JP2002521441A - Propenamide as a CCR5 modulator - Google Patents

Abstract

  (57) [Summary] The present invention relates to substituted anilides that are modulators, agonists or antagonists of the CCR5 receptor. In addition, the present invention relates to the treatment and prevention of conditions mediated by CCR5.

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD [0001] The present invention relates to CCR5 (Nature Medicine, 2, 1174-8, 1996).
Substituted anilide, which is a modulator, agonist or antagonist of the CC chemokine receptor CC-CKR5, referred to as CC-CKR5. In addition, the present invention provides
It relates to the treatment and prevention of conditions mediated by CR5.

BACKGROUND ART [0002] T cells are not only important substances that regulate the immune response to infectious substances, but also play a very important role in initiating and maintaining the inflammatory response in various chronic diseases. . An increase in the number or activation of T cells, especially CD4 + T cells,
In the synovium of rheumatoid arthritis individuals (MJElliott and RNMaini, Int. Arch.
Allergy Immunol. 104: 112-1125, 1994) on the bronchial mucosa of asthmatic patients (CJ Corrigan and ABKay, Immunol. Today 13: 501-506, 1).
992), in multiple sclerosis lesions (R. Martin and HFMcFarl, Crit. Rev. Cli
n.Lab.Sci. 32: 121-182, 1995), in psoriatic lesions (JLJones, J.Be.
rth-Jone, A. Fletcher and PEHutchinson, J. Pathol. 174: 77-82,
1994) and in the fatty streak of atherosclerosis (R. Ross, Annu. Rev. Phy
siol. 57: 791-804, 1995). T cells as well as other inflammatory cells will migrate into tissues in response to production of various chemotactic factors. Of these factors, one superfamily, 8-12
The kDa protein is known as a chemokine. These proteins share structural features such as the presence of 3-4 conserved cysteine residues. Regulated upon
RAN is an abbreviation for Activation Normal T cell Expressed and Secreted
TES is an 8 kDa protein in the CC branch of the chemokine family. These proteins recruit and activate immune and inflammatory cells through interaction with G-protein coupled receptors. The CC branch is defined by the absence of intervening amino acid residues between the first two cysteine residues and members of this family are mononuclear cells,
Induces predominantly the migration of eosinophils and basophils (M. Baggiolini, B. Dewald and B. Moser, Adv. Immunol. 55: 97-179, 1994; and JJOppenhei)
m, COC Zachariae, N. Mukaida and K. Matsushima, Annu. Rev. Immunol. 9: 6
17-648, 1991).

[0003] RANTES effectively chemotaxis T cells, basophils, monocytes and mast cells. RANTES was originally identified as a gene product that is induced late after antigen activation of T-cells (TJ Schall, J. Jongstra, BJDyer, J. Jorgen
sen, et al., J. Immunol. 141: 1018-1025, 1988).
Are epithelial and endothelial cells (C. Stellato, LABeck, GAGorgone, D. Proud et al., J.
Immunol. 155: 410-418, 1995; and A. Marfaing-Koka, O. Devever.
ne, G. Gorgon, A. Portier et al., J. Immunol. 154: 1870-1878, 199.
4), synovial fibroblasts (P. Rathanaswami, M. Hachicha, M. Sadick, TJ Schall et al., J. Biol. Chem. 268: 5834-5839, 1993) and dermal fibroblasts (M. Stickerling, M. Kupper, F. Koltrowitz, E. Bornscheuer et al., J. Invest. Derma
105: 585-591, 1995), glomerular stromal cells (G. Wolf, S. Aberle
F. Thaiss et al., Kidney Int. 44: 795-804, 1994) and platelets (Y.
Koameyoshi, A. Dorschner, AIMallet, E. Christophers, et al., J. Exp. Med. 176.
: 587-592, 1992) have been shown to be synthesized and secreted by various groups of cells. In these cells, RANTES mRNA is rapidly upregulated in response to IL-1 or TNFα. R
ANTES mRNA is not normally detected in normal cells (JMPattison,
PJ Nelson and AM Krensky, Clin. Immunoother. 4: 1-8, 1995) show increased mRNA or protein in diseases characterized by mononuclear infiltrates. For example, RANTES mRNA can be expressed in rejecting renal allografts (JMPattison, PJ Nelson and AMKrensky, Clin. Immunoother. 4: 1-
8, 1995; and KCNadeau, H. Azuma and NITiney, Proc. Natl. Aca
d. USA 92: 8729-8733, 1995), skin of patients with atopic dermatitis after exposure to antigen (S. Ying, L. Taborda-Barata, Q. Meng, M. Humbert et al., J. Exp.
Med. 181: 2153-2159, 1995) and coronary artery endothelial cells with accelerated progression of atherosclerosis after heart transplantation (JMPattison, PJ Nelson
And AMKrensky, Clin. Immunoother. 4: 1-8, 1995) using the in situ hybridization method. Furthermore, RANTES
Increased immunoreactive proteins related to bronchoalveolar lavage fluid (R. Alam, J. York, M.
Boyers et al., Am. J. Resp. Crit. Care Med. 149: A951, 1994) and sputum from asthmatics (CMGelder, PSThomas, DHYates, IMAdcock et al., Thorax 5).
0: 1033-1037, 1995).

[0004] Several receptors that bind to RANTES have been identified. In particular, CCR5 is
When expressed in either 293 cells or CHO cells, it binds to RANTES. This receptor is expressed on T-cells and on monocytes and macrophages, immune / inflammatory cells that play an important role in maintaining a chronic inflammatory response. CCR
5 can be characterized pharmacologically, and the RANTES observed on isolated T cells
It is similar to the binding site. Thus, the antagonism of RANTES against CCR5 and the antagonism of other natural modulators of CCR5 inhibits the recruitment and activation of T cells and macrophages to inflammatory lesions and is novel for treating atopic and autoimmune diseases To provide appropriate therapy. Since T cells express CCR5, they are selective receptor modulators of CCR5,
In particular, the antagonist may be used in all mammals, preferably humans, asthma and atopic disorders (eg, atopic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, sarcoidosis and other fibrotic diseases,
It is believed to provide effective effects in diseases including, but not limited to, psoriasis, autoimmune diseases such as multiple sclerosis and inflammatory bowel disease. Furthermore, CD8 + T cells are involved in chronic obstructive pulmonary injury (COPD),
CCR5 plays a role in its recruitment, and thus antagonists of CCR5 may provide an effective therapy in treating CORD. further,
Because CCR5 is a co-receptor for HIV entry into cells, selective receptor modulators may be useful in treating HIV infection. Surprisingly, a series of non-peptidic compounds, particularly substituted anilides of formula (I), now function as CCR5 receptor modulators, and therefore have utility in the treatment and prevention of conditions mediated by the CCR5 receptor mechanism. It was found to be.

[0005] In one aspect, the present invention provides a compound of formula (I):

Embedded image Wherein the basic nitrogen in the group E may be quaternized with C _1-6 alkyl or may be present as an N-oxide; P ¹ is phenyl, fused bicyclic aryl, 5- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, or 8 to 11 containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur Membered fused bicyclic heterocycle;

L is CONR^{5 '}R^{1 '}And R^{2 '}Is independently hydrogen, C_1-6Alkyl, C_2-6Arche
Nil, C_2-6Alkynyl, C_3-7Cycloalkyl, C_3-6Cycloalkenyl
, (CH₂)_{b '}NR^{6 '}R^{7 '}, (CH₂)_{b '}NR^{6 '}COR^{8 '}, (CH₂) _{b '} NR^{6 '}CO₂R^{9 '}, (CH₂)_{b '}NR^{6 '}SO₂R^{10 '}, (CH₂)_{b '} CONR^{11 '}R^{12 '}, Hydroxy C_1-6Alkyl, C_1-4Alkoxy
Alkyl (C_1-4May be substituted with an alkoxy or hydroxy group),
(CH₂)_{b '}CO₂C_1-6Alkyl, (CH₂)_{c '}OC (O) R^{13 '}, CR^{1 4 '} = NOR^{15 '}, CNR^{16 '}= NOR^{15 '}, COR^{17 '}, CONR^{1 1 '} R^{12 '}, CONR^{11 '}(CH₂)_{d '}OC_1-4Alkyl, CONR^{11 '} (CH₂)_{b '}CO₂R^{18 '}, CONHNR^{19 '}R^{20 '}, CONR^{11 '} SO₂R^{21 '}, CO₂R^{22 '}, Cyano, trifluoromethyl, NR^{6 '}R^{7 '} , NR^{6 '}COR^{8 '}, NR^{23 '}CO (CH₂)_{b '}NR^{23 '}R^{24 '}, N
R^{23 '}CONR^{23 '}R^{24 '}, NR^{6 '}CO₂R^{9 '}, NR^{6 '}SO₂R^{1 0 '} , N = CNR^{23 '}NR^{23 '}R^{24 '}, Nitro, hydroxy, C_1-6A
Lucoxy, hydroxy C_1-6Alkoxy, C_1-6Alkoxy C_1-6Arco
Kishi, OC (O) NR^{25 '}R^{26 '}, SR^{27 '}, SOR^{28 '}, SO₂R^{28 '} , SO₂NR^{29 '}R^{30 '}, Halogen, C_1-6Alkanoyl, CO₂(C
H₂)_{b '}OR^{31 '}Or R^{1 '}Is phenyl or R
^{1 '}Contains 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur
Are 5- to 7-membered heterocycles, wherein one or two R^{32 '}Replaced by
Or R^{1 '}May be completely or partially unsaturated, 5 to 7
An optionally substituted fused carbocycle, or R^{1 '}Is completely or
One or more selected from nitrogen, oxygen or sulfur, which may be partially unsaturated
A 5- to 7-membered optionally substituted fused heterocycle containing 4 heteroatoms
Yes;

R ^{3 ′} is hydrogen or C _1-6 alkyl; R ^{4 ′} is hydrogen, C _1-6 alkyl, C _1-6 alkyl CONH or halogen; R ^{5 ′} is hydrogen or C _1-6 Alkyl; R ^{14 ′} , R ^{15 ′} , R ^{16 ′} , R ^{17 ′} , R ^{18 ′} , R ^{19 ′} , R ^{20 ′} ,
^{R 23 ', R 24',} R 27 ' and ^{R 31'} are independently hydrogen or _{C 1-6} alkyl; R ^{6 'and} R ^7' are independently hydrogen or _{C 1-6} Alkyl or R ^{6 ′} and R ^{7 ′} together with the nitrogen to which they are attached are 5- to 6-
Membered heterocyclic ring, which ring may be substituted with an oxo group and, if there are 6 ring atoms, there may be one oxygen or one sulfur atom in the ring; ^{8 ′} is hydrogen, C _1-6 alkyl or C _1-4 alkoxyalkyl; R ^{9 ′} , R ^{21 ′} and R ^{28 ′} are independently C _1-6 alkyl; R ^{10 ′} is C be _1-6 alkyl or phenyl; ^{R 11 'and R 12'} are independently a hydrogen or _{C 1-6} alkyl, or ^{R 11 'and R 12'} together with the nitrogen to which they are attached To form a 5- to 6-membered saturated heterocycle, having 6 ring atoms, there may be one oxygen or one sulfur atom in the ring;

R ^{13 ′} is C _1-4 alkyl optionally substituted with one C _1-6 alkoxy; R ^{22 ′} is hydrogen or C _1-6 alkyl, C _1-6 alkoxy, hydroxy or NR ^{6 ′} is C _1-6 alkyl optionally substituted with one or two substituents selected from R ^{7 ′} ; R ^{25 ′} and R ^{26 ′} are independently hydrogen or C _{1- And} R ^{25 ′} and R ^{26 ′} together with the nitrogen to which they are attached form a 5- to 6-membered heterocycle, and if there are 6 ring atoms, there may be 6 There may be one oxygen or sulfur atom; R ^{29 ′} and R ^{30 ′} are independently hydrogen or C _1-6 alkyl, or R ^{29 ′} and R ^{30 ′} Forms a 5- or 6-membered heterocycle with nitrogen , If there are 6 ring atoms, there may be one oxygen or one sulfur atom in the ring; ^{R 32 'is} _{hydrogen, C 1-6 alkyl, C 3-6} cycloalkyl, _{C 3 -6} cycloalkenyl, hydroxy C _1-6 alkyl, C _1-6 alkyl OC _1-6 alkyl, CONR ^{33 '} R ^34' , CO ₂ R ^{35 '} , cyano, aryl, trifluoromethyl, NR ^36' R ^{37 '} , Nitro, hydroxy, C _1-6 alkoxy,
R ^{33 ′} , R ^{34 ′} , R ^{35 ′} , R ^{36 ′} and R ^{37 ′} are independently hydrogen or C _1-6 alkyl; a ′ is C _1-6 alkanoyl, acyloxy or halogen; B 'is 1, 2, 3 or 4; c' is 0, 1, 2 or 3; d 'is 1, 2 or 3;

[0009] E is represented by the formula (a):

Embedded image(Where B is oxygen, S (O)_c, CR⁷= CR⁸Or CR⁷R⁸Or B is
NR⁹R¹And R²Is independently hydrogen or C_1-6Is alkyl;
B (CR¹R²)_aIs OCR¹R²CR¹(OH) CR¹R²Or OCR¹R²C
R¹(OCOCH₃) CR¹R²R³And R⁴Is independently hydrogen, C_1-6Alkyl, C_3-7Cycloal
Kill, aralkyl, or together with the nitrogen atom to which they are attached,
Can contain additional heteroatoms selected from oxygen, nitrogen or sulfur
To form an optionally substituted 5- to 7-membered heterocycle, wherein
The substituent is C_1-6Alkyl, aryl, CONR¹⁰R¹¹, NR¹⁰R¹¹, Hi
Droxy, OCOR¹², NHCOC_0-6Alkyl, including alkyl here
Is OH, NHCOCF₃, NHSO₂R¹³And NHCO₂R¹⁴Replaced by
R⁵Is hydrogen, C_1-6Alkyl, aryl, CN, CONR^FifteenR¹⁶, CO ₂ R¹⁷, Trifluoromethyl, NHCO₂R¹⁸, Hydroxy, C_1-6Al
Coxy, benzyloxy, OCH₂CO₂C_1-6Alkyl, OCF₃, S (O) _d R¹⁹, SO₂NR²⁰R²¹Or halogen; R⁶Is hydrogen, C_1-6Alkyl, aryl, trifluoromethyl, hydroxy
, C_1-6Alkoxy or halogen, or R⁶Is R^{5 '}Together with
To form a group D, wherein D is (CR²²R²³)_eOr D is (C
R²²R²³)_f-G, where G is oxygen, sulfur or CR²²= CR²³
, CR²²= N, = CR²²O, = CR²²S or = CR²²-NR²³so
Yes; R⁷, R⁸, R¹⁰, R¹¹, R¹², R^Fifteen, R¹⁶, R¹⁷, R²⁰, R ²¹ , R²²And R²³Is independently hydrogen or C_1-6R is alkyl;⁹Is hydrogen, C_1-6Alkyl or phenyl C_1-6R is alkyl;¹³, R¹⁴, R¹⁸And R¹⁹Is independently C_1-6Alkyl
A is 1, 2, 3 or 4; b is 1 or 2; c and d are independently 0, 1 or 2; e is 2, 3 or 4; 0, 1, 2 or 3), or separately

[0010] E is represented by the formula (b):

Embedded image (Wherein, R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³¹ and R ³² are
Independently, is hydrogen or C _1-6 alkyl; R ³⁰ is hydrogen, C _1-6 alkyl or C _3-7 cycloalkyl; R ³³ is hydrogen, C _1-6 alkyl, trifluoromethyl, hydroxy Or is halogen, or R ³³ and R ^{5 ′} are taken together to form a group: —K—, where K is (CR ³⁴ R ³⁵ ) _i or K is (CR ³⁴ R ³⁵ ) _j- M, where M
Is oxygen, sulfur, CR ³⁴ = CR ³⁵ , CR ³⁴ = N or N = N; J is oxygen, CR ³⁶ R ³⁷ or NR ³⁸ , or J is a group: S (O) _k ; ^{R 34, R 35, R 36} , R 37 and ^{R 38} are, independently, hydrogen or _{C 1 -6} alkyl; g is 1, 2 or 3; h is 1, 2 or 3; i is 2, 3 or 4; j is 0, 1, 2 or 3; k is 0, 1 or 2);

[0011] E is the formula (c):

Embedded image Wherein Q is oxygen, S (O) _n , CR ⁴⁴ = CR ⁴⁵ , CR ⁴⁴ R ⁴⁵ or Q is NR ⁴⁶ ; R ³⁹ and R ⁴⁰ are independently hydrogen or C It is _1-6 alkyl; ^{R 41} is formula (d):

Embedded image Or R ⁴¹ is a group represented by the formula (e):

Embedded image R ⁴² is hydrogen, C _1-6 alkyl, aryl, CN, CONR ⁴⁸ R ⁴⁹ , C
O ₂ R ⁵⁰ , trifluoromethyl, NHCO ₂ R ⁵¹ , hydroxy, C _1-6 alkoxy, benzyloxy, OCH ₂ CO ₂ C _1-6 alkyl, OCF ₃ , S (
O) _s R ⁵² , SO ₂ NR ⁵³ R ⁵⁴ or halogen; R ⁴³ is hydrogen, or R ⁴³ is taken together with R ^{5 ′} to form a group: R, where R is CR ⁵⁵ = CR ⁵⁶ , CR ⁵⁵ = CR ⁵⁶ CR ⁵⁵ R ⁵⁶ or (
CR ⁵⁵ R ⁵⁶ ) _t ; R ⁴⁴ , R ⁴⁵ , R ⁴⁶ , R ⁴⁸ , R ⁴⁹ , R ⁵⁰ , R ⁵³ , R ⁵⁴ , R ⁵⁵ and R ⁵⁶ are independently hydrogen or C _1-6 R ⁴⁷ is hydrogen, C _1-6 alkyl or C _3-7 cycloalkyl; R ⁵¹ and R ⁵² are independently C _1-6 alkyl; l is 0, 1, 2 M is 1 or 2; n is 0, 1 or 2; o, p and q are independently integers of 1, 2 or 3; r is 0, 1, S is 0, 1 or 2; t is 2 or 3);

E is expressed by the following equation (f):

Embedded image Wherein R ⁵⁷ and R ⁵⁸ are independently hydrogen or C _1-6 alkyl; R ⁵⁹ and R ⁶⁰ are independently hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl An optionally substituted 5- to 7-membered, which can be an aralkyl or, together with the nitrogen atom to which they are attached, contain a further heteroatom selected from oxygen, nitrogen or sulfur Wherein the optional substituents include C _1-6 alkyl, aryl, CONR ⁶¹ R ⁶² , NR ⁶¹ R ⁶² , hydroxy, OCOR ⁶³ , NHCOC _0-6 alkyl, wherein alkyl is May be substituted with OH, NHCOCF ₃ , NHSO ₂ R ⁶⁴ and NHCO ₂ R ⁶⁵ ; T is — (CR ⁶⁶ R ⁶⁷ ) _v — or —O (CR ⁶⁶ R ⁶⁷ ) _w- ; W is oxygen, S (O) _x , NR ⁶⁸ , or W is CR ⁶⁹ = CR ⁷⁰ or CR ⁶⁹ R ⁷⁰ ; R ⁶¹ , R ⁶² , R ⁶³ , R ⁶⁶ , R ⁶⁷ , R ⁶⁸ , R ⁶⁹ and R ⁷⁰ are
Independently, is hydrogen or C _1-6 alkyl; R ⁶⁴ and R ⁶⁵ are independently C _1-6 alkyl; u is 1-4; v is 2 or 3; w Is 1, 2 or 3; x is 0, 1 or 2);

[0013] E is the formula (g):

Embedded image Wherein R ⁷¹ is an optionally substituted 5- to 7-membered saturated or partially saturated heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur; Or R ⁷¹ is a 6,6 or 6,5 bicyclic ring optionally substituted containing one nitrogen and one further heteroatom selected from oxygen, nitrogen or sulfur R ⁷² is hydrogen, C _1-6 alkyl, aryl, CN, CONR ⁷⁴ R ⁷⁵ , C;
O ₂ R ^76, trifluoromethyl, NHCO ₂ R ^77, _{hydroxy, C 1-6} alkoxy, _benzyloxy, OCH ₂ CO _{2 C 1-6} alkyl, _OCF 3, S (
O) zR ⁷⁸ , SO ₂ NR ⁷⁹ R ⁸⁰ or halogen; R ⁷³ is hydrogen, C _1-6 alkyl, hydroxy, C _1-6 alkoxy or halogen, or R ⁷³ and R ^{5 ′} together To form a group: -X-,
Where X is (CR ⁸¹ R ⁸² ) _aa or X is (CR ⁸¹ R ⁸² ) _ab −
Y is oxygen, sulfur or CR ⁸¹ ＣＲCR ⁸² ; R ⁷⁴ , R ⁷⁵ , R ⁷⁶ , R ⁷⁹ , R ⁸⁰ , R ⁸¹ and R ⁸² are independently hydrogen or C _1-6 R ⁷⁷ and R ⁷⁸ are independently C _1-6 alkyl; y is 1 or 2; z is 0, 1 or 2; aa is 2, 3 or 4 Ab is 0, 1, 2 or 3);

E is the formula (h):

Embedded image(Where: R⁸³And R⁸⁴Is independently hydrogen or C_1-6R is alkyl;⁸⁵And R⁸⁶Is independently hydrogen, C_1-6Alkyl, C_3-7Cyclo
Alkyl, aralkyl or together with the nitrogen atom to which they are attached
Contain one more heteroatom selected from oxygen, nitrogen or sulfur.
Forming an optionally substituted 5- to 7-membered heterocycle, wherein
Optional substituent is C_1-6Alkyl, aryl, CONR⁸⁸R⁸⁹, NR⁹⁰R ⁹¹ , Hydroxy, OCOR⁹², NHCOC_0-6Including alkyl, where
Alkyl is OH, NHCOCF₃, NHSO₂R⁹³And NHCO₂R⁹⁴ R may be substituted with⁸⁷Is hydrogen, C_1-6Alkyl, C_1-6Is alkoxy or halogen
Or R⁸⁷Is R^{5 '}And forms a group: -AA-, where AA is
(CR⁹⁵R⁹⁶)_adOr AA is (CR⁹⁵= CR⁹⁶)_ae-AB
And AB is oxygen, sulfur, CR⁹⁵= CR⁹⁶, CR⁹⁵= N, CR⁹⁵NR ⁹⁶ Or N = N; Z contains 1-3 heteroatoms selected from oxygen, nitrogen or sulfur
An optionally substituted 5- to 7-membered heterocycle;⁸⁸, R⁸⁹, R⁹⁰, R⁹¹, R⁹², R⁹⁵And R⁹⁶Independently
, Hydrogen or C_1-6R is alkyl;⁹³And R⁹⁴Is independently C_1-6Ac is 0 to 4; ad is 1, 2 or 3; ae is 0, 1 or 2);

E is the formula (i):

Embedded image Wherein R ⁹⁷ and R ⁹⁸ are independently hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached, oxygen, Forming an optionally substituted 5- to 7-membered heterocycle, which may contain one more heteroatom selected from nitrogen or sulfur, wherein the optional substituents are C _1-6 alkyl, ^{aryl, CONR 102 R 103, NR 1} 04 R 105, ^hydroxy, encompasses OCOR 106, _{NHCOC 0-6} alkyl, wherein alkyl in _{OH, NHCOCF 3, NHSO 2 R} 107 and NH
It may be substituted by CO ₂ ^{R 108;} R ⁹⁹ and ^{R 100} is independently hydrogen or _{C 1-6} alkyl; or ^{R 101} is hydrogen or _{C 1-6} alkyl or ^{R 101,} And R ^{5 ′} together form a group: —AD—, wherein AD is (CR ¹⁰⁹ R ¹¹⁰ ) _ai , or AD is (CR ¹⁰⁹ R ¹¹⁰ ) _aj -AE and AE Is oxygen,
AC is oxygen, CR ¹¹¹ R ¹¹² or NR ¹¹³ ; or AC is a group: S (O) _ak ; R ¹⁰² , R ¹⁰³ , R ¹⁰⁴ , R ¹⁰⁵ , sulfur or CR ¹⁰⁹ ＣＲCR ¹¹⁰ ; R ¹⁰⁶ , R ¹⁰⁹ , R ¹¹⁰ ,
R ¹¹¹ , R ¹¹² and R ¹¹³ are independently hydrogen or C _1-6 alkyl; R ¹⁰⁷ and R ¹⁰⁸ are independently C _1-6 alkyl; af is 0, 1, 2 Ag is 1, 2, 3 or 4; ai is 2, 3 or 4; aj is 0, 1, 2 or 3 Ak is 0, 1 or 2) or a pharmaceutically active salt thereof, and the novel use thereof in treating the above-mentioned CCR5-mediated conditions. .

[0016] In another aspect, the invention relates to COPD, asthma and atopic disorders (eg, atopic dermatitis and allergies), rheumatoid arthritis, atherogenic in all mammals, preferably humans CC, including, but not limited to, arteriosclerosis, sarcoidosis and other fibrosis-type diseases, psoriasis, autoimmune diseases such as multiple sclerosis, inflammatory bowel disease and HIV infection.
A method of treating a condition mediated by R5, wherein the mammal in need of such treatment is given the formula (
A method comprising administering anilide of I) or a pharmaceutically active salt thereof. In yet another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier for the compound. In particular, the pharmaceutical compositions of the present invention are useful in all mammals, preferably humans, for asthma and atopic disorders (eg, atopic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, sarcoidosis and other Fibrotic disease, psoriasis,
It is used in the treatment of autoimmune diseases, such as multiple sclerosis, inflammatory bowel disease, CCR5 mediated conditions including, but not limited to, CORD and HIV.

BEST MODE FOR CARRYING OUT THE INVENTION It has now been found that substituted anilides of formula (I) are CCR5 receptor modulators. Furthermore, the selective inhibition of the CCR5 receptor mechanism by treatment with a receptor modulator of formula (I) or a pharmaceutically acceptable salt thereof, is associated with CORD, Asthma and atopic disorders (eg, atopic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, sarcoidosis and other fibrosis-type diseases, psoriasis, autoimmune diseases, eg, multiple sclerosis and inflammatory Various pathologies, including bowel disease ("C
It has been found to provide new therapeutic and prophylactic methods for the treatment of CR5-mediated conditions "). Also, since CCR5 is a co-receptor for HIV entry into cells, selective receptor modulators are useful for treating HIV infection.

The term “alkyl”, as used herein, whenever used herein, unless the chain length is limited, refers to straight or branched chain groups having 1 to 6 carbon atoms, methyl, ethyl, n -Propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t
tert-butyl and the like, but are not limited thereto. Whenever the terms "cycloalkyl" and "cyclic alkyl" are used herein, the term monocyclo or bicyclo-, preferably having 3 to 7 carbon atoms, is used.
Refers to a cyclic group of a fused ring system, which may be additionally unsaturated, and includes, but is not limited to, cyclopropyl, cyclopentyl, cyclohexyl, and the like. The terms "halo" or "halogen" are used interchangeably herein and whenever used, mean a group derived from the elements chlorine, fluorine, iodine and bromine.

The term “heterocycle” as used herein, whenever used herein (unless the ring system is specifically limited) contains one to three heteroatoms selected from oxygen, sulfur or nitrogen. A saturated or partially saturated 5-, 6- or 7-membered ring system,
The ring system may be substituted with C _1-6 alkyl or C _3-7 cycloalkyl. Examples of such rings include, but are not limited to, piperidine, tetrahydropyridine, and piperazine. When a heterocycle is fused to a phenyl group, the "heterocycle" together with the condensed phenyl ring becomes 1,2,3,4
-Including tetrahydroquinoline, 2-oxo-benzoxazole, 3,4-dihydro-3-oxo-1,4-benzoxazine, 3,4-dihydro-1,4-benzoxazine and 2,3-dihydro-indole , Forming a ring, but not limited to, it may be substituted with C _1-6 alkyl or oxo. The term "6,6 or 6,5 bicyclic" contains one nitrogen atom and additionally contains nitrogen,
Means oxygen or one heteroatom may 6,6 or 6,5 bicyclic also contain selected from sulfur, the ring system may be substituted by C _1-6 alkyl. Examples of such ring systems include, but are not limited to, tropane, isoquinuclidine and grananatan rings.

The term “CCR5-mediated condition”, whenever used herein, refers to CC
It refers to any condition mediated (or modulated) by R5. The term "monocyclic heterocycle", whenever used herein, refers to thienyl,
Furyl encompasses pyrrolyl and pyridyl, represented by P ¹ and / or P ^2, oxygen, a single aromatic 5- to 7-membered containing 1 to 3 heteroatoms selected from nitrogen and sulfur Means a ring. The term "fused bicyclic heterocycle," as used herein, whenever used herein, refers to one to three members selected from oxygen, nitrogen and sulfur, including indole, benzofuran, benzothiophene, quinoline and isoquinoline rings. 8 containing heteroatoms
And from 11 to 11 membered fused bicyclic aromatic ring systems. Suitably, pharmaceutically acceptable salts of formula (I) include, but are not limited to, inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide and nitrate. Salt with, or malate, maleate, fumarate, tartrate, succinate,
Includes salts with organic acids such as citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, palmitate, salicylate and stearate.

The compounds of the present invention can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the form of solvation with a pharmaceutically acceptable solvent such as water, ethanol and the like is equivalent to the unsolvated form for the purposes of the present invention. The compounds of the present invention may contain one or more asymmetric carbon atoms,
It may exist in racemic and optically active forms. The stereocenter may be in any combination of R and S configurations, for example, (R, R), (R, S), (S,
S) or (S, R). All of these compounds are within the scope of the present invention. When the compound of the present invention is a 3-aryl or 3-heteroaryl-2-propeneanilide, the geometry around the propenyl double bond is trans unless otherwise specified as cis or (Z). Alternatively, those skilled in the art will understand that the configuration is (E).

Various specific examples of the compounds of formula (I) are as follows. The basic nitrogen in the E group may be quaternized with C _1-6 alkyl or may be present as an N-oxide. P ¹ is suitably a 5- to 7-membered heterocycle containing 1-3 heteroatoms selected from phenyl, fused bicyclic aryl, oxygen, nitrogen and sulfur, or from oxygen, nitrogen and sulfur. 8 containing 1 to 3 heteroatoms selected
Or 11-membered fused bicyclic heterocycle. P ¹ is preferably phenyl, naphthyl, furyl, thienyl, pyridyl, indolyl, benzofuranyl and benzothienyl. P ¹ is more preferably phenyl and naphthalenyl. When R ^{1 ′} is a 5- to 7-membered heterocycle containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur, suitable heterocycles are thienyl, furyl, pyrrolyl, triazolyl, Includes aromatic groups such as diazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl and dioxanyl. Saturated and partially saturated rings are also within the scope of the invention, especially rings containing oxo or thioxo groups such as lactams and thiolactams. Suitably, the heterocycle may be linked to the rest of the molecule via a carbon atom or, if present, a nitrogen atom. Suitable substituents for these rings 1 to include two R ^{32 '.}

L is suitably CONR^{5 '}It is. R^{1 '}And R^{2 '}Is suitably, independently, hydrogen, C_1-6Alkyl, C_{2 -6} Alkenyl, C_2-6Alkynyl, C_3-7Cycloalkyl, C_3-6Shiku
Loalkenyl, (CH₂)_{b '}NR^{6 '}R^{7 '}, (CH₂)_aNR^{6 '}COR^{8 '},
(CH₂)_{b '}aNR^{6 '}CO₂R^{9 '}, (CH₂)_{b '}NR^{6 '}SO₂R^{10 '},
(CH₂)_{b '}CONR^{11 '}R^{12 '}, Hydroxy C_1-6Alkyl, C_1-4 Alkoxyalkyl (C_1-4Substituted with an alkoxy or hydroxy group
), (CH₂)_{b '}CO₂C_1-6Alkyl, (CH₂)_{c '}OC (O) R^{13 '} , CR^{14 '}= NOR^{15 '}, CNR^{16 '}= NOR^{15 '}, COR^{17 '},
CONR^{11 '}R^{12 '}, CONR^{11 '}(CH₂)_{d '}OC_1-4Alkyl, C
ONR^{11 '}(CH₂)_{b '}CO₂R^{18 '}, CONHNR^{19 '}R^{20 '}, CO
NR^{11 '}SO₂R^{21 '}, CO₂R^{22 '}, Cyano, trifluoromethyl, N
R^{6 '}R^{7 '}, NR^{6 '}COR^{8 '}, NR^{23 '}CO (CH₂)_{b '}NR^{23 '}R ^{24 '} , NR^{23 '}CONR^{23 '}R^{24 '}, NR^{6 '}CO₂R^{9 '}, NR^{6 '} SO₂R^{10 '}, N = CNR^{23 '}NR^{23 '}R^{24 '}, Nitro, hydroxy,
C_1-6Alkoxy, hydroxy C_1-6Alkoxy, C_1-6Alkoxy C_{1 -6} Alkoxy, OC (O) NR^{25 '}R^{26 '}, SR^{27 '}, SOR^{28 '}, S
O₂R^{28 '}, SO₂NR^{29 '}R^{30 '}, Halogen, C_1-6Alkanoyl,
CO₂(CH₂)_{b '}OR^{31 '}Or R^{1 '}Is phenyl or
Or R^{1 '}Is 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur
Are 5- to 7-membered heterocycles containing one or two R^{32 '}Put in
It may be replaced.

R ^{1 ′} is also suitably a 5- to 7-membered optionally substituted fused carbocycle, which may be partially or completely unsaturated, or R ^{1 ′} is Selected from nitrogen, oxygen or sulfur, which may be partially or completely unsaturated
5 to 7-membered optionally substituted fused heterocycle containing from 4 to 4 heteroatoms. R ^{1 ′} is preferably hydrogen, C _1-6 alkyl, a fused 3,4- (tetramethylene) group or halogen; R ^{2 ′} is preferably hydrogen or halogen. R ^{1 ′} is more preferably halogen and R ^{2 ′} is more preferably halogen. R ^{1 ′} and R ^{2 ′} are most preferably taken together to form 3,4-dichloro or 3,5-dichloro. R ^{3 ′} is suitably hydrogen or C _1-6 alkyl. R ^{3 ′} is preferably hydrogen. R ^{4 ′} is suitably hydrogen, C _1-6 alkyl, C _1-6 alkyl CONH or halogen. R ^{4 ′} is preferably hydrogen. R ^{5 ′} is suitably hydrogen or C _1-6 alkyl. R ^{5 ′} is preferably hydrogen.

R ^{14 ′} , R ^{15 ′} , R ^{16 ′} , R ^{17 ′} , R ^{18 ′} , R ^{19 ′} , R ^{20 ′} ,
R ^{23 ′} , R ^{24 ′} , R ^{27 ′} and R ^{31 ′} are suitably, independently, hydrogen or C _1-6 alkyl. R ^{6 ′} and R ^{7 ′} are suitably independently hydrogen or C _1-6 alkyl, or R ^{6 ′} and R ^{7 ′} together with the nitrogen to which they are attached
Or a 6-membered heterocyclic ring, which ring may be substituted with an oxo group;
When there are two ring atoms, there may be one oxygen or one sulfur atom in the ring. R ^{8 ′} is suitably hydrogen, C _1-6 alkyl or C _1-4 alkoxyalkyl. R ^{9 ′} , R ^{21 ′} and R ^{28 ′} are suitably, independently, C _1-6 alkyl.

R ^{10 ′} is suitably C _1-6 alkyl or phenyl. R ^{11 ′} and R ^{12 ′} are suitably independently hydrogen or C _1-6 alkyl, or R ^{11 ′} and R ^{12 ′} together with the nitrogen to which they are attached are 5- to When forming a 6-membered saturated heterocycle and there are 6 ring atoms, there may be one oxygen or one sulfur atom in the ring. R ^{13 ′} is suitably C _1-4 alkyl optionally substituted with C _1-6 alkoxy. R ^{22 ′} is suitably hydrogen or C _1-6 alkyl, C _1-6 alkoxy,
Optionally substituted with 1 or 2 substituents selected from hydroxy or NR 6 ^{'R 7'} is also C _1-6 alkyl. R ^{25 ′} and R ^{26 ′} are suitably independently hydrogen or C _1-6 alkyl, or R ^{25 ′} and R ^{26 ′} together with the nitrogen to which they are attached are 5- to When forming a 6-membered heterocycle and there are 6 ring atoms, there may be one oxygen or sulfur atom in the ring.

R ^{29 ′} and R ^{30 ′} are suitably independently hydrogen or C _1-6 alkyl, or R ^{29 ′} and R ^{30 ′} together with the nitrogen to which they are attached. When forming a 5- to 6-membered heterocycle and there are 6 ring atoms, there may be one oxygen or one sulfur atom in the ring. R ^{32 ′} is suitably hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl,
C _3-6 cycloalkenyl, hydroxy C _1-6 alkyl, C _1-6 alkyl O
C _1-6 alkyl, CONR ^{33 ′} R ^{34 ′} , CO ₂ R ^{35 ′} , cyano, aryl, trifluoromethyl, NR ^{36 ′} R ^{37 ′} , nitro, hydroxy, C _1-6 alkoxy, C _1-6 alkanoyl, Acyloxy or halogen. R ^{33 ′} , R ^{34 ′} , R ^{35 ′} , R ^{36 ′} and R ^{37 ′} are suitably, independently, hydrogen or C _1-6 alkyl. a 'is suitably 1, 2 or 3. b 'is suitably 1, 2, 3 or 4. c 'is suitably 0, 1, 2 or 3. d 'is suitably 1, 2 or 3.

E is suitably represented by the formula (a):

Embedded imageIndicated by B is suitably oxygen, S (O)_c, CR⁷= CR⁸Or CR⁷R⁸Is
, Or B is NR⁹It is. B is preferably CR⁷R⁸Or oxygen.
B is more preferably CH₂Or oxygen. R¹And R²Is suitably, independently, hydrogen or C_1-6Is alkyl
. Preferably, R¹And R²Is hydrogen. Separately, B (CR¹R²)_aIs OCR ¹ R²CR¹(OH) CR¹R²Or OCR¹R²CR¹(OCOCH₃) CR¹ R²It is. Preferably, B (CR¹R²)_aIs OCR¹R²CR¹(OCOCH
₃) CR¹R²If R¹And R²Is hydrogen.

R ³ and R ⁴ are suitably, independently, hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached. Forms an optionally substituted 5- to 7-membered heterocycle, which may contain additional heteroatoms selected from oxygen, nitrogen or sulfur, wherein the optional substituents are C _1-6 alkyl, ^{aryl, CONR 10 R 11, NR 10} R 11, ^hydroxy, encompasses OCOR 12, _{NHCOC 0-6} alkyl, here is substituted _OH, in NHCOCF 3, NHSO ₂ R ¹³ and NHCO ₂ R ^{1 4} It may be. R ³ and R ⁴ are preferably both C _1-6 alkyl or, together with the nitrogen atom to which they are attached, contain a further heteroatom selected from oxygen, nitrogen or sulfur. Forming an optionally substituted 5- to 7-membered heterocycle. More preferably, R ³ and R ⁴ are C _3-6 alkyl, or together with the nitrogen to which they are attached, are substituted by one or more C _1-6 alkyl, N-acetamido or hydroxy. To form an optionally 6-membered ring. Most preferably, R ³ and R ⁴ are both isopropyl, or R ³ is isopropyl and R ⁴ is ter
t-butyl or, together with the nitrogen to which they are attached, form 1- (2,
2,6,6-tetramethylpiperidinyl), 1- (4-acetamido-2,2,6,6
-Tetramethylpiperidinyl), 1- (4-hydroxy-2,2,6,6-tetramethylpiperidinyl) or 1- (4-hydroxy-2,2,4,6,6-pentamethylpiperidinyl) Peridinyl).

Preferably, B- (CR ¹ R ² ) _a -NR ³ R ⁴ is ortho to R ⁵ ;
It is meta to L and para to R ⁶ , and R ⁵ is para to L. R ⁵ is suitably hydrogen, C _1-6 alkyl, aryl, CN, CONR ¹⁵ R ¹⁶ , CO ₂ R ¹⁷ , trifluoromethyl, NHCO ₂ R ¹⁸ , hydroxy,
C _1-6 alkoxy, benzyloxy, OCH ₂ CO ₂ C _1-6 alkyl, OC
F ₃ , S (O) _d R ¹⁹ , SO ₂ NR ²⁰ R ²¹ or halogen. R ⁵ is
Preferably, it is C _1-6 alkoxy, SC _1-6 alkyl or halogen;
More preferably it is methoxy or methylthio or iodo; most preferably it is methoxy. When R ⁵ is methoxy, it is preferably para to L. R ⁶ is suitably hydrogen, C _1-6 alkyl, aryl, trifluoromethyl, hydroxy, C _1-6 alkoxy or halogen, or R ⁶ together with R ^{5 ′} forms a group D formed, wherein D is ^(CR 22 ^{R 23)} or is _e, or D is _{^{(CR 22 R 23) f -G}} , where G is oxygen, sulfur or CR ^{2
2 = CR 23, CR 22 =} N, = CR 22 O, a = ^{CR 22} S or ⁼ CR 22 ^{-NR 23.} Preferably, R ⁶ is hydrogen.

R⁷, R⁸, R¹⁰, R¹¹, R¹², R^Fifteen, R¹⁶, R¹⁷, R²⁰, R ²¹ , R²²And R²³Is suitably, independently, hydrogen or C_1-6Archi
It is. R⁹Is suitably hydrogen, C_1-6Alkyl or phenyl C_1-6Alkyl
It is. R¹³, R¹⁴, R¹⁸And R¹⁹Is, independently and independently, C_1-6Al
Kill. a is suitably 1, 2, 3 or 4. a is preferably 2 or 3
More preferably, when B is oxygen, a is 2 or 3;
H₂A is 2; most preferably, when B is oxygen, a is 2
It is. b is suitably 1 or 2. Preferably, b is 1. c and d are suitably independently 0, 1 or 2. e is suitably 2, 3 or 4. f is suitably 0, 1, 2 or 3.

Alternatively, E is suitably represented by formula (b):

Embedded imageIndicated by R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³¹And R³²Is
Suitably, independently, hydrogen or C_1-6Alkyl. R²⁴, R²⁵, R ²⁶ , R²⁷, R²⁸, R²⁹, R³¹And R³²Is preferably hydrogen
You. R³⁰Is suitably hydrogen, C_1-6Alkyl or C_3-7Cycloalkyl
It is. Preferably, R³⁰Is C_1-6Alkyl; more preferably, R^{3 0} Is C_3-6Alkyl; most preferably, R³⁰Is isopropyl. R³³Is suitably hydrogen, C_1-6Alkyl, trifluoromethyl, hydro
Xy or halogen, or R³³And R^{5 '}Together form a group: -K-
Where K is (CR³⁴R³⁵)_iOr K is (CR³⁴R³⁵)_j−
M, where M is oxygen, sulfur, CR³⁴= CR³⁵, CR³⁴= N or N = N
is there. Preferably, R³³Is hydrogen.

J is suitably oxygen, CR ³⁶ R ³⁷ or NR ³⁸ , or J is a group: S (O) _k . Preferably, J is oxygen. Preferably, J is para to L. R ³⁴ , R ³⁵ , R ³⁶ , R ³⁷ and R ³⁸ are suitably, independently, hydrogen or C _1-6 alkyl. g is suitably 1, 2 or 3. Preferably, g is 2 or 3; more preferably, it is 2. h is suitably 1, 2 or 3. Preferably, h is 1. i is suitably 2, 3 or 4. j is suitably 0, 1, 2 or 3. k is suitably 0, 1 or 2.

A preferred sub-group of compounds of formula (I) are compounds of formula (Ia):

Embedded image [Wherein R ^{1 ′} , R ^{2 ′} , R ^{3 ′} , R ^{4 ′} , P ¹ , a ′, L, R ²⁴ , R ²⁵ ,
R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² , R ³³ , J, g and h are as defined above.

Among them, preferred compounds of the present invention are the following compounds: N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3-phenyl- N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3,4-dichlorophenyl) -2-propenamide; N- [ 4-methoxy-3-[(2S)-(1-methyl-2-pyrrolidinyl) methoxy
] Phenyl] -3- (4-methylphenyl) -2-propenamide; N- [4-methoxy-3-[(2S)-(1-methyl-2-pyrrolidinyl) methoxy
] Phenyl] -3- (3,4-dichlorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (4 -Chlorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (3,4-difluorophenyl) -2-propene Amide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2-naphthalenyl) -2-propenamide hydrochloride; N- [3- [ 2- (2,2,6,6-tetramethylpiperidin-1-yl) ethoxy]
-4-methoxy-phenyl] -3- (3,4-dichlorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl]- 3- (3,4-dichlorophenyl) -2-propenamide; N- [1- [2- [bis (1-methylethyl) amino] ethyl] -1,2,3,4-tetrahydroquinol-7-yl ] -3- (3,4-dichlorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (3-chlorophenyl N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (3-chlorophenyl) -2-propenamide; N- [ 3- [2- (cis-2,6-dimethylpiperidin-1-yl) ethoxy] -4
-Methoxyphenyl] -3- (3-chlorophenyl) -2-propenamide; N- [3- [2- (N-cyclohexyl-N-isopropylamino) ethoxy]-
4-methoxy-phenyl] -3- (3-chlorophenyl) -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- ( 4-chlorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (4-chlorophenyl) -2-propenamide; N- [3- [2- (cis-2,6-dimethylpiperidin-1-yl) ethoxy] -4
-Methoxyphenyl] -3- (4-chlorophenyl) -2-propenamide; N- [3- [2- (N-cyclohexyl-N-isopropylamino) ethoxy]-
4-methoxy-phenyl] -3- (4-chlorophenyl) -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methylphenyl] -3- [ (3,4-methylenedioxy) phenyl] -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3-[(3, 4-methylenedioxy) phenyl] -2-propenamide;

N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3-[(3,4-methylenedioxy) phenyl] -2-propenamide; N- [3- [2- (N-cyclohexyl-N-isopropylamino) ethoxy]-
4-methoxy-phenyl] -3-[(3,4-methylenedioxy) phenyl] -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4- Methoxyphenyl] -3- (3,4-difluorophenyl) -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methylphenyl] -3- ( 3,4-difluorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (3,4-difluorophenyl) -2-propenamide; N- [3- [2- (cis-2,6-dimethylpiperidin-1-yl) ethoxy] -4
-Methoxyphenyl] -3- (3,4-difluorophenyl) -2-propenamide; N- [3- [2- (N-cyclohexyl-N-isopropylamino) ethoxy]-
4-methoxy-phenyl] -3- (3,4-difluorophenyl) -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methylphenyl]- 3- (2-naphthalenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (2-naphthalenyl) -2- N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (2-naphthalenyl) -2-propenamide; N- [3- [2 -(N-cyclohexyl-N-isopropylamino) ethoxy]-
4-methoxy-phenyl] -3- (2-naphthalenyl) -2-propenamide; (E) -N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3-chlorophenyl) -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethyl] -2-oxo- (3H
) -Benzoxazol-5-yl] -3- (3,4-dichlorophenyl) -2-propenamide; N- [4- [2- [bis (1-methylethyl) amino] ethyl] -3,4- Dihydro-
3-oxo-2H-1,4-benzoxazin-6-yl] -3- (3,4-dichlorophenyl) -2-propenamide; N- [4- [2- [bis (1-methylethyl) amino] ] Ethyl] -3,4-dihydro-
2H-1,4-benzoxazin-6-yl] -3- (3,4-dichlorophenyl-
2-propenamide; N- [2,3-dihydro-1- [2- [bis (1-methylethyl) amino] ethyl]-
1H-indol-6-yl] -3- (3,4-dichlorophenyl) -2-propenamide; (E) -N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4 -Ethoxy-methoxyphenyl] -3- (5-indolyl) -2-propenamide; (E) -N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl) -3 -(6-Indolyl) -2-propenamide; (E) -...- dimethyl-N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3 -Phenyl-2-propenamide; (Z) -N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl) -.- (acetylamino) -3- (3 , 4-dichlorophenyl) -2-
Propenamide;

N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (3,4-dichlorophenyl)]-2-propenamide; (E)- N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (5,6,7,8-tetrahydronaphth-2-yl) -2-propenamide Trifluoroacetate; N- (spiro [benzofuran-3 (2H), 4′-piperidin] -5-yl) -3- (
3,4-dichlorophenyl) -2-propenamide; N- [1 ′-(isopropyl) spiro [benzofuran-3 (2H) 4′-piperidine
] -5-yl] -3- (3,4-dichlorophenyl) -2-propenamide; (E) -N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxy Phenyl] -3- (4-chloro-3-methylphenyl) -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (4-fluorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- [4- (trifluoromethyl) phenyl ] -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- [3- (trifluoromethyl) phenyl] -2-propene Amide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl ] -3- [3- (trifluoromethyl) phenyl] -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- [ 3- (trifluoromethyl) phenyl] -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2-chlorophenyl)- 2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (2-chlorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (2-chlorophenyl)]-2-propenamide; N- [3- [2- [bis (1-methyl) Ethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2,4-dichlorophene N) [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (2,4-dichlorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (2,4-dichlorophenyl)]-2-propenamide; N- [3- [2 -[Bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2,6-dichlorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) ) Amino] propyl] -4-methoxyphenyl] -3- (2,6-dichlorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4- Methoxyphenyl] -3- (2,6-dichlorophenyl)]-2-propenamide; N- [ - [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3,5-difluorophenyl) -2-propenamide;

N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (3,5-difluorophenyl) -2-propenamide; N- [3 -[3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (3,5-difluorophenyl)]-2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2,5-difluorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] ] Propyl] -4-methoxyphenyl] -3- (2,5-difluorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxy Phenyl] -3- (2,5-difluorophenyl)]-2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2,4-difluorophenyl) -2-propenamide; N- [3- [3- [bis (1 -Methylethyl) amino] propyl] -4-methoxyphenyl] -3- (2,4-difluorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy ] -4-methoxyphenyl] -3- (2,4-difluorophenyl)]-2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl ] -3- (3-Fluorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (3-fluorophenyl ) -2-Propenamide; N- [3- [3- [bis (1-methylethyl) amino] N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] propoxy] -4-methoxyphenyl] -3- (3-fluorophenyl) -2-propenamide -3- (2-chloro-6-fluorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (2 -Chloro-6-fluorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (2-chloro-6- Fluorophenyl)]-2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (4-bromo-2-fluorophenyl)- 2-propenamide; N- [3- [3- [bis (1-methylethyl) a No] propyl] -4-methoxyphenyl] -3- (4-bromo-2-fluorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy]- 4-methoxyphenyl] -3- (4-bromo-2-fluorophenyl)]-2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl ] -3- (4-Chloro-2-fluorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- ( 4-chloro-2-fluorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (4-chloro-2 -Fluorophenyl)]-propenamide;

N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2-chloro-4-fluorophenyl) -2-propenamide; [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (2-chloro-4-fluorophenyl) -2-propenamide; N- [3- [3 -[Bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (2-chloro-4-fluorophenyl) -2-propenamide; N- [3- [2- [bis (1 -Methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2,6-difluorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl ] -4-methoxyphenyl] -3- (2,6-difluorophenyl) -2-prope Amide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (2,6-difluorophenyl)]-2-propenamide; N- [3 -[2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (4-bromophenyl) -2-propenamide; N- [3- [3- [bis (1- Methylethyl) amino] propyl] -4-methoxyphenyl] -3- (4-bromophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4 -Methoxyphenyl] -3- (4-bromophenyl)]-2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- ( 4-chloro-3-nitrophenyl) -2-propenamide; N- [3- [3- [bis (1-meth N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -ethyl) amino] propyl] -4-methoxyphenyl] -3- (4-chloro-3-nitrophenyl) -2-propenamide ] -4-methoxyphenyl] -3- [4- (1-methylethyl) phenyl] -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4- Methoxyphenyl] -3- [4- (1-methylethyl) phenyl] -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl]- 3- [4- (1-methylethyl) phenyl] -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (5 -Bromo-2-methoxyphenyl) -2-propenamide; N- [3- [3- [bis (1- N- [3- [2- [bis (1-methylethyl) amino] ethoxy; tylethyl) amino] propyl] -4-methoxyphenyl] -3- (5-bromo-2-methoxyphenyl) -2-propenamide ] -4-methoxyphenyl] -3-([1,1'-biphenyl] -4-yl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3-([1,1'-biphenyl] -4-yl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy]- 4-methoxyphenyl] -3- (2,3-dihydro-1H-inden-5-yl) -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy]- 4-methoxyphenyl] -3- (3-bromo-4-fluorophenyl) -2-propenamide;

N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (3-bromo-4-fluorophenyl) -2-propenamide; (E) -N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (3-bromo-4-fluorophenyl) -2-propenamide; N- [3- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3,5-dichlorophenyl) -2-propenamide trifluoroacetate; 3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (3,5-dichlorophenyl) -2-propenamide; N- [3- [3- [bis (1-methyl) Ethyl) amino] propoxy] -4-methoxyphenyl] -3- (3,5-dichlorophenyl) ] -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3,4-dimethylphenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (3,4-dimethylphenyl) -2-propenamide; N- [3- [3 -[Bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (3,4-dimethylphenyl) -2-propenamide; N- [3- [2- [bis (1-methyl) Ethyl) amino] ethoxy] -4-methoxyphenyl] -3- (4-cyanophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4- Methoxyphenyl] -3- (4-cyanophenyl) -2-propenamide; N- [3- [3- [bis (1 -Methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (4-cyanophenyl)]-2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -2-fluoro-3-phenyl-2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -2-fluoro -3-phenyl-2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -2-fluoro-3-phenyl-2-propenamide; (E) -N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- [4-chloro-3- (trifluoromethyl) phenyl] -2-
Propenamide; (E) -N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3,4-dichlorophenyl) -.- methyl-2- Propenamide; (E) -N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- [4- (trifluoromethyl) phenyl] -2-propene Amide; N- [3- [2-acetoxy-3- [bis (1-methylethyl) amino] propoxy
] -4-methoxyphenyl] -3- (3,4-dichlorophenyl) -2-propenamide; N- [3- [2- (4-hydroxy-2,2,6,6-tetramethylpiperidine-1)
-Yl) ethoxy] -4-methoxyphenyl] -3- (3,4-dichlorophenyl)-
2-propenamide; N- [1 ′-(1-methylethyl) spiro [benzofuran-3 (2H) 4′-piperidin] -5-yl] -3- (3,5-dichlorophenyl) -2-propenamide ;

N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3-thienyl) -2-propenamide; N- [3- [3 -[Bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (3-thienyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] ] Propoxy] -4-methoxyphenyl] -3- (3-thienyl) -2-propenamide; N- [3- [2- (cis-2,6-dimethylpiperidin-1-yl) ethoxy] -4
-Methoxyphenyl] -3- (3-thienyl) -2-propenamide; N- [3- [2- (N-cyclohexyl-N-isopropylamino) ethoxy]-
4-methoxyphenyl] -3- (3-thienyl) -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methylphenyl] -3- (4 -Pyridinyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (4-pyridinyl) -2-propenamide; N -[3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3-furanyl) -2-propenamide; N- [3- [2- [bis ( 1-methylethyl) amino] ethoxy] -4-methylphenyl] -3- (3-furanyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl]- 4-methoxyphenyl] -3- (3-furanyl) -2-propenamide; N- [3- [2- (cis-2,6 Dimethyl-piperidin-1-yl) ethoxy] -4
-Methoxyphenyl] -3- (3-furanyl) -2-propenamide; N- [3- [2- (N-cyclohexyl-N-isopropylamino) ethoxy]-
4-methoxyphenyl] -3- (3-furanyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (2 -Thienyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (2-thienyl) -2-propenamide; N -[3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2-furanyl) -2-propenamide; N- [3- [2- [bis ( 1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (1H-indol-3-yl) -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ] Ethoxy] -4-methoxyphenyl] -3- (1H-indol-2-yl) -2-propenamide N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (1-methyl-1H-indol-2-yl) -2-propenamide; -[3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (benzo [b] thien-3-yl) -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2-benzofuranyl) -2-propenamide; and N- [3- [2- [bis (1-methyl) Ethyl) amino] ethoxy] -4-methoxyphenyl] -3- (benzo [b] thien-2-yl) -2-propenamide.

Among them, more preferred compounds of the present invention are the following compounds: N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3-phenyl N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3,4-dichlorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (3,4-difluorophenyl) -2-propenamide; N- [3- [2- [ Bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2-naphthalenyl) -2-propenamide hydrochloride; N- [3- [2- (2,2,6,6- Tetramethylpiperidin-1-yl) ethoxy]
-4-methoxy-phenyl] -3- (3,4-dichlorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl]- 3- (3,4-dichlorophenyl) -2-propenamide; N- [1- [2- [bis (1-methylethyl) amino] ethyl] -1,2,3,4-tetrahydroquinol-7-yl ] -3- (3,4-dichlorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (3-chlorophenyl N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (4-chlorophenyl) -2-propenamide; N- [ 3- [2- (N-cyclohexyl-N-isopropylamino) ethoxy]-
4-methoxy-phenyl] -3- (4-chlorophenyl) -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- ( 3,4-difluorophenyl) -2-propenamide; N- [3- [2- (cis-2,6-dimethylpiperidin-1-yl) ethoxy] -4
-Methoxyphenyl] -3- (3,4-difluorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (2-naphthalenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (2-naphthalenyl) -2-propenamide N- [3- [2- (N-cyclohexyl-N-isopropylamino) ethoxy]-
4-methoxy-phenyl] -3- (2-naphthalenyl) -2-propenamide; (E) -N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3-chlorophenyl) -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethyl] -2-oxo- (3H
) -Benzoxazol-5-yl] -3- (3,4-dichlorophenyl) -2-propenamide; N- [4- [2- [bis (1-methylethyl) amino] ethyl] -3,4- Dihydro-
3-oxo-2H-1,4-benzoxazin-6-yl] -3- (3,4-dichlorophenyl) -2-propenamide; N- [2,3-dihydro-1- [2- [bis ( 1-methylethyl) amino] ethyl]-
1H-indol-6-yl] -3- (3,4-dichlorophenyl) -2-propenamide; (E) -N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4 -Methoxyphenyl] -3- (5,6,7,8-tetrahydronaphth-2-yl) -2-propenamide trifluoroacetate;

N- [1 ′-(isopropyl) spiro [benzofuran-3 (2H) 4′-piperidine
] -5-yl] -3- (3,4-dichlorophenyl) -2-propenamide; (E) -N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxy Phenyl] -3- (4-chloro-3-methylphenyl) -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3,5-difluorophenyl) -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (4-bromophenyl)- 2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3-bromo-4-fluorophenyl) -2-propenamide; (E) -N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] 3- (3,5-dichlorophenyl) -2-propenamide trifluoroacetate; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (3 , 5-Dichlorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (3,5-dichlorophenyl)]-2 -Propenamide; N- [3- [2-acetoxy-3- [bis (1-methylethyl) amino] propoxy
] -4-methoxyphenyl] -3- (3,4-dichlorophenyl) -2-propenamide; N- [3- [2- (4-hydroxy-2,2,6,6-tetramethylpiperidine-1)
-Yl) ethoxy] -4-methoxyphenyl] -3- (3,4-dichlorophenyl)-
2-propenamide; and N- [1 '-(1-methylethyl) spiro [benzofuran-3 (2H) 4'-piperidin] -5-yl] -3- (3,5-dichlorophenyl) -2-propene Amides.

Among them, the most preferred compounds of the present invention are the following compounds: N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- ( 3,4-dichlorophenyl) -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2-naphthalenyl) -2-propene Amide hydrochloride; N- [3- [2- (2,2,6,6-tetramethylpiperidin-1-yl) ethoxy]
-4-methoxy-phenyl] -3- (3,4-dichlorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl]- 3- (3,4-dichlorophenyl) -2-propenamide; N- [3- [2- (4-hydroxy-2,2,6,6-tetramethylpiperidine-1)
-Yl) ethoxy] -4-methoxyphenyl] -3- (3,4-dichlorophenyl)-
2-propenamide; and N- [1 '-(1-methylethyl) spiro [benzofuran-3 (2H) 4'-piperidin] -5-yl] -3- (3,5-dichlorophenyl) -2-propene Amides.

Among them, the compounds excluded from the present invention are the following compounds: N- [4-methoxy-3-[(2S)-(1-phenylmethyl-2-pyrrolidinyl)
Methoxy] phenyl] -3- (3,4-dichlorophenyl) -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- ( 3,4-methylenedioxyphenyl) -2-propenamide; N- [3- [2- (cis-2,6-dimethylpiperidin-1-yl) ethoxy] -4
-Methoxyphenyl] -3- (3,4-methylenedioxyphenyl) -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methylphenyl]- 3- (4-chlorophenyl) -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3-pyridinyl) -2- N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (3-pyridinyl) -2-propenamide; N- [3- [3 -[Bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (3-pyridinyl) -2-propenamide; N- [3- [2- (cis-2,6-dimethylpiperidine) -1-yl) ethoxy] -4
-Methoxyphenyl] -3- (3-pyridinyl) -2-propenamide; N- [3- [2- (N-cyclohexyl-N-isopropylamino) ethoxy]-
4-methoxyphenyl] -3- (3-pyridinyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (4 -Pyridinyl) -2-propenamide; N- [3- [2- (cis-2,6-dimethylpiperidin-1-yl) ethoxy] -4
-Methoxyphenyl] -3- (1H-imidazol-4-yl) -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methylphenyl] -3 -(3-pyridinyl) -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (4-pyridinyl) -2-propene Amide; N- [3- [2- (cis-2,6-dimethylpiperidin-1-yl) ethoxy] -4
-Methoxyphenyl] -3- (4-pyridinyl) -2-propenamide; N- [3- [2- (N-cyclohexyl-N-isopropylamino) ethoxy]-
4-methoxyphenyl] -3- (4-pyridinyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (3 -Furanyl) -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2-thienyl) -2-propenamide; N -[3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methylphenyl] -3- (2-thienyl) -2-propenamide; N- [3- [2- (cis- 2,6-dimethylpiperidin-1-yl) ethoxy] -4
-Methoxyphenyl] -3- (2-thienyl) -2-propenamide; N- [3- [2- (N-cyclohexyl-N-isopropylamino) ethoxy]-
4-methoxyphenyl] -3- (2-thienyl) -2-propenamide; and N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- ( 1H-Imidazol-4-yl) -2-propenamide.

Known compounds that overlap with the scope of the invention include the following: E is (a); B is meta to L; B- (CR¹R²)_a-NR ³ R⁴Is O- (CH₂)₃-N (CH₃)₂L is CONH; R⁵, R ⁶ , R^{1 '}, R^{2 '}, R^{3 '}And R^{4 '}Is hydrogen; P¹Is phenyl
Are subordinate compounds of formula (I). Further known sub-compounds of formula (I) are those wherein E is (a);
In the para position; B- (CR¹R²)_a-NR³R⁴Is S- (CH₂)₃-N (CH₃) ₂ L is CONH; R⁵, R⁶, R^{1 '}, R^{2 '}, R^{3 '}And R ^{4 '} Is hydrogen; P¹Is a compound wherein is phenyl. Still further known compounds of the subgroup of formula (I) are those wherein E is (a);
CR¹R²)_a-NR³R⁴Is ortho to L; B is CH₂, NCH
₃, Oxygen, S or SO₂And R¹And R²Is hydrogen or methyl;
a is 0-4; R³And R⁴Is independently hydrogen, C 1-3 alkyl,
Or R³And R⁴Together with the nitrogen to which they bind
Pyrrolidinyl, piperidinyl, morpholino and (4-methyl-1-piperazini)
), (4-phenyl-1-piperazinyl), [4- (2-methoxyphenyl) -1
-Piperazinyl], [4- (4-methoxyphenyl) -1-piperazinyl] or [(
4-fluorophenyl) -1-piperazine] ring; NR³R⁴Met, too
Exists as a chloride quaternary salt;⁵Is hydrogen, methyl, acetyl, trifluoro
L is nitro, nitro, methoxy or chloro; L is CONR^{5 '}R^{3 '}But
Hydrogen; R^{4 '}Is hydrogen or C_1-4Alkyl; R^{5 '}Is hydrogen or
C1-2 alkyl; P¹Is phenyl or 2-thienyl; R^{1 '} And R^{2 '}Independently represent hydrogen, methyl, trifluoromethyl, methoxy,
Compounds that are fluoro or chloro, all of which are U.S. Patents
No. 3,167,556 (issued January 25, 1965); U.S. Pat. No. 3,201,4
No. 01 (issued on August 17, 1965), GB1099829 (January 1, 1968)
7) and Krapcho et al., J. Med. Chem. 1969, 12, 164-6.
Described as 5-HT inhibitors and reported to have 5-HT inhibitory activity
Japanese Patent Application Laid-Open No. 05-255291 (published October 5, 1993)
It is reported to have a lucium antagonist activity.

E is (a); B is para to L; B- (CR¹R²)_aNR³ R⁴Is O- (CH₂)₂-N (Et)₂L is CONH; R^{1 '}Is 5-
Nitro; R⁵, R⁶, R^{2 '}, R^{3 '}And R^{4 '}Is hydrogen; P¹ Wherein R is 2-furyl, is disclosed in JP-A-45-006533 (197).
(Published March 5, 2004) and reported to have anticancer activity. E is (a); B is para to L; B- (CR¹R²)_aNR³ R⁴Is O-CH₂CH (OH) CH₂-NH-tert-butyl; L is CONH
And R⁶, R^{1 '}, R^{2 '}, R^{3 '}, R^{4 '}And R^{5 '}Is hydrogen; R ⁵ Is 3-ethyl; P¹Is phenyl, the compound of formula (I) is ZA68
05360 (February 19, 1970) and is described as adrenergic
It is reported to have blocking activity. E is (a); B is in L position relative to; B- (CR¹R²)_aNR³R⁴ Is O- (CH₂)₂-(1-pyrrolidine); L is CONH; R^{2 '}, R ^{3 '} , R^{4 '}And R⁶Is hydrogen; R⁵Is 3,5-dimethyl; R^{1 '}
Is 2-methyl; P¹Is phenyl, as antiarrhythmic, of the formula (I)
The compounds are described in DE 4036782 (May 21, 1992).

[0048] There at E is (c); Q is in the ortho position with respect to ^{L; Q- (CR 39 R 40} ) l -R 41 is located at the (CH _{2) 2} -3- (2- piperidinyl) R ⁴⁷ is methyl or ethyl; R ⁴² is hydrogen or methoxy; R ⁴³ , R ^{1 ′} , R ^{2 ′} and R ^{3 ′} are hydrogen; L is CONR ^{5 ′} ; R ^{4 ′} and A sub-group of compounds of formula (I), as anti-serotonin agents, wherein R ^{5 '} is independently hydrogen or methyl; P ¹ is phenyl, is disclosed in US Pat. No. 3,931,195 (1976) (Jan. 6, Jan.) and U.S. Pat. No. 4,000,143 (Dec. 28, 1976). E is (g); R ⁷¹ is meta to L; R ⁷¹ is (C0-1 alkyl-1-piperazine); R ⁷² is 4-methoxy; R ^{1 ′} is bromo A 5-HT1D receptor, wherein R ⁷³ , R ^{2 ′} , R ^{3 ′} and R ^{4 ′} are hydrogen; L is CONH; P ¹ is phenyl or 3-thienyl. Compounds of the sub-group of formula (I) as antagonists are described in International Patent Application WO 95/06044, published March 2, 1995.

Formulation of Pharmaceutical Compositions The pharmaceutically active compounds of the present invention (and their pharmaceutically acceptable salts) have the formula (I)
Compounds ("active ingredients") for asthma and atopic diseases (eg, atopic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, sarcoidosis and other fibrotic diseases, psoriasis, autoimmune diseases For example, in an amount sufficient to treat multiple sclerosis, inflammatory bowel disease, CORD and HIV infection.
It is administered in a standard dosage form prepared by combining it with a standard pharmaceutical carrier or diluent according to conventional procedures well known in the art. These operations include mixing, granulating, compressing or dissolving the ingredients as appropriate to provide the desired formulation. The pharmaceutical carrier employed can be, for example, either a solid or liquid. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin,
Gum arabic, magnesium stearate, stearic acid and the like. Examples of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include time delay material well known in the art, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.

A wide variety of pharmaceutical forms can be used. Thus, if a solid carrier is used, the preparation may be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25 mg to about 1000 mg. If a liquid carrier is used, the preparation will be in the form of a sterile injectable solution or non-aqueous liquid suspension such as a syrup, emulsion, soft gelatin capsule, ampoule and the like. The active ingredient can also be administered locally to a mammal in need of treatment or prevention of a CCR5-mediated condition. The amount of active ingredient required for therapeutic action with topical administration will, of course, vary with the compound selected, the nature and severity of the condition being treated, the mammal being treated, and ultimately at the discretion of the consulting physician. It is determined. A suitable dosage for the active ingredient is 1.5 mg to 500 mg for topical administration, the most preferred dosage is 1 mg to 100 mg, for example 5 to 25 mg administered twice or three times a day. Topical administration means non-systemic administration, epidermal application of the active ingredient, topical application to the oral cavity,
And the injection of such compounds into the ear, eye and nose, where the compounds do not significantly enter the bloodstream. By systemic administration is meant oral, intravenous, intraperitoneal and intramuscular administration.

If the active ingredient can be administered alone as the raw chemical, it is preferable to administer it as a pharmaceutical formulation. For topical administration, the active ingredient may be incorporated at 0.001% to 10% w / w, for example 1% to 2% by weight of the formulation.
% W / w may be contained in a large amount, but preferably does not exceed 5% w / w of the preparation, more preferably 0.1% to 1% w / w. The topical formulations of the present invention comprise, for both veterinary and human pharmaceutical uses, one or more acceptable carriers together with the active ingredients, optionally containing other therapeutic ingredients. Is also good. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and must not be harmful to its recipients. Formulations suitable for topical administration are liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation, such as liniment, lotion, cream, ointment or paste, and suitable for administration to the eye, ear or nose Drops are included. Drops of the invention may include sterile aqueous or oily solutions or suspensions, the active ingredient containing a bactericide and / or fungicide and / or other suitable preservative, preferably a surfactant. It is prepared by dissolving in a suitable aqueous or alcoholic solution. The resulting solution is then clarified by filtration, transferred to a suitable container, sealed, autoclaved, or sterilized by maintaining at 98-100 ° C for half an hour. Alternatively, the solution may be sterilized by filtration and transferred to the container by aseptic technique. Fungicides or fungicides suitable for incorporation into drops, for example, phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%) Is mentioned. Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.

The lotions of the present invention include those suitable for application to the skin or eyes. Ophthalmic lotions contain a sterile aqueous solution optionally containing a bactericide and are prepared in a manner similar to the preparation of drops. Lotions or liniments for application to the skin may further comprise agents that promote drying and cooling of the skin, such as alcohol or acetone, and / or humectants such as glycerol or oils such as castor oil or peanut oil. The creams, ointments or pastes according to the invention are semisolid formulations of the active ingredient which are suitable for topical application. These are prepared by mixing the active ingredient in finely divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with a greasy or non-greasy base using a suitable machine. It is prepared by Bases are hydrocarbons, for example, solid, soft or liquid paraffin, glycerol, beeswax, metal soaps; slurries; oils of natural sources such as almonds, corn, peanuts, castor or olive oil; wool fat or derivatives thereof, or Fatty acids, such as stearic acid or oleic acid, may be included with the alcohol, for example, propylene glycol. The formulation may include a suitable surfactant such as an anionic, cationic or non-ionic surfactant such as an ester or a polyoxyethylene derivative thereof.
It may contain suspending agents such as natural gums, cellulose derivatives or inorganic substances such as siliceous silica and other ingredients such as lanolin.

The active ingredients can also be administered by inhalation. "Inhalation" means intranasal and oral inhalation administration. Dosage forms suitable for such administration, such as an aerosol formulation or a metered dose inhaler, can be prepared by conventional techniques. The daily dose of the active ingredient administered by inhalation is about 0.1 mg to 100 mg per day,
Preferably about 1 mg to about 10 mg per day. In one aspect, the present invention relates to a method comprising:
Asthma and atopic disorders (eg, atopic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, sarcoidosis and other fibrosis-type diseases, psoriasis, autoimmune diseases such as multiple sclerosis, inflammatory bowel The present invention relates to a method for treating diseases, CORD and HIV infection, which comprises administering to such a mammal an effective amount of a CCR5 receptor modulator, in particular a compound of formula (I).

The term “treatment” refers to prophylactic or therapeutic treatment. Such compounds of formula (I) can be administered to such mammals in conventional dosage forms prepared by combining the compounds of formula (I) with conventional pharmaceutically acceptable carriers or diluents according to known techniques. Can be administered. Those of skill in the art will understand that the form and properties of a pharmaceutically acceptable carrier or diluent are determined by the dosage of the active ingredients to be combined, the route of administration and other well-known variables. The compound of formula (I)
A mammal in need of treatment for an intervening disease is administered in an amount sufficient to reduce the symptoms associated with these conditions. The route of administration can be oral or parenteral. The term parenteral as used herein includes intravenous, intramuscular, subcutaneous, rectal, vaginal or intraperitoneal administration. In general, parenteral administration in subcutaneous and intramuscular forms is preferred. The daily parenteral dosage is preferably from about 30 mg to about 300 m / day.
g of active ingredient. The daily oral dose is preferably about 1 day.
It will consist of from 00 mg to about 2000 mg of active ingredient.

The optimal amount of the compound of formula (I) and the interval between individual administrations will be determined by the nature and extent of the condition to be treated, the mode of administration, the route and site of administration, and the particular mammal to be treated. One skilled in the art will appreciate that such optimal amounts can be determined by routine methods. Further, the optimal method of treatment, i.e., the dosage of the compound of formula (I) administered daily during a given period of time, can be ascertained by a person skilled in the art using routine treatment decision tests. it is obvious.

Methods of Preparation The compounds of formula (I) are optionally substituted 3-aryl or heteroaryl-2-
Propenoic acid is prepared by condensation with an appropriately substituted aniline using methods known in the art. The compounds are commercially available or are synthesized from commercially available starting materials by methods known in the art. For example, reacting an appropriately substituted 3-aryl or heteroaryl-2-propenoic acid with a suitable reagent, such as thionyl chloride, at a suitable temperature, for example, reflux, to form a 3-aryl or heteroaryl-2-propenoyl chloride. And the 3-aryl or heteroaryl-2-propinoyl chloride is condensed with an appropriately substituted aniline in the presence of a suitable base, for example diisopropylethylamine, in a suitable solvent, for example dichloromethane, to give the compound of the formula (I ) Is obtained. Many additional methods for converting carboxylic acids to amides are known and can be found in standard reference books, such as "Compendi
um of Organic Synthetic Methods ”, Volume I-VI (published by Wiley-Interscience)
Can be seen.

The compounds of the present invention were also prepared using solid phase chemistry as shown in Scheme I and the general methods described in International Patent Application WO 99/01127 (published Jan. 14, 1999). An optionally substituted 3- [2- (alkylamino) ethoxy] aniline I-2, synthesized from commercially available 2-methoxy-5-nitrophenol I-1, for example, according to the procedure described in WO 99/01127. Using 3- [2- (diisopropylamino) ethoxy] -4-methoxyaniline in a suitable solvent, such as dimethylformamide containing 1% acetic acid, using a suitable reducing agent, such as sodium triacetoxyborohydride, By subjecting it to reductive amination, Boojamra
(J. Org. Chem. 1995, 60, 5742-3) obtained according to the general protocol of Merrifield resin-bound aldehyde 1-3.
To obtain 1-4. The resin-bound aniline I-4 can be commercially available, for example, using N-bromosuccinimide and triphenylphosphine in dichloromethane or in combination with dimethylformamide in the presence of an organic base such as pyridine or 3-aryl- or heteroaryl-2-propenoic acid I-5 which can be synthesized, for example,
Acylation with 3- (3,4-dichlorophenyl) -2-propenoic acid gives I-6. For example, I-4 can be replaced by a 10-fold excess of 3-aryl- or heteroaryl-
Reaction with an equimolar mixture of 2-propenoic acid, triphenylphosphine and N-bromosuccinimide in a suitable solvent, for example dichloromethane, followed by 1
A 0-fold excess of a suitable base, such as pyridine, is added and the mixture is left for a suitable time.
For example, gently stirring for 48 hours to obtain resin-bound amide I-6. If desired, dimethylformamide can be added to the resulting mixture to increase the solubility of the 3-aryl- or heteroaryl-2-propenoic acid. Alternatively, I-5 may be converted to the acid chloride by heating with thionyl chloride, and the acid chloride may be condensed with I-4 to give I-6. I-6 is reacted with a suitable acid in a suitable solvent, for example trifluoroacetic acid: dichloromethane: water (50: 48: 2), to give a compound of formula (I), 3-aryl- or hetero- Aryl-2-propenamide I-7 is obtained.

[0058]

Embedded image Scheme I:

(A) Cl (CH ₂ ) ₂ NR ³ R ⁴ , K ₂ CO ₃ , CH ₃ COCH ₃ ; (b) H ₂ ,
5% Pd / C, MeOH; (c) Maryfield resin-bound aldehyde (3), N
_{aBH (OAc) 3, 1%} HOAc / DMF; (d) 3- aryl - or heteroaryl-2-propenoic acid, N- bromosuccinimide, _Ph 3 P, pyridine, C
H ₂ Cl ₂ ; (e) TFA, CH ₂ Cl ₂ , H ₂ O

The present invention will be described with reference to the following examples. It is only an example and does not limit the scope of the invention. In the examples, mass spectrometry was performed on a VG Zab mass spectrometer using fast atom bombardment, unless otherwise specified.

Examples Preparation Example 1 Preparation of 4-methoxy-3- [2- (2,2,6,6-tetramethylpiperidin-1-yl) ethoxy] aniline a) 4-methoxy-1-nitro -3- [2- (2,2,6,6-tetramethylpiperidin-1-yl) ethoxy] benzene 3- (2-bromoethoxy) -4-methoxy-1-nitrobenzene (Mutai et al.
Tetrahedron, 1984, 40, 755) (3 g, 11 mmol) and 2,2,
Sodium iodide (1.65 g, 11 mmol) of 6,6-tetramethylpiperidine (23 g, 163 mmol) and potassium carbonate (2.4 g, 17 mmol)
The solution in dimethylformamide (60 mL) was stirred and heated to 110 ° C. for 16 hours. The mixture was cooled, diluted to 350 mL with dichloromethane, filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with ethyl acetate (350 mL) and water (40 m
Partitioned between L), the organic phase was washed with water (3 × 40 mL), dried (Na ₂ SO ₄₎
And concentrated under reduced pressure, and the residue was purified by flash chromatography (silica gel, dichloromethane, followed by 2% methanol / dichloromethane-0.1% ammonia). The fractions containing the title compound are combined, concentrated under reduced pressure,
The residue was purified by flash chromatography (silica gel, 50% ethyl acetate / hexane) to give the title compound. MS (ES) m / e 337 [M + H] ^< +>.
b) 4-methoxy-3- [2- (2,2,6,6-tetramethylpiperidin-1-yl) ethoxy] aniline The compound of Preparation 1 (a) (0.57 g, 1.7 mmol), A mixture of 5% palladium on carbon (0.40 g) and methanol (100 mL) was added under a hydrogen atmosphere (
Shake at 50 psi) for 3 hours, degas, filter and concentrate the filtrate under reduced pressure to give the title compound. MS (ES) m / e 307 [M + H] ^< +>.

Preparation Example 2 Preparation of 4-methoxy-3- [2- (4-hydroxy-2,2,6,6-tetramethylpiperidin-1-yl) ethoxy] aniline 2,2,6,6-tetra 4-hydroxy-2,2,6, instead of methylpiperidine
The title compound was obtained according to the procedure of Preparation Example 1 (a)-(b) except that 6-tetramethylpiperidine was used.

Preparation Example 3 6-amino-4- [2- [bis (1-methylethyl) amino] ethyl] -2H-1,4
Preparation of -benzoxazin-3 (4H) -one a) 4- [2- [bis (1-methylethyl) amino] ethyl] -6-nitro-2H-1
, 4-Benoxazin-3 (4H) -one sodium hydride (0.97 g of a 60% dispersion in mineral oil, 24 mmol) was added to 6
-Nitro-2H-1,4-benzoxazin-3 (4H) -one (J. Med. Chem.
(1989, 32, 1627-1630) (4.3 g, 22 mmol) in tetrahydrofuran (100 mL) was added portionwise at room temperature to give a yellow heterogeneous mixture. 2- (diisopropylamino) ethyl chloride hydrochloride in water (80 mL)
And sodium carbonate was added until the solution was saturated. The free amine was extracted with toluene (2 × 35 mL), the toluene extract was dried (MgSO ₄ ) and added dropwise to the sodium salt described above. The resulting mixture was heated at reflux for 4 hours, cooled, quenched with water (100 mL) and extracted with ethyl acetate (2 × 100 mL). The organic layers were combined, washed with brine, dried (MgSO _4), and concentrated under reduced pressure. The crude product was triturated with hexane to give the title compound (4.4g, 62%) as an off-white powder. MS (ES) m / e 322.1 [M + H] ^< +>.

B) 6-amino-4- [2- [bis (1-methylethyl) amino] ethyl] -2H-1
, 4-Benoxazin-3 (4H) -one 5% palladium on carbon (0.8 g) was prepared using the compound of Preparation 3 (a) (1.0 g, 3.0 g).
1 mmol) and ethanol (25 mL). The resulting mixture was hydrogenated at 50 psi for 1 hour. The mixture was then filtered through a bed of celite and concentrated under reduced pressure to give the title compound as a white crystalline solid (0.55 g, 61%)
I got MS (ES) m / e 292.1 [M + H] ^< +>.

Preparation Example 4 6-Amino-2,3-dihydro-N, N-bis (1-methylethyl) -4H-1,4
Preparation of -benzoxazine-4-ethanamine a) 2,3-dihydro-N, N- [bis (1-methylethyl) -6-nitro-4H-
1,4-benzoxazine-4-ethanamine boron trifluoride etherate (3.2 mL, 3.5 g, 25 mmol)
Sodium borohydride (0.71 g, 14 mmol) in tetrahydrofuran (4
(5 mL) to the suspension. The heterogeneous mixture was stirred at room temperature for 1 hour, reacted with a solution of the compound of Preparation 3 (a) (2.0 g, 6.2 mmol) in tetrahydrofuran (30 mL), and the mixture was heated at reflux for 2.5 hours. Heat for 5 hours. The mixture was cooled to room temperature, excess reagent was quenched with saturated sodium bicarbonate, and the mixture was concentrated under reduced pressure. The residue was ethanol (20 mL) and 3
Dissolved in N hydrochloric acid (20 mL) and heated at reflux for 1 hour. The mixture was basified with 10% sodium carbonate and extracted with ethyl acetate (2 × 100 mL). The organic layers were combined, washed with brine, dried (MgSO ₄₎ to give the title compound as a yellow oil and concentrated (1.7g, 89%). MS (ES) m / e 308.1 [M + H] ^< +>.

B) 6-amino-2,3-dihydro-N, N-bis (1-methylethyl) -4H-1
, 4-Benoxazine-4-ethaneamine The title compound was obtained according to the procedure of Preparation Example 3 (b) except for using the compound of Preparation Example 4 (a) instead of the compound of Preparation Example 3 (a).

Preparation Example 5 Preparation of 5-amino-3- [2- [bis (1-methylethyl) amino] ethyl] -2 (3H) -benzoxazolone 6-nitro-2H-1,4-benzoxazine- 5 instead of 3 (4H) -one
The title compound was obtained according to the procedure of Preparation Example 3 (a)-(b), except that -nitro-2 (3H) -benzoxazolone (WO95 / 32967) was used.

Preparation Example 6 Preparation of 7-amino-3,4-dihydro-N, N-bis (1-methylethyl) -1 (2H) -quinolinethanamine a) 3,4-dihydro-N, N- Bis (1-methylethyl) -7-nitro-1 (2H)
-Quinolineethanamine Sodium carbonate (2.9 g, 27 mmol) was converted to 7-nitro-1,2,3,4-tetrahydroquinoline (U.S. Pat. No. 5,696,133) (1.2 g, 6.7 mmol), -(Diisopropylamino) ethyl chloride hydrochloride (4.0 g, 20 mmol) and a mixture of ethanol (25 mL). Mix at reflux temperature
Heated for hours, filtered and then concentrated under reduced pressure. The crude product was purified by chromatography (silica gel, dichloromethane then eluted with 5% methanol / dichloromethane) to give the title compound as a yellow oil (1.4 g, 68%).
MS (ES) m / e 306.1 [M + H] ^< +>.

B) 7-amino-3,4-dihydro-N, N-bis (1-methylethyl) -1 (2H)
-Quinolineethaneamine The title compound was obtained according to the procedure of Preparation 3 (b) except for using the compound of Preparation 6 (a) instead of the compound of Preparation 3 (a).

Preparation 7 Preparation of 6-amino-2,3-dihydro-N, N-bis (1-methylethyl) -1H-indole-1-ethanamine 7-nitro-1,2,3,4-tetrahydro Preparation Example 6 (a)-(b) except that 2,3-dihydro-6-nitro-1H-indole was used instead of quinoline.
The title compound was obtained according to the procedure described in (2).

Preparation Example 8 Preparation of N- [1 ′-(1-methylethyl) spiro [benzofuran-3 (2H), 4′-piperidin] -5-amine a) 5- and 7-Nitrospiro [benzofuran-3 (2H), 4'-piperidine] 1'-methyl-5- and 7-nitrospiro [benzofuran-3 (2H), 4'-
Piperidine] (WO 96/11934) (3 g, 12 mmol) and diisopropylethylamine (2.5 g, 19 mmol) in 1,2-dichloroethane (80
solution at room temperature in 1-chloroethyl chloroformate (2.3 g, 16 mmol)
And stirred for 1 hour and heated at reflux for 20 minutes. The mixture is cooled, concentrated under reduced pressure, the residue is dissolved in methanol, heated at reflux for 2 hours, concentrated under reduced pressure, and the residue is diluted between dichloromethane (250 mL) and 5% sodium bicarbonate (50 mL). Distributed. The organic phase was washed with 5% sodium bicarbonate (50 mL) and the combined aqueous phases were extracted with dichloromethane (2 × 50 mL). The combined organic phases were dried (Na ₂ SO ₄ ) and concentrated to give the title compound (2.65 g).

B) 1 ′-(tert-butoxycarbonyl) -5-nitrospiro [benzofuran-3 (
2H), 4'-piperidine] A solution of the compound of Preparation 8 (a) (2.65 g, 1.13 mmol) in tetrahydrofuran (300 mL) was prepared from di-tert-butyl dicarbonate (2.6 g, 12 mmol).
And stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and the residue was crystallized from methanol to give the title compound (2.1 g).

C) 5-Nitrospiro [benzofuran-3 (2H), 4′-piperidine] The compound of Preparation Example 8 (b) (2.1 g, 6.3 mmol) in dichloromethane (50
) and a solution in trifluoroacetic acid (10 mL) were kept at room temperature for 5 hours, concentrated under reduced pressure, and the residue was partitioned between dichloromethane (300 mL) and 5% sodium bicarbonate. The organic phase was washed with 5% sodium bicarbonate and the combined aqueous washes were extracted with dichloromethane. The combined organic phases were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give the title compound (1.45g). MS (ES) m / e 235.1 [
M + H] ⁺ .

D) 1 ′-(1-methylethyl) -5-nitrospiro [benzofuran-3 (2H), 4
'-Piperidine] The compound of Preparation Example 8 (c) (1.45 g, 6.2 mmol), potassium carbonate powder (
A mixture of 0.86 g (6.2 mmol) and dimethylformamide (50 mL) containing 2-iodopropane (1.1 g, 6.4 mmol) was stirred, heated at 50 ° C. for 4 hours, and treated with 2-iodopropane ( (0.17 g, 1 mmol) at 50 DEG C. for 90 minutes, followed by 2-iodopropane (0.1 g, 1 mmol) at 50 DEG C. for 2 hours. The mixture was concentrated under reduced pressure and the residue was taken up in ethyl acetate (200 mL)
And water (20 mL). The organic phase is washed, dried (MgSO ₄ )
After concentration under reduced pressure, the residue was subjected to chromatography (silica gel, 5% methanol / dichloromethane) to obtain the title compound (0.85 g).

E) N- [1 ′-(1-methylethyl) spiro [benzofuran-3 (2H), 4′-piperidin] -5-amine Preparation Example 8 (d) (0.78 g, 2.8 mmol) ), 10% palladium on carbon (
0.375 g) in methanol (250 mL).
sha) for 40 minutes, filtered and concentrated under reduced pressure to give the title compound (0.6 g).

Preparation Example 9 Preparation of 3- [2-acetoxy-3- (diisopropylamino) propoxy] -4-methoxyaniline a) 4-methoxy-3- (oxiranyl) methoxy-1-nitrobenzene 3-chloroperbenzoic acid (11 mmol) in dichloromethane (50 mL) was treated with 1-methoxy-4-nitro-2- (2-propenyloxy) benzene (Molina
Was added dropwise to a solution of Tetrahedron Lett., 1992, 33, 2387-90) (2 g, 9.6 mmol) in dichloromethane (50 mL) and stirred at room temperature for 6 days.
The mixture was washed with 5% sodium sulfite (35 mL), then with 5% sodium bicarbonate. The organic phase was dried (MgSO ₄ ), concentrated under reduced pressure, and the residue was crystallized from ethanol (50 mL) to give the title compound (1 g) as a yellow solid.

B) 3- [3-Diisopropylamino-2- (hydroxy) propoxy] -4-methoxy-1-nitrobenzene The compound of Preparation 9 (a) (1 g, 4.4 mmol) and diisopropylamine (5. 7 g (44 mmol) in 50 mL of ethanol at 50 ° C.
Heat for 5 hours, cool and hold at room temperature for 16 hours, heat to 50 ° C. for 6 hours, cool,
Concentration under reduced pressure gave the title compound as a yellow oil (1.4 g). MS (ES)
m / e 327.0 [M + H] ⁺ .

C) 3- [2-acetoxy-3- (diisopropylamino) propoxy] -4-methoxy-1-nitrobenzene The compound of Preparation 9 (b) (1.4 g, 4.2 mmol) and diisopropylethylamine ( A solution of 0.57 g (4.4 mmol) in dichloromethane (50 mL) was reacted with acetyl chloride (0.35 g, 4.4 mmol) at room temperature and stirred for 16 hours. The mixture was washed with 5% sodium carbonate, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was chromatographed (silica gel, 3% methanol / dichloromethane), the fractions containing the title compound were collected, concentrated under reduced pressure and again chromatographed (silica gel, 1% methanol / dichloromethane) to give the title compound ( 0.9 g). MS (ES) m / e 369.0 [M
+ H] ⁺ .

D) 3- [2-acetoxy-3- (diisopropylamino) proxy] -4-methoxyaniline 10% palladium on carbon of the compound of Preparation 9 (c) (0.27 g, 0.73 mmol) (0.1 g) in a solution of methanol (50 mL) in a hydrogen atmosphere (40 mL).
psi) was shaken at room temperature for 1 hour. The mixture was filtered and concentrated under reduced pressure to give the title compound. MS (ES) m / e 339.0 [M + H] ^< +>.

Preparation Example 10 Preparation of (S) -2-[(2-methoxy-5-nitrophenoxy) methyl] pyrrolidine (S) -1- (tert-butoxycarbonyl) -2-pyrrolidinemethanol (28.
2 g, 0.14 mol) and 2-methoxy-5-nitrophenol (24.1 g,
0.14 mol) was stirred in anhydrous tetrahydrofuran (1.5 L). Triphenylphosphine (36.7 g, 0.14 mol) was added, the mixture was stirred, cooled to 10 ° C. in an ice bath and the reaction temperature kept below 25 ° C., while diethyl azodicarboxylate ( 24.4 g, 0.14 mol) were added over 30 minutes. The mixture is then left at room temperature for 16 hours, concentrated under reduced pressure and the residue is diluted with dichloromethane (1500
ml) and washed with 10% aqueous sodium hydroxide and water. The organic phase was dried (Na ₂ SO ₄ ), filtered and the filtrate was trifluoroacetic acid (100 mL)
And left at room temperature for 16 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in diethyl ether (1.5L). The ether solution was thoroughly extracted with 10% hydrochloric acid, the aqueous phase was washed with ether and made basic with 40% aqueous sodium hydroxide. The product is extracted into ether, the ether solution is washed with water and dried (Na ₂
SO ₄ ) and concentrated under reduced pressure to give the title compound (24.48 g, 70% yield) as a yellow solid. MS (ES) m / e 253 [M + H] ^< +>.

Example 1 Preparation of N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3,4-dichlorophenyl) -2-propenamide A solution of 3,4-dichlorocinnamoyl chloride (0.2 g, 0.85 mmol) prepared from 2,4-dichlorocinnamic acid and thionyl chloride in dichloromethane (10 mL) was treated with 3- [2- (diisopropylamino) ethoxy]. -4-methoxyaniline (W
O95 / 15954) (0.23 g, 0.85 mmol) and diisopropylethylamine (0.11 g, 0.85 mmol) in dichloromethane (10 mL) in one portion and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with dichloromethane (50 mL), washed with 5% aqueous sodium carbonate and dried (Na ₂ S)
O ₄ ), concentrate under reduced pressure and purify the residue by flash chromatography (silica gel, 5% methanol / dichloromethane-0.1% ammonia),
The title compound (250 mg, 63%) was obtained. MS (ES) m / e 465.3 [M
+ H] ⁺ .

Example 2-3 N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3-phenyl-2-propenamide and N- [3- [ Preparation of 2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2-naphthalenyl) -2-propenamide Cinnamic acid and 3-cinnamate instead of 3,4-dichlorocinnamic acid (2-naphthalenyl) -2
-The title compound was obtained according to the procedure of Example 1, except using propenoic acid: N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3. -Phenylpropenamide: MS (ES) m / e 397.3 [M + H
] ⁺ ; And N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2-naphthalenyl) -2-propenamide: MS (ES) m / e 4
46.9 [M + H] ⁺ .

Example 4 (E) —N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- [4-chloro-3- (trifluoromethyl ) Phenyl] -2-propenamide The procedure of Example 1 except that 4-chloro-3- (trifluoromethyl) cinnamic acid was used instead of 3,4-dichlorocinnamic acid and triethylamine was used instead of diisopropylethylamine. To give the title compound. MS (ES) m / e 4
98.7, 500.7 [M + H] ⁺ .

Example 5 (E) —N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3-chlorophenyl) -2-propenamide 3 -Chlorocinnamic acid (0.18 g, 1 mmol), 3- [2- (diisopropylamino) ethoxy] -4-methoxyaniline (WO95 / 15954) (0.27 g)
A solution of BOP reagent (0.44 g, 1 mmol) in acetonitrile (20 mL) was reacted with triethylamine (0.22 g, 2.2 mmol) and stirred at room temperature for 16 hours. The mixture was treated with brine (50 mL) and extracted with ethyl acetate. Washing the combined organic phases with 5% sodium carbonate and brine,
Dry (MgSO ₄ ) and concentrate under reduced pressure. The residue was chromatographed (silica gel, 5% methanol / dichloromethane) to give the title compound (0.2 g). MS (ES) m / e 431.1 [M + H] ^< +>.

Example 6-12 Instead of 3-chlorocinnamic acid, 3- (5-indolyl) -2-propenoic acid, 3-
(6-Indolyl) -2-propenoic acid, ..- dimethylcinnamic acid,-(acetylamino) -3,4-dichlorocinnamic acid, 3- (5,6,7,8-tetrahydronaphth-2-
The following compounds were obtained according to the procedure of Example 5, except that yl) -2-propenoic acid, 4-chloro-3-methylcinnamic acid and 3,4-dichloro -.- methylcinnamic acid were used:

(E) —N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (5-indolyl) -2-propenamide: MS (ES ) M
/ E 435.9 [M + H] ⁺ ; (E) -N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl) -3- (6-indolyl) -2 -Propenamide: MS (ES) m
/ E 436.1 [M + H] ⁺ ; (E) -...- Dimethyl-N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3-phenyl -2-propenamide: MS (
ES) m / e 425.0 [M + H] ⁺ ; (Z) -N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl) -.- (acetylamino) -3- (3,4-dichlorophenyl) -2-
Propenamide: MS (ES) m / e 521.7, 523.6 [M + H] ⁺ ; (E) -N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxy Phenyl] -3- (5,6,7,8-tetrahydronaphth-2-yl) -2-propenamide trifluoroacetate: MS (ES) m / e 450.5 [M + H] ⁺ ; (E)- N- [3- [2- [Bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (4-chloro-3-methylphenyl) -2-propenamide: MS (ES) m / E 444.8, 446.8 [M + H] ⁺ ; and (E) -N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3 , 4-Dichlorophenyl) -.- methyl-2-propenamide: MS (ES) m / e 478.7, 488.7 [M + H ^+.

Examples 13-15 N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (4-fluorophenyl) -2-propenamide; E) -N- [3- [
2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3-
(3,5-dichlorophenyl) -2-propenamide trifluoroacetate; and (
E) Preparation of -N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- [4- (trifluoromethyl) phenyl] -2-propenamide 3 According to the procedure of Example 5, except that -chlorocinnamic acid is replaced by 4-fluorocinnamic acid, 3,5-dichlorocinnamic acid and 4- (trifluoromethyl) cinnamic acid, the title compound is obtained:

N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (4-fluorophenyl) -2-propenamide: MS (ES) m
/ E 414.9 [M + H] ⁺ ; (E) -N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3,5-dichlorophenyl) -2-propenamide trifluoroacetate: MS (ES) m / e 466.8 [M + H] ⁺ ; and (E) -N- [3- [2- [bis (1-methylethyl) amino] ethoxy]. -4-methoxyphenyl] -3-[(4-trifluoromethyl) phenyl] -2-propenamide: MS (ES) m / e 464.8 [M + H] ^< +>.

Example 16 N- [3- [2- (2,2,6,6-tetramethylpiperidin-1-yl) ethoxy]-
Preparation of 4-methoxy-phenyl] -3- (3,4-dichlorophenyl) -2-propenamide The compound of Preparation 1 (b) instead of 3- [2- (diisopropylamino) ethoxy] -4-methoxyaniline The title compound was obtained according to the procedure of Example 1 except that MS (ES) m / e 505.0 [M + H] ^< +>.

Example 17 N- [3- [2- (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-
Yl) ethoxy] -4-methoxyphenyl] -3- (3,4-dichlorophenyl) -2
-Preparation of propenamide The title compound was obtained according to the procedure of Example 16 except that the compound of Preparation Example 2 was used instead of the compound of Preparation Example 1 (b). MS (ES) m / e 521.1,
523.1 [M + H] ⁺ .

Examples 18-22 N- [4- [2- [bis (1-methylethyl) amino] ethyl] -3,4-dihydro-3
-Oxo-2H-1,4-benzoxazin-6-yl] -3- (3,4-dichlorophenyl) -2-propenamide; N- [4- [2- [bis (1-methylethyl) amino] Ethyl] -3,4-dihydro-2H-1,4-benzoxazin-6-yl]-
3- (3,4-dichlorophenyl-2-propenamide; N- [3- [2- [bis (1
-Methylethyl) amino] ethyl] -2-oxo- (3H) -benzoxazole-
5-yl] -3- (3,4-dichlorophenyl) -2-propenamide; N- [2,3
-Dihydro-1- [2- [bis (1-methylethyl) amino] ethyl] -1H-indol-6-yl] -3- (3,4-dichlorophenyl) -2-propenamide; and N- [1 Preparation of-[2- [bis (1-methylethyl) amino] ethyl] -1,2,3,4-tetrahydroquinol-7-yl] -3- (3,4-dichlorophenyl) -2-propenamide

Following the procedure of Example 1 except that the compound of Preparation Example 3-7 was used instead of 3- [2- (diisopropylamino) ethoxy] -4-methoxyaniline, the title compound was obtained: N- [4- [2- [bis (1-methylethyl) amino] ethyl] -3,4-dihydro-
3-oxo-2H-1,4-benzoxazin-6-yl] -3- (3,4-dichlorophenyl) -2-propenamide: MS (ES) m / e 490.0, 491.9.
[M + H] ⁺ ; N- [4- [2- [bis (1-methylethyl) amino] ethyl] -3,4-dihydro-
2H-1,4-benzoxazin-6-yl] -3- (3,4-dichlorophenyl-
2-propenamide: MS (ES) m / e 476.0, 477.9 [M + H] ⁺
N- [3- [2- [bis (1-methylethyl) amino] ethyl] -2-oxo- (3H
) -Benoxazol-5-yl] -3- (3,4-dichlorophenyl) -2-propenamide: MS (ES) m / e 475.9, 477.9 [M + H] ⁺ ; N- [2,3 -Dihydro-1- [2- [bis (1-methylethyl) amino] ethyl]-
1H-Indol-6-yl] -3- (3,4-dichlorophenyl) -2-propenamide: MS (ES) m / e 459.9, 461.9 [M + H] ⁺ ; and N- [1- [ 2- [bis (1-methylethyl) amino] ethyl] -1,2,3,4-tetrahydroquinol-7-yl] -3- (3,4-dichlorophenyl) -2-propenamide: MS (ES) m / e 474.1, 476.1 [M + H] ^< +>.

Example 23 N- (1′-Methylspiro [benzofuran-3 (2H), 4′-piperidin] -5-yl) -3- (3,4-dichlorophenyl) -2-propenamide 3- [2 1'-methyl-5-nitrospiro [benzofuran-3 (2H), 4'-piperidine instead of-(diisopropylamino) ethoxy] -4-methoxyaniline
] (WO96 / 11934), but following the procedure of Example 1 to give the title compound. MS (ES) m / e 418.4 [M + H] ^< +>.

Example 24 N- (spiro [benzofuran-3 (2H), 4′-piperidin] -5-yl) -3- (3
Preparation of 2,4-dichlorophenyl) -2-propenamide A solution of the compound of Example 23 (0.28 g, 0.67 mmol) and diisopropylethylamine (0.13 g, 1 mmol) in 1,2-dichloroethane (15 mL) was prepared. Was reacted with 1-chloroethyl chloroformate (0.12 g, 0.86 mmol), stirred at room temperature for 1 hour and heated to reflux for 20 minutes. Cool the mixture, concentrate under reduced pressure, dissolve the residue in methanol (25 mL), heat to reflux for 2 hours, and add
Stirred for hours. The mixture was cooled, concentrated under reduced pressure and the residue was taken up in dichloromethane (10
0 mL) and washed with 5% sodium carbonate. Dry the organic phase (MgSO ₄
), Concentrated under reduced pressure, treated with dichloromethane, and concentrated several times under reduced pressure to give the title compound. MS (ES) m / e 404 [M + H] ^< +>.

Example 25 N- [1 ′-(1-methylethyl) spiro [benzofuran-3 (2H) 4′-piperidin] -5-yl] -3- (3,4-dichlorophenyl) -2-propene Preparation of Amide The compound of Example 24 (0.15 g, 0.37 mmol) in dimethylformamide containing 2-iodopropane (65 mg, 0.38 mmol) and potassium carbonate powder (56 mg, 0.4 mmol) The solution was heated at 50 ° C. for 15 hours, cooled and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (120 mL) and water (10 mL), the organic phase was washed with water and brine, dried (MgSO _4), and concentrated under reduced pressure. The residue was chromatographed (silica gel, 5% methanol / dichloromethane) to give the title compound. MS (ES) m / e 446.9 [M
+ H] ⁺ .

Example 26 N- [1 ′-(1-methylethyl) spiro [benzofuran-3 (2H) 4′-piperidin] -5-yl] -3- (3,5-dichlorophenyl) -2-propene Preparation of amide Preparation Example 8 (e) using 3,5-dichlorocinnamic acid instead of 3-chlorocinnamic acid and substituting 3- [2- (diisopropylamino) ethoxy] -4-methoxyaniline
The title compound was obtained according to the procedure of Example 5 except for using the compound of formula (I). M
S (ES) m / e 445.0 [M + H] ^< +>.

Example 27 Preparation of N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (3,4-dichlorophenyl) -2-propenamide 3 Instead of-[2- (diisopropylamino) ethoxy] -4-methoxyaniline, 3- [3- (diisopropylamino) propyl] -4-methoxyaniline (WO9
The title compound was obtained according to the procedure of Example 1 except that 9/01127) was used. MS (ES) m / e 462.9 [M + H] ^< +>.

Example 28 Preparation of N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (3,4-dichlorophenyl) -2-propenamide 3 Instead of 3- [2- (diisopropylamino) ethoxy] -4-methoxyaniline, 3- [3- (diisopropylamino) propoxy] -4-methoxyaniline (WO
The title compound was obtained according to the procedure of Example 1, except that 99/01127) was used. MS (ES) m / e 480.7 [M + H] ^< +>.

Example 29 N- [3- [2-acetoxy-3- [bis (1-methylethyl) amino] propoxy]
Preparation of -4-methoxyphenyl] -3- (3,4-dichlorophenyl) -2-propenamide The compound of Preparation 9 (d) instead of 3- [2- (diisopropylamino) ethoxy] -4-methoxyaniline The title compound was obtained according to the procedure of Example 1 except that MS (ES) m / e 538.9 [M + H] ^< +>.

Example 30 Preparation of N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (4-chlorophenyl) -2-propenamide a) [ 3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyaniline / (4-formyl-3,5-dimethoxy-phenoxy) -merryfield resin adduct 4-formyl-3,5-dimethoxy -Phenoxy-Merryfield resin (Boo
J. Org. Chem. 1995, 60, 5742-3), 3- [3- (diisopropylamino) propyl] -4-methoxyaniline (WO 99/01127) and 1% of sodium triacetoxyborohydride. The mixture in dimethylformamide containing acetic acid was shaken to give the title adduct.

B) N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (4-chlorophenyl) -2-propenamide / (4-formyl-
3,5-Dimethoxy-phenoxy) -Merryfield Resin Adduct The resin of Example 30 (a) was placed in an Irori MicroKan and a 10-fold molar excess of equimolar amounts of 4-chlorocinnamic acid, N-bromosuccinimide and triamine Reaction with a mixture of phenylphosphine in dichloromethane was followed by the addition of a 10-fold excess of pyridine. The mixture was gently stirred for 48 hours, after which the resin was washed three consecutive times with dimethylformamide, dichloromethane and methanol to give the title adduct.

C) N- [3- [3- [Bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (4-chlorophenyl) -2-propenamide Example 30 (b) Of trifluoroacetic acid: dichloromethane: water (50: 4
Stir in the mixture of 8: 2), filter and concentrate the filtrate under reduced pressure to give the title compound. MS (ES) m / e 429.0 [M + H] ^< +>.

Examples 31-62 Instead of 3- [3- (diisopropylamino) propyl] -4-methoxyaniline, 3- [2- (diisopropylamino) ethoxy] -4-methoxyaniline (WO9
5/15954), 3- [2- (N-cyclohexyl-N-isopropylamino)
Except for using ethoxy] -4-methoxyaniline (WO99 / 01127) and 3- [2- (cis-2,6-dimethylpiperidin-1-yl) ethoxy] -4-methoxyaniline (WO99 / 01127) 3-chlorocinnamic acid plus 3-
Example 30 (a)-(c) using chlorocinnamic acid, 3,4- (methylenedioxy) cinnamic acid, 3,4-difluorocinnamic acid and 3- (2-naphthalenyl) -2-propenoic acid.
The title compound was obtained according to the procedure in):

N- [3- [2- (cis-2,6-dimethylpiperidin-1-yl) ethoxy] -4
-Methoxyphenyl] -3- (3-chlorophenyl) -2-propenamide: MS
(ES) m / e 443.0 [M + H] ⁺ ; N- [3- [2- (N-cyclohexyl-N-isopropylamino) ethoxy]-
4-methoxyphenyl] -3- (3-chlorophenyl) -2-propenamide: M
S (ES) m / e 471.0 [M + H] ⁺ ; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (4-chlorophenyl)- 2-propenamide: MS (ES) m /
e 431.0 [M + H] ⁺ ; N- [3- [2- (cis-2,6-dimethylpiperidin-1-yl) ethoxy] -4.
-Methoxyphenyl] -3- (4-chlorophenyl) -2-propenamide: MS
(ES) m / e 442.9 [M + H] ⁺ ; N- [3- [2- (N-cyclohexyl-N-isopropylamino) ethoxy]-
4-methoxyphenyl] -3- (4-chlorophenyl) -2-propenamide: M
S (ES) m / e 470.9 [M + H] ⁺ ; N- [3- [2- (N-cyclohexyl-N-isopropylamino) ethoxy]-
4-methoxyphenyl] -3-[(3,4-methylenedioxy) phenyl] -2-propenamide: MS (ES) m / e 481.0 [M + H] ⁺ ;

N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3,4-difluorophenyl) -2-propenamide: MS (ES
) M / e 432.9 [M + H] ^< +>; N- [3- [2- (cis-2,6-dimethylpiperidin-1-yl) ethoxy] -4.
-Methoxyphenyl] -3- (3,4-difluorophenyl) -2-propenamide: MS (ES) m / e 444.9 [M + H] ⁺ ; N- [3- [2- (N-cyclohexyl-N) -Isopropylamino) ethoxy]-
4-methoxyphenyl] -3- (3,4-difluorophenyl) -2-propenamide: MS (ES) m / e 473.0 [M + H] ⁺ ; N- [3- [2- (N-cyclohexyl-) N-isopropylamino) ethoxy]-
4-methoxyphenyl] -3- (2-naphthalenyl) -2-propenamide: MS
(ES) m / e 487.4 [M + H] ^< +>; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- [3- (trifluoromethyl ) Phenyl] -2-propenamide: M
S (ES) m / e 465.2 [M + H] ^< +>; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2-chlorophenyl)- 2-propenamide: MS (ES) m /
e 431.2 [M + H] ⁺ ;

N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2,4-dichlorophenyl) -2-propenamide: MS (ES)
m / e 465.2 [M + H] ⁺ ; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2,6-dichlorophenyl) -2- Propenamide: MS (ES)
m / e 465.2 [M + H] ⁺ ; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3,5-difluorophenyl) -2 -Propenamide: MS (ES
) M / e 433.2 [M + H] ^< +>; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2,5-difluorophenyl)- 2-propenamide: MS (ES
) M / e 433.2 [M + H] ^< +>; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2,4-difluorophenyl)- 2-propenamide: MS (ES
) M / e 433.2 [M + H] ^< +>; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3-fluorophenyl) -2- Propenamide: MS (ES) m
/ E 415.2 [M + H] ⁺ ; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2-chloro-6-fluorophenyl)- 2-propenamide: M
S (ES) m / e 449.2 [M + H] ⁺ ; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (4-bromo-2 -Fluorophenyl) -2-propenamide: M
S (ES) m / e 493.1 [M + H] ^< +>;

N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (4-chloro-2-fluorophenyl) -2-propenamide: M
S (ES) m / e 449.2 [M + H] ⁺ ; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2-chloro-4 -Fluorophenyl) -2-propenamide: M
S (ES) m / e 449.2 [M + H] ⁺ ; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2,6-difluoro Phenyl) -2-propenamide: MS (ES
) M / e 433.2 [M + H] ^< +>; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (4-bromophenyl) -2- Propenamide: MS (ES) m /
e 475.2 [M + H] ⁺ ; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (4-chloro-3-nitrophenyl) -2 -Propenamide: MS
(ES) m / e 476.2 [M + H] ^< +>; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- [4- (1-methyl Ethyl) phenyl] -2-propenamide: MS
(ES) m / e 439.3 [M + H] ^< +>;

N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (5-bromo-2-methoxyphenyl) -2-propenamide: M
S (ES) m / e 505.2 [M + H] ⁺ ; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3-([1,1 ′ -Biphenyl] -4-yl) -2-propenamide: MS
(ES) m / e 473.3 [M + H] ^< +>; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3-bromo-4- (Fluorophenyl) -2-propenamide: M
S (ES) m / e 493.1 [M + H] ⁺ ; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3,4-dimethyl Phenyl) -2-propenamide: MS (ES)
m / e 425.3 [M + H] ⁺ ; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (4-cyanophenyl) -2-propene Amide: MS (ES) m /
e 422.2 [M + H] ⁺ ; and N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -2-fluoro-3-phenyl-2-propenamide: MS (ES) m
/ E 415.2 [M + H] ^< +>.

Examples 63-90 Instead of 4-chlorocinnamic acid, 3,4-difluorocinnamic acid, 3,4-dichlorocinnamic acid, 3-chlorocinnamic acid, 3,4- (methylenedioxy) cinnamic acid and Following the procedure of Example 30 (b)-(c) except using 3- (2-naphthalenyl) -2-propenoic acid, the title compound was obtained: N- [3- [3- [bis (1 -Methylethyl) amino] propyl] -4-methoxyphenyl] -3- (3,4-difluorophenyl) -2-propenamide: MS (ES
) M / e 431.2 [M + H] ^< +>; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (3,4-dichlorophenyl) -2. -Propenamide: MS (ES)
m / e 462.9 [M + H] ⁺ ; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (3-chlorophenyl) -2-propenamide : MS (ES) m /
e 428.9 [M + H] ⁺ ; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3-[(3,4-methylenedioxy) phenyl] -2-propenamide: M
S (ES) m / e 438.9 [M + H] ⁺ ; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (2-naphthalenyl)- 2-propenamide: MS (ES) m / e
445.4 [M + H] ⁺ ;

N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- [4- (trifluoromethyl) phenyl] -2-propenamide: M
S (ES) m / e 463.3 [M + H] ⁺ ; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- [3- (trifluoro Methyl) phenyl] -2-propenamide: M
S (ES) m / e 463.3 [M + H] ^< +>; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (2-chlorophenyl)- 2-propenamide: MS (ES) m /
e 429.2 [M + H] ⁺ ; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (2,4-dichlorophenyl) -2-propenamide : MS (ES)
m / e 463.2 [M + H] ⁺ ; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (2,6-dichlorophenyl) -2- Propenamide: MS (ES)
m / e 463.2 [M + H] ⁺ ; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (3,5-difluorophenyl) -2 -Propenamide: MS (ES
) M / e 431.3 [M + H] ^< +>; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (2,5-difluorophenyl)- 2-propenamide: MS (ES
) M / e 431.3 [M + H] ⁺ ;

N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (2,4-difluorophenyl) -2-propenamide: MS (ES
) M / e 431.3 [M + H] ^< +>; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (3-fluorophenyl) -2- Propenamide: MS (ES) m
/ E 413.3 [M + H] ⁺ ; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (2-chloro-6-fluorophenyl)- 2-propenamide: M
S (ES) m / e 447.2 [M + H] ⁺ ; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (4-bromo-2 -Fluorophenyl) -2-propenamide: M
S (ES) m / e 491.2 [M + H] ⁺ ; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (4-chloro-2 -Fluorophenyl) -2-propenamide: M
S (ES) m / e 447.2 [M + H] ⁺ ; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (2-chloro-4 -Fluorophenyl) -2-propenamide: M
S (ES) m / e 447.2 [M + H] ⁺ ; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (2,6-difluoro Phenyl) -2-propenamide: MS (ES
) M / e 431.3 [M + H] ⁺ ;

N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (4-bromophenyl) -2-propenamide: MS (ES) m /
e 473.2 [M + H] ⁺ ; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (4-chloro-3-nitrophenyl) -2 -Propenamide: MS
(ES) m / e 474.2 [M + H] ⁺ ; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- [4- (1-methyl Ethyl) phenyl] -2-propenamide: MS
(ES) m / e 437.3 [M + H] ⁺ ; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (5-bromo-2- (Methoxyphenyl) -2-propenamide: M
S (ES) m / e 503.2 [M + H] ⁺ ; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (3-bromo-4 -Fluorophenyl) -2-propenamide: M
S (ES) m / e 491.2 [M + H] ⁺ ; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (3,5-dichlorophenyl ) -2-Propenamide: MS (ES)
m / e 463.2 [M + H] ⁺ ; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (3,4-dimethylphenyl) -2 -Propenamide: MS (ES)
m / e 423.3 [M + H] ⁺ ; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (4-cyanophenyl) -2-propene Amide: MS (ES) m /
e 420.3 [M + H] ⁺ ; and N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -2-fluoro-3-phenyl-2-propenamide: MS (ES) m
/ E 413.3 [M + H] ^< +>.

Examples 91-117 Instead of 3- [3- (diisopropylamino) propyl] -4-methoxyaniline, 3- [3- (diisopropylamino) propoxy] -4-methoxyaniline (WO
3-chlorocinnamic acid, 3,4- (methylenedioxy) cinnamic acid, 3,4-difluorocinnamic acid and 3
Using-(2-naphthalenyl) -2-propenoic acid, following the procedure of Example 30 (a)-(c), the title compound was obtained:

N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (3-chlorophenyl) -2-propenamide: MS (ES) m
/ E 444.9 [M + H] ⁺ ; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (4-chlorophenyl) -2-propenamide: MS (ES) m
/ E 444.9 [M + H] ⁺ ; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3-[(3,4-methylenedioxy) phenyl ] -2-Propenamide:
MS (ES) m / e 454.9 [M + H] ^< +>; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (3,4-difluoro Phenyl) -2-propenamide: MS (E
S) m / e 446.9 [M + H] ^< +>; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (2-naphthalenyl) -2-. Propenamide: MS (ES) m /
e 461.6 [M + H] ⁺ ; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- [3- (trifluoromethyl) phenyl] -2. -Propenamide:
MS (ES) m / e 479.3 [M + H] ^< +>; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (2-chlorophenyl)]. -2-propenamide: MS (ES) m
/ E 445.2 [M + H] ⁺ ;

N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (2,4-dichlorophenyl)]-2-propenamide: MS (E
S) m / e 479.2 [M + H] ^< +>; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (2,6-dichlorophenyl)] -2-propenamide: MS (E
S) m / e 479.2 [M + H] ^< +>; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (3,5-difluorophenyl). ] -2-propenamide: MS (
ES) m / e 447.2 [M + H] ^< +>; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (2,5-difluorophenyl) ] -2-propenamide: MS (
ES) m / e 447.2 [M + H] ^< +>; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (2,4-difluorophenyl). ] -2-propenamide: MS (
ES) m / e 447.2 [M + H] ^< +>; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (3-fluorophenyl)]-. 2-propenamide: MS (ES)
m / e 429.3 [M + H] ⁺ ; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (2-chloro-6-fluorophenyl) ] -2-Propenamide:
MS (ES) m / e 463.2 [M + H] ^< +>;

N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (4-bromo-2-fluorophenyl)]-2-propenamide:
MS (ES) m / e 507.2 [M + H] ^< +>; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (4-chloro-2. -Fluorophenyl)]-propenamide: MS
(ES) m / e 463.2 [M + H] ^< +>; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (2-chloro-4- (Fluorophenyl) -2-propenamide:
MS (ES) m / e 463.2 [M + H] ^< +>; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (2,6-difluoro Phenyl)]-2-propenamide: MS (
ES) m / e 447.2 [M + H] ^< +>; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (4-bromophenyl)]-. 2-propenamide: MS (ES) m
/ E 489.2 [M + H] ^< +>; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- [4- (1-methylethyl) phenyl] -2-propenamide: M
S (ES) m / e 453.3 [M + H] ⁺ ; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3-([1,1 ′ -Biphenyl] -4-yl) -2-propenamide: M
S (ES) m / e 487.3 [M + H] ^< +>;

N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (2,3-dihydro-1H-inden-5-yl) -2- Propenamide: MS (ES) m / e 451.3 [M + H] ⁺ ; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (3- Bromo-4-fluorophenyl)]-2-propenamide:
MS (ES) m / e 507.2 [M + H] ^< +>; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (3,5-dichlorophenyl )]-2-Propenamide: MS (E
S) m / e 479.2 [M + H] ^< +>; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (3,4-dimethylphenyl). -2-propenamide: MS (ES
) M / e 439.3 [M + H] ^< +>; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (4-cyanophenyl)]-2. -Propenamide: MS (ES) m
/ E 436.3 [M + H] ⁺ ; and N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -2-fluoro-3-phenyl-2-propenamide : MS (ES)
m / e 429.3 [M + H] ⁺ .

Examples 118-120 Instead of 3- [3- (diisopropylamino) propyl] -4-methoxyaniline, 3- [2- (diisopropylamino) ethoxy] -4-methylaniline (WO99
01127) and 3,4- (methylenedioxy) in place of 4-chlorocinnamic acid
Following the procedure of Example 30 (a)-(c) except using cinnamic acid, 3,4-difluorocinnamic acid and 3- (2-naphthalenyl) -2-propenoic acid, the title compound was obtained: N -[3- [2- [Bis (1-methylethyl) amino] ethoxy] -4-methylphenyl] -3-[(3,4-methylenedioxy) phenyl] -2-propenamide: MS
(ES) m / e 424.9 [M + H] ⁺ ; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methylphenyl] -3- (3,4-difluorophenyl ) -2-Propenamide: MS (ES)
m / e 417.0 [M + H] ⁺ ; and N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methylphenyl] -3- (2-naphthalenyl) -2-propene Amide: MS (ES) m / e 4
31.0 [M + H] ⁺ .

Examples 121-135 In addition to 3- [3- (diisopropylamino) propyl] -4-methoxyaniline, 3- [2- (diisopropylamino) ethoxy] -4-methoxyaniline (WO95
/ 15954), 3- [2- (diisopropylamino) ethoxy] -4-methylaniline (WO99 / 01127), 3- [2- (N-cyclohexyl-N-isopropylamino) ethoxy] -4-methoxyaniline (WO99 / 01127) and 3- [2- (cis-2,6-dimethylpiperidin-1-yl) ethoxy] -4-methoxyaniline (WO 99/01127) using 3 instead of 4-chlorocinnamic acid.
-(3-thienyl) -2-propenoic acid, 3- (4-pyridinyl) -2-propenoic acid,
The title compound was obtained according to the procedure of Example 30 (a)-(c) except that 3- (3-furanyl) -2-propenoic acid and 3- (2-thienyl) -2-propenoic acid were used. :

N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3-thienyl) -2-propenamide: MS (ES) m / e 40
3.0 [M + H] ^< +>; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (3-thienyl) -2-propenamide: MS ( ES) m / e 40
1.0 [M + H] ⁺ ; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (3-thienyl) -2-propenamide: MS ( ES) m / e 4
17.0 [M + H] ⁺ ; N- [3- [2- (cis-2,6-dimethylpiperidin-1-yl) ethoxy] -4
-Methoxyphenyl] -3- (3-thienyl) -2-propenamide: MS (ES
) M / e 415.0 [M + H] ⁺ ; N- [3- [2- (N-cyclohexyl-N-isopropylamino) ethoxy]-
4-methoxyphenyl] -3- (3-thienyl) -2-propenamide: MS (E
S) m / e 443.0 [M + H] ^< +>; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methylphenyl] -3- (4-pyridinyl) -2- Propenamide: MS (ES) m / e 38
2.0 [M + H] ⁺ ; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (4-pyridinyl) -2-propenamide: MS ( ES) m / e
412 [M + H] ⁺ ; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3-furanyl) -2-propenamide: MS (ES) m / e 38
7.4 [M + H] ⁺ ; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methylphenyl] -3- (3-furanyl) -2-propenamide: MS ( ES) m / e 371
0.0 [M + H] ⁺ ; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (3-furanyl) -2-propenamide: MS (ES ) M / e 38
5.0 [M + H] ⁺ ; N- [3- [2- (cis-2,6-dimethylpiperidin-1-yl) ethoxy] -4
-Methoxyphenyl] -3- (3-furanyl) -2-propenamide: MS (ES
) M / e 399.0 [M + H] ⁺ ; N- [3- [2- (N-cyclohexyl-N-isopropylamino) ethoxy]-
4-methoxyphenyl] -3- (3-furanyl) -2-propenamide: MS (E
S) m / e 427.0 [M + H] ^< +>; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (2-thienyl) -2- Propenamide: MS (ES) m / e 40
1.0 [M + H] ⁺ ; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (2-thienyl) -2-propenamide: MS ( ES) m / e 4
17.0 [M + H] ⁺ ; and N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2-furanyl) -2-propenamide: MS (ES) m / e 38
7.1 [M + H] ⁺ .

Example 136 Preparation of N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2-furanyl) -2-propenamide 3-chloro Following the procedure of Example 5 except that 3- (2-furanyl) -2-propenoic acid was used instead of cinnamic acid, the title compound was obtained: MS (ES) m / e.
387.1 [M + H] ⁺ .

Example 137-142 3- (1H-indol-3-yl) -2-propenoic acid, 3- (1H-indol-2-yl) -2-propenoic acid instead of 3-chlorocinnamic acid 3- (1-methyl-1H-indol-2-yl) -2-propenoic acid, 3- (benzo [b] thien-3
-Yl) -2-propenoic acid, 3- (2-benzofuranyl) -2-propenoic acid and 3- (benzo [b] thien-2-yl) -2-propenoic acid, except that Following the procedure, the title compound was obtained: N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (1H-indol-3-yl) -2- Propenamide: MS (E
S) m / e 435.9 [M + H] ⁺ ; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (1H-indol-2-yl ) -2-Propenamide: MS (E
S) m / e 435.9 [M + H] ⁺ ; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (1-methyl-1H-indole -2-yl) -2-propenamide: MS (ES) m / e 439.9 [M + H] ⁺ ; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxy. Phenyl] -3- (benzo [b] thien-3-yl) -2-propenamide: MS (E
S) m / e 452.3 [M + H] ^< +>; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2-benzofuranyl) -2- Propenamide: MS (ES) m /
e 436.9 [M + H] ⁺ ; and N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (benzo [b] thien-2-yl) -2-propenamide: MS (E
S) m / e 452.8 [M + H] ^< +>.

Example 143 N- [4-Methoxy-3-[(2S)-(1-methyl-2-pyrrolidinyl) methoxy]
Preparation of phenyl] -3- (3,4-dichlorophenyl) -2-propenamide a) (S) -2-[(2-methoxy-5-nitrophenoxy) methyl] pyrrolidine / R
EM resin adduct REM resin (264.2 g, 0.64 meq / g) was converted to dimethylformamide (
Stir at room temperature under argon for 30 minutes under argon and add a solution of the compound of Preparation 10 (110.9 g, 0.47 mol) in dimethylformamide (1 L) and stir the mixture at room temperature for 16 hours did. The resin was collected by filtration, washed with dimethylformamide, dichloromethane and methanol, dried at room temperature under reduced pressure to give the title adduct with a theoretical loading of 0.55 meq / g (272.8 g, 89% yield).
) Got.

B) (S) -2-[(2-methoxy-5-aminophenoxy) methyl] pyrrolidine / R
EM resin adduct The adduct (268.1 g) of Example 143 (a) was treated with dimethylformamide (1
L) under argon at room temperature for 30 minutes, dimethylformamide (1 L)
)) (133.5 g, 0.59 mol) in one portion. The mixture was stirred at room temperature under argon for 48 hours, filtered to collect the resin and 10% v
/ W hydrochloric acid: dioxane (1: 1), 10% diisopropylethylamine in dimethylformamide, 50:50 dioxane: water, washed with dioxane, dichloromethane and methanol. The product was dried under vacuum at room temperature to constant weight to give a resin (261 g) with a theoretical loading of 0.61 meq / g.

C) N- [4-Methoxy-3-[(2S)-(1-methyl-2-pyrrolidinyl) methoxy] phenyl] -3- (3,4-dichlorophenyl) -2-propenamide / REM
Resin adduct A double-type Irori Kan was charged with the resin of Example 143 (b) (100 mg), which was dissolved in dichloromethane in 3- (3,4-dichlorophenyl) -2-propenoic acid (12.3).
Mmol) followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.36 g) and 1-hydroxybenzotriazole hydrate (1.88 g). The mixture was stirred at room temperature for 30 minutes. The Kan was stirred at room temperature for 16 hours and then with about 50 minutes each of the following liquids of 50:50 10% hydrochloric acid: dioxane, 10% diisopropylethylamine in dimethylformamide, 50:50 dioxane: water, dioxane, dichloromethane and methanol. Washed.
The Kan was dried at room temperature under reduced pressure for 16 hours.

D) N- [4-Methoxy-3-[(2S)-(1-methyl-2-pyrrolidinyl) methoxy] phenyl] -3- (3,4-dichlorophenyl) -2-propenamide Example 143 washing the resin of (c) with dimethylformamide for 30 minutes,
The liquid was decanted, charged with dimethylformamide (100 mL) and reacted with iodomethane (8.2 mmol). The mixture was stirred at room temperature for 48 hours, and the resin was taken out and washed with dimethylformamide, dioxane, dichloromethane, methanol and diethyl ether for 30 minutes each. The resin was dried at room temperature under reduced pressure, removed from Kan, and treated with 10% triethylamine in dimethylformamide (1 mL) for 16 hours while adding Amberlyst-A21. The mixture was filtered, treated with 1% triethylamine in dimethylformamide (1 mL) and stirred for 3 hours. The solvent was removed by filtration and the residue was washed with dimethylformamide (1 mL) for 1 hour. The solvent was concentrated under reduced pressure to obtain the title compound.

Example 144 N- [4-Methoxy-3-[(2S)-(1-methyl-2-pyrrolidinyl) methoxy]
Preparation of phenyl] -3- (4-methylphenyl) -2-propenamide Substitute 3- (4-methylphenyl) -2-propenoic acid for 3- (3,4-dichlorophenyl) -2-propenoic acid Except for this, Examples 143 (c)-(d)
The title compound was obtained according to the procedure described in.

Biological Data CCR5 Receptor Binding Assay CHO cell membranes (0.25 × 10 ⁴ cells equivalent) from CHO cells stably transfected with CCR5 were combined with 0.3 ¹²⁵ I-RANTES for 96 hours. The well plates were incubated for 45 minutes at room temperature (final reaction volume 200 μl). The reaction was stopped by filtration, and 0.1% bovine serum albumin and 0.0% were added.
The filter (GF / C) was washed twice with a phosphate buffered saline solution containing 5% NaN ₃ . Radioactive filters were measured by liquid scintillation spectroscopy. Non-specific binding was measured in the presence of unlabeled RANTES (10 or 30 nM) and averaged 30-50% of total binding.

CCR5 Receptor Function Assay The cell function assay used to assess the antagonist activity of the compounds was hCCR
RBL 2H ₃ cells stably expressing 5 receptors (RBL 2H ₃ hCCR5)
Kinetics of Ca ²⁺ induced by RANTES in the cell. Agonist activity can be inhibited by a CCR5 selective antagonist, Ca ^{2 in the} same cell
⁺ Measure mobilization. Cells were grown to 80-100% confluence in T-150 flasks and washed with phosphate buffered saline. Treatment with 3 ml of 1 mM EDTA at room temperature for 3 minutes, 5 mM HEPES (pH 7.4), 1 mM CaCl ₂
Krebs Ringer Henseleit buffer (KRH; 118 mM Na) containing 1 mM MgCl ₂ and 0.1% BSA.
Cl, 4.6 mM KCl, 25 mM NaHCO ₃ , 1 mM KH ₂ PO ₄ and 11
The cells were removed from the flask by diluting to 2 × 10 ⁶ cells / ml (mM glucose) and centrifuged at 200 × g for 3 minutes. 2 μM Fura-2A
The cells were resuspended at 2 × 10 ⁶ cells / ml in the same buffer containing M.
Incubated for 5 minutes. The cells are centrifuged at 200 xg for 3 minutes and F
The cells were resuspended in the same buffer without ura-2AM and incubated at 37 ° C. for 15 minutes to terminate the hydrolysis of Fura-2AM in the cells and then centrifuged as described above. Cells (10 ⁶ cells / ml) were converted to 5 mM HEPES (p
H7.4) resuspended in cold KRH containing 1 mM CaCl ₂ , 1 mM MgCl ₂ and 0.1% gelatin and kept on ice until the assay was performed. When experimenting with antagonists, an aliquot of cells (2 ml) was pre-warmed to 37 ° C. for 5 minutes in a 3 ml plastic cuvette, stirred with a magnetic stirrer, and maintained at 37 ° C. while maintaining a fluorometer (Pennsylvania, USA). ,Philadelphia,
The fluorescence was measured by Johnson, Foundation, Biomedical, Group). 340n excitation
m and emission was measured at 510 nm. Various concentrations of antagonist or vehicle were added and the fluorescence was monitored for １５15 seconds to ensure no change in the fluorescence baseline, followed by the addition of 33 nM RANTES. 33nM RANT
The maximum of Ca ²⁺ obtained after stimulation with ES was calculated as described in Grynkiewicz et al. (1985). The maximum% RANTES-induced Ca ²⁺ was determined for each concentration of antagonist and the IC ₅₀ was defined as the concentration of the test compound that inhibited 50% of the maximum response of RANTES at 33 nM by a concentration response curve (5-7 concentrations). Antagonist).

The compounds of the present invention exhibit CCR5 receptor modulator activity with IC ₅₀ values in the range from 0.0001 to 100 μM. Structure for compound of the invention /
The activity relationship has not yet been fully established. However, given the disclosure herein, one of ordinary skill in the art would determine which compounds of formula (I) are modulators of the CCR5 receptor and would bind with IC ₅₀ values ranging from 0.0001 to 100 μM. The assay can be used to perform All publications, including, but not limited to, patent publications and patent application publications cited herein, including each individual publication are specifically and individually referred to herein by reference. It is indicated to be a part, and even if fully disclosed, is hereby incorporated by reference. The above description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration, one skilled in the art can, based on the above description, utilize the present invention to its fullest extent. Therefore, it should be construed that each embodiment is merely an example and does not limit the scope of the present invention. Specific examples of the present invention for claiming exclusive rights and privileges are described below.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/4409 A61K 31/4409 4H006 31/538 31/538 A61P 9/10 A61P 9/10 11/06 11 / 06 17/00 17/00 29/00 29/00 37/00 37/00 C07C 233/29 C07C 233/29 C07D 263/58 C07D 263/58 265/36 265/36 491/107 491/107 // C07D 211/22 211/22 211/46 211/46 (72) Inventor Michael J. Neave United States 19406 Bill Smith Boulevard 414, King of Prussia, PA 1972 (72) Inventor Thomas W.・ Ku United States 19025 Dresher, Pennsylvania, South Wing Way 1413 F term (reference) 4C050 AA04 AA07 BB07 CC16 EE01 FF02 GG04 HH01 4C054 AA02 BB03 CC0 3 DD04 EE01 FF01 FF24 4C056 CA04 CA17 CC01 CD01 FA08 FB04 FC01 4C086 AA01 AA03 BA06 BC17 BC21 CB22 MA04 NA14 ZA45 ZA59 ZA89 ZB07 ZB13 ZB15 4C206 AA01 AA03 GA07 KA01 KA03 MA04 NA14 ZA45 ZA59 ZA89 ZB07 ZB13 ZB15 4H006 AA01 AA03 AB20 AB22 AB25 AC53 BJ50 BM71 BM72 BP30 BV25

Claims (5)

[Claims] 1. A method of treating a CCR5-mediated condition in a mammal, comprising:
In mammals in need of such treatment, an effective amount of Formula (I):Wherein the basic nitrogen in the group E is C_1-6It may be quaternized with alkyl,
May be present as an N-oxide; P¹Is selected from phenyl, fused bicyclic aryl, oxygen, nitrogen and sulfur
5- to 7-membered heterocycle containing 1 to 3 heteroatoms, or oxygen, nitrogen
8 to 11 members containing 1 to 3 heteroatoms selected from and sulfur
Is a fused bicyclic heterocycle; L is CONR^{5 '}R^{1 '}And R^{2 '}Is independently hydrogen, C_1-6Alkyl, C_2-6Arche
Nil, C_2-6Alkynyl, C_3-7Cycloalkyl, C_3-6Cycloalkenyl
, (CH₂)_{b '}NR^{6 '}R^{7 '}, (CH₂)_{b '}NR^{6 '}COR^{8 '}, (CH₂) _{b '} NR^{6 '}CO₂R^{9 '}, (CH₂)_{b '}NR^{6 '}SO₂R^{10 '}, (CH₂)_{b '} CONR^{11 '}R^{12 '}, Hydroxy C_1-6Alkyl, C_1-4Alkoxy
Alkyl (C_1-4May be substituted with an alkoxy or hydroxy group),
(CH₂)_{b '}CO₂C_1-6Alkyl, (CH₂)_{c '}OC (O) R^{13 '}, CR^{1 4 '} = NOR^{15 '}, CNR^{16 '}= NOR^{15 '}, COR^{17 '}, CONR^{1 1 '} R^{12 '}, CONR^{11 '}(CH₂)_{d '}OC_1-4Alkyl, CONR^{11 '} (CH₂)_{b '}CO₂R^{18 '}, CONHNR^{19 '}R^{20 '}, CONR^{11 '} SO₂R^{21 '}, CO₂R^{22 '}, Cyano, trifluoromethyl, NR^{6 '}R^{7 '} , NR^{6 '}COR^{8 '}, NR^{23 '}CO (CH₂)_{b '}NR^{23 '}R^{24 '}, N
R^{23 '}CONR^{23 '}R^{24 '}, NR^{6 '}CO₂R^{9 '}, NR^{6 '}SO₂R^{1 0 '} , N = CNR^{23 '}NR^{23 '}R^{24 '}, Nitro, hydroxy, C_1-6A
Lucoxy, hydroxy C_1-6Alkoxy, C_1-6Alkoxy C_1-6Arco
Kishi, OC (O) NR^{25 '}R^{26 '}, SR^{27 '}, SOR^{28 '}, SO₂R^{28 '} , SO₂NR^{29 '}R^{30 '}, Halogen, C_1-6Alkanoyl, CO₂(C
H₂)_{b '}OR^{31 '}Or R^{1 '}Is phenyl or R
^{1 '}Contains 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur
Are 5- to 7-membered heterocycles, wherein one or two R^{32 '}Replaced by
Or R^{1 '}May be completely or partially unsaturated, 5 to 7
An optionally substituted fused carbocycle, or R^{1 '}Is completely or
One or more selected from nitrogen, oxygen or sulfur, which may be partially unsaturated
A 5- to 7-membered optionally substituted fused heterocycle containing 4 heteroatoms
Yes; R^{3 '}Is hydrogen or C_1-6R is alkyl;^{4 '}Is hydrogen, C_1-6Alkyl, C_1-6Alkyl CONH or halogen
R^{5 '}Is hydrogen or C_1-6R is alkyl;^{14 '}, R^{15 '}, R^{16 '}, R^{17 '}, R^{18 '}, R^{19 '}, R^{20 '},
R^{23 '}, R^{24 '}, R^{27 '}And R^{31 '}Is independently hydrogen or C_{1- 6} R is alkyl;^{6 '}And R^{7 '}Is independently hydrogen or C_1-6Alkyl or
Or R^{6 '}And R^{7 '}Together with the nitrogen to which they are attached
Membered heterocyclic ring, which ring may be substituted with an oxo group, and has 6 ring atoms
Where there may be one oxygen or one sulfur atom in the ring; R^{8 '}Is hydrogen, C_1-6Alkyl or C_1-4R is alkoxyalkyl;^{9 '}, R^{21 '}And R^{28 '}Is independently C_1-6R is alkyl;^{10 '}Is C_1-6R is alkyl or phenyl;^{11 '}And R^{12 '}Is independently hydrogen or C_1-6Is alkyl
Or R^{11 '}And R^{12 '}Together with the nitrogen to which they are attached
When a 6-membered saturated heterocycle is formed and there are 6 ring atoms, one oxygen in the ring
Or there may be one sulfur atom; R^{13 '}Is one C_1-6C optionally substituted with alkoxy_1-4Archi
R; R^{22 '}Is hydrogen or C_1-6Alkyl, C_1-6Alkoxy and hydroxy
Or NR^{6 '}R^{7 '}May be substituted with one or two substituents selected from
C_1-6R is alkyl;^{25 '}And R^{26 '}Is independently hydrogen or C_1-6Is alkyl
Or R^{25 '}And R^{26 '}Together with the nitrogen to which they are attached
When forming a 6-membered heterocyclic ring with 6 ring atoms, one oxygen or
May have a sulfur atom; R^{29 '}And R^{30 '}Is independently hydrogen or C_1-6Is alkyl
Or R^{29 '}And R^{30 '}Together with the nitrogen to which they are attached
When forming a 6-membered heterocyclic ring with 6 ring atoms, one oxygen or
May have one sulfur atom; R^{32 '}Is hydrogen, C_1-6Alkyl, C_3-6Cycloalkyl, C_3-6Shiku
Loalkenyl, hydroxy C_1-6Alkyl, C_1-6Alkyl OC_1-6Al
Kill, CONR^{33 '}R^{34 '}, CO₂R^{35 '}, Cyano, aryl, trifle
Oromethyl, NR^{36 '}R^{37 '}, Nitro, hydroxy, C_1-6Alkoxy,
C_1-6R is alkanoyl, acyloxy or halogen; R^{33 '}, R^{34 '}, R^{35 '}, R^{36 '}And R^{37 '}Is, independently, hydrogen
Or C_1-6A 'is 1, 2 or 3; b' is 1, 2, 3 or 4; c 'is 0, 1, 2 or 3; d' is 1, 2 or 3 E is represented by the formula (a):(Where B is oxygen, S (O)_c, CR⁷= CR⁸Or CR⁷R⁸Or B is
NR⁹R¹And R²Is independently hydrogen or C_1-6Is alkyl;
B (CR¹R²)_aIs OCR¹R²CR¹(OH) CR¹R²Or OCR¹R²C
R¹(OCOCH₃) CR¹R²R³And R⁴Is independently hydrogen, C_1-6Alkyl, C_3-7Cycloal
Kill, aralkyl, or together with the nitrogen atom to which they are attached,
Can contain additional heteroatoms selected from oxygen, nitrogen or sulfur
To form an optionally substituted 5- to 7-membered heterocycle, wherein
The substituent is C_1-6Alkyl, aryl, CONR¹⁰R¹¹, NR¹⁰R¹¹, Hi
Droxy, OCOR¹², NHCOC_0-6Alkyl, including alkyl here
Is OH, NHCOCF₃, NHSO₂R¹³And NHCO₂R¹⁴Replaced by
R⁵Is hydrogen, C_1-6Alkyl, aryl, CN, CONR^FifteenR¹⁶, CO ₂ R¹⁷, Trifluoromethyl, NHCO₂R¹⁸, Hydroxy, C_1-6Al
Coxy, benzyloxy, OCH₂CO₂C_1-6Alkyl, OCF₃, S (O) _d R¹⁹, SO₂NR²⁰R²¹Or halogen; R⁶Is hydrogen, C_1-6Alkyl, aryl, trifluoromethyl, hydroxy
, C_1-6Alkoxy or halogen, or R⁶Is R^{5 '}Together with
To form a group D, wherein D is (CR²²R²³)_eOr D is (C
R²²R²³)_f-G, where G is oxygen, sulfur or CR²²= CR²³
, CR²²= N, = CR²²O, = CR²²S or = CR²²-NR²³so
Yes; R⁷, R⁸, R¹⁰, R¹¹, R¹², R^Fifteen, R¹⁶, R¹⁷, R²⁰, R ²¹ , R²²And R²³Is independently hydrogen or C_1-6R is alkyl;⁹Is hydrogen, C_1-6Alkyl or phenyl C_1-6R is alkyl;¹³, R¹⁴, R¹⁸And R¹⁹Is independently C_1-6Alkyl
A is 1, 2, 3 or 4; b is 1 or 2; c and d are independently 0, 1 or 2; e is 2, 3 or 4; 0, 1, 2 or 3), or alternatively E is a group of formula (b):(Where: R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³¹And R³²Is
Independently hydrogen or C_1-6R is alkyl;³⁰Is hydrogen, C_1-6Alkyl or C_3-7R is cycloalkyl;³³Is hydrogen, C_1-6Alkyl, trifluoromethyl, hydroxy or ha
Rogen or R³³And R^{5 '}Together form the group: -K-
Where K is (CR³⁴R³⁵)_iOr K is (CR³⁴R³⁵)_j−M and M
Is oxygen, sulfur, CR³⁴= CR³⁵, CR³⁴= N or N = N; J is oxygen, CR³⁶R³⁷Or NR³⁸Or J is a group: S (O)_k R³⁴, R³⁵, R³⁶, R³⁷And R³⁸Is independently hydrogen or C_{1 -6} G is 1, 2 or 3; h is 1, 2 or 3; i is 2, 3 or 4; j is 0, 1, 2 or 3; And E is a group represented by the formula (c):(Where Q is oxygen, S (O)_n, CR⁴⁴= CR⁴⁵, CR⁴⁴R⁴⁵Or
Q is NR⁴⁶R³⁹And R⁴⁰Is independently hydrogen or C_1-6R is alkyl;⁴¹Is represented by the formula (d):Or a group represented by R⁴¹Is represented by the formula (e):R is a group represented by⁴²Is hydrogen, C_1-6Alkyl, aryl, CN, CONR⁴⁸R⁴⁹, C
O₂R⁵⁰, Trifluoromethyl, NHCO₂R⁵¹, Hydroxy, C_1-6A
Lucoxy, benzyloxy, OCH₂CO₂C_1-6Alkyl, OCF₃, S (
O)_sR⁵², SO₂NR⁵³R⁵⁴Or halogen; R⁴³Is hydrogen or R⁴³Is R^{5 '}And forms a group: R
Where R is CR⁵⁵= CR⁵⁶, CR⁵⁵= CR⁵⁶CR⁵⁵R⁵⁶Or (
CR⁵⁵R⁵⁶)_tR⁴⁴, R⁴⁵, R⁴⁶, R⁴⁸, R⁴⁹, R⁵⁰, R⁵³, R⁵⁴, R⁵⁵ And R⁵⁶Is independently hydrogen or C_1-6R is alkyl;⁴⁷Is hydrogen, C_1-6Alkyl or C_3-7R is cycloalkyl;⁵¹And R⁵²Is independently C_1-6L is 0, 1, 2 or 3; m is 1 or 2; n is 0, 1 or 2; o, p and q are independently 1, 2 or 3 R is 0, 1, 2 or 3; s is 0, 1 or 2; t is 2 or 3); alternatively, E is a group represented by the formula ( f): embedded image(Where: R⁵⁷And R⁵⁸Is independently hydrogen or C_1-6R is alkyl;⁵⁹And R⁶⁰Is independently hydrogen, C_1-6Alkyl, C_3-7Cyclo
Alkyl, aralkyl or together with the nitrogen atom to which they are attached
Containing an additional heteroatom selected from oxygen, nitrogen or sulfur
Form an optionally substituted 5- to 7-membered heterocycle, wherein any
Is a substituent of C_1-6Alkyl, aryl, CONR⁶¹R⁶², NR⁶¹R⁶² , Hydroxy, OCOR⁶³, NHCOC_0-6Alkyl, where
Luquil is OH, NHCOCF₃, NHSO₂R⁶⁴And NHCO₂R⁶⁵so
T may be-(CR⁶⁶R⁶⁷)_v-Or -O (CR⁶⁶R⁶⁷)_wW is oxygen, S (O)_x, NR⁶⁸Or W is CR⁶⁹= CR⁷⁰Also
Is CR⁶⁹R⁷⁰R⁶¹, R⁶², R⁶³, R⁶⁶, R⁶⁷, R⁶⁸, R⁶⁹And R⁷⁰Is
Independently hydrogen or C_1-6R is alkyl;⁶⁴And R⁶⁵Is independently C_1-6U is 1 to 4; v is 2 or 3; w is 1, 2 or 3; x is 0, 1 or 2); , E is of the formula (g):(Where: R⁷¹Represents one to three heteroatoms selected from nitrogen, oxygen or sulfur
An optionally substituted 5- to 7-membered saturated or partially saturated heterocycle
Or R⁷¹Is selected from one nitrogen and oxygen, nitrogen or sulfur
6, 6 or optionally further containing one optional heteroatom
6,5 bicyclic rings; R⁷²Is hydrogen, C_1-6Alkyl, aryl, CN, CONR⁷⁴R⁷⁵, C
O₂R⁷⁶, Trifluoromethyl, NHCO₂R⁷⁷, Hydroxy, C_1-6A
Lucoxy, benzyloxy, OCH₂CO₂C_1-6Alkyl, OCF₃, S (
O) zR⁷⁸, SO₂NR⁷⁹R⁸⁰Or halogen; R⁷³Is hydrogen, C_1-6Alkyl, hydroxy, C_1-6Alkoxy or ha
Rogen or R⁷³And R^{5 '}And together form a group: -X-,
Where X is (CR⁸¹R⁸²)_aaOr X is (CR⁸¹R⁸²)_ab−
Y is Y, oxygen, sulfur or CR⁸¹= CR⁸²R⁷⁴, R⁷⁵, R⁷⁶, R⁷⁹, R⁸⁰, R⁸¹And R⁸²Independently
, Hydrogen or C_1-6R is alkyl;⁷⁷And R⁷⁸Is independently C_1-6Y is 1 or 2; z is 0, 1 or 2; aa is 2, 3 or 4; ab is 0, 1, 2 or 3) And E is independently of the formula (h):(Where: R⁸³And R⁸⁴Is independently hydrogen or C_1-6R is alkyl;⁸⁵And R⁸⁶Is independently hydrogen, C_1-6Alkyl, C_3-7Cyclo
Alkyl, aralkyl or together with the nitrogen atom to which they are attached
Contain one more heteroatom selected from oxygen, nitrogen or sulfur.
Forming an optionally substituted 5- to 7-membered heterocycle, wherein
Optional substituent is C_1-6Alkyl, aryl, CONR⁸⁸R⁸⁹, NR⁹⁰R ⁹¹ , Hydroxy, OCOR⁹², NHCOC_0-6Including alkyl, where
Alkyl is OH, NHCOCF₃, NHSO₂R⁹³And NHCO₂R⁹⁴ R may be substituted with⁸⁷Is hydrogen, C_1-6Alkyl, C_1-6Is alkoxy or halogen
Or R⁸⁷Is R^{5 '}And forms a group: -AA-, where AA is
(CR⁹⁵R⁹⁶)_adOr AA is (CR⁹⁵= CR⁹⁶)_ae-AB
And AB is oxygen, sulfur, CR⁹⁵= CR⁹⁶, CR⁹⁵= N, CR⁹⁵NR ⁹⁶ Or N = N; Z contains 1-3 heteroatoms selected from oxygen, nitrogen or sulfur
An optionally substituted 5- to 7-membered heterocycle;⁸⁸, R⁸⁹, R⁹⁰, R⁹¹, R⁹², R⁹⁵And R⁹⁶Independently
, Hydrogen or C_1-6R is alkyl;⁹³And R⁹⁴Is independently C_1-6Ac is 0 to 4; ad is 1, 2 or 3; ae is 0, 1 or 2); :(Where: R⁹⁷And R⁹⁸Is independently hydrogen, C_1-6Alkyl, C_3-7Cyclo
Alkyl, aralkyl or together with the nitrogen atom to which they are attached
Contain one more heteroatom selected from oxygen, nitrogen or sulfur.
Forming an optionally substituted 5- to 7-membered heterocycle, wherein
Optional substituent is C_1-6Alkyl, aryl, CONR¹⁰²R¹⁰³, NR^{1 04} R¹⁰⁵, Hydroxy, OCOR¹⁰⁶, NHCOC_0-6Includes alkyl
And the alkyl here is OH, NHCOCF₃, NHSO₂R¹⁰⁷And NH
CO₂R¹⁰⁸R may be substituted with⁹⁹And R¹⁰⁰Is independently hydrogen or C_1-6R is alkyl;¹⁰¹Is hydrogen or C_1-6Alkyl or R¹⁰¹And R^{5 '}But
Together, they form the group: -AD-, where AD is (CR¹⁰⁹R¹¹⁰)_aiso
Or AD is (CR¹⁰⁹R¹¹⁰)_aj-AE, wherein AE is oxygen,
Sulfur or CR¹⁰⁹= CR¹¹⁰AC is oxygen, CR¹¹¹R¹¹²Or NR¹¹³Or AC is a group
: S (O)_akR¹⁰², R¹⁰³, R¹⁰⁴, R¹⁰⁵, R¹⁰⁶, R¹⁰⁹, R¹¹⁰,
R¹¹¹, R¹¹²And R¹¹³Is independently hydrogen or C_1-6Alkyl
R¹⁰⁷And R¹⁰⁸Is independently C_1-6Af is 0, 1, 2, 3 or 4; ag is 1, 2 or 3; ah is 1, 2, 3 or 4; ai is 2, 3 or 4; aj is 0, 1, 2 or 3; ak is 0, 1 or 2), or a pharmaceutically acceptable salt thereof. One
Law. 2. A compound of formula (I) having the formula (Ia): Wherein R ^{1 ′} , R ^{2 ′} , R ^{3 ′} , R ^{4 ′} , P ¹ , a ′, L, R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² , R ³³ , J, g and h
Is the same as described in claim 1]. Or a pharmaceutically acceptable salt thereof. 3. The compound comprising: N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3-phenyl-2-propenamide; N- [3- [ 2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3,4-dichlorophenyl) -2-propenamide; N- [4-methoxy-3-[(2S)- (1-methyl-2-pyrrolidinyl) methoxy
] Phenyl] -3- (4-methylphenyl) -2-propenamide; N- [4-methoxy-3-[(2S)-(1-methyl-2-pyrrolidinyl) methoxy
] Phenyl] -3- (3,4-dichlorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (4 -Chlorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (3,4-difluorophenyl) -2-propene Amide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2-naphthalenyl) -2-propenamide hydrochloride; N- [3- [ 2- (2,2,6,6-tetramethylpiperidin-1-yl) ethoxy]
-4-methoxy-phenyl] -3- (3,4-dichlorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl]- 3- (3,4-dichlorophenyl) -2-propenamide; N- [1- [2- [bis (1-methylethyl) amino] ethyl] -1,2,3,4-tetrahydroquinol-7-yl ] -3- (3,4-dichlorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (3-chlorophenyl N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (3-chlorophenyl) -2-propenamide; N- [ 3- [2- (cis-2,6-dimethylpiperidin-1-yl) ethoxy] -4
-Methoxyphenyl] -3- (3-chlorophenyl) -2-propenamide; N- [3- [2- (N-cyclohexyl-N-isopropylamino) ethoxy]-
4-methoxy-phenyl] -3- (3-chlorophenyl) -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- ( 4-chlorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (4-chlorophenyl) -2-propenamide; N- [3- [2- (cis-2,6-dimethylpiperidin-1-yl) ethoxy] -4
-Methoxyphenyl] -3- (4-chlorophenyl) -2-propenamide; N- [3- [2- (N-cyclohexyl-N-isopropylamino) ethoxy]-
4-methoxy-phenyl] -3- (4-chlorophenyl) -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methylphenyl] -3- [ (3,4-methylenedioxy) phenyl] -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3-[(3, 4-methylenedioxy) phenyl] -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3-[(3,4-methylene Dioxy) phenyl] -2-propenamide; N- [3- [2- (N-cyclohexyl-N-isopropylamino) ethoxy]-
4-methoxy-phenyl] -3-[(3,4-methylenedioxy) phenyl] -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4- Methoxyphenyl] -3- (3,4-difluorophenyl) -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methylphenyl] -3- ( 3,4-difluorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (3,4-difluorophenyl) -2-propenamide; N- [3- [2- (cis-2,6-dimethylpiperidin-1-yl) ethoxy] -4
-Methoxyphenyl] -3- (3,4-difluorophenyl) -2-propenamide; N- [3- [2- (N-cyclohexyl-N-isopropylamino) ethoxy]-
4-methoxy-phenyl] -3- (3,4-difluorophenyl) -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methylphenyl]- 3- (2-naphthalenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (2-naphthalenyl) -2- N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (2-naphthalenyl) -2-propenamide; N- [3- [2 -(N-cyclohexyl-N-isopropylamino) ethoxy]-
4-methoxy-phenyl] -3- (2-naphthalenyl) -2-propenamide; (E) -N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3-chlorophenyl) -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethyl] -2-oxo- (3H
) -Benzoxazol-5-yl] -3- (3,4-dichlorophenyl) -2-propenamide; N- [4- [2- [bis (1-methylethyl) amino] ethyl] -3,4- Dihydro-
3-oxo-2H-1,4-benzoxazin-6-yl] -3- (3,4-dichlorophenyl) -2-propenamide; N- [4- [2- [bis (1-methylethyl) amino] ] Ethyl] -3,4-dihydro-
2H-1,4-benzoxazin-6-yl] -3- (3,4-dichlorophenyl-
2-propenamide; N- [2,3-dihydro-1- [2- [bis (1-methylethyl) amino] ethyl]-
1H-indol-6-yl] -3- (3,4-dichlorophenyl) -2-propenamide; (E) -N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4 -Ethoxy-methoxyphenyl] -3- (5-indolyl) -2-propenamide; (E) -N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl) -3 -(6-Indolyl) -2-propenamide; (E) -...- dimethyl-N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3 -Phenyl-2-propenamide; (Z) -N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl) -.- (acetylamino) -3- (3 , 4-dichlorophenyl) -2-
N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (3,4-dichlorophenyl)]-2-propenamide; (E)- N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (5,6,7,8-tetrahydronaphth-2-yl) -2-propenamide Trifluoroacetate; N- (spiro [benzofuran-3 (2H), 4′-piperidin] -5-yl) -3- (
3,4-dichlorophenyl) -2-propenamide; N- [1 ′-(isopropyl) spiro [benzofuran-3 (2H) 4′-piperidine
] -5-yl] -3- (3,4-dichlorophenyl) -2-propenamide; (E) -N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxy Phenyl] -3- (4-chloro-3-methylphenyl) -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (4-fluorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- [4- (trifluoromethyl) phenyl ] -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- [3- (trifluoromethyl) phenyl] -2-propene Amide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl ] -3- [3- (trifluoromethyl) phenyl] -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- [ 3- (trifluoromethyl) phenyl] -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2-chlorophenyl)- 2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (2-chlorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (2-chlorophenyl)]-2-propenamide; N- [3- [2- [bis (1-methyl) Ethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2,4-dichlorophene N) [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (2,4-dichlorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (2,4-dichlorophenyl)]-2-propenamide; N- [3- [2 -[Bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2,6-dichlorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) ) Amino] propyl] -4-methoxyphenyl] -3- (2,6-dichlorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4- Methoxyphenyl] -3- (2,6-dichlorophenyl)]-2-propenamide; N- [ -[2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3,5-difluorophenyl) -2-propenamide; N- [3- [3- [bis ( 1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (3,5-difluorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] Propoxy] -4-methoxyphenyl] -3- (3,5-difluorophenyl)]-2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxy Phenyl] -3- (2,5-difluorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (2 , 5-difluorophenyl) -2-propenamide; N- [3- [3- [bis (1-methyl Tyl) amino] propoxy] -4-methoxyphenyl] -3- (2,5-difluorophenyl)]-2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2,4-difluorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl]- 3- (2,4-difluorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (2,4- Difluorophenyl)]-2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3-fluorophenyl) -2-propenamide N- [3- [3- [bis (1-methylethyl) amino] propyl] -4 Methoxyphenyl] -3- (3-fluorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (3- Fluorophenyl)]-2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2-chloro-6-fluorophenyl)- 2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (2-chloro-6-fluorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (2-chloro-6-fluorophenyl)]-2-propenamide; N- [3 -[2- [bis (1-methylethyl) amino] ethoxy] -4-methoxy Phenyl] -3- (4-bromo-2-fluorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (4-bromo-2-fluorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (4-bromo- 2-fluorophenyl)]-2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (4-chloro-2-fluorophenyl ) -2-Propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (4-chloro-2-fluorophenyl) -2-propene Amide; N- [3- [3- [bis (1-methylethyl) amino] propoxy ] -4-methoxyphenyl] -3- (4-chloro-2-fluorophenyl)]-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl ] -3- (2-Chloro-4-fluorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- ( 2-chloro-4-fluorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (2-chloro-4 -Fluorophenyl) -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2,6-difluorophenyl) -2- Propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl L] -4-methoxyphenyl] -3- (2,6-difluorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl ] -3- (2,6-difluorophenyl)]-2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (4 -Bromophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (4-bromophenyl) -2-propenamide N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (4-bromophenyl)]-2-propenamide; N- [3- [2 -[Bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (4-chloro -3-nitrophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (4-chloro-3-nitrophenyl ) -2-Propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- [4- (1-methylethyl) phenyl] -2- N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- [4- (1-methylethyl) phenyl] -2-propenamide; N -[3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- [4- (1-methylethyl) phenyl] -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (5-bromo -2-methoxyphenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (5-bromo-2-methoxyphenyl ) -2-Propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3-([1,1′-biphenyl] -4-yl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3-([1,1'-biphenyl] -4-yl)- 2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (2,3-dihydro-1H-inden-5-yl)- 2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3-Bromo-4-fluorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (3 -Bromo-4-fluorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (3-bromo-4- (E) -N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3,5-dichlorophenyl) -2-propenamide trifluoroacetate; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (3,5-dichlorophenyl) -2-propene Amide; N- [3- [3- [bis (1-methylethyl) amino] propoxy]- -Methoxyphenyl] -3- (3,5-dichlorophenyl)]-2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3,4-dimethylphenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (3,4-dimethylphenyl ) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (3,4-dimethylphenyl) -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (4-cyanophenyl) -2-propenamide; N- [3- [3- [ Bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (4-cyanofu N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (4-cyanophenyl)]-2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -2-fluoro-3-phenyl-2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -2-fluoro-3-phenyl-2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -2-fluoro-3-phenyl-2-propenamide; (E) -N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- [4-Chloro-3- (trifluoromethyl) phenyl] -2-
Propenamide; (E) -N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3,4-dichlorophenyl) -.- methyl-2- Propenamide; (E) -N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- [4- (trifluoromethyl) phenyl] -2-propene Amide; N- [3- [2-acetoxy-3- [bis (1-methylethyl) amino] propoxy
] -4-methoxyphenyl] -3- (3,4-dichlorophenyl) -2-propenamide; N- [3- [2- (4-hydroxy-2,2,6,6-tetramethylpiperidine-1)
-Yl) ethoxy] -4-methoxyphenyl] -3- (3,4-dichlorophenyl)-
2-propenamide; N- [1 ′-(1-methylethyl) spiro [benzofuran-3 (2H) 4′-piperidin] -5-yl] -3- (3,5-dichlorophenyl) -2-propenamide N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3-thienyl) -2-propenamide; N- [3- [3- [ Bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (3-thienyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy ] -4-methoxyphenyl] -3- (3-thienyl) -2-propenamide; N- [3- [2- (cis-2,6-dimethylpiperidin-1-yl) ethoxy] -4
-Methoxyphenyl] -3- (3-thienyl) -2-propenamide; N- [3- [2- (N-cyclohexyl-N-isopropylamino) ethoxy]-
4-methoxyphenyl] -3- (3-thienyl) -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methylphenyl] -3- (4 -Pyridinyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (4-pyridinyl) -2-propenamide; N -[3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3-furanyl) -2-propenamide; N- [3- [2- [bis ( 1-methylethyl) amino] ethoxy] -4-methylphenyl] -3- (3-furanyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl]- 4-methoxyphenyl] -3- (3-furanyl) -2-propenamide; N- [3- [2- (cis-2,6 Dimethyl-piperidin-1-yl) ethoxy] -4
-Methoxyphenyl] -3- (3-furanyl) -2-propenamide; N- [3- [2- (N-cyclohexyl-N-isopropylamino) ethoxy]-
4-methoxyphenyl] -3- (3-furanyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl] -3- (2 -Thienyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propoxy] -4-methoxyphenyl] -3- (2-thienyl) -2-propenamide; N -[3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2-furanyl) -2-propenamide; N- [3- [2- [bis ( 1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (1H-indol-3-yl) -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ] Ethoxy] -4-methoxyphenyl] -3- (1H-indol-2-yl) -2-propenamide N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (1-methyl-1H-indol-2-yl) -2-propenamide; -[3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (benzo [b] thien-3-yl) -2-propenamide; N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2-benzofuranyl) -2-propenamide; and N- [3- [2- [bis (1-methyl) The method according to claim 1, wherein the method is selected from ethyl) amino] ethoxy] -4-methoxyphenyl] -3- (benzo [b] thien-2-yl) -2-propenamide. 4. The CCR5-mediated condition is COPD, asthma and atopic disorders, rheumatoid arthritis, atherosclerosis, sarcoidosis and other fibrosis-type diseases, psoriasis, autoimmune diseases such as multiple sclerosis 2. The method of claim 1, wherein the method is selected from: inflammatory bowel disease and HIV infection. 5. N- [3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (3,4-dichlorophenyl) -2-propenamide; 3- [2- [bis (1-methylethyl) amino] ethoxy] -4-methoxyphenyl] -3- (2-naphthalenyl) -2-propenamide hydrochloride; N- [3- [2- (2, 2,6,6-tetramethylpiperidin-1-yl) ethoxy]
-4-methoxy-phenyl] -3- (3,4-dichlorophenyl) -2-propenamide; N- [3- [3- [bis (1-methylethyl) amino] propyl] -4-methoxyphenyl]- 3- (3,4-dichlorophenyl) -2-propenamide; N- [3- [2- (4-hydroxy-2,2,6,6-tetramethylpiperidine-1)
-Yl) ethoxy] -4-methoxyphenyl] -3- (3,4-dichlorophenyl)-
2-propenamide; and N- [1 '-(1-methylethyl) spiro [benzofuran-3 (2H) 4'-piperidin] -5-yl] -3- (3,5-dichlorophenyl) -2-propene A compound of formula (I) selected from amides.