KBr) 3254, 2960, 1639, 1474, 1134, 1019 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.25-1.32 (m, 3H), 1.62-1.72 (m, 4H), 1.78-1.85 (m, 5H), 1.94-1.99 (m, 2H), 2.12-2.17 (m, 4H), 2.26-2.35 (m, 2H), 2.69 (t, J = 6.9 Hz, 2H), 3.81 (s, 3H), 4.79 (br s, 1H), 5.15 (q, J = 5.7 Hz , 1H), 5.52 (d, J = 8.4 Hz, 2H), 6.26-6.34 (m, 2H), 6.72-6.76 (m, 2H), 6.91-6.96 (m, 2H); ESI-MS ( m / z ) 554.40 (M ⁻ H) ⁻ .

Example  101

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -4-oxo-4- (4-methoxy-naphthyl) butanamide:

The title compound was present in EDCI.HCl (277 mg, 1.451 mmol), HOBt (221 mg, 1.459 mmol) and triethylamine (403 μl, 2.905 mmol) in dichloromethane (10 ml) as described in Example 1. Prepared from intermediate 2 (250 mg, 0.965 mmol) and 4- (4-methoxy-1-naphthyl) -4-oxobutanoic acid (274 mg, 1.062 mmol) under 311 mg of the product as a white solid. ; IR (KBr) 3204, 2972, 1632, 1523, 1230, 757 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.67-1.73 (m, 2H), 2.06-2.31 (m, 6H), 2.66-2.71 (m, 2H), 3.31-3.39 (m, 2H), 4.05 (s , 3H), 5.05 (br s, 1H), 6.77 (d, J = 9.0 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.20 ( s, 1H), 7.53-7.61 (m, 2H), 8.20-8.28 (m, 2H), 8.43 (d, J = 8.4 Hz, 1H), 8.86 (d, J = 8.7 Hz, 1H); ESI-MS ( m / z ) 464.17 (M + H) ⁺ .

Example  102

N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -4-hydroxy-4- (4-methoxy naphthyl) butanamide:

Example 101 (200 mg, 0.431 mmol) was added to tetrahydrofuran (10 ml) and methanol (5 ml) using sodium borohydride (932 mg, 0.864 mmol) for 3 h at 0 ° C. Prepared by reduction. The reaction mixture was allowed to warm to rt and concentrated to give 31 mg of product as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.67-1.76 (m, 3H), 2.02-2.09 (m, 3H), 2.25-2.42 (m, 7H), 3.35 (br s, 1H), 3.89 (s, 3H), 5.14 (br s, 1H), 5.36 (br s, 1H), 6.61-6.73 (m, 2H), 6.96-7.05 (m, 2H), 7.34-7.41 (m, 2H), 7.42-7.55 ( m, 1H), 7.96 (br s, 1H), 8.17 (d, J = 8.7 Hz, 1H).

Example  103

N- (6-chloro-2,2-dimethyl-3,4-dihydro- 2H -chromen-4-yl) -4- (2-cyclopentyloxy-3-methoxy) phenylbutanamide:

The title compound was present in EDCI.HCl (270 mg, 1.411 mmol), HOBt (144 mg, 0.941 mmol) and triethylamine (328 μl, 2.352 mmol) in dichloromethane (10 ml) as described in Example 1. Prepared from intermediate 21 (200 mg, 0.941 mmol) and 4- (2-cyclopentyloxy-3-methoxyphenyl) butanoic acid (261 mg, 0.941 mmol) to give 173 mg of the product as a white solid; IR (KBr) 3302, 2958, 1645, 1475, 1261, 1085 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.29 (s, 3H), 1.39 (s, 3H), 1.71-1.79 (m, 8H), 1.95-2.02 (m, 2H), 2.12-2.20 (m, 3H ), 2.70 (t, J = 6.6 Hz, 3H), 3.81 (s, 3H), 4.80 (br s, 1H), 5.25 (q, J = 6.3 Hz, 1H), 5.51 (d, J = 7.8 Hz, 1H), 6.67-6.77 (m, 3H), 6.90-6.97 (m, 1H), 7.05-7.13 (m, 2H); ESI-MS ( m / z ) 472.32 (M + H) ⁺ .

Example  104

N- (6-chloro-3,4-dihydro-2 H -thiochromen-4-yl) -4- (2-cyclopentyloxy-3-methoxyphenyl) -butanamide:

The title compound was present in EDCI.HCl (121 mg, 0.635 mmol), HOBt (97 mg, 0.635 mmol) and triethylamine (176 μl, 1.270 mmol) in dichloromethane (10 ml) as described in Example 1. Prepared from intermediate 19 (100 mg, 0.423 mmol) and 4- (2-cyclopentyloxy-3-methoxyphenyl) butanoic acid (141 mg, 0.508 mmol) to give 87 mg of the product as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.58-1.68 (m, 4H), 1.75-1.85 (m, 4H), 1.90-2.00 (m, 2H), 2.10-2.20 (m, 4H), 2.63-2.70 (m, 2H), 2.95-3.01 (m, 2H), 3.81 (s, 3H), 4.79 (br s, 1H), 5.13 (br s, 1H), 5.60-5.66 (m, 1H), 6.72 (d , J = 7.2 Hz, 2H), 6.92 (t, J = 7.8 Hz, 1H), 7.00-7.09 (m, 2H), 7.17 (s, 1H).

Pharmacological activity

Exemplary embodiments of the invention include Toth, A. et. al . Life Screened for TRPV3 activity according to the modified procedure described in Sciences (2003), 73 , 487-498. The selection of compounds can be performed by other methods and procedures known to those skilled in the art. This screening method is described by Hu, HZ., Et al . J. Biol . Chem . (2004), 279 , 35741-35748; Smith, G. D et al . Nature (2002), 418 , 186-190 and Peier, AM, et al . Science (2002), 296 , 2046-2049.

⁴⁵ calcium  Absorption test TRPV3  Screening for Antagonists:

Inhibition of intracellular uptake of 2-APB induced radioactive calcium was followed by inhibition of TRPV3 receptor activation. The test compound was dissolved in DMSO to prepare a 20 mM stock solution, and then diluted using a simple medium containing 0.1% BSA and 1.8 mM CaCl ₂ to obtain the desired concentration. The final concentration of DMSO in the reaction was 0.5% (v / v). CHO cells expressing human TRPV3 were grown in F-12 DMEM medium containing 10% FBS, 1% penicillin-streptomycin solution, 400 μg / ml of G-418. Cells were aliquoted into 96 well plates 24 h prior to testing to obtain ~ 50,000 cells per well on the day of the experiment. Cells were treated with test compounds for 10 minutes, then 2-APB was added for 4 minutes at a final concentration of 500 μM and 5 μCi / ml ⁴⁵ Ca ⁺² . Cells were washed and lysed with buffer containing 1% Triton X-100, 0.1% deoxycholate and 0.1% SDS. After the addition of the liquid scintillator, the radioactivity of the melt was measured on the Packardt Top count.

Concentration response curves are shown as% of the maximum response obtained in the absence of test antagonist. IC ₅₀ values were calculated from concentration response curves by nonlinear regression using GraphPad PRISM software.

The prepared compounds were tested using the above test procedure and the results obtained are given in Table 2. Percent inhibition at concentrations of 1.0 μM and 10.0 μM is given in the table along with IC ₅₀ (nM) values for the selected examples.

The IC ₅₀ (nM) values of the compounds are shown in Table 2, where "A" refers to IC ₅₀ values of less than 500 nM, "B" refers to IC ₅₀ values in the range of 500.0 to 1000.0 nM, and "C "Refers to IC ₅₀ values in the range from 1000.01 to 2000.0 nM, and" D "refers to IC ₅₀ values below 2000.0 nM.

Table 2 : In Vitro Screening Results of Compounds of the Invention:

Example No. Suppression percentage IC ₅₀ value (nM) 1.0 μM 10.0 μM Example 1 1.7 10.0 - Example 2 12.0 79.0 D Example 3 0.0 33.1 - Example 4 37.2 66.2 - Example 5 11.7 86.8 - Example 6 35.3 89.0 - Example 7 9.2 20.3 - Example 8 3.8 22.5 - Example 9 11.7 68.5 --- Example 10 13.7 92.4 - Example 11 23.6 76.0 - Example 12 - - B Example 13 5.9 87.6 C Example 14 9.8 78.8 - Example 15 - 27.3 - Example 16 0.0 35.2 - Example 17 21.9 70.0 - Example 18 36.1 72.3 - Example 19 23.1 61.7 - Example 20 19.3 50.9 - Example 21 63.5 93.6 B Example 22 35.3 72.1 - Example 23 6.2 65.3 - Example 24 26.9 89.9 C Example 25 19.0 48.0 - Example 26 29.4 46.1 - Example 27 5.3 75.9 - Example 28 58.0 84.3 - Example 29 43.6 88.4 - Example 30 46.8 80.6 - Example 31 78.6 97.4 B Example 32 24.8 43.9 - Example 33 13.5 33.9 - Example 34 5.69 77.1 - Example 35 44.8 97.6 - Example 36 55.5 96.8 - Example 37 46.3 95.7 B Example 38 23.8 82.7 - Example 39 73.8 97.5 B Example 40 6.8 93.5 - Example 41 49.0 96.4 B Example 42 47.2 95.1 B Example 43 64.6 91.7 B Example 44 50.8 88.8 - Example 45 59.2 94.8 B Example 46 53.2 99.7 B Example 47 - - A Example 48 - - B Example 49 35.4 70.1 - Example 50 52.8 77.6 B Example 51 37.1 86.7 C Example 52 39.6 92.5 - Example 53 61.9 91.4 B Example 54 36.2 63.6 - Example 55 - - - Example 56 57.5 87.5 - Example 57 30.3 84.3 - Example 58 61.7 98.7 - Example 59 89.4 96.3 A Example 60 1.2 0.0 - Example 61 45.1 93.8 - Example 62 13.5 82.2 - Example 63 73.3 97.0 - Example 64 37.6 95.4 - Example 65 74.1 99.5 B Example 66 44.6 92.3 - Example 67 17.0 84.7 - Example 68 70.6 91.0 B Example 69 40.3 86.8 - Example 70 66.1 91.2 B Example 71 53.5 95.5 - Example 72 60.3 93.3 B Example 73 61.3 83.3 B Example 74 64.1 90.4 C Example 75 46.6 90.4 - Example 76 23.5 58.8 - Example 77 39.4 81.8 - Example 78 46.1 91.3 B Example 79 51.5 95.5 - Example 80 73.52 98.6 B Example 81 29.1 54.8 - Example 82 24.3 90.9 - Example 83 11.0 83.2 - Example 84 11.0 83.2 - Example 85 76.9 90.4 A Example 86 11.6 66.0 - Example 87 26.7 67.3 - Example 88 17.1 93.2 - Example 89 38.0 87.3 - Example 90 49.2 91.4 - Example 91 51.0 82.5 - Example 92 86.1 95.8 A Example 93 72.8 94.2 B Example 94 79.7 97.2 A Example 95 71.8 96.5 B Example 96 44.4 80.9 - Example 97 60.0 90.3 C Example 98 36.9 69.5 - Example 99 19.9 19.6 - Example 100 19.4 87.0 - Example 101 26.5 63.2 - Example 102 26.6 42.8 - Example 103 69.4 96.4 B Example 104 51.3 92.5 -

Claims (55)

The compound of formula (I)

here,
R ¹ is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted cycloalkyl; Wherein the aryl, heteroaryl and heterocyclic rings are mono, bi or tricyclic; Completely or partially aromatic;
Wherein the substituents on aryl, heteroaryl, heterocyclic ring and cycloalkyl are halogen, hydroxy, nitro, cyano, substituted or unsubstituted amino, substituted or unsubstituted alkyl, linear or branched chain alkyl, linear or branched Chain alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkyl, fully or partially substituted haloalkyl, substituted or unsubstituted haloalkyloxy, completely or partially substituted Haloalkyloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted Not aryloxy, substituted or Unsubstituted arylalkyl, substituted or unsubstituted arylalkoxy, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heteroaryl, -S (O) _p R ^a , -NHS (O) _p R ^a , -O (CH ₂ ) _m NR ^a R ^b , -C (O) -R ^a or -C (O) NR ^a R ^b independently;
R ² is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted hetero Is selected from the group consisting of cyclic groups;
In each case R ^a , R ^b , R ^c and R ^d are hydrogen, nitro, cyano, halogen, -OR ^e , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl , Optionally substituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group;
R ^e is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted hetero Is selected from the group consisting of cyclic groups;
R ³ and R ⁴ are hydrogen, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, linear or branched chain alkyl, linear or branched chain alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted Unsubstituted alkoxy, substituted or unsubstituted haloalkyl, fully or partially substituted haloalkyl, substituted or unsubstituted haloalkyloxy, fully or partially substituted haloalkyloxy, substituted or unsubstituted cycloalkyl, substituted or substituted Independently selected from unsubstituted cycloalkoxy, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkylalkoxy, substituted or unsubstituted aryl;
'm' is an integer selected from 1 to 4;
'n' is an integer selected from 0 to 3;
'p' is an integer selected from 0 to 2;
Or analogs, tautomers, rheomers, stereoisomers, enantiomers, diastereomers or pharmaceutically acceptable salts of said compounds,
Provided that R ^b is not a group selected from -OR ^e , -NR ³ R ⁴ or C (O) NR ³ R ⁴ . The compound of claim 1 represented by formula (II):

here,
R ¹ is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted cycloalkyl; Wherein the aryl, heteroaryl and heterocyclic rings are mono, bi or tricyclic; Completely or partially aromatic;
Wherein the substituents on aryl, heteroaryl, heterocyclic ring and cycloalkyl are halogen, hydroxyl, nitro, cyano, amino, substituted or unsubstituted alkyl, linear or branched chain alkyl, linear or branched chain alkoxy, substitution Or unsubstituted alkenyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkyl, fully or partially substituted haloalkyl, substituted or unsubstituted haloalkyloxy, fully or partially substituted haloalkyloxy, Substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted Arylalkyl, unsubstituted or substituted, Ring or unsubstituted arylalkoxy, substituted or unsubstituted heterocyclic group, substituted or unsubstituted ^{_{heteroaryl, -S (O) p R a}} , -NHS (O) p R a, -O (CH 2) _m NR ^a R ^b , -C (O) -R ^a or -C (O) NR ^a R ^b independently;
In each case R ^a , R ^b , R ^c and R ^d are hydrogen, nitro, cyano, halogen, -OR ^e , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl , Optionally substituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group;
R ^e is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted hetero Is selected from the group consisting of cyclic groups;
R ³ and R ⁴ are hydrogen, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, linear or branched chain alkyl, linear or branched chain alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted Unsubstituted alkoxy, substituted or unsubstituted haloalkyl, fully or partially substituted haloalkyl, substituted or unsubstituted haloalkyloxy, fully or partially substituted haloalkyloxy, substituted or unsubstituted cycloalkyl, substituted or substituted Independently selected from unsubstituted cycloalkoxy, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkylalkoxy, substituted or unsubstituted aryl;
'm' is an integer selected from 1 to 4;
'n' is an integer selected from 0 to 3;
'p' is an integer selected from 0 to 2;
Or analogs, tautomers, rheomers, stereoisomers, enantiomers, diastereomers or pharmaceutically acceptable salts of said compounds,
Provided that R ^b is not a group selected from -OR ^e , -NR ³ R ⁴ or C (O) NR ³ R ⁴ . The compound of claim 1 or 2, wherein R ³ and R ⁴ are hydrogen. The compound of claim 1 or 2, wherein one of R ³ and R ⁴ is hydrogen and the other is hydroxy or alkyl (methyl). The compound of claim 1 or 2, wherein 'm' is an integer of 1. The compound of claim 1 or 2, wherein 'm' is an integer 2. The compound of claim 1 or 2, wherein 'm' is an integer 3. The compound of claim 1, wherein 'n' is an integer of 1 to form a four membered ring. The compound of claim 1, wherein 'n' is an integer 2 to form a 5-membered ring. The compound of claim 1, wherein 'n' is an integer 3 to make a 6 membered ring. The compound of claim 1, wherein R ² is hydrogen. The compound of claim 1 or 2, wherein any one of R ^a , R ^b , R ^c and R ^d is hydrogen or halogen. The compound of claim 12, wherein the halogen is fluorine or chlorine. The compound of claim 1 or 2, wherein any one of R ^a , R ^c and R ^d is hydrogen, hydroxy, alkyl, alkoxy or arylalkoxy. The compound of claim 14, wherein alkyl is methyl. The compound of claim 14, wherein the alkoxy is methoxy. The compound of claim 14, wherein arylalkoxy is benzyloxy. The compound of claim 1 or 2, wherein R ¹ is substituted or unsubstituted aryl, and aryl is wholly or partially aromatic or substituted or unsubstituted heteroaryl. The compound of claim 18, wherein aryl is substituted phenyl. The compound of claim 18, wherein aryl is phenyl. The compound of claim 18, wherein aryl is substituted or unsubstituted naphthyl. The compound of claim 18, wherein the aryl is partially aromatic. The compound of claim 18 or 22, wherein aryl is tetrahydronaphthalene. The compound of claim 18, wherein the heteroaryl is mono, bi or tricyclic. The compound of claim 18 or 24, wherein the monocyclic heteroaryl is pyridine. The compound of claim 18 or 24, wherein the bicyclic heteroaryl is indole, benzodioxol, benzisoxazole, benzofuran, quinoline, or benzodioxin. The compound of claim 18 or 24, wherein the tricyclic heteroaryl is dibenzofuran. The compound of claim 18, 19, or 21, wherein the substituent consists of hydroxy, halogen, alkyl, alkoxy, haloalkoxy , cycloalkoxy, cycloalkylalkoxy, arylalkyloxy, alkylsulfonylamino, alkylaminoalkoxy or heteroaryl. 29. The compound of claim 28, wherein halogen is F, Cl, Br or I. The compound of claim 28, wherein alkyl is methyl. The compound of claim 28, wherein the alkoxy is methoxy, ethoxy, n-propoxy, n-butoxy or iso- propoxy. The compound of claim 28, wherein haloalkoxy is completely or partially substituted _. The compound of claim 32, wherein the partially substituted haloalkoxy is OCHF ₂ . The compound of claim 28, wherein the cycloalkyloxy is cyclopentyloxy. The compound of claim 28, wherein cycloalkylalkoxy is cyclopropylmethoxy. The compound of claim 28, wherein the heteroaryl is pyridine. The compound of claim 28, wherein arylalkyloxy is benzyloxy. The compound of claim 28, wherein the alkylsulfonylamino is —NHS (O) ₂ CH ₃ or NHS (O) ₂ CH (CH ₃ ) ₂ . The compound of claim 28, wherein the alkylaminoalkoxy is —OCH ₂ CH ₂ N (CH ₃ ) ₂ . The compound according to claim 1 or 2, selected from the group consisting of
N- (8-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2-phenylacetamide (Compound No. 1),
N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (2-methoxyphenyl) acetamide (Compound No. 2),
N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclopropane] -4-yl) -2- {2-[(methylsulfonyl) -amino] phenyl} acetamide (Compound No. 3),
N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (2- (cyclopentyloxy) -3-methoxyphenyl) acet Amide (Compound No. 4),
N - [(4 R) -8- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -2- (2-cyclopentyloxy-3-methoxy Phenylacetamide (Compound No. 5),
N - [(4 S) -8- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -2- (2-cyclopentyloxy-3-methoxy Phenylacetamide (Compound No. 6),
N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (3,4-dimethoxyphenyl) acetamide (Compound No. 7 ),
N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2-pyridin-2-ylacetamide (Compound No. 8),
N- (3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (1-naphthyl) acetamide (Compound No. 9),
N- (6-Fluoro- (3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (1-naphthyl) acetamide (Compound No. 10) ,
N - [as (4 R) -6,8- difluoro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -2- (1-naphthyl) - Acetamide (Compound No. 11),
N - [(4 R) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -2- (1-naphthyl) -acetamide (compound No. 12),
N - [(4 S) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -2- (1-naphthyl) acetamide (Compound No 13),
N- (7-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (1-naphthyl) acetamide (Compound No. 14),
N - [(4 R) -8- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -2- (1-naphthyl) -acetamide (compound No. 15),
N - [(4 S) -8- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -2- (1-naphthyl) acetamide (Compound No 16),
N- (5-hydroxy-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (1-naphthyl) acetamide (Compound No. 17),
N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (2-naphthyl) acetamide (Compound No. 18),
N - [(4 R) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -2- (6-methoxy-2-naphthyl) Propanamide (Compound No. 19),
N - [(4 S) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -2- (6-methoxy-2-naphthyl) Propanamide (Compound No. 20),
N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (1,2,3,4-tetrahydronaphthalen-1-yl Acetamide (Compound No. 21),
N -[(6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl)]-2- (1,2,3,4-tetrahydronaphthalene-2 -Yl) acetamide (Compound No. 22),
2- (1,3-benzodioxol-5-yl) - N - (6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) acetamide ( Compound No. 23),
N- (6-fluoro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (5-fluoro-3-methyl-1 H -indole- 2-yl) acetamide (Compound No. 24),
N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (5-methoxy-2-methyl-1 H -indole-3 -Yl) acetamide (Compound No. 25),
2- (1,2-benzisoxazol-3-yl) - N - [(R 4) - (6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4 -Yl) acetamide (Compound No. 26),
2- (1,2-benzisoxazol-3-yl) - N - [(4 S ) - (6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4 -Yl) acetamide (Compound No. 27),
N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-cyclopentyloxyphenyl) propanamide (Compound No. 28) ,
N - [(4 R) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -3- (2-cyclopentyloxy) phenyl-propanamide ( Compound No. 29),
N - [(4 S) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -3- (2-cyclopentyloxy) phenyl-propanamide ( Compound No. 30),
N - [(4 S) - (8- Chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (4-methoxyphenyl) -1-naphthyl Tilpropanamide (Compound No. 31),
N - [(4 S) -8- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane-4-yl] -2- [2- (cyclopentyloxy) phenyl propanamide ( Compound No. 32),
7-benzyloxy- N- (3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-cyclopentyloxyphenyl) propanamide (Compound No. 33 ),
N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- {2-[(isopropylsulfonyl) amino] phenyl} propanamide (Compound No. 34),
N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-pyridin-2-ylphenyl) propanamide (Compound No. 35),
N- (6,8-dichloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-pyridin-3-ylphenyl) propanamide (compound No. 36),
N- (3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-cyclopentyloxy-3-methoxy) phenylpropanamide (Compound No. 37 ),
N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2,3-dimethoxy) phenylpropanamide (Compound No. 38 ),
N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-isopropoxy-3-methoxy) phenylpropanamide ( Compound No. 39),
N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (3-chloro-4-methoxy) phenylpropanamide (Compound No 40),
N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-cyclopropylmethoxy-3-methoxy) phenylpropanamide (Compound No. 41),
N - [(4 R) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl)] - 3- (2-cyclopentyloxy-3-methoxy Methoxy) phenylpropanamide (Compound No. 42),
N - [(4 S) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl)] - 3- (2-cyclopentyloxy-3-methoxy Methoxy) phenylpropanamide (Compound No. 43),
N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-cyclopentyloxy-3-ethoxy) phenylpropanamide ( Compound No. 44),
N- (7-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-cyclopentyloxy-3-methoxy) phenylpropanamide ( Compound No. 45),
N- (8-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-ethoxy-3-methoxy) phenylpropanamide (compound No. 46),
N - [(4 R) -8- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl)] - 3- (2-cyclopentyloxy-3-methoxy Methoxy) phenylpropanamide (Compound No. 47),
N - [(4 S) - (8- Chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (2-cyclopentyloxy-3-methoxy Methoxy) phenylpropanamide (Compound No. 48),
N- (6-chloro-7-methyl-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-cyclopentyloxy-3-methoxy) Phenylpropanamide (Compound No. 49),
N- (5-benzyloxy-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-cyclopentyloxy-3-methoxy) phenylpropanamide (Compound No. 50),
N- (5-hydroxy-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-cyclopentyloxy-3-methoxy) phenylpropanamide (Compound No. 51),
N- (3,4-dihydrospiro [chromen-2,1'-cyclobutane] -5-methoxy-4-yl) -3- (2-cyclopentyloxy-3-methoxy) phenylpropanamide (Compound No. 52),
(4 R) -6- chloro - N - (3,4- dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (2-cyclopentyloxy-3-methyl) Phenylpropanamide (Compound No. 53),
(4 S) -6- chloro - N - (3,4- dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (2-cyclopentyloxy-3-methyl) Phenylpropanamide (Compound No. 54),
N -6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl-3- (2-hydroxy-3-methoxyphenyl) propanamide (Compound No. 55),
N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-benzyloxy-3-methoxy) phenylpropanamide (compound No. 56),
N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- {2-isopropoxy-3-[(methylsulfonyl) amino ] Phenyl} propanamide (Compound No. 57),
N- (8-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- {2-isopropoxy-3-[(methylsulfonyl) amino ] Phenyl} propanamide (Compound No. 58),
N- (6,8-dichloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (2-cyclopentyloxy-3-methoxy) phenylpropane Amide (Compound No. 59),
N- (6,8-dichloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2-{[2- (dimethylamino) ethoxy-3-meth Methoxy] phenyl} propanamide (Compound No. 60),
N- (6,8-dichloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- {2-propoxy-3-[(methylsulfonyl) Amino] phenyl} propanamide (Compound No. 61),
N- (6,8-dichloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- {2-isopropoxy-5-[(methylsulfonyl ) Amino] phenyl} propanamide (Compound No. 62),
N- (6,8-dichloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- {2-butoxy-3-[(methylsulfonyl) Amino] phenyl} propanamide (Compound No. 63),
N- (6,8-dichloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- {2- (cyclopropylmethoxy) -3-[( Methylsulfonyl) amino] phenyl} propanamide (Compound No. 64),
N- (6,8-dichloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- {2-isopropoxy-3-[(methylsulfonyl ) Amino] phenyl} propanamide (Compound No. 65),
N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (1-naphthyl) -propanamide (Compound No. 66),
N- [4 ( S )-(6-Chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (4-methoxy) -1-naph Tilpropanamide (Compound No. 67),
N - [4 R - (6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (4-methoxyphenyl) propan-1-naphthyl Amide (Compound No. 68),
N - [(4 R) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (4-methoxyphenyl) -1-naphthyl Propanamide (Compound No. 69),
N - [(4 S) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (4-methoxyphenyl) -1-naphthyl Propanamide (Compound No. 70),
(4 R) -6- chloro - N - (3,4- dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (4-difluoromethoxy-1-naphthyl Thi) propanamide (Compound No. 71),
(4 S) -6- chloro - N - (3,4- dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (4-difluoromethoxy-1-naphthyl Ethyl) propanamide (Compound No. 72),
N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (1-naphthyl) -propanamide (Compound No. 73),
N - [4 R - (6-chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (6-methoxy-2-naphthyl) propane Amide (Compound No. 74),
N - [4 S - (6-chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -3- (6-methoxy-2-naphthyl) propane Amide (Compound No. 75),
N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- (quinolin-2-yl) propanamide (Compound No. 76),
N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -3- ( 1H -indol-3-yl) propanamide (Compound No. 77),
N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -2- (2-methyl-1-benzofuran-4-yl) propanamide (Compound No. 78),
N - [(4 R) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -3- (7-methoxy-2-methyl-1 -Benzofuran-5-yl) propanamide (Compound No. 79),
N - [(4 S) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] -3- (7-methoxy-2-methyl-1 -Benzofuran-5-yl) propanamide (Compound No. 80),
3- (1,4-benzo dioxin-6-yl) - N - (6-fluoro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) propanamide (Compound No. 81),
3- (1,3-benzodioxol-4-yl) - N - [6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl] propanamide ( Compound No. 82),
3- (1,3-benzodioxol-4-yl) - N - (8- Chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) propanamide ( Compound No. 83),
3- (1,4-benzo dioxin-5-yl) - N - (6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) propanamide ( Compound No. 84),
3-dibenzo [b, d] furan-2-yl - N - [(4 R) -6- chloro-3,4-dihydro -2 H - chromen-4-yl] acetamide (Compound No. 85),
N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclopentan] -4-yl) -3- (2-cyclopentyloxy-3-methoxy) propanamide (compound No. 86),
N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclohexane] -4-yl) -3- (2-cyclopentyloxy-3-methoxy) phenylpropanamide ( Compound No. 87),
N- (2,2-dimethyl-3,4-dihydro- 2H -chromen-4-yl) -3- (2-cyclopentyloxy-3-methoxy) phenylpropanamide (Compound No. 88) ,
N- (6-chloro-3,4-dihydro-2 H -thiochromen-4-yl) -4- (2-cyclopentyloxy-3-methoxyphenyl) propanamide (Compound No. 89),
N- (6-chloro-3,4-dihydro- 2H -thiochromen-4-yl) -3- (2-methoxy-1-naphthyl) propanamide (Compound No. 90),
N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -4- (2-cyclopentyloxyphenyl) butanamide (Compound No. 91) ,
N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -4- [2- (cyclopentyloxy) -3-methoxyphenyl] butane Amide (Compound No. 92),
N - (4 R) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl-4- (2-cyclopentyloxy-3-methoxyphenyl) Butanamide (Compound No. 93),
N - {(4 S) -6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl} -4 - [(2- (cyclopentyloxy) -3 -Methoxyphenyl] butanamide (Compound No. 94),
(4 R) - N - ( 8- Chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -4- (2-cyclopentyloxy-3-methoxy Phenyl) butanamide (Compound No. 95),
(4 S) - N - ( 8- Chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) -4- (2-cyclopentyloxy-3-methoxy Phenyl) butanamide (Compound No. 96),
N- (8-chloro-6-fluoro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -4- (2-cyclopentyloxy-3-methoxy Phenyl) butanamide (Compound No. 97),
N- (6,8-dichloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -4- (2-cyclopentyloxy-3-methoxyphenyl) butane Amide (Compound No. 98),
N- (7-benzyloxy-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -4- (2-cyclopentyloxy-3-methoxyphenyl) butanamide (Compound No. 99),
N- (7-hydroxy-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -4- (2-cyclopentyloxy-3-methoxyphenyl) butanamide (Compound No. 100),
N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -4-oxo-4- (4-methoxynaphthyl) butanamide (compound No. 101),
N- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -4-hydroxy-4- (4-methoxynaphthyl) butanamide ( Compound No. 102),
N- (6-chloro-2,2-dimethyl-3,4-dihydro- 2H -chromen-4-yl) -4- (2-cyclopentyloxy-3-methoxy) phenylbutanamide (compound No. 103), and
N- (6-chloro-3,4-dihydro-2 H -thiochromen-4-yl) -4- (2-cyclopentyloxy-3-methoxyphenyl) butanamide (Compound No. 104) or
Analogs, tautomers, rheomers, stereoisomers, enantiomers, diastereomers or pharmaceutically acceptable salts thereof. A pharmaceutical composition comprising a compound according to any one of claims 1 to 40 in free base or pharmaceutically acceptable salt form, and a pharmaceutically acceptable excipient. The pharmaceutical composition of claim 41, wherein the pharmaceutically acceptable excipient is a carrier or diluent. Preventing, ameliorating, or preventing vanilloid receptor mediated diseases, disorders, or syndromes in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-40. How to treat. The method of claim 43, wherein the vanilloid receptor mediated disease, disorder or syndrome is TRPV3-mediated pain or inflammatory disease, disorder or syndrome. The condition of claim 43, wherein the symptom of the disease, disorder, syndrome, or condition associated with TRPV3 function is pain, acute pain, chronic pain, nociceptive pain, neuropathic pain, post-operative pain, toothache, cancer pain, ischemic myocardium. Heart pain, migraine pain, arthralgia, neuropathy, neuralgia, trigeminal neuralgia, diabetic neuropathy, neurodegeneration, retinopathy, neurotic skin disorders, stroke, bladder hypersensitivity, urinary incontinence, female vulva pain, gastrointestinal disorders such as Inflammatory bowel syndrome, gastro-esophageal reflux disease, enterocolitis, ileitis, gastric-duodenal ulcer, inflammatory bowel disease, Crohn's disease, celiac disease, inflammatory diseases such as pancreatitis, allergic and nonallergic rhinitis, asthma or obstructive pulmonary disease Respiratory disorders, such as irritation of the skin, eyes or mucous membranes, pruritus, urinary pruritus, such as dermatitis, uremia, pruritus, fever, muscle spasms, vomiting, dyskinesia, depression, Huntington's disease, memory disorders, limited brain function, amyotrophic lateral sclerosis (ALS), dementia, arthritis, osteoarthritis, diabetes, obesity, urticaria, actinic keratosis, keratinocytes, alopecia, Ménière's disease, tinnitus, deafness, anxiety disorder And benign prostatic hyperplasia. A method of treating pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 40. The method of claim 46, wherein the pain is acute pain. The method of claim 46, wherein the pain is chronic pain. The method of claim 46, wherein the pain is post-operative pain. A method of treating neuropathic pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 40. A method of treating inflammation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 40. Process for preparing compound of formula (I):

here,
R ¹ is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted cycloalkyl; Wherein the aryl, heteroaryl and heterocyclic rings are mono, bi or tricyclic; Completely or partially aromatic;
Wherein the substituents on aryl, heteroaryl, heterocyclic ring and cycloalkyl are halogen, hydroxy, nitro, cyano, substituted or unsubstituted amino, substituted or unsubstituted alkyl, linear or branched chain alkyl, linear or branched Chain alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkyl, fully or partially substituted haloalkyl, substituted or unsubstituted haloalkyloxy, completely or partially substituted Haloalkyloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted Not aryloxy, substituted or Unsubstituted arylalkyl, substituted or unsubstituted arylalkoxy, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heteroaryl, -S (O) _p R ^a , -NHS (O) _p R ^a , -O (CH ₂ ) _m NR ^a R ^b , -C (O) -R ^a or -C (O) NR ^a R ^b independently;
R ² is hydrogen;
In each case R ^a , R ^b , R ^c and R ^d are hydrogen, nitro, cyano, halogen, -OR ^e , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl , Optionally substituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group;
R ^e is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted hetero Is selected from the group consisting of cyclic groups;
R ³ and R ⁴ are hydrogen, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, linear or branched chain alkyl, linear or branched chain alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted Unsubstituted alkoxy, substituted or unsubstituted haloalkyl, fully or partially substituted haloalkyl, substituted or unsubstituted haloalkyloxy, fully or partially substituted haloalkyloxy, substituted or unsubstituted cycloalkyl, substituted or substituted Independently selected from unsubstituted cycloalkoxy, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkylalkoxy, substituted or unsubstituted aryl;
'm' is an integer selected from 1 to 4;
'n' is an integer selected from 0 to 3;
'p' is an integer selected from 0 to 2;
Provided that R ^b is not a group selected from —OR ^e , —NR ³ R ⁴ or C (O) NR ³ R ⁴ ;
The process includes the following steps:
In the presence of a suitable binder and a suitable solvent, combining the compound of formula (I) (when R ² is H) obtained by the combination of a compound of compound of formula (2) of formula (1) The

The binder of claim 52 wherein the binder combination is selected from the group consisting of 1-hydroxybenzotriazole (HOBt), 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride (EDCI), and triethylamine Process. The process of claim 52, wherein the suitable solvent is dichloromethane. The process of claim 52, wherein the base is triethylamine.