TW201329061A - Chromane derivatives as TRPV3 modulators - Google Patents

Abstract

The present invention provides transient receptor potential vanilloid (TRPV) modulators. In particular, compounds described herein are useful for treating diseases, conditions and/or disorders modulated by TRPV3. Also provided herein are processes for preparing compounds described herein, intermediates used in their synthesis, pharmaceutical compositions thereof, and method s for treating or preventing diseases, conditions and/or disorders modulated by TRPV3.

Description

A chroman derivative as a TRPV3 regulator

The present invention relates to chromane derivatives having transient receptor potential vanilloid 3 (TRPV3) activity.

Ion movement is achieved through the cell membrane through specialized proteins. The TRP channel is a large family of non-selective cation channels that help regulate ion current and membrane potential. The TRP channel is divided into six subfamilies including the TRPV family. TRPV3 is a member of the TRPV class of the TRP channel.

TRPV3 is a channel of calcium permeability, specifically a calcium-permeable, non-selective cation channel. In addition to calcium ions, the TRPV3 channel is permeable to other cations such as sodium ions. Thus, the TRPV3 channel regulates membrane potential by modulating the flow of cations such as calcium and sodium ions. The TRPV3 receptor differs in mechanism from the voltage-gated calcium channel. Typically, voltage-gated calcium channels respond to membrane depolarization and open channels to allow calcium ions to flow from the extracellular matrix, causing an increase in intracellular calcium levels or concentrations. In contrast, long-lasting TRP channels, which act as non-selective cation channels, produce longer lasting changes in ion concentration, and the channel is ligand-gated (via chemical reagents such as 2-aminoethoxy) Diphenylborate [2-APB], heat and vanilloid (adjusted). These differences in mechanism are accompanied by differences in the structure of the voltage-gated channel and the TRP channel. Thus, although there are many different channels in various cell types and in response to numerous stimuli that act to regulate ion flux and membrane potential, it is recognized that the significant differences in structure, function, and mechanism between different types of ion channels are significant. important.

TRPV3 protein is in 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 Etc., Thermocouple channels expressed in Nature (2002), 418, 186-188). TRPV3 is also highly expressed in the skin. In keratinocyte cell lines, stimulation of TRPV3 causes release of an inflammatory mediator, such as interleukin-1. Therefore, TRPV3 can also play an important role in regulating pain and inflammation caused by the release of inflammatory stimuli. As described herein, in particular, the TRPV3 protein can be used in screening assays to identify compounds that modulate the function of TRPV3, including but not limited to human TRPV3, mouse TRPV3, rat TRPV3, and Drosophila TRPV3. The sequence corresponding to human TRPV3, mouse TRPV3 and Drosophila TRPV3 is disclosed in US 2004/0009537 (the '537 application). For example, SEQ ID NOs: 106 and 107 of the '537 application correspond to human nucleic acid sequences and amino acid sequences, respectively. Sequence numbers 108 and 109 of the '537 application correspond to the nucleic acid sequence and amino acid sequence of the mouse, respectively.

The function of TRPV3 basically involves the reception and transduction of pain. Therefore, it is desirable to identify and produce compounds that modulate one or more functions of TRPV3.

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

Benzopyran derivatives are disclosed in WO 2006/065686 and WO 2007/042906.

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

The present invention is directed to a chromanane compound having TRP channel modulating activity, particularly TRPV3 modulating activity. The present invention relates to a compound of formula (I):

Wherein R ^{1 is} selected from a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group or a substituted or unsubstituted cycloalkyl group; wherein, an aryl group or a heteroaryl group And the heterocyclic ring is monocyclic, bicyclic or tricyclic, and wholly or partially aromatic; wherein the substituents on the aryl, heteroaryl, heterocyclic ring and cycloalkyl are independently selected from the following a group consisting of a halogen, a hydroxyl group, a nitro group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted alkyl group, a linear or branched alkyl group, a linear or branched alkoxy group, A substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted haloalkyl group, a wholly or partially substituted haloalkyl group, a substituted or unsubstituted haloalkoxy group, a wholly or partially substituted haloalkoxy group , 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 or unsubstituted arylalkyl, substituted or Heterocyclic group substituted arylalkoxy group, a substituted or unsubstituted, a 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 ; R ^{2 is} selected from the group consisting of hydrogen, substituted or unsubstituted alkyl a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted heteroaryl group or a substituted or unsubstituted heterocyclic group; R ^a , R ^b , R ^c and R ^{d are} independently selected from hydrogen, nitro, cyano, halogen, -OR ^e , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group; R ^{e is} selected from a group consisting of 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 A heterocyclic group; R ³ and R ^{4 are} independently selected from hydrogen, halo, a substituted or unsubstituted amino group, a substituted or unsubstituted alkyl group, a straight-chain or branched alkyl, straight-chain or branched alkoxy Alternate or unsubstituted alkenyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkyl, fully or partially substituted haloalkyl, substituted or unsubstituted haloalkoxy, fully or partially substituted haloalkoxy A substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkoxy group, a substituted or unsubstituted cycloalkylalkyl group, a substituted or unsubstituted cycloalkylalkoxy group, a substituted or unsubstituted aryl group 'm' is an integer selected from 1-4; 'n' is an integer selected from 0-3; 'p' is an integer selected from 0-2; but R ^{b is} not selected from -OR ^e ,- a group of NR ^a R ^b or C(O)NR ^a R ^b .

It will be understood that formula (I) structurally encompasses all stereoisomers, enantiomers and diastereomers and pharmaceutically acceptable salts which may be considered by the chemical structures of the classes described herein. .

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

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

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

According to another embodiment of the invention, R ¹ is a substituted or unsubstituted monocyclic aryl group, preferably a phenyl group. In this embodiment, the substituent is one or more, and is independently selected from halogen (for example, F, Cl or Br), hydroxy, alkyl (for example, methyl), alkoxy (for example, methoxy). And ethoxy, n-propoxy, n-butoxy, isopropoxy), cycloalkoxy (for example, 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):

Wherein R ^{1 is} selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group or substituted or unsubstituted cycloalkyl; wherein aryl, heteroaryl and The heterocyclic ring is monocyclic, bicyclic or tricyclic, and is wholly or partially aromatic; wherein the substituents on the aryl, heteroaryl, heterocyclic ring and cycloalkyl are independently selected from the group consisting of Group consisting of halogen, hydroxy, nitro, cyano, amine, substituted or unsubstituted alkyl, linear or branched alkyl, straight or branched alkoxy, substituted or unsubstituted alkene Alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkyl, fully or partially substituted haloalkyl, substituted or unsubstituted haloalkoxy, fully or partially substituted haloalkoxy, 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 or unsubstituted arylalkyl, substituted or unsubstituted arylalkoxy , A substituted or unsubstituted heterocyclic group, a 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 ; R ^a , R ^b , R ^c and R ^{d are} independently selected from hydrogen, nitro, cyano, halogen, -OR ^e , substituted or Unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or An unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group; R ^{e is} selected from the group consisting of 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 heterocyclic group; R ³ and R ^{4 are} independently selected from hydrogen, halogen, substituted or not Substituted amine, substituted or unsubstituted alkyl, straight or branched alkyl, straight or branched alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkoxy, substituted or not Substituted haloalkyl, all or part Substituted haloalkyl, substituted or unsubstituted haloalkoxy, fully or partially substituted haloalkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted cycloalkyl An alkyl group, a substituted or unsubstituted cycloalkylalkoxy group, a substituted or unsubstituted aryl group; 'm' is an integer selected from 1 to 4; 'n' is an integer selected from 0 to 3; 'p' Is an integer selected from 0-2; but R ^{b is} not a group selected from -OR ^e , -NR ^a R ^b or C(O)NR ^a R ^b .

It will be understood that formula (II) structurally encompasses all stereoisomers, enantiomers and diastereomers, as well as pharmaceutically acceptable salts, which may be considered by the chemical structures of the classes described herein. .

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

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

According to another embodiment of the invention, R ¹ is a substituted or unsubstituted monocyclic aryl group, preferably a phenyl group. In this embodiment, the one or more substituents are independently selected from halo (eg, F, Cl or Br), hydroxy, alkyl (eg, methyl), alkoxy (eg, methoxy, ethoxy) , n-propoxy, n-butoxy, isopropoxy), cycloalkoxy (eg, cyclopentyloxy), cycloalkylalkoxy (eg, cyclopropylmethoxy), alkyl Sulfonamide (eg, -NHS(O) ₂ CH ₃ , -NHS(O) ₂ CH(CH ₃ ) ₂ ), alkylaminoalkoxy (eg, -OCH ₂ CH ₂ N(CH ₃ )) ₂ ) an arylalkoxy group (for example, benzyloxy group) or a heteroaryl group (for example, pyridine or pyrimidine); and 'm' is 1, 2 or 3.

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

According to another embodiment of the invention, R ¹ is a substituted or unsubstituted bicyclic aryl group. In this embodiment, the aryl group is a partial aromatic ring, preferably tetrahydronaphthalene; and '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 monocyclic, bicyclic or tricyclic ring system and is wholly or partially aromatic.

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

According to another embodiment of the present invention, R ¹ is a substituted or unsubstituted bicyclic heteroaryl group, preferably an anthracene, a benzodioxole, a benzisoxazole, a benzofuran, a quinoline. Or benzodioxin. In this embodiment, the one or more substituents are independently selected from halo (eg, F, Cl or Br), alkyl (eg, methyl) or alkoxy (eg, methoxy, ethoxy, N-propoxy, n-butoxy, isopropoxy); and 'm' is 1, 2 or 3.

According to another embodiment of the invention, R ¹ is a substituted or unsubstituted tricyclic heteroaryl group, 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} independently selected from hydrogen, halogen (eg, fluoro, chloro or bromo), substituted or unsubstituted alkyl (eg, methyl).

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 not A substituted aryl (eg, phenyl) or a substituted or unsubstituted arylalkyl (eg, benzyl).

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

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

N- (8-chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-2-phenylacetamide (Compound No. 1); N -(6- Chloro-3,4-dihydrospiro[chromen-2,1'-cyclobutyl]-4-yl)-2-(2-methoxyphenyl)acetamide (Compound No. 2); N -( 6-Chloro-3,4-dihydrospiro[chromen-2,1'-cyclobutan]-4-yl)-2-{2-[(methylsulfonyl)amino]phenyl} acetamidine Amine (Compound No. 3); N- (6-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-2-(2-(cyclopentyloxy) 3-methoxyphenyl)acetamide (Compound No. 4); N -[(4 R )-8-chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]- 4-yl]-2-(2-cyclopentyloxy-3-methoxy)phenylacetamide (Compound No. 5); N -[(4 S )-8-chloro-3,4-dihydro Snail [chromene-2,1'-cyclobutyl]-4-yl]-2-(2-cyclopentyloxy-3-methoxy)phenylacetamide (Compound No. 6); N - (6 -Chloro-3,4-dihydrospiro[chromen-2,1'-cyclobutyl]-4-yl)-2-(3,4-dimethoxyphenyl)acetamide (Compound No. 7) N- (6-Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl)-2-pyridin-2-ylacetamide (Compound No. 8); N -(3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-2-(1-naphthyl)acetamide (Compound No. 9); N- (6-fluoro -(3,4-dihydrospiro[ Alkenyl 2,1'-butoxy] -4-yl) -2- (1-naphthyl) acetyl amine (Compound No. 10); N - [(4 R) -6,8- difluoro-3, 4-Dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl]-2-(1-naphthyl)acetamide (Compound No. 11); N -[(4 R )-6- Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl]-2-(1-naphthyl)acetamide (Compound No. 12); N -[(4 S - 6-chloro-3,4-dihydrospiro[chromen-2,1'-cyclobutyl]-4-yl]-2-(1-naphthyl)acetamide (Compound No. 13); N - (7-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-2-(1-naphthyl)acetamide (Compound No. 14); N -[ (4 R )-8-Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl]-2-(1-naphthyl)acetamide (Compound No. 15) ; N -[(4 S )-8-chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl]-2-(1-naphthyl)acetamide Compound No. 16); N- (5-Hydroxy-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-2-(i-naphthyl)acetamide (compound) No. 17); N- (6-chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-2-(2-naphthyl)acetamide (compound number 18);(2 S )- N -[(4 R )-6-Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4-yl]-2-(6- Methoxy-2-naphthyl)propanamide (Compound No. 19); (2 S )- N -[(4 S )-6-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl]-2-(6-methoxy-2-naphthyl) Propylamine (Compound No. 20); N- (6-Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl)-2-(1,2,3 , 4-tetrahydronaphthalen-1-yl)acetamide (Compound No. 21); N -[(6-chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4- Base]]-2-(1,2,3,4-tetrahydronaphthalen-2-yl)acetamide (Compound No. 22); 2-(1,3-benzodioxole-5 - yl) - N - (6- chloro-3,4-dihydro-spiro [chromene-2,1'-butyl] -4-yl) acetyl amine (compound No. 23); N - (6- fluoro -3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl)-2-(5-fluoro-3-methyl-1 H -indol-2-yl)acetamidine Amine (Compound No. 24); N- (6-Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl)-2-(5-methoxy-2- Methyl-1 H -indol-3-yl)acetamide (Compound No. 25); 2-(1,2-benzisoxazole-3-yl) -N -[(4 R )-(6 -Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl)acetamide (Compound No. 26); 2-(1,2-benzisoxazole-3 -yl) -N -[(4 S )-(6-chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)acetamide (Compound No. 27); N- (6-chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl )-3-(2-cyclopentyloxyphenyl)propanamide (Compound No. 28); N -[(4 R )-6-chloro-3,4-dihydrospiro[chromene-2,1' -cyclobutylidene-4-yl]-3-(3-cyclopentyloxy)phenylpropanamide (Compound No. 29); N -[(4 S )-6-chloro-3,4-dihydrospiro [chromene-2,1'-cyclobutyl]-4-yl]-3-(3-cyclopentyloxy)phenylpropanamide (Compound No. 30); N -[(4 R )-(8- Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl)-3-[2-(cyclopentyloxy)phenyl]propanamide (Compound No. 31); N -[(4 S )-8-Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobut-4-yl]-3-[2-(cyclopentyloxy)phenyl] Propylamine (Compound No. 32); 7-Benzyloxy- N- (3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl)-3-(2-cyclopentyl) Oxyphenyl) propanamide (Compound No. 33); N- (6-chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)-3-{2 -[(isopropylsulfonyl)amino]phenyl}propanamide (Compound No. 34); N- (6-chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutane ]-4-yl)-3-(2-pyridin-2-ylphenyl)propanamide (Compound No. 35); N- (6,8-Dichloro-3,4-dihydrospiro[chromene- 2,1'-cyclobutyl]-4-yl)-3-(2-pyridin-3-ylphenyl)propanamide (Compound No. 36); N- (3,4-dihydrospiro[chromene- 2, 1'-cyclobutanyl-4-yl)-3-(2-cyclopentyloxy-3-methoxy)phenylpropanamide (Compound No. 37); N -(6-chloro-3,4- Dihydrospiro[chromenyl-2,1'-cyclobutyl]-4-yl)-3-(2,3-dimethoxy)phenylpropanamide (Compound No. 38); N- (6-Chlorine -3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl)-3-(2-isopropoxy-3-methoxy)phenylpropanamide (compound number 39); N- (6-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-(3-chloro-4-methoxy)phenyl Propylamine (Compound No. 40); N- (6-Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl)-3-(2-cyclopropylmethyl) Oxy-3-methoxy)phenylpropanamide (Compound No. 41); N -[(4 R )-6-chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutane ]-4-yl)]-3-(2-cyclopentyloxy-3-methoxy)phenylpropanamide (Compound No. 42); N -[(4 S )-6-chloro-3,4 - dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl)]-3-(2-cyclopentyloxy-3-methoxy)phenylpropanamide (Compound No. 43); N- (6-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-(2-cyclopentyloxy-3-ethoxy)phenyl Propylamine (Compound No. 44); N- (7-Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl)-3-(2-cyclopentyloxy) -3-methoxy ) Phenyl-propan-acyl-amine (Compound No. 45); N - (8- chloro-3,4-dihydro-spiro [chromene-2,1'-butyl] -4-yl) -3- (2- Oxy-3-methoxy)phenylpropanamide (Compound No. 46); N -[(4 R )-8-Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutane ]-4-yl)]-3-(2-cyclopentyloxy-3-methoxy)phenylpropanamide (Compound No. 47); N -[(4 S )-(8-chloro-3, 4-Dihydrospiro[chromenyl-2,1'-cyclobutyl]-4-yl)-3-(2-cyclopentyloxy-3-methoxy)phenylpropanamide (Compound No. 48); N- (6-chloro-7-methyl-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl)-3-(2-cyclopentyloxy-3-methyl Oxy)phenylpropanamide (Compound No. 49); N- (5-Benzyloxy-3,4-dihydrospiro[chromenene-2,1'-cyclobutan]-4-yl)-3- (2-cyclopentyloxy-3-methoxy)phenylpropanamide (Compound No. 50); N- (5-hydroxy-3,4-dihydrospiro[chromene-2,1'-cyclobutane ]-4-yl)-3-(2-cyclopentyloxy-3-methoxy)phenylpropanamide (Compound No. 51); N- (3,4-dihydrospiro[chromene-2, 1'-cyclobutylidene-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'-butyl] -4-yl) -3- (2-cyclopentyl-3-methyl) benzene Propan-acyl-amine (Compound No. 53); (4 S) -6- chloro - N - (3,4- dihydro-spiro [chromene-2,1'-butyl] -4-yl) -3- (2 -cyclopentyloxy-3-methyl)phenylpropanamide (Compound No. 54); N -6-chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4- 3-(2-hydroxy-3-methoxyphenyl)propanamide (Compound No. 55); N- (6-chloro-3,4-dihydrospiro[chromene-2,1'-ring Butyl-4-yl)-3-(2-benzyloxy-3-methoxy)phenylpropanamide (Compound No. 56); N- (6-Chloro-3,4-dihydrospiro[Color] Alkene-2,1'-cyclobutyl]-4-yl)-3-{2-isopropoxy-3-[(methylsulfonyl)amino]phenyl}propanamide (Compound No. 57) ; N- (8-chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-{2-isopropoxy-3-[(methylsulfonate) Indenyl)amino]phenyl}propanamide (Compound No. 58); N- (6,8-Dichloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4- 3-(2-cyclopentyloxy-3-methoxy)phenylpropanamide (Compound No. 59); N- (6,8-Dichloro-3,4-dihydrospiro[chromene] -2,1'-cyclobutyl]-4-yl)-3-{[2-(dimethylamino)ethoxy-3-methoxy]phenyl}propanamine (Compound No. 60); N - (6,8- dichloro-3,4-dihydro-spiro [chromene-2,1'-butyl] -4-yl) -3- {2-propoxy-3 - [(methyl Acyl) amino] phenyl} propan-acyl-amine (Compound No. 61); N - (6,8- dichloro-3,4-dihydro-spiro [chromene-2,1'-butyl] -4- 3-)2-isopropoxy-5-[(methylsulfonyl)amino]phenyl}propanamide (Compound No. 62); N- (6,8-dichloro-3, 4-Dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl)-3-{2-butoxy-3-[(methylsulfonyl)amino]phenyl}propene Amine (Compound No. 63); N -(6,8-Dichloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl)-3-{2-(cyclopropane Methoxy)-3-[(methylsulfonyl)amino]phenyl}propanamide (Compound No. 64); N- (6,8-Dichloro-3,4-dihydrospiro[Color] Aceene-2,1'-cyclobutyl]-4-yl)-3-{2-isopropoxy-3-[(methylsulfonyl)amino]phenyl}propanamide (Compound No. 65) N- (6-chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-(1-naphthyl)propanamide (Compound No. 66); N -[4( S )-(6-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-(2-methoxy-1-naphthalene) Propionamide (Compound No. 67); N -[4 S -(6-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutan]-4-yl)-3-( 2-methoxy-1-naphthyl)propanamide (Compound No. 68); N -[(4 R )-6-chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutane ]-4-base) -3-(4-methoxy-1-naphthyl)propanamide (Compound No. 69); N -[(4 S )-6-chloro-3,4-dihydrospiro[chromene-2,1 '-Cyclobutane-4-yl)-3-(4-methoxy-1-naphthyl)propanamine (Compound No. 70); (4 R )-6-Chloro- N -(3,4- Dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl)-3-(4-difluoromethoxy-1-naphthyl)propanamide (Compound No. 71); (4 S ) -6-chloro- N- (3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-(4-difluoromethoxy-1-naphthyl)propane Indoleamine (Compound No. 72); N- (6-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-(2-naphthyl)propanoid Amine (Compound No. 73); N -[4 R -(6-Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl)-3-(6-methoxy Benzyl-2-naphthyl)propanamide (Compound No. 74); N -[4 S -(6-chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl -3-(6-methoxy-2-naphthyl)propanamide (Compound No. 75); N- (6-chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutane ]-4-yl)-3-(quinolin-2-yl)propanamide (Compound No. 76); N- (6-chloro-3,4-dihydrospiro[chromene-2,1'-ring Butyl-4-yl)-3-( 1H -indol-3-yl)propanamide (Compound No. 77); N- (6-chloro-3,4-dihydrospiro[chromene-2, 1'-cyclobutylidene-4-yl)-3-(2-methyl-7- Methoxy-1-benzofuran-4-yl)propanamide (Compound No. 78); N -[(4 R )-6-chloro-3,4-dihydrospiro[chromene-2,1' -cyclobutylidene-4-yl]-3-(7-methoxy-2-methyl-1-benzofuran-5-yl)propanamide (Compound No. 79); N -[(4 S ) -6-Chloro-3,4-dihydrospiro[chromen-2,1'-cyclobutyl]-4-yl]-3-(7-methoxy-2-methyl-1-benzofuran- 5- yl) propan-acyl-amine (compound No. 80); 3- (1,4-benzodioxin-6-yl) - N - (6- fluoro-3,4-dihydro-spiro [chromene -2 ,1'-cyclobutyl]-4-yl)propanamide (Compound No. 81); 3-(1,3-benzodioxol-4-yl) -N- [6-chloro- 3,4-Dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl]propanamide (Compound No. 82); 3-(1,3-benzodioxole- 4- yl) - N - (8- chloro-3,4-dihydro-spiro [chromene-2,1'-butyl] -4-yl) propan-acyl-amine (compound No. 83); 3- (1, 4- benzodioxin-5-yl) - N - (6- chloro-3,4-dihydro-spiro [chromene-2,1'-butyl] -4-yl) propan-acyl-amine (compound No. 84); N- (6-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-(dibenzo[ b,d ]furan-4- Propylamine (Compound No. 85); N- (6-chloro-3,4-dihydrospiro[chromene-2,1'-cyclopenta]-4-yl)-3-(2-cyclopentyl) Oxy-3-methoxy Propylamine (Compound No. 86); N- (6-Chloro-3,4-dihydrospiro[chromene-2,1'-cyclohexa]-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 -thiochromene-4-yl )-3-(2-cyclopentyloxy-3-methoxyphenyl)propanamide (Compound No. 89); N- (6-chloro-3,4-dihydro-2 H -thiochromene 4-yl)-3-(2-methoxy-1-naphthyl)propanamide (Compound No. 90); N- (6-chloro-3,4-dihydrospiro[chromene-2,1 '-Cyclobutane-4-yl)-4-(2-cyclopentyloxyphenyl)butanamine (Compound No. 91); N- (6-Chloro-3,4-dihydrospiro[chromene- 2,1'-cyclobutyl]-4-yl)-4-[2-(cyclopentyloxy)-3-methoxyphenyl]butanamine (Compound No. 92); N -(4 R )- 6-Chloro-3,4-dihydrospiro[chromen-2,1'-cyclobutyl]-4-yl-4-(2-cyclopentyloxy-3-methoxyphenyl)butanamine ( Compound No. 93); N -{(4 S )-6-chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4-yl}-4-[(2-(cyclo) pentyloxy) -3-methoxyphenyl] but-acyl-amine (compound No. 94); (4 R) - N - (8- chloro-3,4-dihydro-spiro [chroman 2,1'-butyl] -4-yl) -4- (2-cyclopentyloxy-3-methoxyphenyl) butan-acyl-amine (Compound No. 95); (4 S) - N - ( 8-Chloro-3,4-dihydrospiro[chromen-2,1'-cyclobutyl]-4-yl)-4-(2-cyclopentyloxy-3-methoxyphenyl)butanamine (Compound No. 96); N- (8-chloro-6-fluoro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl)-4-(2-cyclopentyloxy) 3-methoxyphenyl)butanamine (Compound No. 97); N- (6,8-Dichloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4 -yl)-4-(2-cyclopentyloxy-3-methoxyphenyl)butanamine (Compound No. 98); N- (7-benzyloxy-3,4-dihydrospiro[chromene] -2,1'-cyclobutyl]-4-yl)-4-(2-cyclopentyloxy-3-methoxyphenyl)butanamine (Compound No. 99); N- (7-hydroxy-3) ,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl)-4-(2-cyclopentyloxy-3-methoxyphenyl)butanamine (Compound No. 100) N- (6-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-4-oxo-4-(4-methoxynaphthyl) Indoleamine (Compound No. 101); N- (6-Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl)-4-hydroxy-4-(4-A Oxynaphthyl)butanamine (Compound No. 102); N- (6-Chloro-2,2-dimethyl-3,4-dihydro- 2H -chromen-4-yl)-4-( 2 -cyclopentyloxy-3-methoxy)phenylbutanamine (Compound No. 103); N -(6-chloro-3,4-dihydro- 2H -thiochromene-4-yl)- 4-(2-cyclopentyloxy-3-methoxyphenyl)butanamine (Compound No. 104); and stereoisomers, enantiomers, diastereomers of compounds 1-104 And pharmaceutically acceptable salts are also contemplated.

The invention also provides a pharmaceutical composition comprising 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 contains a therapeutically effective amount of at least one compound described herein. The compounds of the present invention may be combined with a pharmaceutically acceptable excipient such as a carrier or diluent, or may be diluted by a carrier, or enclosed in a carrier in the form of a capsule, sachet, paper or other container.

The compounds and pharmaceutical compositions described herein are useful for treating diseases, disorders, and/or disorders modulated by the TRPV3 receptor.

The invention further provides for treating a disease, disorder, and/or condition modulated by a TRPV3 receptor in a subject by administering one or more compounds described herein effective to inhibit a TRPV3 receptor to a subject in need thereof. The method of obstacles.

Also provided herein are methods of making the compounds described herein.

[detailed description]

The present invention provides chromanane derivatives useful as TRPV3 modulators and methods of synthesizing these compounds. Also provided are pharmaceutically acceptable salts, enantiomers and diastereomers of these compounds having the same activity. Further provided are pharmaceutical compositions comprising the compound together with a pharmaceutically acceptable carrier, excipient or diluent, which are useful for treating diseases, disorders and/or disorders mediated by TRPV3.

The following definitions apply to the terms used in this article:

The term "halogen" or "halo" includes fluoro, chloro, bromo or iodo.

The term "alkyl" refers to a straight or branched hydrocarbon chain radical having from 1 to 8 carbon atoms consisting solely of carbon and hydrogen atoms and having no unsaturation, and is attached to the remainder of the molecule by a single bond For example, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl and 1,1-dimethylethyl (tert-butyl). The term " _C1-6 alkyl" refers to an alkyl chain having from 1 to 6 carbon atoms.

The term "alkenyl" refers to a straight or branched aliphatic hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon double bond. Non-limiting examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, and 2- Butyl.

The term "alkynyl" refers to a straight or branched chain hydrocarbon group having from 2 to about 12 carbon atoms and having at least one carbon-carbon triple bond (a group having from 2 to about 10 carbon atoms is Preferred) are, for example, ethynyl, propynyl and butynyl.

The term "alkoxy" denotes an alkyl group attached to the remainder of the molecule through an oxygen linkage. Representative examples of such groups are -OCH ₃ and -OC ₂ H ₅ .

The term "cycloalkyl" denotes a non-aromatic monocyclic or polycyclic ring system of from 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of polycyclic cycloalkyl groups include, but are not limited to, perhydronaphthyl, adamantyl and norbornyl groups, bridged ring groups or spirobicyclic groups (eg, spiro(4,4)壬-2- base).

The term "cycloalkylalkyl" refers to a cyclic ring-containing group having from 3 to about 8 carbon atoms attached directly to an alkyl group. A cycloalkylalkyl group can be attached to the main structure at any carbon atom in the alkyl group to produce a stable structure. Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.

The term "cycloalkenyl" refers to cyclic ring-containing groups having from 3 to about 8 carbon atoms having at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl.

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

The term "arylalkyl" means a direct bonded as above defined aryl radical as defined above in the alkyl group, e.g. -CH ₂ C ₆ H ₅ or _{-C 2 H 4 C 6 H 5} .

The terms "heterocyclyl" and "heterocyclic ring" refer to a stable 3-15 membered ring radical consisting of a carbon atom and one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur. For the purposes of the present invention, a heterocyclic ring group may be a monocyclic, bicyclic or tricyclic ring system, may comprise a fused ring system, a bridged ring system or a spiro ring system, and nitrogen, phosphorus, carbon, in the heterocyclic ring group, Oxygen or sulfur atoms can optionally be oxidized to various oxidation states. Further, the nitrogen atom may be optionally quaternized; and the cyclic group may be partially saturated or fully saturated (ie, heterocyclic or heteroaryl). Examples of such heterocyclic ring groups include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl. , carbazolyl, porphyrinyl, dioxolanyl, pyridazinyl, naphthyridinyl, perhydroaza Base, phenazinyl, phenothiazine, phenoxazinyl, pyridazinyl, pyridyl, pteridinyl, fluorenyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetra Azyl, imidazolyl, tetrahydroisoquinolinyl, acridinyl, pyridazinyl, 2-oxooxazinyl, 2-oxoacridinyl, 2-oxopyrrolidinyl, 2-oxonitrogen miscellaneous Base, aza , pyrrolyl, 4-acridone, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, indane , isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, fluorenyl, isodecyl , porphyrin, isoxalinyl, octahydroindenyl, octahydroisoindolyl, quinolyl, isoquinolinyl, decahydroisoquinolinyl, benzimidazolyl, thio Diazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuranyl, tetrahydropyranyl, thienyl, benzothienyl, thiomorpholinyl, thio Alkyl hydrazide, thiomorpholinyl hydrazine, dioxaphospholyl, oxadiazolyl, chromanyl and isochroman. The heterocyclic ring group can be attached to the main structure at any heteroatom or carbon atom to produce a stable structure.

The term "heterocyclylalkyl" refers to a heterocyclic ring group attached directly to an alkyl group. The heterocyclylalkyl group can be attached to the main structure at any carbon atom in the alkyl group to give a stable structure.

The term "heteroaryl" refers to an aromatic heterocyclic ring group. A heteroaryl ring group can be attached to the main structure at any heteroatom or carbon atom, resulting in a stable structure.

The term "heteroarylalkyl" refers to a heteroaryl ring radical attached directly to an alkyl group. A heteroarylalkyl group can be attached to the main structure at any carbon atom in the alkyl group to produce a stable structure.

The term "substituted" as used herein, unless otherwise specified, refers to one or more substituents including: hydroxy, halo, carboxy, 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 cycloalkenylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, Substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted anthracene, -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 , -(= N -N(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 , -SR ^x , -SOR ^x , -SO ₂ R ^x and -ONO ₂ , wherein R ^x , R ^y and R ^{z are} independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkene Alkyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted Amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted heterocyclic ring . The substituent in the above "substituted" group cannot be further substituted. For example, when the substituent on the "substituted alkyl group" is a "substituted aryl group", the substituent on the "substituted aryl group" cannot be a "substituted alkenyl group".

The term "treatment" state, disorder or condition includes:

(1) preventing or delaying the onset of clinical symptoms of a condition, disorder or condition that develops in a subject having or susceptible to the state, disorder or condition but has not yet experienced or shown Clinical or subclinical symptoms of the condition, disorder or condition;

(2) inhibiting the state, disorder or condition, ie, preventing or reducing the progression of the disease or at least one of its clinical or subclinical symptoms;

(3) Eliminating the disease, ie causing the state, disorder or condition or at least one of its clinical or subclinical symptoms to subside.

The benefit to the subject being treated is statistically significant, or at least perceptible to the subject or physician.

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

"Therapeutically effective amount" means an amount of a compound that, when administered to a subject in need of a therapeutic state, disorder or condition, is sufficient to effect an effect on the treatment. A "therapeutically effective amount" will vary with the compound, the disease, its severity, and the age, weight, physical condition, and responsiveness of the subject to be treated.

The compounds described in the present invention can form salts. Non-limiting examples of pharmaceutically acceptable salts that form part of the invention include inorganic hydrazine derived salts, organic hydrazine salts, chiral guanidine salts, salts of natural amino acids, and salts of unnatural amino acids. Certain compounds of the invention can exist as stereoisomers (e.g., diastereomers and enantiomers). With respect to all compounds of formula (I), the invention extends to its stereoisomeric forms and mixtures thereof. The various stereoisomeric forms of the invention may be separated from one another by methods known in the art, or may be obtained by stereospecific or asymmetric synthesis, as long as the prior art teaches the synthesis or isolation of particular stereoisomers. isomer. Tautomeric forms and mixtures of the compounds described herein are also contemplated.

Drug composition

The pharmaceutical compositions of the present invention comprise at least one compound described herein and at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition under consideration contains a compound described herein in an amount sufficient to inhibit the TRPV3 receptor in the subject.

Subjects considered include, for example, living cells and mammals including human mammals. The compounds of the invention may be combined with or diluted with a pharmaceutically acceptable excipient such as a carrier or diluent, or enclosed in a carrier in the form of a capsule, sachet, paper or other container.

Examples of suitable carriers include, but are not limited to, water, saline solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, gypsum powder, sucrose, dextrin, carbonic acid Magnesium, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or cellulose low alkyl ether, citric acid, fatty acid, fatty acid amine, fatty acid single Glycerides and diglycerides, pentaerythritol fatty acid ethers, polyoxyethylene, hydroxymethylcellulose, and polyvinylpyrrolidone.

The carrier and diluent may comprise a sustained release material such as glyceryl monostearate or glyceryl distearate (alone or mixed with paraffin).

The pharmaceutical composition may further comprise one or more pharmaceutically acceptable adjuvants, wetting agents, emulsifiers, suspending agents, preservatives, salts which affect the osmotic pressure, buffers, sweeteners, flavoring agents, coloring agents or Any combination of the above. The pharmaceutical compositions of the present invention may also be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a subject by procedures known in the art.

The pharmaceutical compositions described herein can be prepared by conventional techniques known in the art, such as those described in Remington: The Science and Practice of Pharmacy, 20th Edition, 2003 (Lippincott Williams & Wilkins). For example, the active compound may be mixed with the carrier or diluted in a carrier or enclosed in a carrier in the form of an ampule, capsule, sachet, paper or other container. When the carrier serves as a diluent, it can be a solid, semi-solid or liquid material which acts as an excipient, excipient or medium for the active compound. The active compound can be adsorbed onto a granular solid container, such as in a sachet.

The pharmaceutical composition may be in a conventional form such as a capsule, a tablet, an aerosol, a solution, a suspension or a topically applied product.

The route of administration can be any route that effectively delivers the active compound of the invention to the appropriate or desired site of action. Suitable administration routes include, but are not limited to, oral administration, nasal administration, pulmonary administration, buccal administration, subdermal administration, intradermal administration, transdermal administration, parenteral administration. Medicine, rectal administration, depot administration, subcutaneous administration, intravenous administration, intraurethral administration, intramuscular administration, intranasal administration, ocular administration (eg use of ophthalmic solution) Or local administration (such as the use of topical ointment). It is preferably an oral administration route.

Solid oral preparation forms include, but are not limited to, tablets, capsules (soft gelatin or hard gelatin), dragees (containing active ingredients in powder or pellet form), troches and lozenges. Tablets, dragees or capsules having talc and/or carbohydrate carriers or binders and the like are especially suitable for oral use. Liquid preparations include, but are not limited to, syrups, emulsions, soft gelatin, and sterile injectable liquids, such as aqueous or nonaqueous liquid suspensions or solutions. For parenteral applications, injectable solutions or suspension formulations are especially suitable.

A typical tablet prepared by conventional tabletting techniques may comprise: (1) a core: an active compound (such as a free compound or a salt thereof), 250 mg of colloidal cerium oxide (Aerosil) ), 1.5 mg microcrystalline cellulose (Avicel) ), 70 mg modified cellulose gum (Ac-Di-Sol) And 7.5 mg of magnesium stearate; (2) coating: HPMC, about 9 mg of Mywacett 9-40 T and about 0.9 mg of deuterated monoglyceride.

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

For parenteral use, injectable solutions or suspension formulations are especially suitable, preferably aqueous solutions with active compound in polyhydroxylated castor oil.

treatment method

The invention provides compounds and pharmaceutical formulations thereof for use in the treatment of diseases, disorders and/or disorders modulated by TRPV3. The link between therapeutic effects 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; All references are incorporated herein by reference for their purpose.

The invention further provides a method of treating a disease, disorder, and/or disorder modulated by TRPV3 in vivo in a subject in need thereof by administering a therapeutically effective amount of a compound or pharmaceutical composition of the invention.

Diseases, conditions, and/or disorders that are thought to be modulated by TRPV3 include, but are not limited to, migraine, joint pain, heartburn caused by ischemic myocardium, acute pain, chronic pain, neuropathic pain, postoperative pain, and neuropathic pain. Pain (eg, post-herpetic neuralgia or trigeminal neuralgia), pain due to diabetic neuropathy, toothache and cancer pain, inflammatory pain conditions (eg arthritis and osteoarthritis).

Diseases, conditions, and/or disorders that are thought to be regulated by TRPV3 include, but are not limited to, pain, nociceptive pain, toothache, heartache caused by ischemic myocardium, pain caused by migraine, joint pain, neuropathy, neurodegenerative disease , retinopathy, neurological skin disorders, stroke, bladder allergy, urinary incontinence, vulvodynia, gastrointestinal disorders such as irritable bowel syndrome, gastroesophageal reflux disease, enteritis, ileitis, stomach-duodenal ulcer, Inflammatory bowel disease, Crohn's disease, celiacisease; inflammatory diseases such as pancreatitis; respiratory disorders such as allergic and non-allergic rhinitis, asthma or chronic obstructive pulmonary disease; skin, eye or mucous membrane Stimulation; dermatitis; pruritus, such as uremia pruritus; fever; muscle spasm; vomiting; dyskinesia; depression; Huntington's disease; memory loss; brain function limitation; amyotrophic lateral sclerosis (ALS); Dementia; arthritis, osteoarthritis; diabetes; obesity; urticaria; actinic keratosis; keratocanthoma; alopecia; Neil's disease; tinnitus; hyperacusis (hyperacusis); anxiety; and benign prostatic hyperplasia.

General preparation method

The compounds described herein (including formula (I) and formula (II) and specific examples) are prepared using techniques known to those of ordinary skill in the art. The compounds described herein were prepared by the reaction sequences described in Schemes 1 and 2 below. It is envisioned that all possible isomers are also within the scope of the invention.

Starting materials for use in the following reaction schemes are either commercially available or can be prepared by methods known to those skilled in the art. In general, the compounds described herein can be prepared by the reaction scheme shown below, wherein all symbols are as defined above.

a compound of the 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) may be according to the synthesis scheme 1 Preparation was carried out. Thus, a spirocyclic amine of formula (1) is coupled with an aryl-substituted carboxylic acid of formula (2) to form a decylamine of formula (I). According to known reaction conditions, in the presence of an activating agent such as 1-hydroxybenzotriazole (HOBt) and hydrazine, a suitable coupling agent (for example, dicyclohexylcarbodiimide) is used in a suitable solvent. (DCC) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI)) achieves the formation of a guanamine bond.

Synthetic scheme 1

Alternatively, a compound of the 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 may be 1) a spirocyclic amine and a hydrazine halide of the formula (3) wherein X is a halogen are prepared in the presence of a suitable hydrazine (eg, triethylamine) in a suitable solvent (eg, tetrahydrofuran) to form formula (I) compound of.

Synthetic scheme 2

The starting material 3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4-one is commercially available or can be produced by the appropriately substituted 2-hydroxyacetophenone and cyclic ketone in the presence of hydrazine. The reaction is carried out as described in Kabbe, HJ. et al., Angewandte Chemie (1982), 94 , 254-262. All unsubstituted and substituted 3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-amines from 3,4-dihydrospiro[chromene-2,1'-cyclobutyl]- The 4-ketone is prepared in two steps by its hydrazine intermediate as described in Ram, P. et al., Indian J. Chem. Sec B , (1981), 12, 1063-1067. Preparation of optically pure or enriched 3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-amine by resolution of the corresponding amine using a suitable chiral acid as a resolving reagent isomer. The best results were obtained when optically pure N -toluenesulfonyl valine was used as the resolving agent. Both enantiomers of N -toluenesulfonylproline were prepared as described in Izumiya, N. et al., Bull. Chem. Soc . Japan. (1953), 26 , 53-56.

Certain phenylacetic acid derivatives used in this study are commercially available. Uncommercially available derivatives are prepared by suitable benzaldehyde carbonation. Tetrahydronaphthalene acetic acid is prepared from the corresponding tetralone by Wittig-Horner reaction followed by catalytic hydrogenation and ester hydrolysis. Indole-3-acetic acid was prepared from substituted phenylhydrazines and γ-keto acids by the Fischer® synthesis described in the literature: Fox, SS et al., J. Am. Chem. Soc . (1951) , 73, 756-2758 and Jackson et al., Canadian J. Res. Sec. B , (1935), 13, 170-172. Benzoisoxazole acetic acid is prepared from 4-hydroxycoumarin as described in Casini, G. et al . J. Heterocyclic Chemistry , (1969), 6 , 279-283.

The arylpropionic acid is prepared from an aromatic aldehyde and malonic acid by using a Knoevenagel condensation reaction (as described in Rubenstein et al., J. Chem. Soc. , (1926), 650) as a key reaction. Biaryl propionic acid is prepared by subjecting 2-mercaptoboronic acid to a thiol Suzuki coupling reaction with an aryl halide; and then subjecting the resulting aldehyde to a carbonation reaction by malonic acid condensation.

All aryl butyric acids were prepared from aromatic aldehydes by sequential Wittig carbonation. Therefore, the methoxymethylene (triphenyl)phosphoric acid phosphinic acid is used to increase the carbonation reaction of the substituted benzaldehyde to obtain the corresponding phenylacetaldehyde derivative, and then (triphenylphosphoranylidene)acetic acid is used. The methyl ester further undergoes a carbonation reaction of the derivative to form a substituted methyl phenylbutenoate. The substituted methyl phenylbutenoate is subjected to catalytic hydrogenation and then hydrolyzed to obtain the desired arylbutyric acid derivative.

Experimental procedure

3,4-Dihydrospiro[chromene-2,1'-cyclobutan]-4-one:

All of the starting materials, chromen-4-ones required for the synthesis of 3,4-dihydrospirosyl-4-amine, were prepared by the following reaction: commercially available 2-hydroxyacetophenone (1) Equivalent) and cycloalkanone (1 equivalent) were reacted in refluxing methanol in the presence of excess triethylamine (2-3 equivalents).

3,4-Dihydrospiro[chromene-2,1'-cyclobutyl]-4-amine:

3,4-Dihydrospiro[chromene-2,1'-cyclobutane]-4(3 H )-one (1.0 eq.) in ethanol (10 V) in the presence of aqueous NaOH (3 eq.) react with hydroxylamine hydrochloride (1.5 eq), to generate a good yield (4 E) -6- chloro-spiro [chromene-2,1'-butoxy] -4 (3 H) - one oxime. The resulting hydrazine intermediate (1.0 eq.) was reduced in glacial acetic acid (10 vol.) by zinc powder (2-3 eq.) to afford the free amine. All 4-aminochromene intermediates (Table 1) prepared by this method were characterized by spectroscopic analysis.

General procedure for the preparation of L-amine:

A solution of (±) 3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-amine derivative (1.0 equivalent) in isopropanol (10-12 ml) was refluxed 10 In minutes, a clear solution was formed. Then, L -valine tosylate (0.5 equivalent) in isopropanol (10 ml) was added over 15 minutes, and further stirred at the same temperature for 30 minutes. The resulting mixture was allowed to cool to room temperature, and the precipitated diastereomer salt was collected by filtration. The resulting precipitate was dissolved in isopropanol (10 vol) under reflux and slowly cooled to room temperature. The resulting mixture was further stirred for 18 h. The precipitated salt was collected by filtration. A suspension of the obtained salt in water was basified to pH 8.0 by addition of aqueous K ₂ CO ₃ . The resulting solution was extracted with ethyl acetate (3×50 ml). The combined organic extracts were dried K ₂ CO ₃ and evaporated in vacuo to give 30-38% of the pure enantiomer. The enantiomeric purity of the obtained material was analyzed by using a n-hexane:isopropanol:diethylamine (98:2:0.1) as a mobile phase through a 250 x 4.6 mm CHIRALPAK-I A column.

General procedure for the preparation of dextroamine:

As described above, D -valine tosylate (0.5 equivalents) of (±) 3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-amine derivative (1.0) Equivalent) was optically resolved to give a dextrose in an isolated yield of 30-38%. The enantiomeric purity of the obtained material was determined by using a hexane:isopropanol:diethylamine (98:2:0.1) as a mobile phase through a 250 x 4.6 mm CHIRALPAK-I A column.

All of the prepared intermediates were characterized by spectroscopic analysis prior to use in the preparation of the compounds of the present invention. The structural details and selected physicochemical details of 3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-amine are given in Table 1.

Spectral analysis data for the selected 3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-amine have been given below.

Intermediate 1

8-Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-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, 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[chromene-2,1'-cyclobutyl]-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-dihydrospiro[chromene-2,1'-cyclobutyl]-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 the dominant enantiomer: 26.23 min; ee = 96.06%; specific optical rotation: [α] _D = -6.63 °, c = 1%, in methanol.

Intermediate 4

(4 S )-8-Chloro-3,4-dihydrospiro[chromene-2,1 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 the dominant enantiomer: 30.57 min; ee = 97.14%; specific optical rotation: [α] _D = +6.30 °, c = 1%, in methanol.

Intermediate 5

3,4-Dihydrospiro[chromene-2,1'-cyclobutyl]-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[chromene-2,1'-cyclobutyl]-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. (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[chromene-2,1'-cyclobutyl]-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, 1H), 6.96 (d, J = 9.0 Hz, 1H).

Intermediate 8

(4 R )-6-Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-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, 1H), 6.69 (d, J = 7.2 Hz, 1H), 7.04 (dd J = 2.4, 6.3 Hz, 1H), 7.36 (s, 1H); HPLC: retention time of the dominant enantiomer: 26.57 min; ee = 98.03%; specific optical rotation: [α] _D = +8.64 °, c = 1%, in methanol.

Intermediate 9

(4 S )-6-Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-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, 1H), 6.69 (d, J = 7.2 Hz, 1H), 7.04 (dd J = 2.4, 6.3 Hz, 1H), 7.36 (s, 1H); HPLC: retention time of the dominant enantiomer: 27.26 min; ee=99.88%; specific optical rotation: [α] _D = -8.19°, c=1% in methanol.

Intermediate 10

7-Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-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[chromene-2,1'-cyclobutyl]-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[chromene-2,1'-cyclobutyl]-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[chromene-2,1'-cyclobutyl]-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, 1H), 6.90-6.96 (m, 1H), 7.43 (s, 2H); ESI-MS (m/) z) 258.20(M+H) ⁺ .

Intermediate 14

(6-chloro-7-methyl)-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-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[chromene-2,1'-cyclobutyl]-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 (brs, 2H, interchangeable with D ₂ O ), 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[chromene-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[chromene-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[chromene-2,1'-cyclobutyl]-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, 1H), 4.66-4.72 (m, 1H), 7.17-7.26 (m, 2H).

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 clarified by the following examples, which are not to be construed as limiting the scope of the disclosure, but are intended to be illustrative only.

Example 1

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

Add EDCI‧HCl (258 mg, 1.348 mmol), HOBt (206 mg, 1.348 mmol) to a solution of Intermediate 1 (200 mg, 0.898 mmol) in dichloromethane (10 mL). ), phenylacetic acid (183 mg, 1.348 mmol) and triethylamine (375 μl, 2.696 mmol). The resulting reaction mixture was stirred under nitrogen for 16 h at rt. The reaction mixture was diluted with water (10 ml) and the layers were separated. The aqueous layer (2 × 10 ml) and extracted with chloroform, washed (30 ml) The combined organic layers were washed with water (2 × 30 ml), brine, and dried over Na ₂ SO _4. The crude product obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography using 10% acetone in petroleum ether to afford 210 mg of white solid product; 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[chromenene-2,1'-cyclobutyl]-4-yl)-2-(2-methoxyphenyl)acetamide:

The title compound was obtained from the intermediate 2 (200 mg, 0.763 mmol) and 2-methoxyphenylacetic acid (190 mg, 1.148 mmol) in EDCI HCl (219 mg, 1.148 mmol), HOBt, as described in Example 1. 175 mg, 1.148 mmol) and triethylamine (318 μl, 2.289 mmol) were prepared in dichloromethane (10 ml). 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[chromenene-2,1'-cyclobutyl]-4-yl)-2-{2-[(methylsulfonyl)amino]phenyl }Acetamine:

Step 1: N- (6-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-2-(2-nitrophenyl)acetamide: This compound was synthesized from the intermediate 2 (500 mg, 1.923 mmol) and 2-nitrophenylacetic acid (348 mg, 1.923 mmol) in EDCI HCl (191 mg, 1.789 mmol), HOBt (153 mg, Prepared in dichloromethane (10 ml) in the presence of 1.789 mmol) and triethylamine (802 μl, 2.289 mmol), 550 mg of white solid product: ⁶ 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'-butyl] -4-yl) acetyl amine: at room temperature, the solution was added (5 ml) and stirred fully to the ethanol procedure described for intermediate 1 (200 mg, 0.512 mmol) in water (3 ml) of _{NH 4 Cl (276 mg, 5.102} mmol). The resulting reaction mixture was stirred at the same temperature for 15 minutes and then heated to 80 ° C over 15 minutes. Iron (86 mg, 1.552 mmol) was added at the same temperature. The resulting reaction mixture was further refluxed for 2 h. The residue obtained after evaporation of the solvent was extracted with chloroform (2×50 ml). The chloroform layer was passed through diatomaceous earth. Separate the layers. The organic layer was washed with water (2×30 ml), brine (30 ml) and dried over Na ₂ SO ₄ . The solvent was evaporated to give 150 mg of product.

Step 3: N- (6-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclopropanyl]-4-yl)-2-{2-[(methylsulfonyl)amino Phenyl}acetamide: To a solution of the intermediate 2 (150 mg, 0.420 mmol) in dichloromethane (5 ml), pyridine (1 ml). Methanesulfonate chloride (52 mg, 0.462 mmol) was added dropwise at the same temperature. The resulting reaction mixture was stirred at room temperature under nitrogen overnight. The reaction mixture was diluted with water (20 ml) and the layers were separated. The aqueous layer (2 × 20 ml) and extracted with chloroform, washed (30 ml) The combined organic layers were washed with water (2 × 30 ml), brine, and dried over Na ₂ SO _4. The crude product obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography to give 210 mg of pale white solid product as of EtOAc (EtOAc, EtOAc, EtOAc, 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 (MH) ^- .

Example 4

N- (6-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-2-(2-(cyclopentyloxy)-3-methoxybenzene Ethylamine:

The title compound was obtained from the intermediate 2 (200 mg, 0.763 mmol) and [2-(cyclopentyloxy)-3-methoxyphenyl] in dichloromethane (10 ml) as described in Example 1. Acetic acid (283 mg, 1.153 mmol) was prepared in the presence of EDCI HCl (221 mg, 1.153 mmol), HOBt (178 mg, 1.153 mmol) and triethylamine (321 μl, 2.307 mmol). Product; 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-dihydrospiro[chromene-2,1'-cyclobutan]-4-yl]-2-(2-cyclopentyloxy-3-methyl Oxy)phenyl phenyl acetamide:

The title compound was obtained from Intermediate 3 (150 mg, 0.675 mmol) and 2-(2-cyclopentyloxy-3-methoxyphenyl)acetic acid (167 mg, 0.675 mmol) in EDCI as described in Example 1. ‧ Preparation of HCl (192 mg, 1.047 mmol), HOBt (154 mg, 1.047 mmol) and triethylamine (275 μl, 2.008 mmol) in dichloromethane (10 ml), 181 mg over 5 h White solid product; 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 (MH) ^- .

Example 6

N -[(4 S )-8-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl]-2-(2-cyclopentyloxy-3-methyl Oxyphenyl) phenethylamine:

The title compound was obtained from Intermediate 4 (150 mg, 0.675 mmol) and 2-(2-cyclopentyloxy-3-methoxyphenyl)acetic acid (167 mg, 0.675 mmol) in EDCI as described in Example 1. ‧ Preparation of HCl (192 mg, 1.047 mmol), HOBt (154 mg, 1.047 mmol) and triethylamine (275 μl, 2.008 mmol) in dichloromethane (10 ml) ;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) 2,0. 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 (MH) ^- .

Example 7

N- (6-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-2-(3,4-dimethoxyphenyl)acetamide:

The title compound was obtained from the intermediate 2 (200 mg, 0.763 mmol) and 3,4-dimethoxyphenylacetic acid (224 mg, 1.145 mmol) in EDCI HCl (219 mg, 1.145 mmol) as described in Example 1. Prepared in the presence of HOBt (175 mg, 1.145 mmol) and triethylamine (425 μl, 3.053 mmol) in dichloromethane (10 ml) afforded 217 mg of white solid product: 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[chromenene-2,1'-cyclobutyl]-4-yl)-2-pyridin-2-ylacetamide:

The title compound was obtained from the intermediate 2 (200 mg, 0.898 mmol) and 2-pyridylacetic acid (234 mg, 1.448 mmol) in EDCI HCl (258 mg, 1.48 mmol), HOBt (206 mg) as described in Example 1. Prepared in dichloromethane (10 ml) in the presence of triethylamine (375. , 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[chromenene-2,1'-cyclobutyl]-4-yl)-2-(1-naphthyl)acetamide:

The title compound was obtained from the intermediate 5 (150 mg, 0.806 mmol) and 1-naphthylacetic acid (150 mg, 0.806 mmol) in EDCI HCl (230 mg, 1.209 mmol), HOBt (185 mg) as described in Example 1. , 1.209 mmol) and triethylamine (336 μl, 2.418 mmol) were prepared in dichloromethane (10 ml), 151 mg of white solid product was obtained in 3 h; 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[chromenene-2,1'-cyclobutyl]-4-yl)-2-(1-naphthyl)acetamide:

The title compound was obtained from the intermediate 6 (300 mg, 1.611 mmol) and 1-naphthylacetic acid (400 mg, 1.933 mmol) in EDCI HCl (463 mg, 2.455 mmol), HOBt (246 mg) as described in Example 1. Prepared in methylene chloride (10 ml) in the presence of triethylamine ( </RTI></RTI><RTIgt;</RTI></RTI><RTIgt; , 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 )-6,8-Difluoro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl]-2-(1-naphthyl)acetamidine amine:

The title compound was obtained from the intermediate 7 (95 mg, 0.421 mmol) and 1-naphthylacetic acid (117 mg, 0.632 mmol) in EDCI HCl (121 mg, 0.632 mmol), HOBt (96 mg) as described in Example 1. Prepared in methylene chloride (10 ml) in the presence of triethylamine ( EtOAc, EtOAc, EtOAc, EtOAc (EtOAc) , 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-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl]-2-(1-naphthyl)acetamide:

The title compound was obtained from the intermediate 8 (150 mg, 0.674 mmol) and 1-naphthylacetic acid (188 mg, 1.011 mmol) in EDCI HCl (193 mg, 1.011 mmol), HOBt (154 mg) as described in Example 1. , 1.011 mmol) and triethylamine (281 μl, 2.022 mmol) in methylene chloride (10 ml) afforded 123 mg of white solid: ield: </ RTI> (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-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl]-2-(1-naphthyl)acetamide:

The title compound was obtained from the intermediate 9 (200 mg, 0.896 mmol) and 1-naphthylacetic acid (200 mg, 1.076 mmol) in EDCI HCl (257 mg, 1.345 mmol), HOBt (206 mg) as described in Example 1. Prepared in dichloromethane (10 ml) in the presence of triethylamine (3741 mmol), EtOAc (EtOAc: EtOAc, EtOAc (EtOAc) , 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[chromenene-2,1'-cyclobutyl]-4-yl)-2-(1-naphthyl)acetamide:

The title compound was obtained from the intermediate 10 (200 mg, 0.761 mmol) and 1-naphthylacetic acid (171 mg, 0.913 mmol) in EDCI HCl (221 mg, 1.141 mmol), HOBt (176 mg) as described in Example 1. Prepared in THF (5 ml) in the presence of triethylamine (1,1,1,1,3,3,3,3,3,3,3,3,3,3,2,2,2,2 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-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl]-2-(1-naphthyl)acetamide:

The title compound consisted of intermediate 3 (100 mg, 0.448 mmol) and 1-naphthylacetic acid (99 mg, 0.531 mmol) in EDCI HCl (128 mg, 0.672 mmol), HOBt (102 mg) as described in Example 1. , 0.672 mmol) and triethylamine (185 μl, 2.022 mmol) in methylene chloride (10 ml) to give 100 mg of white solid product; 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-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl]-2-(1-naphthyl)acetamide:

The title compound was obtained from Intermediate 4 (150 mg, 0.668 mmol) and 1-naphthylacetic acid (149 mg, 0.801 mmol) in EDCI HCl (193 mg, 1.008 mmol), HOBt (154 mg) as described in Example 1. Prepared in methylene chloride (10 ml) in the presence of triethylamine ( </RTI><RTIID=0.0></RTI></RTI></RTI><RTIgt; 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[chromenene-2,1'-cyclobutyl]-4-yl)-2-(1-naphthyl)acetamide:

Step 1: N- (5-Benzyloxy-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-2-(1-naphthyl)acetamide: The title compound was obtained from the title compound (872 mg, 2.254 mmol) and 1-naphthylacetic acid (500 mg, 2.685 mmol) in EDCI HCl (772 mg, 4.027 mmol), HOBt (411 mg, Prepared in dichloromethane (10 ml) in the presence of EtOAc (EtOAc, EtOAc (EtOAc) 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); APCIMS (m/z) 464.5 ( M+H) ⁺ .

Step 2: N- (5-Hydroxy-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-2-(1-naphthyl)acetamide: in Paar instrument Deprotection of the Step 1 intermediate (400 mg, 0.863 mmol) was carried out using a 50% Pd/C (80 mg) in methanol (70 ml) over 8 h. The reaction mixture was filtered through a bed of diatomaceous earth. The filtrate was concentrated under reduced pressure to give the crude residue was carried out by silica gel column chromatography of the residue afforded 115 mg 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[chromenene-2,1'-cyclobutyl]-4-yl)-2-(2-naphthyl)acetamide:

The title compound was obtained from the intermediate 2 (200 mg, 0.764 mmol) and 2-naphthylacetic acid (213 mg, 1.141 mmol) in EDCI HCl (213 mg, 1.145 mmol), HOBt (176 mg) as described in Example 1. Prepared in methylene chloride (10 ml) in the presence of triethylamine ( EtOAc, EtOAc, EtOAc, EtOAc (EtOAc) , 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

(2 S )- N -[(4 R )-6-Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4-yl]-2-(6-methoxy -2-naphthyl)propanamine:

The title compound was obtained from the intermediate 8 (200 mg, 0.769 mmol) and ( 2S )-2-(6-methoxy-2-naphthyl)propanoic acid (213 mg, 0.923 mmol) as described in Example 1. Prepared in dichloromethane (10 ml) in the presence of EDCI HCl (221 mg, 1.153 mmol), HOBt (176 mg, 1.153 mmol) and triethylamine (321 μl, 2.307 mmol) to give 112 mg white Solid product; 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

(2 S )- N -[(4 S )-6-Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4-yl]-2-(6-methoxy -2-naphthyl)propanamine:

The title compound was obtained from the intermediate 9 (200 mg, 0.769 mmol) and ( 2S )-2-(6-methoxy-2-naphthyl)propanoic acid (213 mg, 0.923 mmol) as described in Example 1. Prepared in dichloromethane (10 ml) in the presence of EDCI HCl (221 mg, 1.153 mmol), HOBt (176 mg, 1.153 mmol) and triethylamine (321 μl, 2.307 mmol) to give 103 mg white Solid product; 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, 1H), 7.67-7.76 (m, 3H); APCI-MS (m/z) 436.37 (M +H) ⁺ .

Example 21

N- (6-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-2-(1,2,3,4-tetrahydronaphthalen-1-yl Ethylamine:

The title compound was obtained from the intermediate 2 (212 mg, 0.951 mmol) and 5,6,7,8-tetrahydronaphthalen-1-ylacetic acid (150 mg, 0.791 mmol) in EDCI HCl as described in Example 1. 227 mg, 1.663 mmol), HOBt (121 mg, 0.791 mmol) and triethylamine (330 μl, 2.371 mmol) were obtained in dichloromethane (10 ml). ^{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, 6H); ESI-MS (m/z) 394.76 (MH) ^- .

Example 22

N -[(6-chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)]-2-(1,2,3,4-tetrahydronaphthalene-2 -yl)acetamide:

The title compound was obtained from the intermediate 2 (218 mg, 1. 053 mmol) and 1,2,3,4-tetrahydronaphthalen-2-yl acetic acid (200 mg, 1.053 mmol) in EDCI HCl as described in Example 1. Preparation of 302 mg, 1.585 mmol), HOBt (241 mg, 1.585 mmol) and triethylamine (439 μl, 3.165 mmol) in dichloromethane (10 ml) ^{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'-butoxy] -4 -yl)acetamide:

The title compound was obtained from the intermediate 2 (200 mg, 0.892 mmol) and 1,3-benzodioxol-4-yl acetic acid (161 mg, 0.881 mmol) in EDCI as described in Example 1. Prepared in dichloromethane (10 ml) in the presence of EtOAc ( EtOAc (EtOAc: EtOAc (EtOAc) 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); MS (m/z) 384.16 (MH) ^- .

Example 24

N- (6-fluoro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-2-(5-fluoro-3-methyl-1 H -indole- 2-yl) acetamamine:

The title compound was obtained from Intermediate 6 (200 mg, 0.963 mmol) and (5-fluoro-3-methyl- 1H -indol-2-yl)acetic acid (200 mg, 0.963 mmol) as described in Example 1. Prepared in dichloromethane (10 ml) in the presence of EDCI HCl (276 mg, 1.145 mmol), HOBt (221 mg, 1.145 mmol) and triethylamine (401 μl, 3.003 mmol) to give 18 mg white 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, 1H); ESI-MS (m/z) 397.33 (M+H) ⁺ .

Example 25

N- (6-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-2-(5-methoxy-2-methyl-1 H -indole Indole-3-yl)acetamide:

The title compound was obtained from the intermediate 2 (200 mg, 0.896 mmol) and (5-methoxy-2-methyl- 1H -indol-3-yl)acetic acid (195 mg, 0.896) as described in Example 1. Prepared in dichloromethane (10 ml) in the presence of EDCI HCl (256 mg, 1.345 mmol), HOBt (205 mg, 1.345 mmol) and triethylamine (374 μl, 3.003 mmol) Mg white solid product; 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 (MH) ^- .

Example 26

2-(1,2-Benzisoxazol-3-yl) -N -[(4 R )-(6-chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl] 4-yl) acetamamine:

The title compound was obtained from the intermediate 8 (200 mg, 0.763 mmol) and 1,2- benzisoxazole-3-yl acetic acid (148 mg, 0.839 mmol) in EDCI HCl (219 mg) as described in Example 1. Prepared in dichloromethane (10 ml) in the presence of HOBt (175 mg, 1.145 mmol) and triethylamine (425 μl, 3.053 mmol) to give 176 mg of white solid product; 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-dihydrospiro[chromene-2,1'-cyclobutyl] 4-yl) acetamamine:

The title compound was obtained from the intermediate 9 (200 mg, 0.763 mmol) and 1,2- benzisoxazole-3-yl acetic acid (148 mg, 0.839 mmol) in EDCI HCl (219 mg) as described in Example 1. Prepared in dichloromethane (10 ml) in the presence of HOBt (175 mg, 1.145 mmol) and triethylamine (425 μl, 3.053 mmol) to give 176 mg of white solid product; 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[chromenene-2,1'-cyclobutyl]-4-yl)-3-(2-cyclopentyloxyphenyl)propanamine:

The title compound consisted of intermediate 2 (200 mg, 0.779 mmol) and 3-(2-cyclopentyloxyphenyl)propanoic acid (181 mg, 0.779 mmol) in EDCI HCl (222 mg) as described in Example 1. Prepared in methylene chloride (10 ml) in the presence of EtOAc (1, EtOAc, EtOAc, EtOAc (EtOAc) 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-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl]-3-(3-cyclopentyloxy)phenylpropane Guanamine:

The title compound was obtained from the intermediate 8 (100 mg, 0.448 mmol) and 3-(3-cyclopentyloxyphenyl)propanoic acid (105 mg, 0.448 mmol) in EDCI HCl (128 mg) as described in Example 1. , 0.672 mmol), HOBt (102 mg, 0.672 mmol) and triethylamine (187 μl, 1.344 mmol) in dichloromethane (10 ml) 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-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl]-3-(3-cyclopentyloxy)phenylpropane Guanamine:

The title compound was obtained from the intermediate 9 (104 mg, 0.444 mmol) and 3-(3-cyclopentyloxyphenyl)propanoic acid (100 mg, 0.444 mmol) in EDCI HCl (128 mg) as described in Example 1. , 0.672 mmol), HOBt (102 mg, 0.672 mmol) and triethylamine (186 μl, 1.344 mmol) in methylene chloride (10 ml). 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 R )-(8-chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-[2-(cyclopentyloxy)- 1-phenyl]propanamine:

The title compound consisted of intermediate 3 (100 mg, 0.448 mmol) and 3-(2-cyclopentyloxyphenyl)propionic acid (125 mg, 0.536 mmol) in EDCI HCl (128 mg) as described in Example 1. , 0.672 mmol), HOBt (102 mg, 0.672 mmol) and triethylamine (186 μl, 1.344 mmol) in dichloromethane (10 ml) 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, 2H), 7.14 - 7.19 (m, 3H); ESI-MS (m/z) 440.34 (M+H) ⁺ .

Example 32

N -[(4 S )-8-Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobut-4-yl]-3-[2-(cyclopentyloxy)phenyl] Propylamine:

The title compound was obtained from Intermediate 4 (100 mg, 0.448 mmol) and 3-(2-cyclopentyloxyphenyl)propionic acid (115 mg, 0.494 mmol) in EDCI HCl (129) as described in Example 1. Prepared in methylene chloride (10 ml) in the presence of EtOAc (EtOAc, EtOAc, EtOAc) 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, 2H), 7.14 - 7.19 (m, 3H); ESI-MS (m/z) 440.34 (M+H) ⁺ .

Example 33

7-Benzyloxy- N- (3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-(2-cyclopentyloxyphenyl)propanamide:

The title compound was obtained from the intermediate 12 (200 mg, 0.603 mmol) and 3-(2-cyclopentyloxyphenyl)propanoic acid (169 mg, 0.723 mmol) in EDCI. Prepared in dichloromethane (10 ml) in the presence of EtOAc (EtOAc EtOAc (EtOAc) 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[chromene-2,1'-cyclobutyl]-4-yl)-3-{2-[(isopropylsulfonyl)amino]benzene Acetylamine:

Step 1: (2 E) - N - (6- chloro-3,4-dihydro-spiro [chromene-2,1'-butyl] -4-yl) -3- {2 - [(isopropyl sulfo acyl) amino] phenyl} acrylamide: as described in Example 1, the compound 2 (150 mg of intermediate, 0.576 mmol) and (2 E) -3- {2 - [(2- Isopropyl sulfonyl)amino]phenyl}acrylic acid (186 mg, 0.692 mmol) in EDCI HCl (165 mg, 0.865 mmol), HOBt (132 mg, 0.865 mmol) and triethylamine (240 μl, 1.732) under mmol) is present, in dichloromethane (10 ml) was prepared, to give 125 mg 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[chromenene-2,1'-cyclobutyl]-4-yl)-3-{2-[(isopropylsulfonyl)amine Base phenyl}propanamide: The intermediate of step 1 (110 mg, 0.232 mmol) was reduced to 1.5 in a Paar apparatus at 5% Pd/C (30 mg) in ethyl acetate at 30 psi. h. The reaction mixture was filtered through EtOAc (EtOAc) (EtOAc m. (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, 1H); ESI-MS (m/z) 477.95 (M) ⁺ .

Example 35

N- (6-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-(2-pyridin-2-ylphenyl)propanamide:

Step 1: (2 E) - N - (6- chloro-3,4-dihydro-spiro [chromene-2,1'-butyl] -4-yl) -3- (2-pyridin-2-yl phenyl) acrylamide: as described in Example 1, the title compound 2 (300 mg of intermediate, 1.153 mmol) and (2 E) -3- (2- phenyl-pyridin-2-yl) acrylic acid (260 Preparation of mg, 1.153 mmol) in dichloromethane (10 ml) in the presence of EDCI HCl (332 mg, 1.730 mmol), HOBt (177 mg, 1.153 mmol) and triethylamine (402 μl, 2.084 mmol) , 400 mg of a white solid product; 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[chromenene-2,1'-cyclobutyl]-4-yl)-3-(2-pyridin-2-ylphenyl)propanoid Amine: The intermediate of Step 1 (300 mg, 0.696 mmol) was reduced for 3 h using a Pd/C (50 mg) in methanol in a Paar apparatus at 40 psi. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated to give a crude compound. EtOAc EtOAc EtOAc Product; 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[chromenene-2,1'-cyclobutyl]-4-yl)-3-(2-pyridin-3-ylphenyl)propanoid amine:

The title compound was obtained from the intermediate 13 (100 mg, 0.340 mmol) and 3-(2-pyridin-2-ylphenyl)propanoic acid (85 mg, 0.374 mmol) in EDCI HCl (97) as described in Example 1. mg, 0.509 mmol), HOBt ( 78 mg, 0.511 mmol) and triethylamine (142 μl, under 2.884 mmol) is present, prepared in methylene chloride (5 ml) to give 59 mg 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[chromenene-2,1'-cyclobutyl]-4-yl)-3-(2-cyclopentyloxy-3-methoxy)phenylpropanamine:

The title compound was obtained from the intermediate 5 (113 mg, 0.604 mmol) and 3-[2-(cyclopentyloxy-3-methoxy)phenyl]propanoic acid (150 mg, 0.604 mmol Prepared in dichloromethane (10 ml) in the presence of EDCI HCl (172 mg, 0.906 mmol), HOBt (137 mg, 0.906 mmol) and triethylamine (249 μl, 1.835 mmol) to give 125 mg White solid product; 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 (MH) ^- .

Example 38

N- (6-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-(2,3-dimethoxy)phenylpropanamine:

The title compound was obtained from Intermediate 2 (200 mg, 0.898 mmol) and 3-(2,3-dimethoxyphenyl)propionic acid (207 mg, 0.988 mmol) in EDCI HCl as described in Example 1. 258 mg, 1.348 mmol), HOBt (206 mg, 1.384 mmol) and triethylamine (372 μl, 2.695 mmol) were obtained in dichloromethane (10 ml). 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[chromenene-2,1'-cyclobutyl]-4-yl)-3-(2-isopropoxy-3-methoxy)phenyl Propylamine:

The title compound was obtained from the intermediate 2 (200 mg, 0.898 mmol) and 3-(2-isopropoxy-3-methoxyphenyl)propionic acid (235 mg, 0.988 mmol) as described in Example 1. Prepared in dichloromethane (10 ml) in the presence of EDCI HCl (258 mg, 1.348 mmol), HOBt (206 mg, 1.448 mmol) and triethylamine (372 μl, 2.695 mmol) 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[chromenene-2,1'-cyclobutyl]-4-yl)-3-(3-chloro-4-methoxy)phenylpropanamide :

The title compound was obtained from the intermediate 2 (200 mg, 0.763 mmol) and 3-(3-chloro-4-methoxyphenyl)propionic acid (198 mg, 0.923 mmol) in EDCI HCl as described in Example 1. (221 mg, 1.153 mmol), HOBt (175 mg, 1.153 mmol) and triethylamine (321 μl, 2.307 mmol), methylene chloride (10 ml) (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. (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[chromenene-2,1'-cyclobutyl]-4-yl)-3-(2-cyclopropylmethoxy-3-methoxy) Phenylpropionamide:

The title compound was obtained from the intermediate 2 (200 mg, 0.769 mmol) and 3-(2-cyclopropylmethoxy-3-methoxyphenyl)propanoic acid (232 mg, 0.923 mmol) as described in Example 1. Prepared in dichloromethane (10 ml) in the presence of EDCI HCl (221 mg, 1.153 mmol), HOBt (176 mg, 1.153 mmol) and triethylamine (321 μl, 2.307 mmol) to give 134 mg White solid product; 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, 3H), 6.95-7.04 (m, 2H); ESI-MS (m/) z) 456.38 (M+H) ⁺ .

Example 42

N -[(4 R )-6-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutan]-4-yl]-3-(2-cyclopentyloxy-3-methyl Oxy)phenylpropanamide:

The title compound was obtained from Intermediate 8 (150 mg, 0.674 mmol) and 3-(2-cyclopentyloxy-3-methoxyphenyl)propionic acid (213 mg, 0.674 mmol) as described in Example 1. EDCI. Prepared in dichloromethane (10 ml) in the presence of EtOAc (EtOAc EtOAc (EtOAc) 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-dihydrospiro[chromenene-2,1'-cyclobutan]-4-yl]-3-(2-cyclopentyloxy-3-methyl Oxy)phenylpropanamide:

The title compound was obtained from Intermediate 9 (150 mg, 0.674 mmol) and 3-(2-cyclopentyloxy-3-methoxyphenyl)propionic acid (195 mg, 0.741 mmol) as described in Example 1. Prepared in the presence of EDCI HCl (193 mg, 1.011 mmol), HOBt (154 mg, 1.011 mmol) and triethylamine (281 μl, 2.022 mmol) in dichloromethane (10 ml) Product; 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[chromenene-2,1'-cyclobutyl]-4-yl)-3-(2-cyclopentyloxy-3-ethoxy)phenyl Propylamine:

The title compound was obtained from the intermediate 2 (150 mg, 0.571 mmol) and 3-(2-cyclopentyloxy-3-ethoxyphenyl)propionic acid (177 mg, 0.631 mmol) as described in Example 1. Prepared in the presence of EDCI HCl (166 mg, 0.863 mmol), HOBt (133 mg, 0.863 mmol) and triethylamine (241 μl, 1.734 mmol) in dichloromethane (10 ml) Product; 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[chromenene-2,1'-cyclobutyl]-4-yl)-3-(2-cyclopentyloxy-3-methoxy)phenyl Propylamine:

The title compound was obtained from the intermediate 10 (200 mg, 0.769 mmol) and 3-(2-cyclopentyloxy-3-methoxyphenyl)propanoic acid (243 mg, 0.923 mmol) 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) ;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[chromenene-2,1'-cyclobutyl]-4-yl)-3-(2-ethoxy-3-methoxy)phenylpropane Guanamine:

The title compound was obtained from the intermediate 1 (200 mg, 0.893 mmol) and 3-(2-ethoxy-3-methoxyphenyl)propionic acid (240 mg, 1.074 mmol) in EDCI as described in Example 1. ‧ Preparation of HCl (257 mg, 1.346 mmol), HOBt (205 mg, 1.346 mmol) and triethylamine (497 μl, 3.563 mmol) in dichloromethane (10 ml) ;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, 1H); ESI-MS (m/z) 430.31 (M+H) ⁺ .

Example 47

N -[(4 R )-8-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutan]-4-yl)]-3-(2-cyclopentyloxy-3- Methoxy)phenylpropanamide:

The title compound was obtained from the intermediate 3 (150 mg, 0.674 mmol) and 3-(2-cyclopentyloxy-3-methoxyphenyl)propanoic acid (213 mg, 0.824 mmol) as described in Example 1. Prepared in THF (10 ml) in the presence of EtOAc (EtOAc: EtOAc, EtOAc, EtOAc (EtOAc) 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-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-(2-cyclopentyloxy-3- Methoxy)phenylpropanamide:

The title compound was obtained from intermediate 4 (150 mg, 0.676 mmol) and 3-(2-cyclopentyloxy-3-methoxyphenyl)propionic acid (212 mg, 0.892 mmol) as described in Example 1. EDCI HCl (193 mg, 1.013 mmol), HOBt (154 mg, 1.013 mmol) and triethylamine (203 μl, 2.107 mmol) eluted in dichloromethane (10 ml) 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[chromene-2,1'-cyclobutyl]-4-yl)-3-(2-cyclopentyloxy-3-methyl Oxy)phenylpropanamide:

The title compound was obtained from the intermediate 14 (200 mg, 0.841 mmol) and 3-(2-cyclopentyloxy-3-methoxyphenyl)propionic acid (222 mg, 0.841 mmol) as described in Example 1. Prepared in the presence of EDCI HCl (242 mg, 1.262 mmol), HOBt (129 mg, 0.841 mmol) and triethylamine (351 μl, 2.524 mmol) in dichloromethane (10 ml) Product: 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[chromenene-2,1'-cyclobutyl]-4-yl)-3-(2-cyclopentyloxy-3-methoxy) Phenylpropionamide;

The title compound was obtained from Intermediate 11 (246 mg, &lt;RTI ID=0.0&gt;&gt; Prepared in the presence of EDCI HCl (218 mg, 1.137 mmol), HOBt (116 mg, 0.756 mmol) and triethylamine (316 μl, 2.274 mmol) in dichloromethane (10 ml) Product; 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[chromenene-2,1'-cyclobutyl]-4-yl)-3-(2-cyclopentyloxy-3-methoxy)phenyl Propylamine:

Deprotection of Example 50 (140 mg, 0.258 mmol) under nitrogen for 4 h was carried out in a Paar apparatus at a pressure of 45 psi using Pd/C (28 mg) in methanol. The reaction mixture was filtered through a bed of diatomaceous earth. The filtrate was concentrated under reduced pressure to give a crude compound. m. 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, 1H, interchangeable with D ₂ O); ESI-MS (m/z) 452.51 (M+H) ⁺ .

Example 52

N- (3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-5-methoxy-4-yl)-3-(2-cyclopentyloxy-3-methoxy) Phenylpropionamide:

The title compound was obtained from the intermediate 15 (165 mg, 0.757 mmol) and 3-(2-cyclopentyloxy-3-methoxyphenyl)propanoic acid (200 mg, 0.757 mmol) as described in Example 1. Prepared in dichloromethane (10 ml) in the presence of EDCI HCl (218 mg, 1.137 mmol), HOBt (116 mg, 0.757 mmol) and triethylamine (317 μl, 2.273 mmol). Product; 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-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-(2-cyclopentyloxy-3-methyl Phenylpropionamine:

The title compound was obtained from the intermediate 8 (100 mg, 0.449 mmol) and 3-(2-cyclopentyloxy-3-methylphenyl)propanoic acid (122 mg, 0.491 mmol) in EDCI as described in Example 1. ‧ HCl (129 mg, 0.675 mmol), HOBt (103 mg, 0.673 mmol) and triethylamine (187 μl, 1.346 mmol) in dichloromethane (10 ml) 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[chromenene-2,1'-cyclobutyl]-4-yl)-3-(2-cyclopentyloxy-3-methyl Phenylpropionamine:

The title compound was obtained from Intermediate 9 (100 mg, 0.449 mmol) and 3-(2-cyclopentyloxy-3-methylphenyl)propanoic acid (122 mg, 0.491 mmol) in EDCI as described in Example 1. ‧ Preparation of HCl (129 mg, 0.675 mmol), HOBt (103 mg, 0.673 mmol) and triethylamine (187 μl, 1.346 mmol) in dichloromethane (10 ml) 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'-cyclobutyl]-4-yl-3-(2-hydroxy-3-methoxyphenyl)propanamine:

Step 1: (2 E) - N - (6- chloro-3,4-dihydro-spiro [chromene-2,1'-butyl] -4-yl) -3- (2-benzyloxy-3 - methoxyphenyl) acrylamide: as described in Example 1, the compound 2 (500 mg of intermediate, 1.938 mmol) and (2 E) -3- [2- (benzyloxy) -3 -methoxyphenyl]acrylic acid (575 mg, 2.023 mmol) in the presence of EDCI HCl (555 mg, 2.897 mmol), HOBt (443 mg, 2.897 mmol) and triethylamine (806 μl, 5.791 mmol) prepared dichloromethane (15 ml) to give 633 mg product 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'-cyclobutyl]-4-yl-3-(2-hydroxy-3-methoxyphenyl)propanoid Amine: Step 1 intermediate (200 mg, 0.408 mmol) was carried out under nitrogen at 45 psi using a 5% Pd/C (50 mg) in ethyl acetate (20 ml). Deprotection and reduction of h. The reaction mixture was filtered through a bed of diatomaceous earth. The filtrate was concentrated under reduced pressure to give crude compound; used in 1% methanol in chloroform, the compound was purified by silica gel column chromatography to give 121 mg 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, 1H), 6.67-6.76 (m, 4H), 6.82-6.86 (m, 1H), 7.04 (dd, J = 6.3, 1.8 Hz, 1H).

Example 56

N- (6-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-(2-benzyloxy-3-methoxy)phenylpropane Guanamine:

To room temperature, Example 55 N -6-chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4-yl-3-(2-hydroxy-3-methoxy K ₂ CO ₃ and benzyl bromide (70 mg, 0.411 mmol) were added dropwise to a solution of propyl hydrazide (150 mg, 0.371 mmol) in dimethylformamide (5 ml). Stir at the same temperature overnight. The obtained reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. Ethyl acetate layer was washed with water (2 × 20 ml), ( 20 ml) washed with brine, dried over Na ₂ SO ₄ and concentrated. The crude product obtained was purified by silica gel column chromatography using 10% acetone in petroleum ether to afford 130 mg of white solid product: 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[chromenene-2,1'-cyclobutyl]-4-yl)-3-{2-isopropoxy-3-[(methylsulfonate) Amino]phenyl}propanamine:

The title compound was obtained from Intermediate 2 (100 mg, 0.384 mmol) and 3-{2-isopropoxy-3-[(methylsulfonyl)amino]phenyl}propanoic acid as described in Example 1. (116 mg, 0.384 mmol) in dichloromethane (5 ml) in the presence of EDCI HCl (111 mg, 0.576 mmol), HOBt (59 mg, 0.384 mmol) and triethylamine (134 μl, 0.961 mmol) be prepared, to give 122 mg white ^{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[chromenene-2,1'-cyclobutyl]-4-yl)-3-{2-isopropoxy-3-[(methylsulfonate) Amino]phenyl}propanamine:

The title compound was obtained from Intermediate 1 (100 mg, 0.384 mmol) and 3-{2-isopropoxy-3-[(methylsulfonyl)amino]phenyl)propanoic acid as described in Example 1. (116 mg, 0.384 mmol) in dichloromethane (5 ml) in the presence of EDCI HCl (111 mg, 0.576 mmol), HOBt (59 mg, 0.384 mmol) and triethylamine (134 μl, 0.961 mmol) Preparation was carried out to give 121 mg of a white solid product: 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, 1H), 7, 37 (d, J = 7.8 Hz, 1H) ;ESI-MS (m/z) 507.46 (M+H) ⁺ .

Example 59

N- (6,8-Dichloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-(2-cyclopentyloxy-3-methoxy Phenylpropionamine:

The title compound was obtained from Intermediate 13 (150 mg, 0.511 mmol) and 3-[2-(cyclopentyloxy-3-methoxy)phenyl]propanoic acid (127 mg, 0.511 mmol Prepared in dichloromethane (10 ml) in the presence of EDCI HCl (147 mg, 0.766 mmol), HOBt (78 mg, 0.511 mmol) and triethylamine (249 μl, 1.788 mmol) to give 85 mg White solid product; 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[chromenene-2,1'-cyclobutyl]-4-yl)-3-{[2-(dimethylamino)ethoxylate 3-methoxy]phenyl}propanamine:

The title compound was obtained from Intermediate 13 (100 mg, 0.339 mmol) and 3-{2-[2-(dimethylamino)ethoxy]-3-methoxyphenyl} as described in Example 1. Propionic acid (102 mg, 0.407 mmol) in dichloromethane (10 ml) in the presence of EDCI HCl (97 mg, 0.509 mmol), HOBt (78 mg, 0.509 mmol) and triethylamine (141 μl, 1.017 mmol) The preparation was carried out to give 57 mg of a white solid product: 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, 1H); APCI-MS (m/ z) 507.81 (M+H) ⁺ .

Example 61

N- (6,8-Dichloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-{2-propoxy-3-[(methyl Sulfhydryl)amino]phenyl}propanamide:

The title compound was obtained from Intermediate 13 (100 mg, 0.339 mmol) and 3-{3-[(methylsulfonyl)amino]-2-propoxyphenyl}propanoic acid as described in Example 1. 103 mg, 0.339 mmol) in dichloromethane (10 ml) in the presence of EDCI HCl (98 mg, 0.509 mmol), HOBt (52 mg, 0.339 mmol) and triethylamine (119 μl, 0.848 mmol) preparation, to give 119 mg white ^{solid; 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[chromene-2,1'-cyclobutyl]-4-yl)-3-{2-isopropoxy-5-[(A Alkylsulfonyl)amino]phenyl}propanamine:

The title compound was obtained from intermediate 13 (100 mg, 0.339 mmol) and 3-{2-isopropoxy-5-[(methylsulfonyl)amino]phenyl)propanoic acid as described in Example 1. (112 mg, 0.372 mmol) in dichloromethane (5 ml) in the presence of EDCI HCl (98 mg, 0.509 mmol), HOBt (78 mg, 0.509 mmol) and triethylamine (142 μl, 1.017 mmol) Preparation was carried out to give 90 mg of a white solid product: NMR (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[chromenene-2,1'-cyclobutyl]-4-yl)-3-{2-butoxy-3-[(methyl) Sulfhydryl)amino]phenyl}propanamide:

The title compound was obtained from intermediate 13 (100 mg, 0.339 mmol) and 3-{2-butoxy-3-[(methylsulfonyl)amino]phenyl)propanoic acid as described in Example 1. 107 mg, 0.339 mmol) in dichloromethane (10 ml) in the presence of EDCI HCl (98 mg, 0.509 mmol), HOBt (52 mg, 0.339 mmol) and triethylamine (119 μl, 0.848 mmol) prepared by 3h to give 107 mg 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[chromene-2,1'-cyclobutyl]-4-yl)-3-{2-(cyclopropylmethoxy)-3 -[(methylsulfonyl)amino]phenyl}propanamine:

The title compound was obtained from Intermediate 13 (100 mg, 0.339 mmol) and 3-{2-(cyclopropylmethoxy)-3-[(methylsulfonyl)amino]benzene as described in Example 1. Propionate (107 mg, 0.339 mmol) in EDCI HCl (98 mg, 0.509 mmol), HOBt (52 mg, 0.339 mmol) and triethylamine (119 μl, 0.848 mmol) Prepared in 10 ml) to give 140 mg of white solid product: 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, 1H), 7.37 (d, J = 7.2 Hz, 1H); ESI-MS (m/z) 553.60 (M) ⁺ .

Example 65

N- (6,8-Dichloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl)-3-{2-isopropoxy-3-[(A Alkylsulfonyl)amino]phenyl}propanamine:

The title compound was obtained from Intermediate 13 (100 mg, 0.339 mmol) and 3-{2-isopropoxy-3-[(methylsulfonyl)amino]phenyl)propanoic acid as described in Example 1. (103 mg, 0.339 mmol) in dichloromethane (10 ml) in the presence of EDCI HCl (98 mg, 0.509 mmol), HOBt (52 mg, 0.339 mmol) and triethylamine (119 μl, 0.848 mmol) The preparation was carried out, and 85 mg of a white solid product was obtained over 3h; 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[chromenene-2,1'-cyclobutyl]-4-yl)-3-(1-naphthyl)propanamine:

The title compound was obtained from the intermediate 2 (200 mg, 0.896 mmol) and 1-naphthylpropionic acid (178 mg, 0.896 mmol) in EDCI HCl (256 mg, 1.345 mmol), HOBt (205) as described in Example 1. mg, 1.345 mmol) and triethylamine (371 μl, under 2.690 mmol) is present, prepared in methylene chloride (10 ml) to give 160 mg 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-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-(2-methoxy-1-naphthyl) Propylamine:

The title compound was obtained from Intermediate 8 (100 mg, 0.449 mmol) and 3-(2-methoxy-1-naphthyl)propanoic acid (113 mg, 0.494 mmol) in EDCI HCl as described in Example 1. 129 mg, 0.677 mmol), HOBt (103 mg, 0.677 mmol) and triethylamine (187 μl, 1.348 mmol) in the presence of, prepared in methylene chloride (10 ml) to give 91 mg 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, 1H), 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[chromenene-2,1'-cyclobutyl]-4-yl)-3-(2-methoxy-1-naphthyl) Propylamine:

The title compound was obtained from the intermediate 9 (100 mg, 0.449 mmol) and 3-(2-methoxy-1-naphthyl)propanoic acid (113 mg, 0.494 mmol) in EDCI HCl as described in Example 1. 129 mg, 0.677 mmol), HOBt (103 mg, 0.677 mmol) and triethylamine (187 μl, 1.348 mmol) in the presence of, prepared in methylene chloride (10 ml) to give 117 mg 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, 1H), 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-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-(4-methoxy-1-naphthyl) ) propylamine:

The title compound was obtained from Intermediate 8 (100 mg, 0.449 mmol) and 3-(4-methoxy-1-naphthyl)propanoic acid (102 mg, 0.449 mmol) in EDCI HCl as described in Example 1. Preparation of 129 mg, 0.677 mmol), HOBt (103 mg, 0.677 mmol) and triethylamine (187 μl, 1.348 mmol) in dichloromethane (10 ml). 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-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-(4-methoxy-1-naphthyl) ) propylamine:

The title compound was obtained from the intermediate 9 (100 mg, 0.449 mmol) and 3-(4-methoxy-1-naphthyl)propanoic acid (102 mg, 0.449 mmol) in EDCI HCl as described in Example 1. Preparation of 129 mg, 0.677 mmol), HOBt (103 mg, 0.677 mmol) and triethylamine (187 μl, 1.348 mmol) in dichloromethane (10 ml). 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-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-(4-difluoromethoxy-1- Naphthyl)propanamine:

The title compound was obtained from the intermediate 8 (100 mg, 0.447 mmol) and 3-(4-difluoromethoxy-1-naphthalenyl)propanoic acid (142 mg, 0.536 mmol) in EDCI as described in Example 1. Prepared in dichloromethane (10 ml) in the presence of EtOAc (EtOAc (EtOAc,EtOAc) 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-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-(4-difluoromethoxy-1- Naphthyl)propanamine:

The title compound was obtained from the intermediate 9 (100 mg, 0.449 mmol) and 3-(4-difluoromethoxy-1-naphthalenyl)propanoic acid (142 mg, 0.536 mmol) in EDCI as described in Example 1. Prepared in dichloromethane (10 ml) in the presence of EtOAc (EtOAc (EtOAc,EtOAc) 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[chromenene-2,1'-cyclobutyl]-4-yl)-3-(2-naphthyl)propanamine:

The title compound was obtained from the intermediate 2 (100 mg, 0.506 mmol) and 3-(2-naphthyl)propanoic acid (103 mg, 0.506 mmol) in EDCI HCl (143 mg, 0.751 mmol) as described in Example 1. Prepared in the presence of HOBt (114 mg, 0.751 mmol) and triethylamine (209 μl, 1.518 mmol) in dichloromethane (10 ml). 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-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-(6-methoxy-2-naphthyl) Propylamine:

The title compound was obtained from the intermediate 8 (150 mg, 0.674 mmol) and 3-(6-methoxy-2-naphthyl)propanoic acid (170 mg, 0.741 mmol) in EDCI HCl as described in Example 1. 193 mg, 1.017 mmol), HOBt (154 mg, 1.011 mmol) and triethylamine (281 μl, 2.022 mmol) in the presence of, prepared in methylene chloride (10 ml) to give 190 mg 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-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-(6-methoxy-2-naphthyl) Propylamine:

The title compound was obtained from the intermediate 9 (150 mg, 0.674 mmol) and 3-(6-methoxy-2-naphthyl)propanoic acid (170 mg, 0.741 mmol) in EDCI HCl as described in Example 1. 193 mg, 1.017 mmol), HOBt (154 mg, 1.011 mmol) and triethylamine (281 μl, 2.022 mmol) eluted in dichloromethane (10 ml) 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[chromenene-2,1'-cyclobutyl]-4-yl)-3-(quinolin-2-yl)propanamide:

Step 1: (2 E) - N - (6- chloro-3,4-dihydro-spiro [chromene-2,1'-butyl] -4-yl) -3-quinolin-2-yl Bing Xixi amine: as described in Example 1, the compound 2 (200 mg, 0.894 mmol) and from intermediate (2 E) -3- quinolin-2-yl acrylate (213 mg, 1.073 mmol) in EDCI‧HCl ( 257 mg, 1.342 mmol), HOBt (205 mg, 1.342 mmol) and triethylamine (248 μl, under 2.684 mmol) is present, prepared in methylene chloride (10 ml) to give 167 mg 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[chromenene-2,1'-cyclobutyl]-4-yl)-3-(quinolin-2-yl)propanamine: Step 1 intermediate (150 mg, 0.388 mmol) was reduced to 2 h under nitrogen at 50 psi using a 10% Pd/C (50 mg) in ethyl acetate (25 ml). . The reaction mixture was filtered through diatomaceous earth bed, the filtrate was concentrated under reduced pressure to give crude compound; used in 1% methanol in chloroform, the compound was purified by silica gel column chromatography to give 121 mg product as a white solid; 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[chromenene-2,1'-cyclobutyl]-4-yl)-3-(1 H -indol-3-yl)propanamine:

The title compound was obtained from the intermediate 2 (200 mg, 0.894 mmol) and 3-( 1H -indol-3-yl)propionic acid (187 mg, 0.988 mmol) in EDCI HCl (258) as described in Example 1. Prepared in methylene chloride (10 ml) in the presence of EtOAc (EtOAc: EtOAc, EtOAc (EtOAc) 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[chromenene-2,1'-cyclobutyl]-4-yl)-3-(2-methyl-7-methoxy-1-benzo) Furan-4-yl)propanamine:

The title compound was obtained from Intermediate 2 (200 mg, 0.896 mmol) and 3-(2-methyl-7-methoxy-1-benzofuran-4-yl)propionic acid as described in Example 1. Preparation of mg, 0.896 mmol) in dichloromethane (10 ml) in the presence of EDCI HCl (256 mg, 1.345 mmol), HOBt (205 mg, 1.345 mmol) and triethylamine (371 μl, 2.690 mmol) 60 mg of a white solid product obtained by 4 h; 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) 495.63 (M+H) ⁺ .

Example 79

N -[(4 R )-6-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl]-3-(7-methoxy-2-methyl -1-benzofuran-5-yl)propanamine;

The title compound was obtained from Intermediate 8 (200 mg, 0.894 mmol) and 3-(7-methoxy-2-methyl-1-benzofuran-4-yl)propanoic acid as described in Example 1. Preparation of mg, 1.078 mmol) in dichloromethane (10 ml) in the presence of EDCI HCl (258 mg, 1.345 mmol), HOBt (206 mg, 1.345 mmol) and triethylamine (375 μl, 2.684 mmol) 231 mg of a white solid product; 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. 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-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl]-3-(7-methoxy-2-methyl -1-benzofuran-5-yl)propanamine:

The title compound was obtained from Intermediate 9 (200 mg, 0.898 mmol) and 3-(7-methoxy-2-methyl-1-benzofuran-5-yl)propanoic acid as described in Example 1. </ RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI><RTIgt; 199 mg of a white solid product; 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-benzodioxin-6-yl) - N - (6- fluoro-3,4-dihydro-spiro [chromene-2,1'-butyl] -4-yl) propanoate Guanamine:

The title compound consisted of intermediate 6 (200 mg, 0.963 mmol) and 3-(2,3-dihydro-1,4-benzodioxin-6-yl)propanoic acid (187 mg) as described in Example 1. Prepared in dichloromethane (10 ml) in the presence of EDCI HCl (276 mg, 1.441 mmol), HOBt (221 mg, 1.441 mmol) and triethylamine (403 μl, 2.891 mmol). Yield 16 mg of the product as a white solid; NMR (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 (MH) ^- .

Example 82

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

The title compound consisted of intermediate 2 (150 mg, 0.679 mmol) and 3-(1,3-benzodioxol-4-yl)propanoic acid (169 mg, 0.892) as described in Example 1. Prepared in dichloromethane (10 ml) in the presence of EDCI HCl (192 mg, 1.005 mmol), HOBt (154 mg, 1.005 mmol) and triethylamine (135 μl, 1.341 mmol) Mg white solid product; 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'-butoxy] -4 -based) propylamine:

The title compound was obtained from Intermediate 1 (150 mg, 0.679 mmol) and 3-(1,3-benzodioxol-4-yl)propanoic acid (169 mg, 0.892) as described in Example 1. Prepared in dichloromethane (10 ml) in the presence of EDCI HCl (192 mg, 1.005 mmol), HOBt (154 mg, 1.005 mmol) and triethylamine (135 μl, 1.341 mmol). Mg white solid product; 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-benzodioxin-5-yl) - N - (6- chloro-3,4-dihydro-spiro [chromene-2,1'-butyl] -4-yl) propanoate Guanamine:

The title compound was obtained from Intermediate 2 (200 mg, 0.769 mmol) and 3-(2,3-dihydro-1,4-benzodioxin-5-yl)propanoic acid as described in Example 1. Prepared in dichloromethane (10 ml) in the presence of EDCI HCl (221 mg, 1.153 mmol), HOBt (176 mg, 1.153 mmol) and triethylamine (321 μl, 2.307 mmol) , to give 141 mg 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

N- (6-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-(dibenzo[ b , d ]furan-4-yl)propane Guanamine:

The title compound was obtained from the intermediate 2 (200 mg, 0.896 mmol) and 3-dibenzo[ b , d ]-furan-4-ylpropanoic acid (214 mg, 0.896 mmol) in EDCI HCl as described in Example 1. (256 mg, 1.345 mmol), HOBt (205 mg, 1.345 mmol) and triethylamine (371 μl, 2.690 mmol) in dichloromethane (10 ml). 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[chromenene-2,1'-cyclopenta]-4-yl)-3-(2-cyclopentyloxy-3-methoxy)propanoid amine:

The title compound was obtained from the intermediate 16 (200 mg, 0.841 mmol) and 3-(2-cyclopentyloxy-3-methoxyphenyl)propionic acid (266 mg, 1.09 mmol) as described in Example 1. Prepared in dichloromethane (10 ml) in the presence of EDCI HCl (241 mg, 1.261 mmol), HOBt (193 mg, 1.261 mmol) and triethylamine (351 μl, 2.504 mmol) Product; 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[chromenene-2,1'-cyclohexyl]-4-yl)-3-(2-cyclopentyloxy-3-methoxy)phenyl Propylamine:

The title compound was obtained from the intermediate 17 (209 mg, 0.833 mmol) and 3-(2-cyclopentyloxy-3-methoxyphenyl)propanoic acid (200 mg, 0.758 mmol) as described in Example 1. Prepared in the presence of EDCI HCl (116 mg, 0.756 mmol), HOBt (218 mg, 1.137 mmol) and triethylamine (316 μl, 2.274 mmol) in dichloromethane (10 ml) Product; 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- 2H -chromen-4-yl)-3-(2-cyclopentyloxy-3-methoxy)phenylpropanamide :

The title compound was obtained from the intermediate 18 (200 mg, 1.129 mmol) and 3-(2-cyclopentyloxy-3-methoxyphenyl)propanoic acid ( 328 mg, 1.42 mmol) as described in Example 1. Prepared in dichloromethane (10 ml) in the presence of EDCI HCl (324 mg, 1.671 mmol), HOBt (259 mg, 1.671 mmol) and triethylamine (471 μl, 3.383 mmol). 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)-3-(2-cyclopentyloxy-3-methoxyphenyl)propanamine:

The title compound was obtained from the intermediate 19 (100 mg, 0.423 mmol) and 3-[2-[(cyclopentyloxy)-3-methoxyphenyl]propanoic acid (134 mg, 0.508) as described in Example 1. Prepared in dichloromethane (10 ml) in the presence of EDCI HCl (121 mg, 0.635 mmol), HOBt (97 mg, 0.635 mmol) and triethylamine (176 μl, 1. Mg white solid product; 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)propanamine:

The title compound was obtained from the intermediate 19 (100 mg, 0.423 mmol) and 3-(2-methoxy-1-naphthyl)propanoic acid (146 mg, 0.508 mmol) in EDCI HCl as described in Example 1. 121 mg, 0.635 mmol), HOBt (97 mg, 0.635 mmol) and triethylamine (176 μl, under 1.270 mmol) is present, prepared in methylene chloride (10 ml) to give 67 mg 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[chromenene-2,1'-cyclobutyl]-4-yl)-4-(2-cyclopentyloxyphenyl)butanamine:

The title compound was obtained from the intermediate 2 (150 mg, 0.579 mmol) and 4-(2-cyclopentyloxyphenyl)butyric acid (158 mg, 0.639 mmol) in EDCI HCl (166 mg) as described in Example 1. , 0.863 mmol), HOBt (133 mg, 0.863 mmol) and triethylamine (241 μl, 2.043 mmol) in methylene chloride (5 ml). 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, 4H); ESI-MS (m/z) 454.30 (M) ⁺ .

Example 92

N- (6-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-4-[2-(cyclopentyloxy)-3-methoxybenzene Butylamine:

The title compound was obtained from Intermediate 2 (200 mg, 0.772 mmol) and 4-(2-cyclopentyloxy-3-methoxyphenyl)butyric acid (214 mg, 0.772 mmol) as described in Example 1. Prepared in the presence of EDCI HCl (222 mg, 1.158 mmol), HOBt (118 mg, 0.772 mmol) and triethylamine (273 μl, 2.702 mmol) in dichloromethane (10 ml) Product; 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); MS (m/z) 482.44 (MH) ^- .

Example 93

N -(4 R )-6-Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl-4-(2-cyclopentyloxy-3-methoxy Phenyl)butanamine:

The title compound was obtained from Intermediate 8 (100 mg, 0.449 mmol) and 4-(2-cyclopentyloxy-3-methoxyphenyl)butyric acid (124 mg, 0.449 mmol) as described in Example 1. Prepared in the presence of EDCI HCl (129 mg, 0.672 mmol), HOBt (69 mg, 0.450 mmol) and triethylamine (157 μl, 1.123 mmol) in dichloromethane (10 ml) Product; 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); MS (m/z) 482.44 (MH) ^- .

Example 94

N -{(4 S )-6-Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl}-4-[(2-(cyclopentyloxy)- 3-methoxyphenyl]butanamine:

The title compound was obtained from the intermediate (100 mg, 0.449 mmol) and 4-(2-cyclopentyloxy-3-methoxyphenyl)butyric acid (132 mg, 0.474 mmol) in EDCI as described in Example 1. Preparation of HCl (129 mg, 0.672 mmol), HOBt (69 mg, 0.450 mmol) and triethylamine (157 μl, 1.123 mmol) in dichloromethane (10 ml) ; 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 (MH) ^- .

Example 95

(4 R )- N -(8-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-4-(2-cyclopentyloxy-3-methyl Oxyphenyl phenyl guanamine:

The title compound was obtained from Intermediate 3 (150 mg, 0.619 mmol) and 4-(2-cyclopentyloxy-3-methoxyphenyl)butyric acid (205 mg, 0.739 mmol) as described in Example 1. Prepared in dichloromethane (10 ml) in the presence of EDCI HCl (193 mg, 1.012 mmol), HOBt (154 mg, 1.012 mmol) and triethylamine (279 μl, 2.043 mmol) Product; 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-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-4-(2-cyclopentyloxy-3-methyl Oxyphenyl phenyl guanamine:

The title compound was obtained from Intermediate 4 (150 mg, 0.619 mmol) and 4-(2-cyclopentyloxy-3-methoxyphenyl)butyric acid (205 mg, 0.739 mmol) as described in Example 1. Prepared in dichloromethane (10 ml) in the presence of EDCI HCl (193 mg, 1.012 mmol), HOBt (154 mg, 1.012 mmol) Product; 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, 3H), 6.91-7.05 (m, 4H), 7.20 (s, 1H); ESI-MS (m/) z) 484.21(M) ⁺ .

Example 97

N- (8-chloro-6-fluoro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-4-(2-cyclopentyloxy-3-methoxy Butylamine

The title compound was obtained from the intermediate 20 (200 mg, 0.719 mmol) and 4-(2-cyclopentyloxy-3-methoxyphenyl)butyric acid (200 mg, 0.719 mmol) as described in Example 1. Prepared in the presence of EDCI HCl (207 mg, 1.079 mmol), HOBt (110 mg, 0.719 mmol) and triethylamine (250 μl, 1.798 mmol) in dichloromethane (10 ml) Product; 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, 3H), 6.91-6.96 (m, 2H); ESI-MS (m/z) 500.38 (MH ) ^- .

Example 98

N- (6,8-Dichloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-4-(2-cyclopentyloxy-3-methoxy Phenyl)butanamine:

The title compound was obtained from the intermediate 13 (150 mg, 0.511 mmol) and 4-(2-cyclopentyloxy-3-methoxyphenyl)butyric acid (142 mg, 0.511 mmol) as described in Example 1. Prepared in the presence of EDCI HCl (147 mg, 0.766 mmol), HOBt (78 mg, 0.511 mmol) and triethylamine (178 μl, 1.277 mmol) in dichloromethane (10 ml) Product; 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, 2H), 6.91-6.96 (m, 1H), 7.01 (s, 1H), 7.20 (s, 1H) ;ESI-MS (m/z) 518.17 (M) ⁺ .

Example 99

N- (7-benzyloxy-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-4-(2-cyclopentyloxy-3-methoxybenzene Butylamine:

The title compound was obtained from Intermediate 12 (200 mg, &lt;RTI ID=0.0&gt;&gt; Prepared in dichloromethane (10 ml) in the presence of EDCI HCl (173 mg, 0.904 mmol), HOBt (138 mg, 0.904 mmol) and triethylamine (335 μl, 2.413 mmol) The solid ^{product; IR (KBr) 3254,2960,1639,1269,1134,1019cm -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 (MH) -.

Example 100

N- (7-Hydroxy-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-4-(2-cyclopentyloxy-3-methoxyphenyl) Butylamine:

The title compound was treated with 10% Pd/C (30 mg) in methanol (10 ml) over a period of 2 hrs to give Example 99 (100 mg, 0.181 mmol) Prepared by debenzylation under nitrogen to give 53 mg of a white solid product: 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 (MH) ^- .

Example 101

N- (6-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-4-oxo-4-(4-methoxynaphthyl)butane amine:

The title compound was obtained from Intermediate 2 (250 mg, 0.965 mmol) and 4-(4-methoxy-1-naphthyl)-4-oxobutyric acid (274 mg, 1.062 mmol) as described in Example 1. Prepared in dichloromethane (10 ml) in the presence of EDCI HCl (277 mg, 1.451 mmol), HOBt (221 mg, 1.459 mmol) and triethylamine (403 μl, 2.905 mmol) Solid product; 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[chromenene-2,1'-cyclobutyl]-4-yl)-4-hydroxy-4-(4-methoxynaphthyl)butanamine :

The title compound was prepared by reduction of the title compound (200 mg, 0.441 mmol) EtOAc (EtOAc) The reaction mixture was warmed to room temperature and concentrated to afford 31 mg 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-2 H -chromen-4-yl)-4-(2-cyclopentyloxy-3-methoxy)benzene Butylamine:

The title compound was obtained from Intermediate 21 (200 mg, 0.941 mmol) and 4-(2-cyclopentyloxy-3-methoxyphenyl)butyric acid (261 mg, 0.941 mmol) as described in Example 1. Prepared in dichloromethane (10 ml) in the presence of EDCI HCl (270 mg, 1.411 mmol), HOBt (144 mg, 0.941 mmol) and triethylamine (328 μl, 2.352 mmol) Product; 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)butanamine:

The title compound was obtained from the intermediate 19 (100 mg, 0.423 mmol) and 4-(2-cyclopentyloxy-3-methoxyphenyl)butyric acid (141 mg, 0.508 mmol) as described in Example 1. Prepared in the presence of EDCI HCl (121 mg, 0.635 mmol), HOBt (97 mg, 0.635 mmol) and triethylamine (176 μl, 1.270 mmol) in dichloromethane (10 ml) 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 2.7. (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

According to (a) T The improved process described in Th, A., et al, Life Sciences, 2003, 73, 487-498 screens for TRPV3 activity of exemplary embodiments of the invention. Screening of compounds can be carried out by other methods and procedures known to those skilled in the art. Such screening can be found in Hu, HZ., et al, J. Biol. Chem . (2004), 279, 35741-35748; Smith, GD et al. Nature (2002), 418, 186-190 and Peier, AM, et al, Science (2002), 296, 2046-2049.

Screening of TRPV3 antagonists using ⁴⁵ calcium absorption assay

Inhibition of TRPV3 receptor activation was examined by inhibition of 2-APB-induced cellular uptake of radioactive calcium. The test compound was dissolved in DMSO to prepare a 20 mM stock solution, which was then diluted with a plain 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). Human TRPV3 expressing CHO cells was grown in F-12 DMEM medium containing 10% FBS, 1% penicillin-streptomycin solution, and 400 μg/ml G-418. At 24 h prior to analysis, cells were seeded in 96-well plates such that ~50,000 cells/well were obtained on the day of the experiment. The cells were treated with the test compound for 10 minutes and then added to a final concentration of 500 μM of 2-APB and 5 μCi/ml of ⁴⁵ Ca ⁺² over 4 minutes. The cells were washed and lysed using a buffer containing 1% Triton X-100, 0.1% deoxycholate and 0.1% SDS. The radioactivity in the lysate was measured in a Packardt Top count after the addition of a liquid scintillant.

The concentration response curve was plotted as the maximum response % obtained in the absence of the test antagonist. Using the GraphPad PRISM software, IC ₅₀ values can be calculated from the concentration response curve by nonlinear regression analysis.

Each of the prepared compounds was tested using the above analytical procedure, and the results obtained are shown in Table 2. For the selected examples, % inhibition at 1.0 μM and 10.0 μM along with IC ₅₀ (nM) values are shown in the table.

The IC ₅₀ (nM) values of the compounds are shown in Table 2, wherein "A" means an IC ₅₀ value of less than 500 nM, "B" means an IC ₅₀ value of 500.0-1000.0 nM, and "C" means an IC ₅₀ value of 1000.01. -2000.0 nM. "D" means an IC ₅₀ value greater than 2000.0 nM.

Claims (10)

a compound of formula (I), Or an analog, tautomer, regioisomer, stereoisomer, enantiomer, diastereomer or pharmaceutically acceptable salt thereof, wherein 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 ring are monocyclic, bicyclic or tricyclic a ring, and wholly or partially aromatic; wherein the substituents on the aryl, heteroaryl, heterocyclic ring and cycloalkyl are independently selected from the group consisting of halogen, hydroxy, Nitro, cyano, substituted or unsubstituted amino, substituted or unsubstituted alkyl, straight or branched alkyl, straight or branched alkoxy, substituted or unsubstituted alkenyl, substituted or not Substituted alkoxy, substituted or unsubstituted haloalkyl, fully or partially substituted haloalkyl, substituted or unsubstituted haloalkoxy, fully or partially substituted haloalkoxy, 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 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 ; R ^{2 is} selected from the group consisting of 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 heterocyclic group; R ^a , R ^b , R ^c and R ^{d are} independently selected from Hydrogen, nitro, cyano, halogen, -OR ^e , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or not a substituted cycloalkenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group; R ^{e is} selected from the group consisting of hydrogen, Substituted or unsubstituted alkyl, substituted or unsubstituted Substituted alkenyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclic group; R ³ and R ⁴ are independently selected from Hydrogen, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, straight or branched alkyl, straight or branched alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted Alkoxy, substituted or unsubstituted haloalkyl, fully or partially substituted haloalkyl, substituted or unsubstituted haloalkoxy, fully or partially substituted haloalkoxy, substituted or unsubstituted cycloalkyl, substituted or not a substituted cycloalkoxy group, a substituted or unsubstituted cycloalkylalkyl group, a substituted or unsubstituted cycloalkylalkoxy group, a substituted or unsubstituted aryl group; 'm' is an integer selected from 1-4; 'n' is an integer selected from 0-3; 'p' is an integer selected from 0-2; but R ^{b is} not selected from -OR ^e , -NR ³ R ⁴ or C(O)NR ³ R ⁴ a group; wherein: preferably R ³ and R ⁴ are hydrogen; or one of R ³ and R ⁴ is hydrogen and the other is hydroxy or alkyl (methyl); preferably R ^a , R ^b , R ^c and R ^d are any of Hydrogen or halogen, wherein the halogen is fluoro or chloro; preferred system of any of R ^a, R ^c and R ^d are a hydrogen, hydroxyl, alkyl (methyl), alkoxy (methoxy) alkoxy or aryl (benzyloxy); preferably R ¹ is substituted phenyl, phenyl, substituted or unsubstituted naphthyl, tetrahydronaphthalene, pyridine, hydrazine, benzodioxole, benzo Isoxazole, benzofuran, quinoline, benzodioxin or dibenzofuran, wherein the substituent includes a hydroxyl group, a halogen (F, Cl, Br or I), an alkyl group (methyl), an alkoxy group ( Methoxy, ethoxy, n-propoxy, n-butoxy or isopropoxy), haloalkoxy (all or partially substituted, preferably OCHF ₂ ), cycloalkoxy (cyclopentyloxy) , cycloalkylalkoxy (cyclopropylmethoxy), arylalkoxy groups (benzyloxy), alkylsulfonyl group (-NHS (O) ₂ CH _3, or NHS (O) ₂ CH ( CH ₃ ) ₂ ), alkylaminoalkoxy (-OCH ₂ CH ₂ N(CH ₃ ) ₂ ) or heteroaryl (pyridine). The compound of claim 1, wherein the compound is a compound represented by the formula (II): Or an analog, tautomer, regioisomer, stereoisomer, enantiomer, diastereomer or pharmaceutically acceptable salt thereof, wherein 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 ring are monocyclic, bicyclic or tricyclic a ring, and partially or wholly aromatic; wherein the substituents on the aryl, heteroaryl, heterocyclic ring and cycloalkyl are independently selected from the group consisting of halogen, hydroxy, Nitro, cyano, amine, substituted or unsubstituted alkyl, straight or branched alkyl, straight or branched alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkoxy , substituted or unsubstituted haloalkyl, fully or partially substituted haloalkyl, substituted or unsubstituted haloalkoxy, fully or partially substituted haloalkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted ring Alkoxy, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkylalkoxy , substituted or unsubstituted aryl, substituted or unsubstituted 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 ; R ^a , R ^b , R ^c and R ^{d are} independently selected from hydrogen, nitro, cyano, halogen, —OR ^e , substituted or unsubstituted alkyl, substituted or unsubstituted alkene Alkyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted a heterocyclic group; R ^{e is} selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted An aryl group, a substituted or unsubstituted heteroaryl group or a substituted or unsubstituted heterocyclic group; R ³ and R ^{4 are} independently selected from hydrogen, halogen, substituted or unsubstituted amino group, substituted or unsubstituted alkyl group , linear or branched alkyl, a chain or branched alkoxy group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted haloalkyl group, a wholly or partially substituted haloalkyl group, a substituted or unsubstituted haloalkoxy group, All or partially substituted haloalkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkylalkoxy , substituted or unsubstituted aryl; 'm' is an integer selected from 1-4; 'n' is an integer selected from 0-3; 'p' is an integer selected from 0-2; but R ^b is not Is 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 the compound is selected from the group consisting of N- (8-chloro-3,4-dihydrospiro[chromene-2,1'- Cyclobutylidene-4-yl)-2-phenylacetamide (Compound No. 1); N- (6-chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4 -yl)-2-(2-methoxyphenyl)acetamide (Compound No. 2); N- (6-chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl] 4-yl)-2-(2-[(methylsulfonyl)amino]phenyl}acetamide (Compound No. 3); N- (6-chloro-3,4-dihydrospiro[chromene] -2,1'-cyclobutyl]-4-yl)-2-(2-(cyclopentyloxy)-3-methoxyphenyl)acetamide (Compound No. 4); N -[(4 R )-8-Chloro-3,4-dihydrospiro[chromen-2,1'-cyclobutyl]-4-yl]-2-(2-cyclopentyloxy-3-methoxy)phenyl Indoleamine (Compound No. 5); N -[(4 S )-8-Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4-yl]-2-(2- Cyclopentyloxy-3-methoxy)phenylacetamide (Compound No. 6); N- (6-chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4 -yl)-2-(3,4-dimethoxyphenyl)acetamidine (Compound No. 7); N- (6-chloro-3,4-dihydrospiro[chromene-2,1'- Cyclobutylidene-4-yl)-2-pyridin-2-ylacetamide (Compound No. 8); N - (3,4-Dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-2-(1-naphthyl)acetamide (Compound No. 9); N- (6-fluoro- (3,4-Dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-2-(1-naphthyl)acetamide (Compound No. 10); N -[(4 R ) -6,8-difluoro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl]-2-(1-naphthyl)acetamide (Compound No. 11); N -[(4 R )-6-Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl]-2-(1-naphthyl)acetamide (compound) No. 12); N -[(4 S )-6-chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl]-2-(1-naphthyl) Indoleamine (Compound No. 13); N- (7-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-2-(1-naphthyl)acetamidine Amine (Compound No. 14); N -[(4 R )-8-Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4-yl]-2-(1-naphthalene Ethylamine (Compound No. 15); N -[(4 S )-8-Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4-yl]-2- (1-naphthyl)acetamide (Compound No. 16); N- (5-hydroxy-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-2-( 1-naphthyl)acetamide (Compound No. 17); N- (6-chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-2-(2 -naphthyl)acetamide (Compound No. 18); (2 S )- N -[(4 R - 6-Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl]-2-(6-methoxy-2-naphthyl)propanamine (compound) No. 19); (2 S )- N -[(4 S )-6-Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4-yl]-2-(6 -Methoxy-2-naphthyl)propanamide (Compound No. 20); N- (6-chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl) -2-(1,2,3,4-tetrahydronaphthalen-1-yl)acetamide (Compound No. 21); N -[(6-chloro-3,4-dihydrospiro[chromene-2, 1'-cyclobutyl]-4-yl)]-2-(1,2,3,4-tetrahydronaphthalen-2-yl)acetamide (Compound No. 22); 2-(1,3-Benzene dioxol-5-yl) - N - (6- chloro-3,4-dihydro-spiro [chromene-2,1'-butyl] -4-yl) acetyl (compound No 23); N- (6-fluoro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-2-(5-fluoro-3-methyl-1 H - Indole-2-yl)acetamide (Compound No. 24); N- (6-chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl)-2- (5-methoxy-2-methyl-1 H -indol-3-yl)acetamide (Compound No. 25); 2-(1,2-benzisoxazole-3-yl) -N -[(4 R )-(6-chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)acetamide (Compound No. 26); 2-(1, 2-Benzisoxazole-3-yl) -N -[(4 S )-(6-chloro-3,4-dihydro Snail [chromene-2,1'-cyclobutyl]-4-yl)acetamidine (Compound No. 27); N- (6-chloro-3,4-dihydrospiro[chromene-2,1'- Cyclobutylidene-4-yl)-3-(2-cyclopentyloxyphenyl)propanamide (Compound No. 28); N -[(4 R )-6-chloro-3,4-dihydrospiro[ Chromene-2,1'-cyclobutyl]-4-yl]-3-(3-cyclopentyloxy)phenylpropanamide (Compound No. 29); N -[(4 S )-6-chloro- 3,4-Dihydrospiro[chromenyl-2,1'-cyclobutyl]-4-yl]-3-(3-cyclopentyloxy)phenylpropanamide (Compound No. 30); N -[( 4 R )-(8-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-[2-(cyclopentyloxy)phenyl]propanoid Amine (Compound No. 31); N -[(4 S )-8-Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobut-4-yl]-3-[2-(cyclic Pentyloxy)phenyl]propanamide (Compound No. 32); 7-Benzyloxy- N- (3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl)- 3-(2-cyclopentyloxyphenyl)propanamide (Compound No. 33); N -(6-chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4- 3-(2-[(isopropylsulfonyl)amino]phenyl}propanamide (Compound No. 34); N- (6-chloro-3,4-dihydrospiro[chromene- 2,1'-cyclobutyl]-4-yl)-3-(2-pyridin-2-ylphenyl)propanamide (Compound No. 35); N -(6,8-Dichloro-3,4- Dihydrospiro [chromene-2,1'-cyclobutyl]-4-yl)-3-(2-pyridin-3-ylphenyl)propanamide (Compound No. 36); N- (3,4-dihydrospiro) [chromene-2,1'-cyclobutyl]-4-yl)-3-(2-cyclopentyloxy-3-methoxy)phenylpropanamide (Compound No. 37); N -(6- Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-(2,3-dimethoxy)phenylpropanamide (Compound No. 38); N- (6-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-(2-isopropoxy-3-methoxy)phenyl Propylamine (Compound No. 39); N- (6-Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl)-3-(3-chloro-4- Methoxy)phenylpropanamide (Compound No. 40); N- (6-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-( 2-cyclopropylmethoxy-3-methoxy)phenylpropanamide (Compound No. 41); N -[(4 R )-6-chloro-3,4-dihydrospiro[chromene-2 ,1'-cyclobutyl]-4-yl)]-3-(2-cyclopentyloxy-3-methoxy)phenylpropanamide (Compound No. 42); N -[(4 S )-6 -Chloro-3,4-dihydrospiro[chromen-2,1'-cyclobutyl]-4-yl)]-3-(2-cyclopentyloxy-3-methoxy)phenylpropanamide (Compound No. 43); N- (6-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-(2-cyclopentyloxy-3- Ethoxylated benzene Propan-acyl-amine (Compound No. 44); N - (7- chloro-3,4-dihydro-spiro [chromene-2,1'-butyl] -4-yl) -3- (2-cyclopentyloxy- 3-methoxy)phenylpropanamide (Compound No. 45); N- (8-chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl)- 3-(2-ethoxy-3-methoxy)phenylpropanamide (Compound No. 46); N -[(4 R )-8-Chloro-3,4-dihydrospiro[chromene-2 ,1'-cyclobutan-4-yl)]-3-(2-cyclopentyloxy-3-methoxy)phenylpropanamide (Compound No. 47); N -[(4 S )-( 8-Chloro-3,4-dihydrospiro[chromen-2,1'-cyclobutyl]-4-yl)-3-(2-cyclopentyloxy-3-methoxy)phenylpropanamide (Compound No. 48); N -(6-chloro-7-methyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)-3-(2-cyclopentyl) Oxy-3-methoxy)phenylpropanamide (Compound No. 49); N- (5-Benzyloxy-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4 -yl)-3-(2-cyclopentyloxy-3-methoxy)phenylpropanamide (Compound No. 50); N- (5-hydroxy-3,4-dihydrospiro[chromene-2 ,1'-cyclobutyl]-4-yl)-3-(2-cyclopentyloxy-3-methoxy)phenylpropanamide (Compound No. 51); N- (3,4-dihydrospiro) [chromene-2,1'-cyclobutyl]-5-methoxy-4-yl)-3-(2-cyclopentyloxy-3-methoxy)phenylpropanamide ( Compound No. 52); (4 R )-6-Chloro- N- (3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-(2-cyclopentyloxy) 3-methyl)phenylpropanamide (Compound No. 53); (4 S )-6-Chloro- N- (3,4-dihydrospiro[chromene-2,1'-cyclobutyl]- 4-yl)-3-(2-cyclopentyloxy-3-methyl)phenylpropanamide (Compound No. 54); N -6-chloro-3,4-dihydrospiro[chromene-2, 1'-cyclobutyl]-4-yl-3-(2-hydroxy-3-methoxyphenyl)propanamide (Compound No. 55); N- (6-chloro-3,4-dihydrospiro[ Chromene-2,1'-cyclobutyl]-4-yl)-3-(2-benzyloxy-3-methoxy)phenylpropanamide (Compound No. 56); N- (6-chloro- 3,4-Dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl)-3-{2-isopropoxy-3-[(methylsulfonyl)amino]phenyl }propanamide (Compound No. 57); N- (8-Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl)-3-{2-isopropoxy 3-[(methylsulfonyl)amino]phenyl}propanamide (Compound No. 58); N- (6,8-Dichloro-3,4-dihydrospiro[chromene-2, 1'-cyclobutyl]-4-yl)-3-(2-cyclopentyloxy-3-methoxy)phenylpropanamide (Compound No. 59); N- (6,8-Dichloro-3 ,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl)-3-{[2-(dimethylamino)ethoxy-3-methoxy]phenyl} C Indoleamine (Compound No. 60); N- (6,8-Dichloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl)-3-{2-propoxy 3-[(methylsulfonyl)amino]phenyl}propanamide (Compound No. 61); N- (6,8-Dichloro-3,4-dihydrospiro[chromene-2, 1'-cyclobutanyl-4-yl)-3-{2-isopropoxy-5-[(methylsulfonyl)amino]phenyl}propanamine (Compound No. 62); N -( 6,8-Dichloro-3,4-dihydrospiro[chromen-2,1'-cyclobutyl]-4-yl)-3-{2-butoxy-3-[(methylsulfonyl) Amino]phenyl}propanamide (Compound No. 63); N- (6,8-Dichloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl) -3-{2-(cyclopropylmethoxy)-3-[(methylsulfonyl)amino]phenyl}propanamide (Compound No. 64); N- (6,8-dichloro- 3,4-Dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl)-3-{2-isopropoxy-3-[(methylsulfonyl)amino]phenyl }propanamide (Compound No. 65); N -(6-chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl)-3-(1-naphthyl) Propylamine (Compound No. 66); N -[4( S )-(6-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-( 2-methoxy-1-naphthyl)propanamide (Compound No. 67); N -[4 S -(6-chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl] -4-yl)-3- (2-methoxy-1-naphthyl)propanamide (Compound No. 68); N -[(4 R )-6-chloro-3,4-dihydrospiro[chromene-2,1'-cyclo Butyl-4-yl)-3-(4-methoxy-1-naphthyl)propanamide (Compound No. 69); N -[(4 S )-6-Chloro-3,4-dihydrospiro [chromene-2,1'-cyclobutyl]-4-yl)-3-(4-methoxy-1-naphthyl)propanamine (Compound No. 70); (4 R )-6-Chloro- N- (3,4-Dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-(4-difluoromethoxy-1-naphthyl)propanamide (compound number ( 4S )-6-Chloro- N- (3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3-(4-difluoromethoxy -1-naphthyl)propanamide (Compound No. 72); N- (6-chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutan]-4-yl)-3-( 2-naphthyl)propanamide (Compound No. 73); N -[4 R -(6-Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl)- 3-(6-methoxy-2-naphthyl)propanamide (Compound No. 74); N -[4 S -(6-chloro-3,4-dihydrospiro[chromene-2,1'-- Cyclobutylidene-4-yl)-3-(6-methoxy-2-naphthyl)propanamide (Compound No. 75); N- (6-Chloro-3,4-dihydrospiro[chromene- 2,1'-cyclobutyl]-4-yl)-3-(quinolin-2-yl)propanamide (Compound No. 76); N- (6-chloro-3,4-dihydrospiro[chromene] -2,1'-cyclobutyl]-4-yl)-3-(1 H -Indol-3-yl)propanamide (Compound No. 77); N- (6-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-3 -(2-methyl-7-methoxy-1-benzofuran-4-yl)propanamide (Compound No. 78); N -[(4 R )-6-chloro-3,4-dihydrogen Snail [chromen-2,1'-cyclobutyl]-4-yl]-3-(7-methoxy-2-methyl-1-benzofuran-5-yl)propanamide (Compound No. 79 N -[(4 S )-6-chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl]-3-(7-methoxy-2- methyl-1-benzofuran-5-yl) propan-acyl-amine (compound No. 80); 3- (1,4-benzodioxin-6-yl) - N - (6- fluoro-3,4 -Dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl)propanamide (Compound No. 81); 3-(1,3-benzodioxol-4-yl) ) - N - [6- chloro-3,4-dihydro-spiro [chromene-2,1'-butyl] -4-yl] propan-acyl-amine (compound No. 82); 3- (1,3-phenylene and dioxol-4-yl) - N - (8- chloro-3,4-dihydro-spiro [chromene-2,1'-butyl] -4-yl) propan-acyl-amine (compound No. 83); 3- (1,4-benzodioxin-5-yl) - N - (6- chloro-3,4-dihydro-spiro [chromene-2,1'-butoxy] -4 -yl)propanamide (Compound No. 84); N- (6-chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl)-3-(dibenzo [b, d] furan-4-yl) Amides (Compound No. 85); N - (6- chloro-3,4-dihydro-spiro [chromene-2,1'-cyclopentyl] -4-yl) -3- (2-cyclopentyloxy - 3-methoxy)propanamide (Compound No. 86); N- (6-Chloro-3,4-dihydrospiro[chromenene-2,1'-cyclohexan]-4-yl)-3-( 2-cyclopentyloxy-3-methoxy)phenylpropanamide (Compound No. 87); N -(2,2-dimethyl-3,4-dihydro- 2H -chromene-4- 3-(2-cyclopentyloxy-3-methoxy)phenylpropanamide (Compound No. 88); N- (6-chloro-3,4-dihydro-2 H -thiochrome En-4-yl)-3-(2-cyclopentyloxy-3-methoxyphenyl)propanamide (Compound No. 89); N- (6-Chloro-3,4-dihydro-2 H -thiochromene-4-yl)-3-(2-methoxy-1-naphthyl)propanamide (Compound No. 90); N- (6-chloro-3,4-dihydrospiro[Color Alkene-2,1'-cyclobutyl]-4-yl)-4-(2-cyclopentyloxyphenyl)butanamine (Compound No. 91); N- (6-chloro-3,4-dihydrol Snail [chromene-2,1'-cyclobutyl]-4-yl)-4-[2-(cyclopentyloxy)-3-methoxyphenyl]butanamine (Compound No. 92); N - (4 R )-6-Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4-yl-4-(2-cyclopentyloxy-3-methoxyphenyl) Butylamine (Compound No. 93); N -{(4 S )-6-Chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutyl]-4- }[-4-(cyclopentyloxy)-3-methoxyphenyl]butanamine (Compound No. 94); (4 R )- N -(8-chloro-3,4-di Hydrogen snail [chromene-2,1'-cyclobutyl]-4-yl)-4-(2-cyclopentyloxy-3-methoxyphenyl)butanamine (Compound No. 95); (4 S ) - N - (8- chloro-3,4-dihydro-spiro [chromene-2,1'-butyl] -4-yl) -4- (2-cyclopentyloxy-3-methoxybenzoate Butylamine (Compound No. 96); N- (8-chloro-6-fluoro-3,4-dihydrospiro[chromenene-2,1'-cyclobutan]-4-yl)-4-( 2-cyclopentyloxy-3-methoxyphenyl)butanamine (Compound No. 97); N- (6,8-Dichloro-3,4-dihydrospiro[chromene-2,1'- Cyclobutylidene-4-yl)-4-(2-cyclopentyloxy-3-methoxyphenyl)butanamine (Compound No. 98); N- (7-benzyloxy-3,4-di Hydrogen snail [chromen-2,1'-cyclobutyl]-4-yl)-4-(2-cyclopentyloxy-3-methoxyphenyl)butanamine (Compound No. 99); N -( 7-Hydroxy-3,4-dihydrospiro[chromen-2,1'-cyclobutyl]-4-yl)-4-(2-cyclopentyloxy-3-methoxyphenyl)butanamine (Compound No. 100); N -(6-chloro-3,4-dihydrospiro[chromenene-2,1'-cyclobutyl]-4-yl)-4-oxo-4-(4-methoxy Naphthyl)butanamine (Compound No. 101); N- (6-chloro-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)-4-hydroxy-4- (4 -Methoxynaphthyl)butanamine (Compound No. 102); N- (6-Chloro-2,2-dimethyl-3,4-dihydro- 2H -chromen-4-yl)-4 -(2-cyclopentyloxy-3-methoxy)phenylbutanamine (Compound No. 103); and N- (6-chloro-3,4-dihydro-2 H -thiochromene-4 -yl)-4-(2-cyclopentyloxy-3-methoxyphenyl)butanamine (Compound No. 104); or an analog, tautomer, geometric isomer, stereoisomer of the above compound A conformation, enantiomer, diastereomer or pharmaceutically acceptable salt. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3 and a pharmaceutically acceptable excipient, in the form of a free sputum or a pharmaceutically acceptable salt; Preferably, the pharmaceutically acceptable excipient is a carrier or diluent. A method of preventing, ameliorating or treating a vanilloid receptor mediated disease, disorder or syndrome in a subject in need thereof, comprising administering to the subject a therapeutically effective amount as in claims 1 to 3 A compound according to any one of the items. The method of claim 5, wherein the vanilloid receptor-mediated disease, disorder or syndrome is a pain or inflammatory disease, disorder or syndrome mediated by TRPV3. The method of claim 5, wherein the symptom of the disease, disorder, syndrome or condition associated with TRPV3 function is selected from the group consisting of: pain; acute pain; chronic pain; nociceptiveness Pain; neuropathic pain; postoperative pain; toothache; cancer pain; heartache caused by ischemic myocardium; pain caused by migraine; joint pain; neuropathy; neuralgia; trigeminal neuralgia; nerve injury; diabetic neuropathy; Degenerative diseases; retinopathy; neurological skin disorders; stroke; bladder allergy; urinary incontinence; vulvar pain; gastrointestinal disorders, such as irritable bowel syndrome, gastroesophageal reflux disease, enteritis, ileitis, stomach-duodenal ulcer , inflammatory bowel disease, Crohn's disease, celiac disease; inflammatory diseases such as pancreatitis; respiratory disorders such as allergic and non-allergic rhinitis, asthma or chronic obstructive pulmonary disease; irritation of the skin, eyes or mucous membranes; Dermatitis; pruritus, such as uremia, itching; fever; muscle spasm; vomiting; dyskinesia; depression; Huntington's disease; memory loss; Functional limitation; amyotrophic lateral sclerosis (ALS); dementia; arthritis; osteoarthritis; diabetes; obesity; urticaria; actinic keratosis; keratoacanthoma; Disease; tinnitus; hypersensitivity; anxiety; 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 3, preferably wherein the pain is Acute pain, chronic pain, or postoperative pain. A method of treating neuropathic pain or 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 3. a method of preparing a compound of formula (I), Wherein R ^{1 is} selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group or substituted or unsubstituted cycloalkyl; wherein aryl, heteroaryl and The heterocyclic ring is monocyclic, bicyclic or tricyclic, and is wholly or partially aromatic; wherein the substituents on the aryl, heteroaryl, heterocyclic ring and cycloalkyl are independently selected from the group consisting of Group consisting of halogen; hydroxy, nitro, cyano, substituted or unsubstituted amino, substituted or unsubstituted alkyl, linear or branched alkyl, straight or branched alkoxy, substituted Or an unsubstituted alkenyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted haloalkyl group, a wholly or partially substituted haloalkyl group, a substituted or unsubstituted haloalkoxy group, a wholly or partially substituted haloalkoxy group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkoxy group, a substituted or unsubstituted cycloalkylalkyl group, a substituted or unsubstituted cycloalkylalkoxy group, a substituted or unsubstituted aryl group, Substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyl, substituted or not Substituted arylalkoxy group, a substituted or unsubstituted heterocyclic group, a 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 ; R ² is hydrogen; R ^a , R ^b , R ^c and R ^{d are} independently selected from hydrogen, nitro , cyano, halogen, -OR ^e , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl a substituted, unsubstituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group; R ^{e is} selected from the group consisting of 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 heterocyclic group; R ³ And R ^{4 are} independently selected from hydrogen, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, straight or branched alkyl, straight or branched alkoxy, substituted or unsubstituted alkene Alkyl, substituted or unsubstituted alkoxy, substituted or not a haloalkyl group, a wholly or partially substituted haloalkyl group, a substituted or unsubstituted haloalkoxy group, a wholly or partially substituted haloalkoxy group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkoxy group, a substituted or unsubstituted cycloalkylalkyl group, a substituted or unsubstituted cycloalkylalkoxy group, a substituted or unsubstituted aryl group; 'm' is an integer selected from 1 to 4; 'n' is selected from 0 An integer of -3; 'p' is an integer selected from 0-2; but R ^{b is} not a group selected from -OR ^e , -NR ³ R ⁴ or C(O)NR ³ R ⁴ ; The following procedure is carried out by coupling a compound of formula (1) with a compound of formula (2) in the presence of a suitable coupling agent combination and a suitable solvent to give a compound of formula (I) (when R ² is H) : Wherein the preferred coupling agent combination is selected from the group consisting of 1-hydroxybenzotriazole (HOBt), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and triethylamine; preferably a suitable solvent is dichloromethane; preferably the oxime is triethylamine.