TW200817341A - Diamine-containing, tetra-substituted piperazine compounds having identical 1-and 4-substituents - Google Patents

Abstract

There is provided compounds having the formula of structure I: wherein the groups-C(R8)(CH2)vCH(R9)(CH2)y-Q and -C(R8)(CH2)vCH(R9)(CH2)y-J are the same, and R1a, R1b, R2a, R2b, R8, R9, J, Q, W, X, L2, v and y have meanings given in the description. The use of such compounds in the treatment of a condition responsive to changes in melanocortin receptor function in a human or non-human mammal (e.g. male sexual dysfunction, female sexual dysfunction, an eating disorder, above optimal body weight, obesity, below-optimal body weight or cachexia) is also described.

Description

200817341 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to a four-substituted brigade well compound in which a diamine group unites one or more melanocortin receptors and one or more melanin skins A agonist, antagonist, mixed agonist, antagonist, inverse agonist or antagonist of an inverse agonist, and relates to its use in the treatment of metabolism, immunity, infection The use of conditions and other melanocortin receptor mediated conditions includes the treatment of obesity and related energy balance disorders and diseases. [Prior Art] The melanocortin receptor type and subtype family have been identified, including melanocortin-丨 receptor (MCI-R) expressed on normal human melanocytes and melanoma cells, and adrenal cells. Among the ACTH (corticotropin) acne-pyridin-2 ^: body (MC2-R), mainly in the hypothalamus, midbrain and brain stem cells, the melanocortin-3 receptor and black The cortisol-4 receptor (MC3_r& MC4-R) and the melanocortin_5 receptor (MC5-R) expressed in widely distributed tissues. In general, the compound specific to MC1-R Suitable for the treatment of melanoma. Salty or MC4-R specific compounds are suitable for regulating energy balance, including agents for reducing food intake and weight gain, for treating anorexia, for use as weight gain aids, for treating obesity and for treating other food intakes And metabolic related purposes. Compounds specific for MC3-R and MC4-R are additionally useful as agents for the treatment of sexual dysfunction, including male erectile dysfunction and female sexual dysfunction. Other compounds specific for the melanocortin receptor (such as the MCRq agonist) are useful as chemopreventive agents for increasing the melanin production of skin melanin and acting as a detrimental agent against uv solar radiation. Compounds of MCR-UMCR-3 (d) may additionally be useful for modulating the inflammatory process. There is an urgent need for a human that is highly specific for discrete melanocortin receptors and a 1 'purine that acts as an agonist or antagonist of a specific melanocortin receptor. High-affinity compounds of the melanocortin receptor can be used as agonists or antagonists to develop various physiological responses associated with melanocortin receptors. In addition, the melanocortin receptor has a role in the activity of various cytokines, and a high affinity compound of the melanin receptor can be used to regulate cytokine activity. It is known to identify piperphine and piperidine compounds specific for melanocortin or related receptors, such as disclosed in WO 02/070511 (BHst() l_Myers

Squibb Company) ^ WO 02/059095 (Eli Lilly and Company) and WO 00/74679 (Merck & Co., lnc). However, in general, such compounds have up to two functional group-substituted groups of V groups, have relatively poor affinity and specificity, and are unsuitable for use as pharmaceutical compounds. There is an urgent need for compounds that are highly specific for discrete receptors such as melanocortin and other receptors, as well as agonists or antagonists of such receptors. The 6-specific receptor affinity compounds can be used as agonists or antagonists for the development of various physiological responses associated with such receptors. Therefore, there is a need for compounds that are more selective (including higher affinity and specificity), and in particular compounds having at least 3 or 4 biologically active substituted groups. The present invention addresses its needs. Presented to The Proctor & Gamble, 乂 乂 〇 122 122 122 122 122 122 122 122 122 122 122 122 698 698 698 698 698 698 698 698 698 698 698 698 698 698 698 698 698 698 698 698 698 698 698 698 698 698 698 698 698 698 698 698 698 698 698 698 698 698 698 698 698 698 698 698 698 698. a pipetting structure of more than one substituted group, a method of synthesizing a piperene structure, a method of synthesizing a piperidine structure having four or more substituted groups, or a method of synthesizing an optically pure structure, and additionally not revealing a single Substituent (ie single; 〇_1>1^ or 〇_

The structure of the Nal residue, or a derivative or homolog of the amine-terminated group, as the case may be. The co-pending U.S. Patent Application Serial No. 10/837, No. 5, the disclosure of which is incorporated herein by reference in its entirety by reference in its entirety in its entirety, the disclosure of the disclosure of the entire disclosure of a tripping compound having four substituted groups, wherein one substituted group includes a diamine hetero atom unit having at least one cationic center, a hydrogen bond donor or a hydrogen bond acceptor, and each of the remaining three substituted groups Includes a ring structure. The present application claims priority to commonly owned International Patent Application No. PCT/US06/31472 (published as WO 2007/021990). For the first time, the application discloses a number of specific four-substituted bridging compounds, in which the substituents on the two N atoms of the brigade ring are the same. For specific purposes, methods, synthetic processes, uses, applications, definitions, protocols, and other disclosures, this application is related to the title "Piperazine"

Melanocortin-Specific Compounds'', U.S. Patent Application Serial No. 10/762,079, filed on Jan. 21, 2004, and the title of 'Peptidomimetics of Biologically Active Metallopeptides, International Application No. PCT/US02, filed on August 12, 2002 /25574, International Publication No. WO 03/0 13 571, and the description of each of the foregoing is hereby incorporated by reference in its entirety in its entirety by reference in its entirety. Treatment of conditions associated with energy balance adjustment (including drugs for reducing food intake and weight gain d) compounds for the treatment of obesity and for the treatment of other food intake and metabolism related purposes. [Description of the Invention] According to the present invention, a compound of formula I:

Or an enantiomer, a stereoisomer or a diastereomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 a, R 1 b, 2 a fen p 2 b gem One or both are independently (^ to (6 aliphatic or branched) and the remaining Rla, Rlb, 2, , R and 11 are gases, the constraint being at least one of R and R and R2a至少; at least one of the singers, or one of Rla, Rlb, R2a, and R2b

Or the remaining Rla, Rlb, R2a & R2b are hydrogen; or RU and Rlb together form = 〇 and R2a and R2b are a < one is ^ to a steroidal group 122698.doc -9- 200817341 straight or branched chain,

And the remaining R2a&R y is an independent index value of 0 to 5 in each case; w is a diamine hetero atom unit having at least one cationic center, hydrogen bond donor or hydrogen bond acceptor; 〇〇L2 is a bond or (ch2)z ; z is the index value of 1 to 6; X is CH2, C = 〇 or C = S; group -C(R8)(CH2)vCH(R9)(CH2)y_Q and -C(R8) (CH2)vCH(R9)(CH2)yJ is the same and in the same group: R8 is Η or =0; R9 is hydrogen or N(R10a)R〇b; R and Rl〇b are independently hydrogen , ethyl hydrazino, methyl, ethyl, propyl isopropyl, butyl, pentyl, hexyl, isobutyl, benzyl, benzhydryl hexyl, propyl sulfonyl, butyl fluorenyl, pentamidine, g Anthracenyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclohexyl, cyclohexylmethyl or polyethylene glycol; V is an index of 0 to 2; and Q and J are the same and represent An aromatic carbocyclic ring selected from the group consisting of a phenyl group, a substituted phenyl group, a naphthyl group, and a substituted naphthyl group; wherein the carbon atom labeled with an asterisk has any stereochemical configuration. 122698.doc 200817341 It may have a molecular weight of between 100 and 50,000 when polyethylene glycol is present. Compounds of structure I may be mentioned. Do not include compounds in which R8 is =0. In the structure I compound, Q may be

Wherein R3a, R3b and r3c are % substituents which may be employed, and when one or more are present, they are the same or different and are independently hydroxy, halo, alkyl, _0-alkyl, aryl or _ 〇 _ aryl. In one aspect, at least one of R3a, 3c or 11 is -ch3 or -o-CH3. In another aspect, at least one of R3a, 3b κ or R is _C1 or -CF3. Alcohol, Carboxylic Acid In the structure 1 compound, W may include an amine, a guanamine ether, an ester or a urea. Therefore, in one aspect, w is ··

R "Mr

FT wherein R4 is: NH, 〇' is limited to R5 comprising a diamine, CH2, the restriction is that R5 comprises a diamine, and GH5' is limited to R5 comprising a diamine, n(-ch2)z, wherein N( CH2)z together with anaesthesia 5 form a production of n(-(ch2vch3), clothing 122698.doc • 11 - 200817341 NH-C(=〇), NH-C(=〇)_NH, with the restriction that R5 does not contain N , C(=〇) 'There is a limitation that R5 contains a diamine, C(=0)-NH, C(-0)-〇', and the restriction condition is that R5 contains a diamine, or 0_C(=0)' The condition is that R5 comprises a diamine; R5 is NH2', the restriction condition is that r4 contains one n, and the hydroxyl group is limited to R4 comprising a diamine, CH3, and the restriction condition is that R4 comprises a diamine, NH-(CH2)Z' NIHCh2)z together form a ring, NH-(CH2)y_CH3, N(-(CH2)y-CH3)2, NH-(CH2)Z_NH2, NH-(CH2)z-NH-(CH2)y-CH3, NH-(CH2)zN-((CH2)y-CH3)2, N(-(CH2)y-CH3), (CH2)z-NH(CH2)y-CH3, N(-(CH2)rCH3)_ (CH2)zN((CH2)rCH3)2, NH-C(=〇HCH2)rNH2, 〇-(CH2)y-CH3' is limited to R4 containing diamine, S02-NH2, S02-NH-(CH2 )y-CH3, so2-n(-(ch2vch3)2, S〇2-(CH2)y-CH3 'The restriction is that R4 contains a diamine, 122698.doc -12- 3 4200817341

'where zero, one or more of positions 1 to 5 are = two positions selected from the following and positions 2 to 5 are S, 0 or bribe, with the constraint that the right R contains N, then only one N exists; Rule 4 contains two outer R5 $ diamines, then there is no N,

Ο 2R 'where the zeros of positions 1 to 5, or both are the positions of the hetero atom selected from below and the position of the connection r6 (if the position does not contain 〇N and other positions are s, 〇 or legs , the restriction condition is that if the Han 4 contains n, the V including r6 only contains -N; if the rule 4 contains a diamine, and R6 is further included, and R5 contains a diamine, then N is absent.

ί , wherein the bond between at least one adjacent ring atom is a double bond, and zero or one or more of positions 1 to 5 are heteroatoms selected from the group consisting of position 1 and any double bond position N, and position 2 to 5 is additionally s, 〇 or nh, the restriction condition is that at most one position is § or 〇, and another restriction condition is that if R4 contains N, only -N is present; if r4^ contains diamine and another R5 Containing a diamine, there is no N,

R, wherein the bond between at least one adjacent ring atom is a double bond and - or more of the positions 1 to 5 are heteroatoms selected from the following: position 1, position of R6 (if the position does not contain c) and any double bond position is N, and positions 2 to 5 are additionally s, 〇 4Nh, with the restriction that at most one position is S or Ο, and another restriction condition is that if R4 contains N, R5 including R6 Contains only one N; if...contains diamine and additionally includes 122698.doc •13· 200817341 r6^r5 contains diamine, then there is no Ν, 'At least one of them is clear?* ^ ^ phase between & between atoms The bond is a double bond, the pendant oxy group is attached to the loamy carbon, and the remaining (d) positions 1 to 5 - or more are optionally selected from the following heteroatoms. The position w is 1 and any double bond position is N and Positions 1 to 5 are additionally s, 〇 or bribes, with the restriction that at most - the ring position is s or 〇 ' and the other - the restriction condition is that if the genus 4 contains n, only one is present.

N broadly contains a diamine and the other contains a diamine, then there is no n, Ο Ο 其中' wherein the bond between at least one adjacent ring atom is a double bond, the pendant oxy group is attached to the ring carbon, and in position (1) One or more conditions are selected from the following heteroatoms: position, position to connect R6 (if the position does not contain C) and any double bond position is N, and positions 2 to 5 are additionally s, 〇 or NH, the limit The condition is that at most one position is 8 or 〇, and the other limitation is that if R4 contains N, % includes R6, R5 only contains -N; if <diamine and additionally contains diamine, then there is no N right 2 3 1 2 'One of the positions 1 to 6 or more is selected from the following

Atom: position 1 is Ν and position 2 to 6 is s, 〇 or simplification, with the proviso that if R2 contains N, then R5 together with R6 contains only one n; if R contains hexamine and R6 contains R6 Diamine, then there is no N, ^ 122698.doc -14· 1 , wherein zero, one or both of positions 1 to 6 are selected from heteroatoms of 2: position 1 and position of R6 (if The position does not contain C) 200817341 is N and the other positions are S, 〇 or NH, and the restriction condition is that if R 4 contains N, R62R5 includes only one N, · If R4 contains diamine and R5 contains rR6 contains two An amine, wherein N is absent, wherein the bond between at least one adjacent ring atom is a double bond, and one or more of positions 1 to 6 is a hetero atom selected from the following: position i and any double bond position is N and position 2 to 6 are additionally s, 〇4NH4N_

(H2)y CH3, the restriction condition is that at most two positions are s or ο, and another restriction condition is that if R4 contains Ν, then Han 5 together with R6 contains only one N; if R4 contains diamine and additionally includes r6 R5 comprises a diamine, wherein N, 3 is absent, wherein the bond between at least one adjacent ring atom is a double bond, and one or more of positions 1 to 6 are optionally selected from the following hetero atom positions 1 and Any double button position is N and position 2 to 6 is additionally S, 〇

U

Or NH 'with the proviso that at most two positions are § or 〇, and the other restriction is that if R4 contains N, then the ruler 5 including the ruler 6 contains only one n; if the R4 gas contains a diamine and additionally includes "Conducting a diamine, there is no n, wherein the bond between at least one adjacent ring atom is a double bond, the pendant oxy group is attached to the ring carbon, and the _ position (1) - or more is selected from the following Heteroatoms: position 1 and any double bond position is N and positions 2 to 6 are additionally S, Ο or NH, with the constraint that at most two positions are S or 〇 'and the other - the constraint is (4) contains N, then There is only one 122698.doc -15- 200817341 Ν; if R4 contains a diamine and another han 5 contains a diamine, then no Ν, or v^5

:〇' wherein the bond between at least one adjacent ring atom is a double bond' side oxy is attached to the ring carbon, and one or more of positions 1 to 6 are heteroatoms selected from the following: position i , the position where R6 is connected (if the position does not contain c) and any double bond position is N, and the position 2 to 6 is additionally S, Ο or NH, the restriction condition is that at most two positions are s or 〇, and another 1) A limiting condition is that if R4 contains N, then "including" contains only one N, right R contains a diamine and additionally R62R5 contains a diamine, then N is absent; R is an L group (CH2VCH3, (CH2) y-NH2, NH2, NH-(CH2)y-CH3 or N(_(CH2)y-CH3)2; t is an index value of 0 to 6; y is independently an index value of 〇5 in each case And Z is an index value of 1 to 6; the limiting condition is that any of the aforementioned erythrene VIII VIII JH or NH2 may be substituted by N-Prg or NH-Prg, respectively, wherein each Prg is independently an amine protecting group. In the description of the structure of the coat containing the coat of clothing, it should be understood that the ring structure can only include a double 鐽吱 push with π 廿 non-heart m and special μ, use ^ non-dark _ possible double bond as Prg In the meantime, each Prg may independently be a sulfhydryl group, a benzyl group, a benzyl group, a: &amp; soil, an adamantry base, ^ 4 „ ^ Α dibutoxycarbonyl, a stilbene benzene-2- Sulfonyl, 4-mercapto-2,3-6-dimethyl-#**-methyl·sulfonyl, 2,2,4,6,7-pentamethyldi 122698.doc -16 - 200817341 Hydroquinonefuran-5-sulfonyl, 2,2,5,7,8-pentamethylnonane_6_sulfonyl or toluenesulfonyl. In another aspect of the structure I compound , w is: wherein R4 is: NH, 〇, the restriction condition is that R5 contains a diamine, Ο

CH2' is limited to the fact that R5 comprises a diamine, N(-CH2)Z, wherein n(CH2)z forms a ring together with R5, N(-(CH2)rCH3), NH-C(=0), NH- C(=0)-NH, the restriction condition is that R5 does not contain N, C(=0), and the restriction condition is that R5 contains diamine, C(=0)-NH, C(=0)-0' The condition is that R5 comprises a diamine, or 0-C(=0)', the restriction condition is that R5 comprises a diamine; R5 is NH2', and the restriction condition is that r4 comprises an n, a hydroxyl group, and the restriction condition is that R4 comprises a diamine, CH3 'There is a restriction that r4 contains a diamine, NH-(CH2)Z, wherein ΝΗ-((:Η2)Ζ together with R4 forms a ring, NH-(CH2)y-CH3, N(-(CH2)y- CH3)2, 122698.doc -17- 200817341 nh-(ch2)z-nh2, NH-(CH2)z_NH-(CH2)y-CH3, NH-(CH2)zN-((CH2)y-CH3)2 , N(-(CH2)y-CH3)-(CH2)z-NH(CH2)y_CH3, n(-(ch2vch3hch2)zn((ch2vch3)2, NH-C(=0)_(CH2)y_NH2, 0 -(CH2)y-CH3, with the limitation that R4 comprises a diamine, SO2-NH2, ΟS02-NH-(CH2)rCH3, S〇2-N(-(CH2)y-CH3)2, S〇2 】(CH2)y_CH3, the restriction condition is that r4 contains a diamine,

One or more of its positions 1 to 5 are selected from the following: heteroatoms: positions and positions 2 to 5 are 8, 〇 or jobs, with the proviso that if R4 contains N, then only one N exists; If R4 contains a diamine and additionally R5 contains a diamine, then N, 4 is absent.

Wherein the position is zero to zero, one or both are heteroatoms selected from the group consisting of the position L and the position of the connection R6 (if the position does not include N and the other positions are S, 〇 or pass, the limitation is If r4 contains a heart, R5 including R6 contains only one N; * R6P5 contains a diamine, and N is present.

The bond between at least one adjacent ring atom is double and 122698.doc 200817341 j is set to zero or one or more of 1 to 5 is a hetero atom selected from the group consisting of: position and any double bond position is Ν 'and position 2 to 5 is additionally s, 0 or simplification, wherein: 4 conditions are at most one position of 8 or 0, and another p 5 匕 3 N, then only one N exists; if R4 contains a diamine and additionally contains a diamine, Then there is no N,

Ο R, wherein the bond between at least one adjacent ring atom is a double bond, and one or more of 1 to 5 are heteroatoms selected from the following: position 1 and position of R6 (if the position * Contains C) where the double bond position is N and the position 2 to 5 is additionally s, 〇 or nh, with the constraint that the position is S or 至, and the other constraint is that if r4 contains n, then 6 includes R6 R5 contains only one N; *r4 contains a diamine and additionally includes r6, and r5 contains a diamine, and N is not present.

Ο wherein the bond between at least one adjacent ring atom is a double bond, the pendant oxy group is attached to the ring carbon, and one of the remaining positions i to 5 is selected from the following heteroatoms: position 41 and any double bond position 2 to 5 is additionally S, Ο or NH, with the constraint that at most one ring position is S or Ο, and another restriction is that if R4 contains N, then only one Ί R4 contains a diamine and the other R5 contains Diamine, there is no N,

, 〇 'the ten bond between at least one adjacent ring atom is a double bond, the hydroxy group is attached to the ring carbon, and the positions 1 to 5 - or more are selected from the following heteroatoms W i, the position of the connection r6 (if the position is not 122698.doc -19- 200817341 contains C) and any double bond position is N, and the position 2 to 5 is additionally s, 〇 or nh, the restriction condition is at most one position s or 〇, and another restriction condition is that if R contains N, R5 including R6 contains only one N, and if n 4 contains 6 diamine and additionally includes anti-6 han 5 containing diamine, then n is absent.

C

L

Wherein one or more of positions 1 to 6 are heterogenes selected from the group consisting of y, position 1 being N, and position 2 to 6 being 8, sputum or brain, with the proviso that if R4 contains N, then R5 together with R6 Containing only one 1; if Han 4 contains a-amine and additionally includes "Jun 5 contains a diamine, then n is absent, where zero, one or both of positions 1 to 6 are heteroatoms selected from the following : position i and the position of the connection r6 (if the position does not include 〇N and other positions are s, 〇 or NH, the limitation is that if N is included, then RkR5 includes only one (four); and the reference 4 contains diamine and includes R5 of eR6 contains a diamine, and N does not exist.

, wherein the bond between at least one adjacent ring atom is a double bond, and the position 1 to 6 or more - or more is a hetero atom selected from the group consisting of any double bond position N and position 2 to 6 s, 〇 or bribe or 义 (CH2) y-CH3, the restriction condition is that at most two positions are ^ or 〇, - the restriction condition is that if r4 contains N, then r5 together with r6 only contains N; if R4 contains two Amine and additionally including the ruler 5 of the ruler 6 in N, 匕a-amine, there is no 122698.doc •20- 6 200817341

Hr6 2:4 wherein the bond between at least one adjacent ring atom is a double bond, and one or more of positions 1 to 6 are heteroatoms selected from the following: position 1 and any double bond positions are N and positions 2 to 6 are additionally s, 〇 or NH, with the constraint that at most two positions are s or 〇, and another constraint is that if R4 contains N, then R62R5 includes only one N, • if R4 The ruler 5 containing a diamine and additionally including ... contains a diamine, and there is no n right Γ

3, wherein the bond between at least one adjacent ring atom is a double bond, the pendant oxy group is attached to the ring carbon, and one or more of the remaining positions 丨 to 6 are heteroatoms selected from the following: D and any double bond positions are at positions 2 to 6 and additionally S, 〇 or NH, with the constraint that at most two positions are S or 〇, and another restriction condition is that if R4 contains n, only one N exists; If R4 contains a diamine and additionally... contains a diamine, then n is not present, or

Wherein the bond between at least one adjacent ring atom is a double bond: the side fluorenyl group is attached to the ring carbon, and one or more of the positions (1) is a hetero atom selected from the following: a position 丨, a connection R6 The position (if the setting does not include a C) and any double bond position is N, and the position 2 to 6 is additionally or NH, the restriction condition is that at most two positions are $ or 〇, and another restriction condition is if R4 Including N, then r^r5 comprises only one N; if 114 comprises a diamine and R5 comprising R6 comprises a diamine, then N is absent; 122698.doc •21- 200817341 R is fluorenyl (CH2)y -CH3, (CH2)y-NH2, ΝΗ2, NH-(CH2)y CH3 or N(-(CH2)y-CH3)2; R7 is a ring containing a ring-burning or aromatic ring substituted by a woman's condition to ~ An aliphatic group; y is independently an index value of 〇 to 5 in each case; and z is an index value of 1 to 6; wherein any of the aforementioned NH or NH2 may be substituted by N_PrplNH_prg, respectively, wherein each Prg is independently an amine protecting group . Ο Ο In the foregoing description of the ring structure containing a ring in the ring, it should be understood that the ring structure may include only one double bond or may include more than one double bond, and in particular, the use of a ring does not imply all possible doubles. The keys are all present. Herein, in the presence of Prg, each Prg may independently be an ethyl sulfonyl group, an adamantyloxy group, a benzindenyl group, a benzyl group, a benzyloxycarbonyl group, a third butoxycarbonyl group, a mesitylene-2-sulfonyl group, 4_曱oxy-2,3_6_tridecyl-benzenesulfonyl, 2,2,4,6,7-pentamethyldihydrobenzinofuran-5-sulfonyl, 2,2,5, 7,8-pentamethylnonane-6-sulfonyl, 9-fluorenyloxycarbonyl or anthracenesulfonyl. Among the aspects of the structure I compound, one of them is:

Or the remaining R2a &amp; R2b and both Rh and Rib are hydrogen. The invention further provides a compound having the structural formula: 122698.doc -22- 200817341 R8

::::::Zhao's heterogeneous Zhao or diastereomeric pro- or its medicine. Among them: 1 to C 6 aliphatic, its restriction strip

One of τ ^ or both of Rla, Rlb, R2a and R2b is c straight or branched and the remaining Rla, Rib, R2a & R2b are 3 pieces of at least one of Rla and Rlb and RZa and RZb To the air;

Or one of Rla, Rlb, R2a &amp; R2b is:

Or RU and Rlb are formed together and one of R2a&amp; R2b is q to Q month straight or branched,

or

And the remaining R2a and R2b are hydrogen R4, NH, N(-(CH2)y-CH3), NH_c(=〇) or c(=〇&gt;NH; R5a^NH2 ^ NH.(CH2)y.CH3,icN (.(CH2)y-CH3)2; y is independently the index value of 〇5 in each case; 122698.doc -23 - 200817341 Group-C(R8)CH(R9)(CH2)yQ and - C(R8)CH(R9)(CH2)yJ is the same, and in these groups: R8 is Η or =〇; R9 is hydrogen or N(R1Ga)R10b; ulnar and Ri〇b are independently Hydrogen, acetyl, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, isobutyl, benzyl, benzhydryl, hexyl, propyl, butyl, Pentamidine, heptyl, cyclopropyl, cyclopropyl-p-methyl, cyclobutyl, cyclobutylmethyl, cyclohexyl or cyclohexylmethyl; Q and J are the same and are selected from phenyl, substituted phenyl An aromatic carbocyclic ring of a group consisting of naphthyl and substituted naphthyl groups; and z is an index value of 1 to 6; the carbon atom labeled with oysters in octa can have any stereochemical configuration. In the aspect, a pharmaceutical composition comprising a structure or a structure and a pharmaceutically acceptable carrier is provided. Use of the composition of the invention, such as for the administration of the pharmaceutical composition to visualize the "melanocortin receptor function" in a human or non-human mammal. In addition, the use of a pharmaceutical composition is provided. It is used to prepare a drug for the treatment of changes in melanocortin receptor function in human &amp; non-human mammals. In this application, the condition may be free of male sexual function, P Early obstruction, female sexual dysfunction, eating disorder, over optimal body weight, obesity lower than optimal body weight and cachexia composition. The present invention additionally provides as a melanin receptor (including (4), MC5_R - or more a compound of the m-effect agent. The compound such as 5 °H is a melanocortin receptor (including one or more of MCl-R, MC3_122698.doc -24-200817341 R, MC4-R or MC5-R) Antagonists. Alternatively, the compounds are inverse agonists of a melanocortin receptor (including one or more of MCl-R, MC3_R, MC4_R or MC5_R). Alternatively, the compounds are melanocortin. Receptor (including one or more of MC1-R, MC3_R, MC4_R4MC5_r . An antagonist of a reverse agonist. The invention further comprises a method for altering a condition or condition associated with melanocortin receptor activity, comprising administering to a patient a therapeutically effective amount of a compound of the invention In an embodiment, the condition or condition is an eating disorder, such as cachexia. In another embodiment, the condition or condition is obesity and a dysfunction associated with energy balance. In yet another embodiment, the condition or condition is a sexual dysfunction, such as erectile dysfunction or female sexual dysfunction. One of the objectives of the present invention is to provide a conformational limitation of the tetra-substituted piperene and optical purity = the pendant group of the octagonal octene is an amino acid moiety, an amino acid side chain moiety or a living organism thereof such that the resulting cyclic compound Biologically related related inverted structures.另 Another goal of this month is to provide a method for synthesizing optically pure tetra-substituted arable compounds. Another objective of the present invention is to provide a pendant nucleophilic compound having a side group therein. The side group such as 16$ is a side group of a virgin acid or a side chain portion comprising an amino acid. • Another goal of this month is to provide a tetra-substituted piperculosis compound in which the compound is specific for one or more melanocortin receptors. Another option for the month is to provide a method for synthesizing the four-substituted bridging compound of the present invention. In the present invention, it is disclosed that a pipette ring having four descriptors can be used, and each descriptor in 122698.doc -25-200817341 is a side group attached to a given ring red atom, and wherein - a description An amine group is included. At least two and eight 俨士士慧# I wish (1) / brother all [the remaining side base package 3 clothing structure, wherein the ring in each descriptor or side group is a carbon ring and at least two of the rings in the basin are aromatic . By using four descriptors, the inventors have discovered that the ring is opposite to the palm of the hand and generally the stereoscopic structure & ^ 餸, and the mouth structure is fixed to the dryness. Simulate the desired pharmacophore, and the descriptors are placed in the relevant chemical space. 〇 In addition, it is also prepared for an enantiomeric pure tetra-extract, which is preferably ', or a synthetic process disclosed herein or a variant thereof. Blood-type plough soil is a six-membered ring structure with dynamic configuration. It can exist in a variety of configurations, commonly referred to as a chair, boat, twisted chair or twisted boat configuration. Because this = the dynamics of the state', the position of the descriptor on the ring plays an important role in stabilizing the ring into an early-configuration state; if the proper configuration is chosen, it helps the molecule to have more receptors for it. Selectivity. For example, placing two large descriptors axially generally causes an unfavorable space 0# interaction between the two groups, and thus makes the chair configuration less energetically unstable. Therefore, the #-configuration is less preferred, which results in a twisted chair or boat configuration. The twisted # or ship configuration results in a specific stereochemical arrangement of the descriptors, which is specifically related to the interaction of the . Thus, the configuration resulting from the 1&gt;3' axial placement of the two descriptors produces a structure that is more selective for a given receptor subtype. In yet another embodiment, the invention describes a tetrasubstituted purine compound wherein one substituted group includes a diamine, the compounds being specific for a G protein coupled receptor system, including but not limited to Melanin or melanin 122698.doc -26 - 200817341 Quality receptors (MCl-R, MC3-R, MC4-R&amp; MC5_r). [Embodiment] Definitions Before continuing to carry out embodiments of the present invention, certain terms are defined as described herein. The term "waste shame" as used in the present invention and the terms used in the specification and patent application include known naturally occurring protein amino acids, which are represented by their common three-letter abbreviations and one-letter abbreviations. General see

Synthetic Peptides: A User, Guide, GA Grant, W.H·

Freeman &amp; Co., New York, 1992, the teachings (including the text and tables described above) are incorporated herein by reference. As mentioned above, the term "蜃" also includes naturally occurring protein amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, mimetic amino acids. Stereoisomers and modifications of the design or structure of the design and its analogs. Modified and uncommon amino acids are generally described in the Synthetic Peptides: A User, s Guide; Hruby VJ, A1-obeidi F and Kazmierski W: Biochem J 268: 249-262, 1990; and Toniolo C: Int J Peptide Protein Res 35: 287-300, 1990; all teachings are hereby incorporated by reference. As used herein, the term "substantially different" includes any side chain of any amino acid (as defined herein, the term "蜃"), including any derivative of an amino acid side chain moiety (eg, The term defined in this article, Shulan Bed &quot;). This therefore includes the side chain moieties present in the naturally occurring amino acid. Also included are modified side chains of naturally occurring amino acids (such as glycosylated amino acids) 122698.doc -27- 200817341. The sickle additionally includes naturally occurring protein 皙 I I deficiency, ^ ^ your heart greedy N-based acid 'non-protein amine-oxime, modified amino acid after transesteration, amino acid derived from the mouth, derivatized amino acid, design of aramid acid or έ fly, Ό structure and the like The stereoisomer of the substance and the side key portion of the decoration. The side chain portion of any of the amino acids disclosed herein is included in the definition of the amino acid side chain moiety. The &quot;the side chain portion of the amino acid includes any modification or change to the side chain portion of any amino acid', including the repair of the side chain portion of the amino acid in the day (4), and the derivatization of the side chain portion of the amino acid. The inclusions include straight or branched chains, % or acyclic &amp; substituted or unsubstituted, saturated or unsaturated, alkyl, aryl or aryl moiety. Ο Ο In the list of compounds of the present invention, conventional amino acid residues have the conventional meanings as given in Chapter 2400 of the 8th edition of the ual of pafent Examining Procedure. Therefore, Nle, is a positive leucine;,, Asp, is aspartic acid; "His" is histidine;,, D_Phe, is D_phenylalanine;,, Arg·, is fine Aminic acid; "Trp" is tryptophan; "Lys" is lysine; "Gly" is glycine, 'Pro' is valine; "Tyr" is tyrosine; "Ser" is silk Amino acid and so on. In the specification and the scope of the patent application, the term "shoulder #" includes, but is not limited to, (a) a D-amino acid residue or a side chain substituted L-amino acid residue side chain, (... after translation Residue or side chain to replace the residue or side chain, (c) non-peptide or other modified amino acid residue or side chain based on another residue or side chain, such as phenylglycine; for phenylalanine Residues are homophenylalanine, ring-substituted halogenated and alkylated or arylated phenylalanine; diaminopropionic acid; diaminobutyric acid; ornithine; lysine and high-precision for arginine residues Aminic acid; and its analogous 122698.doc -28 - 200817341, and (d) any amino acid residue or side chain, coder or other, or structure or structure of a mimetic amino acid residue or side chain, and In the case of a saturated aliphatic side bond, a functionalized aliphatic side chain, an aromatic side chain or a heteroaromatic side chain, it has at least one side chain having a similar charge (neutral, positive or negative), preferably The class II is hydrophobic or hydrophilic and preferably resembles a side chain. The term "sand" includes unsaturated hydrocarbons containing one or more carbon-carbon double bonds. Examples of the group include ethylene, propylene, and the like. The term "tolerance" includes a linear monovalent hydrocarbon group having 2 to 6 carbon atoms or a branch chain having 3 to 6 carbon atoms containing at least one double bond. The monovalent hydrocarbon group; the κ examples thereof include an ethyl fluorenyl group, a 2-propenyl group, and the like. The term "tiger difference" as used herein includes the alkyl groups configured for a straight chain or a branched chain. Examples of such alkyl groups Including methyl, ethyl, propyl, isopropyl, butyl, t-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and the like. The term π silencing includes a linear monovalent hydrocarbon group having 2 to 6 carbon atoms or a branched chain monovalent hydrocarbon group having 3 to 6 carbon atoms; at least one of which includes an ethynyl group, a propynyl group, a butynyl group and the like. The term ''spray difference π' includes 6 to 12 ring atoms and optionally, independently, one or more selected from the group consisting of alkyl, _alkyl, cycloalkyl, alkoxy, alkylthio, halo, nitrate Base, mercapto, cyano, amine, monosubstituted amine, disubstituted amine, hydroxy, carboxy or alkoxy Monocyclic or bicyclic aromatic hydrocarbon groups substituted with substituents. Examples of aryl groups include phenyl, biphenyl, naphthyl, naphthyl and 2-naphthyl, derivatives thereof and the like. The radical π includes a group -RaRb, wherein Ra is a stretching group (divalent sinter 122698.doc -29-200817341 yl) and R is an aryl group as defined above. Examples of the aralkyl group include a benzyl group and a benzene group. Ethyl, 3-(3-chlorophenyl)-2-indenylpentyl and the like. The term ''waste family, including compounds having a hydrocarbon chain, such as alkanes, alkenes, fast smoke and derivatives thereof The term ''艏 difference," includes the group RC〇_, wherein R is an organic group. An example is ethyl hydrazino CH3CO-. When an alkyl or substituted alkyl group as defined above is passed through one or more groups When [-(C-0)-] is bonded, the group or aliphatic moiety is "preserved,". "ω 蜃 蜃 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 蜃 包括 蜃 蜃 蜃 蜃 蜃 蜃 蜃 蜃Poor, including monoterpenes and bicyclic aromatic rings containing 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur. The 5- or 6-membered heteroaryl is a monocyclic heteroaryl ring; examples thereof include thiazole, oxazole, Thiophene, furan, pyrrole, imidazole, isoxazole, pyrazole, diazole, thiadiazole, tetrazole, oxadiazole, pyridine, indole, pyrimidine, pyridin and the like. Bicyclic heteroaryl rings include (but Not limited to) benzothiazole, hydrazine, benzoquinone, benzofuran, benzazole, benzoxazole, benzothiazole, quinoline, benzotriazole, benzoxazole, isoquinoline , 嘌呤, 11 幷 幷 幷 n n 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括Indoleamine and its analogs. ''Mother's 蜃'' includes compounds containing quinone imine (-CO-NH-CO-). "Strict" includes amine-containing (_nh2) Compounds. Hydrazine includes a compound which is a carboxylic acid derivative and which contains a 122698.doc -30-200817341 (-CN) group attached to an organic group. When the side chain includes a hydrogen bond donor and/or a hydrogen bond acceptor, the side chain portion of the amino acid is a π hydrogen bond." "Agaric mushroom" includes any end group attached via a terminal amine, including Not limited to any amine derivative, mercapto or terminal aryl or aralkyl group, including; groups such as Cl to C6 straight or branched chain, such as fluorenyl, dimethyl, ethyl, yl, Propyl, isopropyl, butyl, isobutyl, pentyl or hexyl; such as allyl, cyclopropanemethyl, hexyl, hexyl, ethyl, propyl, butyl, phenyl ethyl Base, cyclohexylethyl fluorenyl, naphthylethyl fluorenyl, cinnamyl phenyl, benzyl, rhodium, 12-Ado, 7,-aminoheptanyl, heart Ahx, Amc or 8-Aoc Or a molecule such as polyethylene glycol having a molecular weight of between 1 〇〇 and 5 〇, 〇〇〇. As in pharmaceutical compositions, the term, composition &quot; is intended to encompass inclusion of active injury And a product constituting the inert component of the carrier, and by combining, compounding or agglomerating any two or more components, or dissociating one or more components, or Any product produced directly or indirectly by other types of reactions or interactions of various components. Accordingly, the pharmaceutical compositions of the present invention encompass the use of a compound of the present invention with one or more pharmaceutically acceptable carriers. And/or any combination of excipients and, as the case may be, or a mixture of other pharmaceutically active ingredients and agents. A variety of chemicals and compounds are used throughout the month, and the following abbreviations have a given meaning: B〇C third butoxycarbonyl

CbZ oxygen-reducing group 122698.doc -31 - 200817341 DCM dichloromethane DIAD azodicarboxylate diisopropyl cool DMF N,N-dimethylformamide DMSO dimethyl slate wind. EDC Ν-(3·2 Methylaminopropyl)-N, ethylcarbodiimide hydrochloride, EtOAc, ethyl acetate Fmoc 9-burial methoxycarbonyl (HEPES 4-(2-hydroxyethyl) 1-° Chen Geng Rhein HOAt 1-hydroxy-7-azabenzotriazole IBCF Isobutyl chlorohydrazide LAH Lithium aluminum hydride NMM N-methylmorpholine Pd/C / carbon TBTU 2_(1Η·benzotriazole- 1_base)-1,1,3,3·tetramethylpyrenetetramine TEA borate triethylamine THF tetrahydrogenate TPP triphenylphosphine as used herein ''four-substituted piperene') A group other than hydrazine and preferably comprising an amino acid residue or an amino acid side chain moiety is attached to each ring oxime member, and further preferably comprises an amine side acid side chain moiety in addition to ruthenium, osmium, S or halogen alone. The group is linked to a piperidine compound or a derivative thereof of two ring c members. 122698.doc -32- 200817341 &quot;姪矽逄姪矽逄” means any disease that inhibits or impairs normal sexual function (including sexual intercourse) The term is not limited to physiological conditions and includes psychotic conditions or sensory dysfunction without formal diagnosis of pathology or conditions. Sexual dysfunction includes erectile dysfunction in male mammals and dysfunction of female mammals. Mammals are unable to achieve a condition of functional ejaculation or both. Therefore, erectile dysfunction and sexual incompetence... and may include erections that do not achieve or maintain adequate sexual rigidity. Symptoms of erectile dysfunction include failure to achieve or maintain an erection Failure to ejaculate, early or incapable of reaching orgasm, these symptoms may occur alone or in any #: occurrence. Increased erectile dysfunction is usually associated with age or may be caused by a physical illness or as a side effect of medication. "A condition that includes sexual arousal disorder. The term "not ambiguous, obstructive" includes continuous or recurrent inability to obtain or maintain sexual excitement, and the monthly response to sexual activity is completed until the sexual activity is completed.

Sexual south tide is inhibited and sexual intercourse is difficult. This is painful or difficult to carry out. H sexual dysfunction includes (but is not limited to) m. sinensis diseases, conditions and conditions, hypothyroidism, lack of sexual pleasure, sex Awakening obstacles, difficulty in sexual intercourse and squatting. Loss of libido includes, loss of or loss of sporadic, causing persistence or reversion... or a condition that is difficult for interpersonal communication. The disease can be caused by the tiredness or dissatisfaction of the long-term, or the side effects or the agitation of prescription drugs. Lack of sexual pleasure, including sexual activity, can be caused by depression, Chinese or "heart or missing. Sexual pleasures or interpersonal fathers. Sexual arousal disorders 122698.doc -33- 200817341 can be reduced by estrogen Caused by illness or diuretic, antihistamine, anti-inhibition agent or anti-high a pressure treatment. Sexual intercourse difficulties and vaginal fistula are characterized by painful painful conditions that cause pain during penetration, and which can be reduced, for example, by Caused by a drug that is full of slip, endometriosis, pelvic inflammatory disease, inflammatory bowel disease, or urinary tract problems. The melanopisomein &quot;activator&quot; means an endogenous substance or drug comprising a compound of the present invention. A substance or compound that interacts with a melanocortin receptor and elicits a pharmacological response characteristic of a melanocortin receptor. A melanocortin receptor ''antagonist'" means a drug or compound comprising a compound of the invention against a melanocortin receptor-related response normally induced by a melanocortin receptor agonist. Affinity means the ability of a compound or drug to bind to its biological target. The chemical naming scheme and structure diagram used in this paper depends on the ChemDraw program (purchased from Cambridges〇ft c〇rp) or isis

Chemical naming features used by Draw (MDL Information Systems, Inc.). In particular, compound nomenclature is obtained from the structure using an automatic naming scheme such as ChemDraw Chuanjia or ISIS Draw. Clinical Applications The compounds disclosed herein are useful in medical applications and in animal husbandry or veterinary applications. This product is commonly used in humans but can also be used in other mammals. The term 'patient' is intended to mean a mammalian subject and is thus used throughout the specification and claims. The primary application of the invention relates to human patients, but the invention can also be applied to laboratories, farms, zoos, wildlife, 122698.doc -34- 200817341 Pets, competitive animals or other animals. The melanocortin receptor-specific compound (MC丨_R specific compound) of the present invention can be used to resist sunlight induced in human skin (such as by uv radiation) a chemopreventive agent that induces neoplastic activity. The MC1_R agonist compound of the present invention can be used to stimulate epidermal melanocytes to produce melanin and to convert pseudomelanin into true melanin. It is considered that dark brown or black colored true melanin is yellow or Red-colored pseudo-melanin is more photoprotective. The process of melanin production involves 2MC1_R stimulation in epidermal melanocytes, which mediates tyrosinase stimulation in these pigment cells and induces the conversion of tyrosine to dopa. (dopa) and then converted to true melanin via d〇paquin〇ne. Due to direct exposure to sunlight, The result is that the sunbathing produces the melanin-promoting peptide in the epidermis by the local production of the melanin peptide by the POMC gene. Therefore, stimulating the production of melanin and converting pseudomelanin to melanin can block the sun- or UV-induced skin-stimulating activity. The advantageous chemistry prevents malignancy. Therefore, the effective, high-affinity and highly selective MCI-R agonist compounds of the present invention can be used as a treatment for harmful sunlight or UV exposure against the neoplastic activity of the skin melanocytes. Sex chemopreventive agent. In another embodiment, a compound of the invention including, but not limited to, a compound that acts as an MC4-R agonist, partial agonist or functional inactivating agent can be used to improve energy metabolism and feeding behavior Therapeutic agents, including the treatment of pathological obesity and related conditions. In addition to the treatment of patients clinically diagnosed as obese, the compounds of the invention can be used in individuals over the optimal body weight for use as weight loss aids, including but not limited to The compounds of the invention of MC4-R antagonists are useful as therapeutic agents for eating disorders, such as for the treatment of anorexia and cachexia (which is made up of 1226) 98.doc •35- 200817341 Malnutrition and elimination caused by illness. In addition to the treatment of patients diagnosed with anorexia or cachexia, the compounds of the invention are useful for individuals with suboptimal body weight and especially for A patient in need of additional muscle mass is needed. In yet another embodiment, the compounds of the invention are useful as therapeutic agents for the treatment of sexual dysfunction, including treatment of male erectile dysfunction and female sexual dysfunction. The compound of the present invention can be used as a therapeutic agent for treating inflammation, and particularly includes MC1-R, MC3-R and MC5-R agonists. In still another embodiment of the present invention, there is a specificity of 51 The compound of the present invention is useful as an agent for reducing sebum production, and thus is effective for treating acne and related diseases. The compounds of the present application may be conveniently formulated for topical administration, e.g., via gels, lotions, creams, or other topical formulations. In still other embodiments, the compounds of the invention are useful in the treatment of pharmaceutical or alcohol dependence, depression, anxiety, and related conditions and indications. Formulations and administration/etc. may be formulated by any means known in the art including, but not limited to, lozenges, capsules, caplets, suspensions, powders, dry preparations, and air/agents. The formulation is nebulized and can be combined with a buffer, a binder, an antioxidant, and other agents known in the art. Such compounds can be administered by any of the king or topical means known in the art including, but not limited to, intravenous injection, y 'primary injection, transmucosal administration, oral administration, dermal administration, dermal patching. Tablets, aerosols and the like. 122698.doc -36 - 200817341 接 == A compound comprising a compound of the invention and a pharmaceutically acceptable or mixed composition. Thus, the compounds of the present invention may be formulated to sterilize at least one of the compounds of the present invention together with, if desired, a pharmaceutically acceptable carrier, such carriers, carriers, carriers Excipients of such analogues and such as stabilizers,

Shape: two spoons! I: additives for additives, buffers and the like. Formulations 脒 a polyethylene mouth than 嘻 bite, gelatin, cellulose, arabinol, sodium citrate or sodium citrate. For injections = other liquid administration formulations, &apos;containing at least one or more buffer groups & is mouth-compatible&apos; and stabilizers, preservatives and solubilizing agents may also be employed. For solid dosage formulations, any of a variety of thickeners, fillers, accumulators, and carrier additives, such as powders, sputum, fatty acids, and the like, can be employed. For topical administration formulations, any of a variety of peat, ointments, gels, lotions, and the like can be employed. For most pharmaceutical formulations, the inactive ingredients will make up a larger portion of the formulation (by weight or volume). For pharmaceutical formulations, it is also desirable to employ any of a variety of measured release, sustained release or timed release formulations and additives such that the dosage can be adjusted to effect delivery of the compound of the invention over a period of time. The compounds of the invention may be in any pharmaceutically acceptable salt form. The acid addition salts of the compounds of the invention are prepared from the compound and excess acid in a suitable solvent such as hydrochloric acid, hydrobromic acid, sulfuric acid, acid, acetic acid, trifluoroacetic acid, maleic acid, Succinic acid or methane sulfonic acid. The acetate form is especially suitable. When the compound of the present invention comprises an acidic moiety, a suitable pharmaceutically acceptable salt of 122698.doc-37-200817341 may include, by reference, an alkali metal salt of the salt of the salt, and an alkaline earth metal salt such as a calcium salt or a magnesium salt. The compound of the present invention and the pharmaceutical composition may be administered by injection, and the injection J is intravenous, subcutaneous, intramuscular, ψp, ^^ pancreatic fistula/main shot or hunting by the technique= Any other way to inject. In general, any route of administration in which the present invention is inserted across the epidermal layer of the cells can be employed. Medication method Mucosal injection! Oral administration, oral administration, dermal administration, 〇, 〇, 〇, “贞 方式. The therapeutic dose is sufficient to cause the desired therapeutic effect by any previous sputum ° ^, a favorable route of administration is Nasal administration + ^ isoindole, such as hunting in liquid spray, gel or powder. In the way of the drug, the use of aqueous solution, it is good to help the drug delivery device.", ##授翁&quot; It means any of the intranasal administration forms of any of the compounds of the invention and pharmaceutical compositions. Thus, in one: application, the compounds and pharmaceutical compositions of the present invention comprise an aqueous solution formulated for redundancy, such as a solution comprising physiological saline, a salt or a conventional excipient or preservative. . In another embodiment, the compounds and pharmaceutical compositions of the present invention comprise anhydrous or formulation formulations formulated for intranasal administration. Intranasal formulations can be in a variety of forms, such as in the form of nasal drops, nasal sprays, gels, ointments, creams, powders or suspensions. A variety of dispensers and delivery vehicles are known in the art, including single dose bottles, dose metering devices, nebulizers, nebulizers, I, nasal patches, nasal cotton, nasal capsules, and the like. The pharmaceutical composition can be in solid, semi-solid or liquid form. For solid shapes 122698.doc -38- Ο

200817341 The compound can be mixed with the other components (4) by blending, drum mixing, freeze drying, solvent evaporation, co-milling, spray drying, and/or other techniques known in the art. The semi-solid pharmaceutical composition suitable for the nasal (10) drug can be in the form of an aqueous or oily base gel or ointment. For example, the compound and other components may be mixed with starch, gelatin, collagen, dextran, polypropyl vinegar 1 vinegar or microspheres forming a hydrophilic condensate. In one embodiment, the microspheres may be internally loaded or coated with a compound that forms a gel that adheres to the nasal mucosa after administration. In the embodiment, 'the formulation is a liquid' should be understood as a compound and other components. Depending on the physicochemical properties, it includes, for example, aqueous solutions, aqueous suspensions, oil solutions, oily suspensions or emulsions. For liquid formulations, excipients necessary or desired for formulation, stability, and/or bioavailability may be included in the pharmaceutical compositions. Exemplary excipients include sugars (such as glucose, sorbitol, mannitol or sputum), absorption enhancers (such as polyglucosamine), thickeners, and stability enhancers (such as cellulose, polyvinylpyrrole). A broad buffer of ketone, starch, and the like, a preservative, and/or an acid for modulating the pH. In one embodiment, the pharmaceutical composition includes a component that promotes absorption. An exemplary group that promotes absorption. Ingredients include interfacial activity _ 'such as lysine, glycocholic acid, taurocholic acid and other bile acid derivatives; polyglucamine and cyclodextrin. Pharmaceutical compositions may additionally include optional agents and the like. Moisture loss of the substance and, as the case may be, moisturizing nasal moist materials, such as components for glycerin or propylene glycol, such as humectants, anti-agents or moisturizers to reduce the pharmaceutical combination mucosa. Exemplary moisturizers include suction, polyethylene Alcohols, polysaccharides and the like 122698.doc -39- 200817341 bacteria and other microorganisms grow, such as 0.05% benzyl chloride. Preservatives can be used to prevent or limit the fine one can use this preservative for chlorine Ammonium. Other The humic agent includes, for example, sputum, scorpion, decyl p-hydroxybenzoate, propyl p-hydroxybenzoate, p-hydroxybenzoic acid, chlorobutanol, phenylethyl alcohol, phenylmercuric acetate and analog. The pharmaceutical composition may also include a rheology modifier to, for example, alter the beta degree of the pharmaceutical composition. 1. The bio-modified agent includes polymers and the like, such as sodium carboxymethylcellulose, alginic acid, carrageenan. (Qing_η): Carbow (Carb〇 window), polygalactomannose, (tetra)-methylcellulose, propylcellulose, 'alkol polyglycol, polyvinyl alcohol, polyvinylpyrrolidone, Carboxymethyl quercetin H methyl dextran, sodium methyl starch, celery and combinations of the foregoing. These agents can also be used as bioadhesives to extend the residence time of the compounds of the invention in the nasal mucosa. Depending on the formulation and the route of administration, the aqueous solution of the compound or pharmaceutical composition of the present invention may be suitably buffered by means of physiological saline, acetate, dishate, sulphuric acid salt, acetate or other buffering agent, which is physiological. Any pH value acceptable above is generally from about pH 4 to about pH 8. Combinations of buffers such as phosphate buffered saline, physiological saline and acetate buffers and the like may also be employed. In the case of physiological saline, a 0.9% physiological saline solution can be used. In the case of acetate, phosphate, citrate, acetate and the like, a 5 mM solution can be used. The compound of the present invention and the pharmaceutical composition are directly administered to the lung by another route of administration. Intrapulmonary administration can be carried out by means of a metered dose inhaler, i.e., a device in which the compound of the present invention and the pharmaceutical composition of the present invention are dosed 122666.doc -40 - 200817341 when the patient is activated during inhalation. Dry powder inhalation and spray aerosols can be used. Accordingly, it is possible and contemplated that the compounds and pharmaceutical compositions of the present invention may be in the form of dry microparticles. In one embodiment, the particles are between about 〇5 and 6 〇^, so that the particles have sufficient mass to stay on the surface of the lungs without being exhaled, but small enough that they do not deposit before reaching the lungs. On the surface of the airway. Dry powder particles can be made using any of a variety of different techniques including, but not limited to, micro-milling, spray drying, and rapid freezing of the aerosol followed by lyophilization. For microparticles, these constructs can be deposited at the deep lungs, thereby providing rapid and efficient absorption into the bloodstream. Moreover, in this way, since a percutaneous, nasal or oral mucosal delivery route is sometimes necessary, penetration enhancers are not required: any variety of inhalers can be used, including propeller-based aerosols, sprayers, singles Dose dry secrets ^ and multi-dose dry powder inhaler. Current use: A commonly used device includes a metered dose inhaler&apos; which delivers a drug for the treatment of snoring, spastic obstructive pulmonary disease and the like. Preferred devices include a cloud or aerosol that is designed to form a fine powder having a particle size of less than about 6 bark. The particle size including the average size distribution can be controlled by means of a preparation method. For micro-grinding, t, the head size, rotor speed, processing time, and the like control the particle size. For spray drying, nozzle size, flow rate, dryer heat, and the like control particle size. The nozzle size, flow rate, aerosolized solution concentration, and the like are used to control the particle size for the f (four) speed of the east aerosol. These and other parameters can be employed to control particle size. The compounds and pharmaceutical compositions of the present invention may be formulated for injection 'such as 122698.doc 200817341 deep intramuscular injection (such as in the gluteal or deltoid), or may be injected by means of a controlled release in the above manner. Things to vote for. In the examples, the compound or pharmaceutical composition of the present invention is formulated with, for example, poly(ethylene glycol) 3 and, if appropriate, other excipients and preservatives including: but not limited to, for example An excipient of salt, polysorbate 8 〇, pH-adjusting sodium hydroxide or hydrogen acid and the like. In another embodiment, the compound or pharmaceutical composition of the present hair beta is combined with poly(original acid vinegar) and, as appropriate (,

In one or more other C-conditions, the poly(original acid vinegar) can be an autocatalytic poly(ortho vinegar) having any different percentage of lactic acid in the palatate backbone. In one embodiment, 'poly(D,L-propylene vinegar-co-acetate) polymer (PLGA polymer) is used, preferably a PLGA poly σ having a hydrophilic end group such as from B〇ehnnger Ingelheim, Inc ((四)仙―

Ge lets ny) PLGA RG5〇2H. For example, by adding a compound of the present invention in a suitable agent such as Ai? to pLGA in a mixture of dichloromethane + and adding it to the reactor under suitable mixing conditions. The continuous phase solution of polyethylene glycol is used to prepare the formulations. In general, any of a variety of injectable and biodegradable polymers may be employed in the time-controlled release injectable formulation, preferably such polymers are also Adhesive polymers. The teachings of U.S. Patent Nos. 4'938'763, 6'432'438 and 6,673,767, and the biodegradable polymers and methods of formulation thereof, are incorporated herein by reference. Depending on the amount of construction, the rate of biodegradation, and other factors known to those skilled in the art, it may be formulated to require one injection per week, month, or other period. Medically effective amount 122698.doc -42- 200817341 In general, the actual amount of a compound of the invention administered to a patient will vary over a wide range depending on the mode of administration, the formulation employed, and the desired response. The therapeutic dose is by any of the foregoing means or Any other means known in the art is sufficient to cause the desired effect. This can be readily accomplished by those skilled in the art by, for example, pharmacokinetic studies, plasma half-life: (d), dose escalation studies, and the like. The amount determined by the method includes a quantity sufficient to induce a desired effect of the compound or pharmaceutical composition of the present invention. Generally, a compound of the present invention is highly active, and its dose response is as low as 0.01 pg. /kg, optimal or peak dose response is generally between about 〇_〇1 pg/kg and 25 pg/kg depending on the particular compound and route of administration. For example, depending on the particular compound selected, the desired response, and the administration Depending on the route, formulation, and other factors known to those skilled in the art, each kilogram of body weight may be administered, 0.05, 〇·1, 〇·5, 1, 5, 1 〇, 5 〇, 1 〇〇 or 5 〇〇盹 compounds. Conventional dose-response studies and other pharmacological methods can be used to determine the optimal dose to achieve the desired effect with a given compound, a given formulation, and a given route of administration. Combination Therapy and Weight The compounds of the invention may also be used in combination with other drugs or agents for the treatment of various body weight and feeding-related disorders. The compounds of the invention may be used as dietary auxiliaries or for reducing food intake and/or Use of any other agent or combination of body weights to reduce food intake and/or body weight The compounds of the present invention may additionally be used in combination with any other agent or drug used to date to increase food intake and/or body weight to increase food intake and / 122,698. Doc -43- 200817341 or body weight. Drugs that reduce energy intake include, in part, various medical agents known as anorectic drugs, which are used as adjuvants in behavioral therapies in weight loss programs. Categories of anorectics include (but not Limited to noradrenergic agents and serotonergic agents. Noradrenergic drugs can be described as drugs that generally retain the appetite-lowering effect of amphetamine but have weaker stimulant activity. Noradrenergic drugs (other than phenylpropanolamine) generally act by causing an anorectic central mediated pathway in the hypothalamus. Phenylpropanolamine, which is a racemic mixture of norepinephrine, causes the release of norepinephrine throughout the body and stimulates the hypothalamic receptor to reduce appetite. Suitable noradrenergic agents include, but are not limited to, diethylpropion, such as TENUATETM (1-propanone, 2-(diethylamino)-1-phenyl-, hydrogen available from Merrell Chlorate); mazindol (or 5-(p-phenylene)·2,5-dihydro-3H-imidazolium [2,la]isoindole-5-ol), such as commercially available SANOREXTM from Novartis or MAZANORTM available from Wyeth Ayerst; Phenylpropanolamine (or benzyl alcohol, α-(1-aminoethyl)-, hydrochloride); Phentermine (or phenol, 3- [[4,5-Dihydro-1Η-imidazol-2-yl)ethyl](4-methylphenyl)amino], monohydrochloride), such as ADIPEX-PTM available from Lemmon, FASTINTM &amp; available from Smith-Kline Beecham IonaminTM available from Medeva; phendimetrazine (or (28,38)-3,4-dimethyl-2 phenyl morphine L-(+ ) - Tartrate (1:1)), such as METRATM available from Forest, PLETINETM available from Wyeth-Ayerst • available from Boehringer 122698.doc -44 - 200817341

Ingelheim's PRELU-2TM and STATOBEXTM available from Lemmon; phendamine tartrate, such as THEPHORINTM (2,3,4,9-tetrahydro-2-A available from Hoffmann-LaRoche Benzyl-9-phenyl-1H-nonanol [2, lc]pyridine L-(+)-tartrate (1:1)); methamphetamine, such as DESOXYNTM lozenge available from Abbott ( (S)--N,(α)-dimercaptophenethylamine hydrochloride; and phendimetrazine tartrate, such as BONTRILTM sustained release capsules (A-3) available from Amarin , 4-dimethyl-2-phenylmorphine tartrate). Suitable serotonergic agents include, but are not limited to, sibutramine, such as MERIDIATM capsules available from Knoll ((+) and (a) cyclobutane methylamine enantiomer racemic mixture, 1 -(4-phenylphenyl)_team&gt;1-dimethyl-((1)-(2-methylpropyl)-, hydrochloride, monohydrate), fluoroamphetamine, such as commercially available From the ruler 1) 1 ^ 113? 011^111丨1111^(phenethylamine, |^_ethyl-α-methyl-3-(trifluoromethyl)-, hydrochloride); dexfenfluramine, such as commercially available ReduxTM from Interneuron (phenylethylamine, N-ethyl-α-methyl-3-(trifluoromethyl)-, hydrochloride). Fluebuprofen and dexfenfluramine stimulate serotonin release and inhibit its resorption. Nome Ting inhibits re-absorption of serotonin, norepinephrine and dopamine, but does not stimulate the secretion of ginseng. Other serotonergic agents suitable for use in the practice of the invention include, but are not limited to, certain anorectic gene 5HT1a inhibitors (brain, serotonin), such as U.S. Patent No. 6,207,699, incorporated herein by reference. Revealing carbidopa and benserazide; and certain miracles 122698.doc -45- 200817341 kinin 1 receptor antagonists and selective serotonin reuptake inhibitors, including U.S. Patent No. 6,162,805 Fluoxetine, fiuv〇xajnine, paroxtine, sertraline, and other suitable compounds disclosed in the text (which is incorporated herein by reference) . Other possible agents that may be employed include, for example, 5HT2c agonists. Other suitable compounds for reducing energy uptake include, but are not limited to, certain aryl-substituted cyclobutylalkylamines as disclosed in U.S. Patent No. 6,127,424, the disclosure of which is incorporated herein by reference. Certain of the trifluoromethylthiophenylethylamine derivatives disclosed in U.S. Patent No. 4,148,923, the disclosure of which is incorporated herein by reference in its entirety in U.S. Pat. Certain of the compounds disclosed herein; such as certain kainite or AMPA receptor antagonists as disclosed in U.S. Patent No. 6,191,117, incorporated herein by reference herein; Certain neuropeptide receptor subtypes 5 are disclosed in U.S. Patent No. 6,140,354, the disclosure of which is incorporated herein by reference. Some of the revealed (X blockers. In addition, several peptides and hormones regulate feeding behavior. For example, cholecystokinin and quercetin are used to reduce appetite and food intake. Alizarin (a hormone produced by fat cells) Control food intake Energy expenditure. In obese individuals who are not using drugs and lose weight, weight loss is associated with a decrease in the content of alizarin cycle, indicating the role of alizarin in weight balance. Obese patients with g-mudin content are second to Downregulation of peripheral leptin resistance. Non-limiting examples of compounds suitable for influencing feeding behavior include such a 122698.doc • 46 as disclosed in WO 01/21647, which is incorporated herein by reference. - 200817341 a receptor for stimulating leptin lipolysis; certain linonic acid diesterase inhibitors as disclosed in WO 01/35970, which is incorporated herein by reference; </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; Compounds, including peroxisome proliferator-activated receptors (PPARs), as disclosed in WO 01/3 0343 and U.S. Patent No. 6,033,656, the disclosure of which is incorporated herein by reference. And certain polypeptides of the fibroblast growth factor-10 polypeptide as disclosed in WO 01/1 8210, which is incorporated herein by reference. In addition, monoamine deuteration which reduces energy uptake or increases energy expenditure. Enzyme inhibitors are suitable for use in the practice of the invention. Suitable, but non-limiting examples of monoamine oxidase inhibitors include befoxaxone, moclobemide, br〇far〇mine ), phenoxathine, esuprone, bef〇1, 〇xoxaxone, pirind〇1, amiamine (amiflamine), sercl〇remine, bazinaprine, lazabemide, milacemide, caraxaxane, and Certain other compounds disclosed by w (which is incorporated herein by reference). Certain compounds that increase lipid metabolism are also suitable for use in practicing the present invention. Such compounds include, but are not limited to, ev〇diamine compounds 122698.doc-47-200817341 as disclosed in U.S. Patent No. 6,214,831, incorporated herein by reference. Agents and digestion inhibitors are another strategy for treating obesity by interfering with the absorption or absorption of dietary fat in the gastrointestinal tract. The stomach and the adrenal fat enzymes make the meal &amp; glycerol tris s formed to form the free fat that is subsequently absorbed in the small intestine: it contributes to its crystallization. Inhibition of these enzymes leads to dietary glycerol (at) such as XENICALTM gel available from Roche Laboratories

Ο ( ((8)_2_ 曱 胺 _ 4 4 _ _ _ _ _ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ Vinegar) and certain benzoquinones as described in WO 00/40247, which is incorporated herein by reference. Odo 0 ketone compound. An agent that increases energy expenditure is also called a fever drug. Non-biometric examples of suitable febrile medications include yellow, such as coffee and tea, and a selective beta-% adrenergic agonist, such as one of U.S. Patent No. 4,626,549, incorporated herein by reference. Some of the compounds and the growth hormone compounds as described in U.S. Patent Nos. 4,937,267 and 5,120,713, the disclosures of each of which are incorporated herein by reference. In general, when used in combination with a compound of the present invention, the total dose of the above-described obesity controlling agent or drug may be from 0.1 to 3,000 mg per day, preferably from 1 to 1 per day, in a single or two to four divided doses. , 〇〇〇mg and better in the range of about 2 〇〇mg per day. However, the exact dose will be determined by the attending clinician and will depend on factors such as the potency of the compound administered, the patient's age, weight, condition, and response. Agents or drugs for increasing food intake and/or body weight include appetite thorns 122698.doc -48- 200817341 stimulants, such as megestrol acetate; adrenal cortices such as prednisolone and Dexamethasone, cyproheptidine; serotonergic drugs such as fenfluramine, neuropeptide Y; and androgen antagonists such as flutamide, nilutamide and The zanoterone sputum assay and animal model test selected compounds in assays to determine binding and functional status' and test feeding behavior in animal models as described below. The following assays and animal models were used and the modifications as discussed in the examples were used. Use of [I125]-NDP_a-MSH for competitive inhibition assay using HEK-293 cells expressing BMC4-R, hMC3-R or hMC5-R and B-16 mouse melanoma cells (with endogenous MCI-R) The prepared membrane homogenate was subjected to a competitive inhibition binding assay. In some cases, HEK-293 cells expressing recombinant hMCl-R were used. In the following examples, all MC3-R, MC4-R and MC5-R values are values for human recombinant receptors. The MC1-R value is the value of B-16 mouse melanoma cells, unless the heading is &quot;hMCl-Rn, in the case of nhMCl-R", this value is the value of human recombinant MC1-R. Bovine serum albumin (Fraction V) pre-coated 96-well GF/B microporous multi-screen filter culture plate (MAFB NOB10) was assayed at 0·2 nM (for hMC4-R), 0.4 nM (pair) For MC3-R and MC5-R) or 〇·1 ηΜ (for mouse Β16 MC1-R or hMCl_R) [I125]-NDP-a-MSH (Perkin Elmer) and containing 100 mM NaCl, 2 mM CaCl2, 2 mM MgCl2, 0·3 mM 1, 10-Fallin and 0.2% bovine serum white 122698.doc -49- 200817341 Protein 25 mM HEPES buffer (pH 7.5) in buffer increased concentration Test compound incubation membrane homogenate. After incubation for 60 minutes at 37 ° C, the assay mixture was filtered and the membrane was washed three times with ice-cold buffer. The filtrate was dried and the bound radioactivity was counted in a gamma counter. Non-specific binding was measured by inhibition of [I125]-NDP-a-MSH binding in the presence of NDP-a-MSH. Maximum specific binding (100%) was defined as the presence and absence of cells in the absence and presence of 1 μΜ NDP-a_MSH The difference in combined radioactivity (cpm). The radioactivity (cpm) obtained in the presence of the test compound is normalized to 100% specific binding to determine the percent inhibition of [I125]-NDP-a-MSH binding. The assay was performed three times and the actual average was described, and the result of less than 〇% was reported as 〇%. The Ki value of the test compound was determined using the Graph-Pad Prism® curve-fitting software. Competition using [I125]-AgRP (83-132) Sex binding assays were performed using a membrane homogenate isolated from cells expressing hMC4-R using a competitive binding assay using [I125]-AgRP (83-132) pre-coated with 0.5% bovine serum albumin (Fraction V). The assay was performed in a 96-well GF/B microporous multi-screen transition culture plate (MAFB NOB 10). The assay mixture contained 1 mM NaCn, 2 mM CaCl2, 2 mM MgCl2, 0.3 mM 1,10-morpholine, 0.5%. Bovine serum albumin, membrane homogenate, radioligand [I125]-AgRP (83-132) (Perkin Elmer) 25 mM HEPES buffer (pH 7.5) and increasing concentrations of compound in a total volume of 200 pL. Binding was measured at a radioactive ligand concentration of 0.2 nM. After incubation at 37 °C for 1 hour, the reaction mixture was filtered and washed with assay buffer containing 500 mM NaCl. The drying tray was knocked out from the plate and counted on a gamma counter. The total combination of the radioligands is not more than 10% of the count added to the reaction mixture. The Ki value of the test compound was determined using a Graph-Pad Prism® curve fitting software. Assay for agonist activity The ability of the test compound to elicit a functional response in HEK-293 cells expressing MC4-R was measured to detect accumulation of intracellular cAMP. Overgrown HEK-293 cells expressing recombinant hMC4-R were isolated from culture plates by incubation in enzyme-free cell dissociation buffer. Disperse the cells in suspension containing 10 mM HEPES (pH 7.5), 1 mM MgCl2, 1 mM glutamic acid, 0.5% albumin, and 0.3 mM 3-isobutyl-1-methyl-xanthine (IBMX) (phosphoric acid Diesterase inhibitor) in Earle's Balanced Salt Solution. Cells were plated in 96-well plates at a density of 0.5 x 105 cells per well and pre-incubated for 30 minutes. The cells were exposed to the test compound for 1 hour at 37 ° C, and the compounds were dissolved in DMSO (final DMSO concentration of 1%) in a concentration range of 0.05 - 5 000 η 以 in a total assay volume of 200 μί. NDP-a-MSH was used as a reference agonist. At the end of the incubation period, cells were disrupted by the addition of 50 pL of lysis buffer (cAMP EIA kit, Amersham) followed by vigorous pipetting. The cAMP content in the lysate was determined using a cAMP EIA kit (Amersham). Data analysis was performed by nonlinear regression analysis using Graph-Pad Prism® software. The maximum efficacy of the test compound was compared to that achieved with reference to the melanocortin agonist NDP-aMSH. Food intake and body weight after IN and 1P administration The changes in food intake and body weight were evaluated for selected compounds. Male C57BL/6 mice were obtained from the laboratory (Bar Harbor, ME) at Jackson 122698.doc -51 - 200817341. Animals were individually housed in a conventional resin glass suspension cage and maintained in a controlled 丨 2 hour light/matte cycle. Water and block (Harlan Teklad 2018 18% Protein Rodent Diet) food is available at will. Mouse IP (by intraperitoneal injection) or vehicle or selected compound (〇1_3 mg/kg, and in some cases up to 10 mg/kg) IN after 24 hours of fasting Administered by intranasal administration. At the beginning of the 'no light' phase, all animals were dosed once daily (or up to four consecutive days). Changes in food intake relative to control animals administered vehicle were determined during the 4 hour and 20 hour period after dosing. The body weight was measured 4 hours before the administration and 20 hours after the administration, and the change in body weight of the control animals relative to the vehicle was measured. Mass Determination and Nuclear Magnetic Resonance Analysis The mass values were determined using a positive mode using a Waters MicroMass ZQ device. The mass measurement is compared to the calculated value and appears as a mass weight plus 1 (M+1 or M+H). Proton NMR data was obtained using a Bruker 300 MHz mass spectrometer. The spectrum is obtained after dissolving the compound in a deuterated solvent (if appropriate, such as chloroform, DMSO or methanol). Synthetic Methods of the Invention A general strategy involves the development of linear intermediates using a posterior segment of the construction of a palmitic organism such as an amino acid. The linear intermediate can be cyclized using a Mitsunobo reaction strategy or by a spontaneous cyclization reaction of a reactive group such as a reaction between an amine functional group and an ester functional group or between an amine functional group and an aldehyde functional group. In these cyclization reactions, the intramolecular reaction drives the intermolecular reaction. 122698.doc -52- 200817341 The force is a thermodynamically favorable reaction for the formation of a six-membered ring structure. In many cases, methodologies incorporate conditions that do not involve reversal or racemization of the palm center. In the case where some small percentage of racemates are observed, such as the use of alpha-amines in certain locations, the desired palmitic product can be readily purified by methods known in the art, such as silicone. Column column flash chromatography. : A Q-ring-containing group can be obtained by using an aldehyde derivative of D-amino acid. By using ... amine (iv), the resulting group has the most basic form of the general structure: 〇 QH^H2 〇 For example, when the D-Phe aldehyde derivative is used in the synthesis, 2 of the obtained compound is! And q is a phenyl group. # However, it can be easily found that any of the D-amino acids listed above can be used as the aldehyde derivative, and it can be further found that one or two hydrogen atoms in -NH2 can be substituted with an amine-terminated group. In the synthesis, ruthenium is fermented with an N-protected oxime-amino acid, wherein the N-protecting group is conveniently Boc or Fmoc. Because of the inherent instability of the cardioamine aldehyde in solution. Compounds such as hai are preferably synthesized immediately prior to use. Two different methods are used for the synthesis. In the first place, add TBTU (1 eq.) to n-protected amino acid in dichloromethane (such as in Boc- or Fmoc-base, y, 丄). Depending on the context, here and elsewhere π eq · '' is the 曰&gt;, 4 Fengtian $ abbreviation) &amp; NMM (1 eq). The mixture was scrambled for half an hour and hydrazine, hydrazine dimethyl carbazide nitrogenate (1 nick) and NMM (1 eq.) were added. The reaction was allowed to proceed overnight. The solvent was removed and (10) alpha was added. . 122698.doc -53 - 200817341 The organic phase was washed with aqueous sodium bicarbonate, brine and dried over sodium sulfate. After evaporating the solvent and drying under vacuum, the residue was dissolved in THF under nitrogen. To this solution, LAH (1 μi·5 eq· in THF) was slowly added. The solution was stirred for another half an hour. The reaction was diluted with ether and quenched with aqueous potassium hydrogen sulfate. The organic phase was washed with 1 N HCl, water, brine and dried over sodium sulfate. After removing the solvent, the aldehyde was used in the next reaction without purification. ^ In the second method, boron-fired _THF 〇 M, eq·) is slowly added to the N-protected amino acid (such as a Boc- or Fmoc- group) in THF at 〇 °C. The temperature was allowed to rise to room temperature and the solution was stirred for 2 hours. The reaction was quenched with &lt;N&gt; HC1 and the solvent was evaporated. The crude product was purified on a silica gel column to give a pure N-protected amine alcohol. This alcohol was dissolved in anhydrous methylene chloride and Dess-Martin peri〇dinane (11 eq) was added. The solution was stirred for 1 hour and the reaction was diluted with EtOAc. The organic phase was washed with saturated sodium bicarbonate of sodium thiosulfate, followed by water, then brine, and dried over sodium sulfate. The solvent was removed and the crude product was used in the next reaction without further purification. The D-amino acid aldehyde can be used in the synthesis method employed. In the sentence, y is used to apply for the correction of the methods of the corpse. In particular, the sentence 把 匕 专利 专利 专利 专利 专利 专利 837 837 837 837 837 837 837 837 837 837 837 837 837 837 837 837 837 837 837 837 837 837 837 837 837 837 837 837 837 In the case of the number of hours, it is D-amino acid. 122698.doc -54- 200817341 Process 1

U

1-6 1-5 122698.doc 55- 200817341

Fmoc_Lys(Trt)-OH was partially dissolved in DCM. To this mixture was added TBTU (1.1 eq.) and NMM (1.5 eq.). After the mixture was stirred at room temperature for 45 minutes under nitrogen, NH2-CH(R2)-122698.doc-56-200817341 COOMe (i.e., HD-Leu-OMe.HCl) (1.05 eq·) and NMM were added. (1·1 eq·). The reaction was allowed to proceed overnight at room temperature. The solvent was evaporated and the residue was partitioned between EtOAc and water. The organic layer was washed with 1 N EtOAc, sat. NaHC.sub.3, water and dried over sodium sulfate. The product was obtained after removal of the solvent and the product was used in the next reaction without further purification. Compound 1-1 was dissolved in 30% Et2NH in EtOAc. The solution was stirred at room temperature for 2 hours. Remove the solvent. The crude product ι-2 was used in the next reaction without further purification. Compound 1-2 was partially dissolved in anhydrous DMF. The mixture was heated at 90 ° C for three days under nitrogen. The reaction was stopped and the DMF was removed under vacuum. This crude product was purified on a silica gel column eluting with EtOAc / EtOAc (EtOAc) elute The final product was collected after evaporation of &gt; granules. Compound 1-3 was suspended in THF at 0 ° C under nitrogen. LAH (3.5 eq·) was added dropwise to this suspension. After the LAH addition is complete, the suspension becomes a clear solution. The reaction was stirred at room temperature for 45 minutes and refluxed overnight. The reaction mixture was quenched by the sequential addition of water, 15% NaH and water at 〇 °c. The mixture was stirred at room temperature for 2 minutes. The solid was removed by filtration and washed with diethyl ether. Compound 1-4 was dissolved in THF. To this solution was added benzyl chloroformate (3 eq.), followed by water and sodium bicarbonate (5 eq). The reaction mixture was stirred at room temperature for 3 hours. Water and Et〇Ac were added to the mixture. Separate the organic layer and wash it with water until the water layer is neutral? 11 values. The organic layer was dried over 122,698.doc -57 - 200817341 sulfuric acid. The solvent was evaporated and the residue was purified on EtOAc EtOAc EtOAc EtOAc EtOAc Compound 1-5 was dissolved in a 5% TFA / 1% TIS / DCM solution, and the mixture was stirred for 1 hour. The reaction mixture was diluted with DCM. The organic phase was washed with saturated sodium bicarbonate, water, brine and dried over sodium sulfate. After evaporating the solvent, the crude product 1- 6 was used in the next reaction. Compound 1-6 was dissolved in DCM. Here. (: Pyridinium (10 eq·) was added to this solution, and then 2 nitrobenzene was added to the mash (2 eq ). The temperature was raised to warmness and stirred overnight. The solvent was removed. The residue was dissolved in EtOAc, EtOAc (EtOAc)EtOAcEtOAcEtOAcjjjjjjjjjjj The compound 丨_7 is obtained afterwards. Compound 1_7, TPP (3 eq·) and N-Boc 2 hydroxy-ethylamine (3 □) are dissolved in anhydrous scorpion. Toluene is added to the solution under 〇. Diad (3 eq.). After 30 minutes, the temperature was allowed to warm to room temperature and the solution was stirred overnight. The solvent was removed and the residue was purified on toluene column eluted with 50% iEt 〇Ac in heptane. After the solvent, the compound 1-8 was obtained. The compound 丨-8 was dissolved in anhydrous acetonitrile, and potassium carbonate (6 eq·) and 'nonylphenol (4·5 eq) were added to the solution. The mixture was stirred at room temperature. The mixture was removed and the residue was partitioned between EtOAc and water. The crude compound was used in the next reaction. The compound W-9 was dissolved in THF/water (2:1), then sodium bicarbonate (5 eq.) and dibutyl succinate (s) were added to the solution. 2)). The mixture was stirred at room temperature. </ br> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> The residue was purified on a hydrazine cartridge eluting with 25% EtOAc in heptane. The solvent was removed to give the product 1-10. Compound 1-10 at room temperature under hydrogen (1 atm.) Treatment with a catalytic amount of Pd/carbon in ethanol overnight. The solvent was removed after filtration over a pad of Celite. The crude product was dried in vacuo and used in the next step without further purification.

Q-C00H (i.e., Boc_D_2-naphthylalanine) (4 eq.), EDC (4 eq.), and HOAt (4 eq.) were dissolved in DMF. The mixture was stirred at 0 ° C for 30 minutes. Compound 1 -10 was added in one portion to this solution. The reaction was allowed to proceed overnight at room temperature. The solvent was removed and the residue was purified on a silica gel column to afford product 1-11. Compound 1-11 was treated with TFA for 3 hours at room temperature. After the solvent was removed, the residue was purified by HPLC to give the product 1-12. Process 2

122698.doc -59- 200817341 Γ

OH

Cbz R2, NHBoc, NBoc

R

NH

Cbz R2, NBoc

Cbz R2 , NHB〇c , NBoc

The mixture of Cbz-Glu (OtBu)-OH, TBTU (1.1 eq.) and NMM (1.5 eq.) in 100 mL DCM was stirred at room temperature under nitrogen for 30 min. Nh2-ch(r2)-COOMe (1.05 eq.) and NMM (1.13 eq.) in the form of hydrochloride were added to the solution. The mixture was stirred overnight at room temperature. The solvent was removed and the residue was dissolved in EtOAc EtOAc. The organic solvent was washed with water, i N HCl, a saturated aqueous solution of sodium bicarbonate, water and dried over sodium sulfate. After the solvent was removed, the product (2-1) was used in the next reaction without further purification. Compound 5-1 was dissolved in EtOAc. It was subjected to hydrogen treatment at 1 atm for 3 days at room temperature in the presence of pd/c. The reaction mixture was filtered through celite, and then washed with methanol. The solvent was removed and the product 2-2 was used in the next reaction without purification. Compound 2-2 was dissolved in DMF. The solution was heated at 90 °C for three days. Remove the solvent and dissolve the residue in DCM and take it! N HC1 wash. The organic layer was separated and dried over sodium sulfate. The product 2 - 3 was obtained after removal of the solvent. The suspension of compound 2-3 in THF was stirred at 0 °C. Lithium aluminum hydride (4_6 eq·) was added to the suspension. The mixture was placed in a crucible. (: stirring for 25 minutes and stirring at room temperature for 4 hours and then refluxing under nitrogen overnight. The reaction was quenched by adding water, 1 5% sodium hydroxide and water. The mixture was allowed to stand at room temperature. The mixture was stirred for another 30 minutes. The solid was removed by hydrazine and washed with EtOAc. The solvent was removed and dried under vacuum to give crude compound 孓4. Compound 2-4 was dissolved in THF. Benzyl benzoate (2.5 eq·) was added, followed by water and sodium bicarbonate (6 eq) to give a ratio of thf to water of 2 to 1. The mixture was stirred overnight at room temperature. The organic layer was washed with water and dried over sodium sulfate. The solvent was removed and the residue was dissolved in methanol and 1N sodium hydroxide (3.). The reaction was allowed to warm to three days. The solvent was removed and the residue obtained was taken in EtOAc. EtOAc (EtOAc)EtOAc. Purification on column to give product 2-5. Compound 2-5 was dissolved in DCM. To the solution was added Dess Martin's high iododine (1.1 eq·). The reaction was allowed to continue at room temperature for 15 hours. Add diethyl ether. • Dilute the mixture and stop by adding sodium thiosulfate to saturated sodium bicarbonate solution. The organic layer was washed with the same solution and dried over sodium sulfate. After solvent was removed, the crude product 6 was used in the next reaction without further purification. To compound 2-6 and N-Boc- Molecular sieves were added to the solution of the amine (10.5 eq) in thf. The mixture was stirred at room temperature for 3 hours. To the mixture was added triethylphosphonium hydride (1.5 eq.). Stir at room temperature overnight and remove the solids by filtration. After the solvent was removed, the residue was partitioned between EtOAc and water. Dry over sodium sulfate. After removing the solvent, the residue was dissolved in THF and water (volume ratio = 2:1). To this solution was added di, dibutyl succinate (1.2 eq) and sodium bicarbonate (5 eq The mixture was stirred overnight at room temperature. EtOAc was added and the organic layer was taken Washing and drying with thiophene. After removing the solvent, the residue is purified on a Shih-Hui column to obtain: product 2-7. Compound 2-7 is dissolved in ethanol and present in a catalytic amount of pd/c. Treatment with hydrogen at atmospheric pressure. The reaction was allowed to proceed overnight at room temperature. The solid was filtered and washed several times with ethanol. The solvent was removed to give the product 2-8. HOAT (4 eq·) and EDC (4 eq_) were added to the solution in DMF. After the mixture was stirred for 30 minutes, compound 2-8 was added to this mixture 122698.doc-62-200817341. The reaction was continued overnight at room temperature. The solvent was removed and the residue was purified on a silica gel column to afford product 2-9. Compound 2-9 was treated with TFA for 3 hours at room temperature. After the solvent was removed, the residue was purified by HPLC to yield compound 2-10. Process 3

OTRnM.q

Process 4 122698.doc •63 - 200817341

Scheme 5 (addition of heterocyclic groups)

122698.doc -64· 200817341 According to another aspect of the present invention, there is provided a method of preparing a compound of formula III: Η η2ν

R‘

III Ο wherein each R1 is the same such that the compound of structure I is symmetric about R1, wherein r1 is of the formula: R9

Q a is an index value of 0 to 2; b is an index value of 0 to 4; R8 is Η or =〇; R9 is Η or N(R1()a)(Ri〇b); pl〇a ητ rilOb Μ, And R are each independently hydrogen, ethyl hydrazide, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, isobutyl, benzyl, benzhydryl, hexyl, propyl Mercapto, butyl thiol, pentamidine, heptyl, cyclopropyl, propylpropylmethyl, cyclobutyl, cyclobutylmethyl, cyclohexyl, cyclohexylmethyl or polyethylene glycol; Q is selected from phenyl An aromatic carbocyclic ring of a group consisting of substituted phenyl, naphthyl and substituted naphthyl; one of R and R2y is a straight or branched chain of hydrazine to steroid, 122698.doc • 65- 200817341

And the remaining R2x and R2y are hydrogen; and c is an index value of 0 to 4; the method comprises the following steps: (1) providing a precursor of the formula IV: Ο

Wherein Pg1 is the first protecting group; (2) reacting the precursor of formula IV with at least 2 equivalents of amino acid residues, the amino acid residue comprising at least one selected from the group consisting of phenyl, substituted, and naphthalene An aromatic carbocyclic ring of a group consisting of a substituted naphthyl group; and hydrazine (3) removing the first protecting group Pg1 and any other protecting groups. In one aspect, the compound of Formula 1V can be a compound of Formula V:

Providing a precursor of formula IV: 122698.doc -66 - 200817341 ig1

May include the precursor of the supplied vi: 〇

Pg1— Υ^Ν-Ρ92 丨 2,N\/^R2y 丨 R2x

Pg wherein Pg2 is a second protecting group Pg2 which is not related to Pg1. In the above process, the amino acid residue comprising at least one carbocyclic ring of the aryl group is a D-amino acid. The D. amino acid can be protected D 2 —naphthylpropanoid (IV). The base acid may be protected D. phenylalanine, wherein the benzene ring optionally includes one, two or three ring substituents, and when more than one substituent is present, the ring substituents are the same or different and independently It is a hydroxyl group, a halogen, an alkyl group, an alkyl group, an aryl group or an yl group. Representative amino acid residues comprising at least one aromatic carbocyclic ring include D-amino acids such as ^&amp;11, ;^&amp;12, (Bzl)Nal2, (N-PhEt)Nal2, pF-Phe , Phe(4-Br), Phe(4-CF3), Phe(4-Cl), Phe(3-Cl), Phe(2-Cl), Phe(2,4-diCl), Phe(3, 4-diCl), Phe(5-Cl), Phe(2-Cl,4-CF3), Phe(2-Cl,4-protecting group; and selectively remove 122698.doc •67- 200817341

Me), Phe(3,4-di F), Phe(2-F,4-Cl), Phe(2,4-:F), Phe(4-I), Phe(4-Me), Phe( 2,4-diMe), Phe(4-〇Me), Phe(3,4-di-OMe), Phe(2-Me,4-C1), Phe(4-NC), Phe(4-N02 ), Phe(4-phenyl) or Phg. In this method, the amino acid residue comprising at least one aromatic carbocyclic ring can be a protected amino acid residue, such as wherein the protecting group is

Pg2. In a related aspect, the amino acid residue comprising at least one aromatic carbocyclic ring can be a D-beta-amino acid. In this method, reacting a precursor of Formula IV with at least 2 equivalents of an amino acid residue comprising at least one aromatic carbocyclic ring can comprise including a precursor of the formula with at least 2 equivalents of an amino acid residue (1-Ethyl_3_[弘dimethylaminopropyl]carbodiimide hydrogenate) and reacted in a solution of hydrazine-dimethylformamide in the presence of aziridine. Alternatively, the precursor of the formula can be combined with an amino acid residue of about 4 equivalents each, (丨_ethyl_3_[3-dimethylaminopropyl]carbodiimide hydrochloride) and 1 -Hydroxy-7-azabenzotriazole is reacted in a solution of hydrazine, hydrazine-dimethylformamide. In the above process, the compound of the formula V can be produced by a process comprising the steps of: Fmoc-Lys(Trt)-OH and HD-Leu-OMe HC1 in the presence of 2-(1Η-benzoquinone di-sal-1-yl) The reaction of -1,1,3,3-tetramethyltetrafluoroborate and methyl-morpholine in an inert solvent to produce the crude product of formula VII. 122698.doc -68- 200817341 NHTrt

The product of formula VII is cyclized by heating the product of formula VII in anhydrous N,N-dimethylguanamine and the product of formula VIII is recovered:

The keto group of the product of formula VIII is removed by a reduction reaction and a benzyloxycarbonyl (Cbz) protecting group is introduced to protect the piped ring nitrogen and the product of formula IX is recovered:

IX; by selectively removing the Trt group to modify the TrtNH group, adding a third protecting group instead of the Trt group, reacting the resulting compound with N-Boc-2-hydroxy-ethylamine to remove the third protection Base, reacting the product with di-tert-butyl carbonate in a solution containing sodium bicarbonate and recovering the product of formula X: 122698.doc •69- 200817341

Boc

X ; and - Hunting is carried out in ethanol in the catalytic amount / carbon is pulled into * V V. Ten must rr / v. τ enhanced X product to remove

Cbz protecting group; Γ, wherein Pgl is Boc. In this method, the reduction reaction may include hydrogenation (chain. The introduction/protection group may be included in the tetrachloroethylene group to react with the gas (tetra) vinegar. In the above method for preparing the structural hydrazine compound, when substituted, each The Q ring may be substituted with one or more ring substituents selected from the group consisting of a thiol group, a dentate, a sulfonamide, an alkyl group, an alkyl group, an aryl group, an aryl group, a _0-aryl group, and combinations thereof. Representative compound f Example 1 Ο(R)-2-Amino-l-{(2R,5S)-4-[(R)-2-amino-3-(2,4-diphenyl) Propionyl]-5-[3-(2-aminoethylamino)propyl 2-isobutyl bridging-1-yl}-3-(2,4-carbyl)propan-1 _ Net • The following compounds were synthesized by the method of Scheme 2 using Boc-D-2,4·di-phenylalanine as Q-COOH and D-Leu-OMe as NH2-CH(R2)-COOMe. The compounds were tested as described above and the results are shown below. The mass was analyzed to be 672.3 (M+H). 122698.doc -70- 200817341

H2n NH

Cl is inhibited by 1 pM (NDP-a-MSH) hMCl-R MC3-R MC4-R MC5-R 23% 41% 89% 55%

Ki(nM)(NDP-a-MSH)

hMCl-R MC3-R MC4-R MC5-R

309 574 44 ND In the mouse model IN feeding study at dose levels of 0.1 and 0.3 mg/kg, body weight was observed to decrease by an average of 0.7% and 3.1%, respectively, at 20 hours compared to control animals. Example 2 (R)-2_Amino_l_[(2R,5S)-5-[3-(2-Aminoethylamino)propyl]_4-((R)-2-Amino-3-Cai -2 -yl-propyl aryl)-2 -isobutyl 〃 well _ 1 -yl]-3 -ca-2 -yl-propan-1-ketone by the method of Scheme 2, using Boc-D-2' -Naphthylalanine as Q-COOH and D-Leu-OMe as NH2-CH(R2)-COOMe to synthesize the following compounds. After purification, the compounds were tested as described above and the results are shown below. The mass was analyzed to be 636.6 (M+H). 122698.doc -71 - 200817341

ΝΗ

Inhibition at 1 pM (NDP-a-MSH) hMCl-R MC3-R MC4-R MC5-R 40% 79% 96% 57%

Ki (nM) (NDP-a-MSH) hMCl-R MC3-R MC4-R Ο

MC5-R

135 127 13 At the 0.1, 0.3, and 1 mg/kg dose levels of the mouse model IN feeding study, body weight was observed to decrease by an average of 1%, 3%, and 3.2% at 20 hours, respectively, compared to control animals. Example 3 (11)-2-Amino-1-{(211,58)-4-[(1〇-2-amino-3-(2,4-dimethylphenyl)propanyl]- 5-[3-(2-Aminoethylamino)propyl]-2-cyclohexylmethylpipedino-1-yl}-3-(2,4-dimethyl-phenyl)propan-1- The following compounds were synthesized by the method of Scheme 2 using Boc-2,4-dimethylphenylalanine as Q-COOH and D-cyclohexylalanine as NH2-CH(R2)-COOMe. After purification, as above The test compound and the results are shown below. The mass was analyzed to be 632.8 (M+H). 122698.doc -72- 200817341

Inhibition at 1 pM (NDP_a-MSH) hMCl-R MC3-R MC4-R MC5-R 35 22 83 43

Ki (nM) (NDP-a-MSH)

f S MC1-R MC3-R MC4-R MC5-R -- — 81 — Example 4 (R)-2·Amino-l-{(2R,5S)-4-[(R)-2-Amino _3-(2,4-diphenylphenyl)propanyl]-5-[3-(2-aminoethylamino)propyl]-2-cyclohexylmethylpiped-1-yl}- 3-(2,4-diphenyl)-propan-1·one by using the method of Scheme 2, using Boc-2,4-dichlorophenylalanine as Q-C02H and D-cyclohexylalanine as NH2- CH(R2)-C02Me was used to synthesize a compound of I. After purification, the compounds were tested as described above and the results are shown below. The mass was analyzed to be 712.6 (M+H).

122698.doc -73- 200817341 Example 5 (R)-2-Amino-l-[(2R,5S)-5-[3-(2-aminoethylamino)propyl]-4-((R)- 2-amino-3-xan-2-yl-propyl-)-2-cyclohexylmethyl 〃 -1-1 ·yl]-3 -cain-2-yl-propan-1 - Γ

Inhibition of hMCl-R MC3-R MC4-R MC5-R 27% 36% 83% 31% Ki (nM) (NDP-a-MSH) MC1-R MC3-R MC4- with 1 pM(NDP-a-MSH) R MC5-R ND ND 74 ND The following compounds were synthesized by the method of Scheme 2 using Boc-D-21-naphthylalanine as Q-C02H and D-cyclohexylalanine as NH2-CH(R2)-C02Me . After purification, the compounds were tested as described above and the results are shown below. The mass was analyzed to be 676·6 (M+H).

NH

Ki (nM) (NDP-a-MSH) hMCl-R MC3-R MC4-R MC5-R 22 36 81 30

Ki (nM) (NDP-a-MSH)

MC1-R MC3-R MC4-R MC5-R — 99 — Example 6 (R)_2-Amino_1-{(28,511)-4-[(11)-2-Amino-3-(2,4 -Dimethylphenyl) 122698.doc -74- 200817341 Propionyl]-2-[3-(2-aminoethylamino)propyl]-5-isobutylpiper. Well (2,4-dimethylphenyl)propan-1-indole by the method of Scheme 2, using Boc-2,4-dimercaptophenylamine as Q-COOH and D-Leu_OMe as NH2-CH (R2 )-COOMe to synthesize the following compounds. After purification, the compounds were tested as described above and the results are shown below. The mass was analyzed to be 592.9 (M+H).

Inhibition at 1 pM (NDP-a-MSH) hMCl-R MC3-R MC4-R MC5-R 22% 14% 83% 38%

Ki (nM) (NDP-a-MSH)

hMCl-R MC3-R MC4-R MC5-R

ND ND 60 ND Example 7 (R)-2-Amino-l-{(2R,5S)-4-[(R)-2.Amino·3_(2,4-diphenyl)propyl fluorenyl ]·5-[4-(2-Aminoethylamino)butyl]-2-isobutylpiped-l-yl}·3-(2,4-diphenyl)propane-1 嗣The following compounds were synthesized by the method of Scheme 1 using Boc-2,4-dioxalic acid as Q-COOH and D-Leu-OMe as NH2-CH(R2)-COOMe. After purification, the compounds were tested as described above and the results are shown below. The mass was analyzed to be 687 (M+H). 122698.doc -75- 200817341 Η

Inhibition at 1 pM (NDP-a_MSH) hMCl-R MC3-R MC4-R MC5-R 36% 59% 97% 47%

Ki (nM) (NDP-a-MSH)

Ο

hMCl-R MC3-R MC4-R MC5-R 754 327 36 296 Example 8 (R)-2-Amino-l-[(2R,5S)-5-[4-(2-Aminoethylamino) Butyl]-4-((11)-2-amino-3-carboxy-2-yl-propyl)-2-isobutyl brigade-1 -yl]-3-tea-2-yl- The following compounds were synthesized by the method of Scheme 1, using Boc-D-2f-naphthylalanine as Q-COOH and D-Leu-OMe as NH2-CH(R2)-COOMe. After purification, the compounds were tested as described above and the results are shown below. The mass was analyzed to be 651.3 (M+H). Η

Inhibition of 1 pM (NDP-a-MSH) hMCl-R MC3-R MC4-R MC5-R 68% 62% 99% 49% 122698.doc -76- 200817341

Ki (nM) (NDP-a-MSH) hMCl-R MC3-R MC4-R 215 321 9 MC5-R 253 In a mouse model IN feeding study at a dose level of 0.1 and 0.3 mg/kg in a feeding animal, Body weight was observed to decrease by an average of 1.2 and 3%, respectively, at 20 hours compared to control animals. Example 9 (R)-2-Amino-l-{(2R,5S)_4-[(R)-2-amino-3-(2,4-dimethylphenyl)propanyl b-5-[ 4-(2-Aminoethylamino)butyl]-2-isobutylpiped·1-*}-3-(2,4-dimethylphenyl)propan-1-one by Scheme 1 The following compounds were synthesized using Boc-2,4-dimercapto-phenylalanine as Q-COOH and D-Leu-OMe as NH2-CH(R2)-COOMe. After purification, the compounds were tested as described above and the results are shown below. The mass was analyzed to be 607.4 (M+H).

Inhibition at 1 pM (NDP-a-MSH) hMCl-R MC3-R MC4-R MC5-R 39% 55% 95% 51%

Ki (nM) (NDP-a-MSH)

hMCl-R MC3-R MC4-R MC5-R 567 1047 83 450 Example 10 122698.doc -77- 200817341 (R)-2-Amino-l-{(2S,5R)_4-[(R)-2 _Amino-3_(3,4_di-phenylphenyl)propanyl]-2-[4-(2-aminoethylamino)butyl]-5-isobutylpiperidin-1-yl b 3_ (3,4-diphenyl)propyl-1·ketone by the method of Scheme 1, using Boc-3,4-dichlorophenylalanine as q_COOH^D_Leu-OMe as NH2-CH(R2)_CO〇Me To synthesize the following compounds. After purification, the compounds were tested as described above and the results are shown below. The mass was analyzed to be 687.2 (M+H).

Ki (nM) (NDP-a-MSH)

hMCl-R MC3-R MC4-R MC5-R 116 69 4 179 In the mouse model IN feeding study at dose levels of 0·1 and 0.3 mg/kg, body weights were observed at 20 hours compared to control animals. The average reduction was 0.6% and 4.9%. Example 11 (R)-2-Amino-l-[(2S,5R)-2-[4-(2-aminoethylamino)butyl]-4-((R)_2-amino-3 -naphthalen-2-yl-propenyl)-5-cyclohexylmethylpiperidin-1-yl]-3-naphthalen-2-yl-propan-1 - oxime by the method of Scheme 1, using Boc-D -2'-Naphthylalanine was synthesized as q.COOH and D-cyclohexylalanine as NH2-CH(R2)-COOMe. After purification, the compounds were tested as described above and the results are shown in 122698.doc-78-200817341 as follows. The mass was analyzed to be 691.3 (M+H). Η

Ki (nM) (NDP-a-MSH)

hMCl-R MC3-R MC4-R MC5-R 153 435 20 l〇3 Observation in a mouse model IN feeding study at dose levels of 0.1 and 0.3 mg/kg compared to control animals at 20 hours The average weight loss was 1.6% and 2.6%, respectively. Example 12 (11)-2-Amino-1-{(28,511)_4-[(尺)-2-amino-3-(2,4-diphenyl)propyl]-2-[4 -(2-Aminoethylamino)butyl]-5-cyclohexylfluorenyl fluorenyl-1-yl//3-(2,4-diphenyl)-propan-1-pyrene

U The compound was synthesized by the method of Scheme 1 using Boc-2,4-dichlorophenylalanine as C〇2H and D_cyclohexylalanine as NH2_CH(R2)-C〇2Me. After purification, the compounds were tested as described above and the results are shown below. The mass was analyzed to be 727 (M+H). 122698.doc -79- 200817341

Η k I

Ki (nM) (NDP-a-MSH) hMCl-R MC3-R MC4-R MC5-R 270 443 17 139 Example 13

(11)-2-Amino-1-{(211,58)-4-[(11)-2-amino-3-(2,4-diphenylphenyl)propanyl]-5-[ 3-(2-Aminoethylamino)propyl]-2-mercaptopiperidin-1-yl}-3_(2,4-diphenyl)propyl hydrazine by the method of Scheme 2, using Boc- 2,4-Dichlorophenylalanine was synthesized as Q-COOH and D-Ala_OMe as NH2-CH(R2)_COOMe. After purification, the compounds were tested as described above and the results are shown below. The mass was analyzed to be 631 (M+H).

Inhibition at 1 pM (NDP-a-MSH) hMCl-R MC3-R MC4-R MC5-R 67% 89% 98% 93%

Ki (nM) (NDP-a-MSH)

hMCl-R MC3-R MC4-R MC5-R

ND ND 41 ND 122698.doc -80- 200817341 Example 14 (R)-2-Amino-1-{(2ίΙ,58)-4-[(Κ)-2-amino-3-(2,4- Dimethylphenyl)propanyl]-5-[3-(2-aminoethylamino)propyl 2-methylpiped-1-yl}-3-(2,4-dimethyl Phenyl)propan-1-one The following compounds were synthesized by the method of Scheme 2 using Boc-2,4-dimethylphenylalanine as Q-COOH and D-Ala-OMe as NH2-CH(R2)-COOMe . After purification, the compounds were tested as described above and the results are shown below. The mass was analyzed to be 551.3 (M+H).

Inhibition at 1 pM (NDP-a-MSH) hMCl-R MC3-R MC4-R MC5-R 53% 57% 96% 76%

Ki (nM) (NDP-a-MSH)

hMCl-R MC3-R MC4-R MC5-R

ND ND 64 ND Example 15 (R)-2_Amino-l-[(2R,5S)-5_[3-(2-Aminoethylamino)propyl]-4-((11)-2-amino- 3 -Cai-2 -yl-propyl aryl)-2 -methyl p-well-1 -yl]-3 -tea-2-yl-propan-1-yl ketone by the method of Scheme 2, using Boc-D- 2'-naphthylalanine was synthesized as Q2-COOH and D-Ala-OMe as NH2-CH(R2)-COOMe to give the following composition 122698.doc-81 - 200817341. After purification, the compounds were tested as described above and the results are shown below. The mass was analyzed to be 595.2 (M+H).

Inhibition at 1 pM (NDP-a-MSH) hMCl-R MC3-R MC4-R MC5-R 62% 79% 93% 73% Γ

Ki (nM) (NDP-a-MSH)

hMCl-R MC3-R MC4-R MC5-R

ND ND 42 ND Example 16 (11)-2_Amino-1-{(211,58)_4-[(11)_2_Amino-3-(3,4-diphenyl)propyl] -5-[3-(2-Aminoethylamino)propyl]·2-indolyl 〃 -1-1 -yl}-3_(3,4_diphenyl)propan-1-one by means of In the procedure of Scheme 2, the following compounds were synthesized using Boc-3,4-dichlorophenylalanine as Q-COOH and D-Ala-OMe as NH2-CH(R2)-COOMe. After purification, the compounds were tested as described above and the results are shown below. The mass was analyzed to be 631 (M+H).

122698.doc •82- 200817341 Inhibition of 1 pM(NDP-a-MSH) hMCl-R MC3-R MC4-R MC5-R 77% 94% 96% 84%

Ki (nM) (NDP-a-MSH) hMCl-R MC3-R MC4-R MC5-R ND ND 19 ND f Example 17 (R)-2-Amino group 1_{(28,5Ι〇·4-[ (Κ)-2·Amino-3_(3,4-dimercapto]-2-[4-(2-aminoethylamino)butyl]-5-methylpiped-1-one* gas The compound of the formula 17 was prepared by the method of the above Scheme 1 Fmoc-Lys(Trt)-OH, D-Ala-OMe and Boc-D-3,4-OH. Kib 3-(3,4· ' which uses di-Cl-Phe-

Example 18 (R)-2-Amino-l-{(2S,5R)-4-[(R)-2-amino-3-(2,4-dipropenyl)-2-[4- Preparation of the compound of Example 18 by the method of the above Scheme 1 (2-aminoethylamino)butyl]-5-methylanthracene (2,4-didecylphenyl)propan-1-one

Fmoc-Lys(Trt)-OH, D-Ala_OMe and Boc-D-3,4_dimethylphenyl) -1-yl}-3_ </ </ RTI> used, methyl-Phe-122698.doc -83 - 200817341

OH

C Example 19 (R)-2·Amine small {(2S,5R)-2-[4-(2-aminoethylamino)butyl]_4-[(R)-2-amino-3 (4-Trifluoromethylphenyl)propanyl]_5-isobutyl piperazine 3_(4-trifluorodecyl-phenyl)propan-1-one Prepared by the method of the above Scheme 1 Example 19 A compound in which Fmoc-Lys (Trt), OH, D_Leu-OMe and Boc_D_4_trifluoromethyl _Phe.OH are used.

Example 20 (R)_2_Amino-l-{(2S,5R)-4-[(R)-2-amino-3-(4_phenylphenyl)propene 122698.doc -84- 200817341 base]- 2-[4-(2·Aminoethylamino)butyl]·5-isobutyl lining-1-yl}_3-(4-carbene)propan-1 - oxime by the above Scheme 1 Method for preparing the compound of Example 20, wherein

Fmoc_Lys(Trt)_OH, D-Leu_〇Me and Boc-D-4_Cl-Phe-OH.

Example 21 (R)-2-Amino-l-{(2R,5S)-5-[4-(2-aminoethylamino)butyl]_4-[(R)-2-amino-3- (3-dimethylmethyl) propyl]-2-isobutyl brace_1_yl}_3_(3-trifluoromethyl-phenyl)propan-1-one by the method of the above Scheme 1 The compound of Example 21 was prepared, wherein ◎ Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-3-trifluoromethyl-Phe-OH were used. 122698.doc -85- 200817341

Example 22 1-{(2R,5S)_5-丨4-(2-Aminoethylamino)butyl 4-[3-(3,4-diphenylphenyl)propanyl]-2-iso The compound of Example 22 was prepared by the method of the above Scheme 1 using butylpiped-1-yl}-3-(3,4-diphenyl)propan-1-one using Fmoc-Lys(Trt)-OH , D-Leu-OMe and 3,4-di-CH-propionic acid.

Example 23

Nl-(4-{(2S,5R)_l,4-bis-[3_(3,4_diphenyl)propyl]-5-isobutylpiped_2_yl}•butyl) Alkyldiamine The compound of Example 23 was prepared by the method of Scheme 1 above, wherein

Fmoc-Lys(Trt)-〇H, D-Leu-OMe and 3,4-di-C1·propionic acid. The 3,4-di-C1-propionic acid is converted to the corresponding aldehyde for use in the reductive alkylation reaction. 122698.doc -86- 200817341

Example 24 (R) 3-Amino-l-{(2R,5S)-4-[(R)-3-amino-4-(2,4-diphenylphenyl)butanyl]-5-[4- (2-Aminoethylamino)butyl]·2·isobutylpiperyl p-butyl 4·(2,4-diphenyl)butan-1-one Prepared Example 24 by the method of the above Scheme 1. Compound

Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-(R)-3-amino.4-(2 4- 'mono-)-butyric acid.

Example 25 (R)_3-Amino-l-{(2S,5R)-4-[(R)-3-Amino-3·(2,4-diphenylphenyl)propanyl]·2- [4-(2-Aminoethylamino)butyl]-5-isobutyl peptin-i-kib 3-(2,4-diphenyl)propyl-;[_ketone by the above procedure The compound of Example 25 was prepared by the method of 1, wherein 122,698.doc -87 - 200817341 was used.

Fmoc-Lys(Trt)_OH, D-Leu-OMe and Boc-(S)-3-amino-4-(2,4-diphenyl)butyric acid.

Example 26 (R)-2-Amino-1-{(28,511)-4-[(1^)-2-amino-3-(4-a-2-methylphenyl)propanyl]- 2-[4-(2-Aminoethylamino)butyl]-5-isobutyl brigade, well-1-yl}-3-(4- gas-2-methyl-phenyl)propane-1 - Preparation of the compound of Example 26 by the method of Scheme 1 above, wherein

Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-2-methyl-4-chloro-Phe-OH 〇

Example 27 (Amino)-2-amino-1-{(28,51^)_4-[(1^)-2-amino]3-(2-indole-4-ylphenyl)propanyl ]-2-[4_(2-Aminoethylamino)butyl b-5-isobutyl piperazine 3_(2- gas-4-methyl-phenyl)propan-1 -嗣122698.doc - 88-200817341 The compound of Example 27 was prepared by the method of the above Scheme 1, wherein

Fmoc-Lys(Trt)-OH, D-Leu-〇Me and Boc-D-4-mercapto-2-chloro-Phe·OH.

Example 28 (R)_2_Amino-l-{(2S,5R)-4-[(R)_2-amino-3-(3,4-difluorophenyl)propanyl b-2-[4-( Preparation of the compound of Example 28 by the method of the above Scheme 1, wherein 2-aminoethylamino) butyl-isobutyl-peptin-^^^^(3,4--phenylene)propan-1 - oxime was prepared by the method of the above Scheme 1, wherein use

Fmoc_Lys(Trt)-OH, D-Leu-OMe and Boc-D-3,4-di-F-Phe· U OH 〇

Example 29 122698.doc 200817341 (R)_2·Amino-l_[(2R,5S)_5-[4_(2·aminoethylamino)butyl]_4-((R)-2-amino-4 -Phenyl-butanyl)-2-isobutylpiperin-1-yl]-4-phenylbutan-1-one The compound of Example 29 was prepared by the method of Scheme 1 above using Fmoc-Lys (Trt) -OH, D-Leu_OMe and Boc-D-high_Phe-OH 〇

〇Example 30 (R)-2-Amino-l-{(2R,5S)-4-[(R)_2-Amino-3-(4-tributylphenyl)propanyl]-5 -[4-(2-Aminoethylamino)butyl]-2-isobutylpiped-1-yl}-3-(4-tributylphenyl)propan-1-one by the above Method of Scheme 1 The compound of Example 30 was prepared using Fmoc-Lys(Trt)-OH, D_Leu-OMe and Boc-D-4-tBu_Phe_OH.

Example 31 l-{(2R,5S)-5-[4-(2-aminoethylamino)butyl]4-[3-(3,4-dimethylbenzene 122698.doc -90- 200817341 Benzyl)-2-isobutylpiperidinyl 3 gas 3, cardiodimethylphenyl)propan-1-one The compound of Example 3 is prepared by the method of the above Scheme 1, wherein

Fmoc-Lys(Trt)-OH, D-Leu-〇Me and 3,4-dimethyl-propionic acid.

Example 32 (R)-2_Amino-1_{(2R,5S)-4_((R)_2_Aminonaphthalen-2-yl-propenyl)-2-isobutyl-5-[3-([ 1,3,4]thiadiazol-2-ylamino)propyl]piped-1-yl}-3-cha-2 _yl-propan-1 -oxime prepared by the methods of the above Schemes 2 and 3 The compound of Example 32, wherein Fmoc_Glu(OtBu)_OH, D_Leu_〇Me, and Boc-D-2-Nal-OH were used. Incorporation of 2-amino-1,3,4-thiadiazole using Method C of Scheme 5 .

122698.doc -91 - 200817341 Example 33 (R)-2-Amino-l-{(2S,5R)-4-[(R)-2-amino-3-(3,4-dimethylbenzene) )) 醯 醯 2- 2-[4-(2-Aminoethylamino)butyl]-5-isobutyl piperidin-1-yl}-3· (3,4-dimethylphenyl) The propan-1-one was prepared by the method of the above Scheme 1, using Finoc-Lys(Trt)-OH, D-Leu_OMe and Boc-D-3,4-di-methyl-Phe-OH oxime.

Example 34 (R)-2-Amino-l-{(2S,5R)-4-[(R)_2-Amino-3-(4·Ga-3-methylphenyl)propyl]- 2-[4-(2-Aminoethylamino)butyl]-5-isobutyl brace-1-yl}-3_(4-a-3-methyl-phenyl)propan-1-oxime The compound of Example 34 was prepared by the method of the above Scheme 1, using Fmoc_Lys(Trt)-OH, D-Leu-OMe and Boc-D-2-methyl-4-gas-Phe_OH 〇122698.doc-92- 200817341 α

Cl Example 35 a (R)-2_Amino_l_{(2R,5S)-5-[4-(2-Aminoethylamino)butyl 4-[(R)-2-amino-3 -(4-methoxyphenyl)propanyl-2-isobutylpiped-1-yl}-3-(4-methoxyphenyl)propan-1-indole by the method of the above Scheme 1 Preparation of the compound of Example 3 5, wherein

Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-4-methoxy-Phe-OH.

Example 36 (R)-2-Amino-l_{(2R,5S)-4_((R)-2-amino-3-biphenyl-4-yl-propenyl)-5-[4-( 2-Amino-ethylamino)butyl]-2-isobutyl n-cylindole-1-yl b-3-biphenyl-4-yl-propan-1-pyrene 122698.doc -93- 200817341 by The compound of Example 36 was prepared by the method of the above Scheme 1, wherein Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-4-phenyl-Phe-OH were used.

Example 37 (R)_2-Amino-l_[(2R,5S)-4-((R)-2-amino3-3-naphthalen-2-yl-propionyl)-2-isobutyl-5- (3-[l,2,4]Sanjun-l-yl-propyl) brigade p-l-yl]_3-naphthalene_2-yl-propan-l__ by the method of the above schemes 2 and 3 A compound of 37, wherein Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH are used. The 1,2,4-triazole was incorporated using Method C of Scheme 5.

Example 38 (R)-2_Amino-l-{(2R,SS)-4_((R)-2_Aminonaphthalene-2-propenyl)_2·Isobutyl_5-[3-([1 , 2,4]trimethyl-4-ylamino)propyl]pitricin j-based}_3 naphthalene-122698.doc -94- 200817341 2-based-propionyl-propionation method by the above methods 2 and 3 The compound of Example 38 was prepared in which Fmoc-Glu(OtBu)-OH, D-Leu_OMe and Boc-D_2-Nal-OH were used to incorporate 4-amino-4H-1,2,4- using Scheme C of Scheme 5. Triazole. 1)

Example 39 (R)-2-Amino-l-{(2R,5S)-4-((R)-2-amino-3-carbo-2-yl-propyl)-2-isobutyl 5-5-[3-(oxime-2-ylamino)propyl] brigade p-l-yl}-3-tea-2-yl-propan-1-oxime by the methods of the above schemes 2 and 3 The compound of Example 39 was prepared using Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal_OH. 2-Aminothiazole was incorporated using Method C of Scheme 5.

Example 40 122698.doc -95- 200817341 (R)_2-Amino·1-{(2Κ,58)-4-((Κ)-2_amino-3-naphthalene-2-yl-propenyl) 2-isobutyl-5-[3-(5-methylthiazol-2-ylamino)propyl]piped_]μ基卜3_naphthalene_2-yl-propion-1- 1 by hydrazine The compound of Example 40 was prepared by the procedures of the above Schemes 2 and 3, using Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH. 2-Amino-5-methylthiazole was incorporated using Method C of Scheme 5.

Example 41 ϋ (R)-2-Amino-l-{(2R,5S)-4-((R)-2-amino-3-naphthalen-2-yl-propenyl)-2-isobutyl 5-[3-(4-mercaptothiazol-2-ylamino)propyl]piped-1-yl}-3-naphthalen-2-yl-propan-1-indole by the above Scheme 2 Method 3 The compound of Example 41 was prepared using Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH. 2-Amino-4-methyl sigma is incorporated using Method C of Scheme 5. 122698.doc -96 - 200817341

Example 42 (R)-2-Amino-l_{(2R,5S)-4-((R)-2-amino-3-naphthalen-2-yl-propenyl)-2-isobutyl 5·[3_(5_methyl-[1,3,4]嗟disthylamino)propyl]Breakyl}-3-茶-2-yl-prop-1-e by the above scheme 2 And a compound of Example 42, wherein Fmoc-Glu(OtBu)-OH, D-Leu-〇Me and Boc-D-2-Nal-OH were used. 2-Amino-5-methyl-oxime, 3,4·嗟二峻 is incorporated using Method C of Scheme 5.

Example 43 Ethylamino-3-naphthalene-2-yl-propionyl)-yl-propyl) tl tl_yl]-1_naphthalene_2·yl N-{(R)-2-[( 2S,5R)-4-((R)-2-Ethyl 5-isobutyl-2-(3_[l,2,4]triazol-1-ylmethyl-2-oxo-ethyl }-Ethylamine The compound of Example 43 was obtained from the compound of Example 37, wherein the free amine group was acetylated by reacting acetic anhydride with the compound of Example 37 in the presence of pyridine 122698.doc-97-200817341 σ.

0 Example 44 (R)_2_Amino_1-{(2R,5S)_4-((R)_2_Amino-3-naphthalen-2-yl-propenyl)-2_isobutyl-5- [3-(3-Methylisoxazole-5-ylamino)propyl]Peptin-1-ylbu 3-Cai-2-yl-propan-1 - oxime by the methods of the above Schemes 2 and 3 The compound of Example 44 was prepared using Fmoc_Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2, Nal-OH. 5-Amino-3-methylisoxazole was incorporated using Method C of Scheme 5.

Example 45 (R)-2-Amino-l-{(2R,5S)-4-((R)-2-amino-3-naphthalene-2-ylpropanyl)-2-isobutyl · 5-[3-(5-Methylisoxazol-3-ylamino)propyl]Pultivated-1_Kib3-122698.doc -98- 200817341 Cai-2 ·K-Pro--1制备 The compound of Example 45 was prepared by the methods of the above Schemes 2 and 3, wherein Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used, and the method C of Scheme 5 was used. 3-amino-5-methylisoxazole was added.

Example 46 (R)-2-Amino-l-{(2R,5S)-4-((R)-2-amino-3-naphthalen-2-yl-propenyl)-2-isobutyl -5-[3-(pyrimidin-4-ylamino)propyl]piped-1-yl}-3-naphthalen-2-yl-propan-1-one

The compound of Example 46 was prepared by the methods of the above Schemes 2 and 3, wherein Fmoc-Glu(OtBu)-OH, D_Leu-OMe and Boc-D-2-Nal-OH were used, and the amine group was incorporated using the method C of Scheme 5. Pyridine.

Example 47 (R)-2-Amino-l-{(2R,5S)-4-((R)-2-amino-3-naphthalen-2-yl-propenyl)-2-122698.doc -99- 200817341 Isobutyl-5-[3-(isooxaguan-3-ylamino)propyl] 〃井-i-yl}-3-naphthalen-2-yl-propan-1 _嗣The compound of Example 47 was prepared by the procedures of the above Schemes 2 and 3, using Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc_D-2-Nal-〇H. Method 3-incorporation of 3-aminoisoxazole using Method C of Scheme 5.

Example 48 (R)-2-Amino-l-{(2R,5S)-4-((R)-2-amino-3-naphthalen-2-yl-propenyl)-2-isobutyl -5-[3-(pyrimidin-2-ylamino)propyl]piped-1-yl}-3-naphthalene-2-yl-propan-1 -oxime Prepared by the method of the above Schemes 2 and 3 A compound of 83, wherein Fmoc-Glu(OtBu)_OH, D-Leu-OMe and Boc-D-2_Nal-OH are used. 2-Aminopyrimidine is incorporated using Method C of Scheme 5.

Example 49 (R)-2-Amino-l-{(2R,5S)-4-((R)-2-amino-3-naphthalene-2-ylpropanyl)-5-[2- (1Η-imidazole-2·yl)ethyl]-2-isobutylpiped-1-yl b.3·naphthalen-2-yl-propion_122698.doc -100- 200817341 1-ketone by the above scheme 2 And the method of 3, the compound of Example 49 was prepared using Fm〇C-Glu(0tBu)-OH, D-Leu_〇Me&amp;B〇c_D 2 Nai/_〇H. The imidazolyl group is formed by oxidizing a hydroxyl group to an aldehyde via Dess Martin and then reacting with a glyoxal trimer and ammonium acetate in acetic acid under microwave conditions at 10 (rc for 5 minutes).

Example 50 (S)-2-Amino-l-{(2R,5S)-4_丨(R)-2-amino}_3_(2,4_二气笨基) propyl-based]_2_ Butyl-5-[3-([1,3,4]coxadiazol-2-ylamino)propyl]branches 1-yl}-3-(2,4-di-phenyl)propene- 1 - 制备 Preparation of the compound of Example 50 by the method of the above Scheme 4, wherein

Boc-D-2,4-di-Cl-Phe_OH is used as QCOOH 〇

Example 51 (R)_2-Amino-i-[(2R,5S)_5-[4-(2-aminoethylamino)butyl]·4_((κ)_2_Amino-3-p-tolyl- Propionyl)-2-isobutylpiperyl]_3_p-tolyl-propan-1- 1 嗣122698.doc -101 - 200817341 The compound of Example 51 was prepared by the method of the above Scheme 1, wherein

Fmoc-Lys(Trt)-OH, D_Leu-〇Me and B〇c_D_4_ methyl-Phe-ΟΗ 〇 (/^NH2

The foregoing examples can be successfully repeated similarly by substituting the reactants and/or synthetic conditions used in the above-described examples for the reactants and/or synthetic conditions described herein. The present invention has been described in detail with particular reference to the preferred embodiments, but other embodiments may achieve the same. Variations and modifications of the present invention are obvious to those skilled in the art and are intended to cover all such modifications and equivalents. All references, applications, patents and publications cited above and the entire contents of the corresponding disclosure are hereby incorporated by reference.

V 122698.doc -102-

Claims (1)

200817341 X. Patent application scope: 1 · A compound of formula I: Stereoisomer or diastereomeric Or an enantiomer thereof, a salt of a scientifically acceptable salt, wherein: the isomer or its drug KV and the XV of the drug are independently Γ 5 Γ this ^ linear or branched chain and the remaining Rla , R lb, R 2a 2 16 pieces are Rla &amp; Ru &gt; $ ii 2 R is gas, which limits the chlorine; at least one of them and at least one of -b is one of R2a and R2b: Or Rla, Rib υ and the remaining Rla, Rlb, R2a and R2b are hydrogen; or R and the ruler together form =0 and the R2a and R2bf family are straight or branched, One is (^ to (6 grease and the remaining R2> R2b y is an independent index value of 〇 to 5 in each h case; 122698.doc 200817341 w is having at least one cationic center, hydrogen bond donor or hydrogen bond One of the acceptor amine heteroatoms; L is a bond or (CH2)Z; z is an index of 1 to 6; X is ch2, c = 〇 or c = s; group and -C(R8)(CH2 vCH(R9)(CH2)r J are the same and in their groups: R8 is Η or =〇; Is hydrogen or N(RiUa)Ri R~ and R10b are independently hydrogen, ethyl hydrazide, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, isobutyl, benzyl, benzyl Stuffed base, hexyl fluorenyl, propyl fluorenyl, butyl sulfhydryl, A fluorenyl, hydrazino, % propyl, propyl propyl I, cyclobutyl, cyclobutylmethyl, cyclohexyl, cyclohexylmethyl or polyethyl a diol; V is an index value of 0 to 2; and -Q is the same and is not selected from the group consisting of a phenyl group, a substituted phenyl group, a naphthyl group, and a substituted naphthyl group; wherein the mark is marked with an asterisk The carbon atom can be 0, and ^ y卞j has any stereochemical configuration. 2. A compound such as #, wherein R8 is diterpene. 3. A compound according to claim 1 or 2, wherein q is: wherein R3 R3b and r3c are optional soil substituents and when present or more than 122698.doc 200817341, they are the same or different and are independently hydroxy, halo, alkyl, alkyl, aryl or aryl. 4. A compound according to claim 3, wherein at least one of R3a, R3b or R3c is -CH3 or _〇_CH3. 5. The compound of claim 3, wherein at least one of R3a, R3b or r3c is -C1 or -CF3. 6. A compound according to claim 1 or 2, wherein w comprises an amine, a guanamine, an alcohol, a carboxylic acid, an ether, an ester or a urea. 7. A compound of the formula π: R8 Or an enantiomerically acceptable salt thereof: a stereoisomer or a diastereomer or a pharmaceutically acceptable κ thereof, and both of which are independently (^ to a lipid in a straight or branched chain and remaining Rla, Rlb, 曰, , R and 11 are hydrogen, the restriction is at least one of R and R and 2a hydrogen; at least one of singular is either one of Rla, Rlb, R2a & R2b for 122698.doc 200817341 and the remaining R, Rlb, R2a &amp; R2b are hydrogen; 4RllRlb together form = 0 and one of R2lR2b is (: 丨 to 匕 aliphatic straight chain or branched chain, - and the remaining R2a&amp;R2b is hydrogen; R4a is NH, N(.(CH2)y-CH3), NH-C(=0) or C(=〇)-Li; f) R5a is 丽2, NH_(CH2 y-CH3 or N(-(CH2)y-CH3)2; y is independently an index value of 0 to 5 in each case; group -C(R8)CH(R9)(CH2)yQ and -C (R8)CH(R9)(CH2)yJ is the same, and in the same group: R8 is Η or =〇; R9 is hydrogen or N(R1Ga)R10b; R 〇a and R10b are independently hydrogen, Ethyl, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, isobutyl, benzyl, benzhydryl, hexyl, propyl, butyl, pentyl , heptyl, 'I propyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclohexyl^ or cyclohexylmethyl; Q and J are the same and are not selected from phenyl, substituted phenyl, An aromatic carbocyclic ring of a naphthyl group and a substituted naphthyl group; and Z is an index value of from 1 to 6; wherein the carbon atom marked with an asterisk may have any stereochemical configuration. 8. The compound of any one of claims 2 and 7, wherein the compound is 122698.doc 200817341 is selected from the group consisting of: (1) (R)-2-amino-1-{(211,58)-4- [(11)_2-Amino-3-(2,4-dichlorophenyl)propanyl]-5-[3-(2-aminoethylamino)propyl]-2-isobutylphen (1)(R)_2-Amino-l-[(2R,5S)-5-[3- (2-Aminoethylamino)propyl]-4-((R)-2-amino-3-naphthalen-2-yl-propenyl)-2-isobutylpiperidin-1-yl] 3-na-2-yl-propan-1 -copper; (3) (R)-2-aminol-l-{(2R,5S)-4-[(R)-2-amino-3- (2,4-Dimethylphenyl)propanyl]-5-[3-(2-aminoethylamino)propyl]-2-cyclohexylmethylpiperazine-1-yl}-3 -(2,4-dimethyl-phenyl)propan-1-one; (4) (R)-2-aminol_l-{(2R,5S)-4-[(R)-2-amino -3-(2,4-Dichlorophenyl)propanyl]-5-[3-(2-aminoethylamino)propyl]-2-cyclohexylmethylpiperazine·1_yl}- 3-(2,4-dichloro-phenyl)-propan-1-one; (5) (11)-2-amino-1-[(211,5 8)-5-[3-(2- Aminoethylamino)propyl]-4-((R)-2-amino-3-naphthalen-2-yl-propenyl)-2-cyclohexylmethylpipen-1-yl]-3 -Qin-2-yl-propyl-1 -anthracene; (6) (R)-2-amine Base-l-{(2S,5R)-4-[(R)-2-amino-3-(2,4-dimethylbasin)propanyl]-2-[3-(2-amino) Ethylamino)propyl]-5-isobutyl-injection 1-yl}-3-(2,4-didecylphenyl)-propan-1-yl; (7) (R)-2 -amino-1-{(211,58)-4-[(11)-2-amino-3_(2,4-dichlorophenyl)propanyl]-5-[4-(2-amine Ethylamino)butyl]-2-isobutylpiped-1-yl}-3-(2,4-dichlorophenyl)propan-1-one; (8) (1〇-2-amine 1-[(211,58)-5-[4-(2-Aminoethylamino)butyl]4-((R)-2-amino-3-naphthalen-2-yl-propanyl醯-)-2-isobutyl bridging group]·3_ 122698.doc 200817341 Naphthalen-2-yl-propan- ketone; (9) (R)-2-Amino-l-{(2R,5S)- 4-[(R)-2-amino-3-(2,4-dimercaptophenyl)propanyl]-5-[heart (2-aminoethylamino)butyl]-2-iso Butyl ___ 1-yl}-3-(2,4-dimethylphenyl)propan-1-one; (10) (R)_2-amino-1-{(28,51〇-4 -[()-2-amino-3-(3,4-dichlorophenyl)propanyl]-2-[4-(2-aminoethylamino)butyl]-5-isobutyl Benzyl-1-yl}-3-(3,4-dichlorophenyl)-propan-1-yl; (11) (foot)-2_amino-1-[(28,5 ft)- 2-[4-(2-Aminoethylamino)butyl]-4_((R)-2-amino-3-naphthalen-2-yl-propionium -5-cyclohexylmethylpipen-1-yl; μ 3-naphthalen-2-yl-propan-1-one; (12) (R)-2-amino-1-{(23,511)-4 -[(1〇-2_amino-3-(2,4-dichlorophenyl)propanyl]-2-[4·(2-aminoethylamino)butyl]-5-cyclohexyl Methylpiped-1-yl}-3-(2,4-dichloro-phenyl)-propan-1-one; (13) (R)-2-amino-1-((211,58) -4-[(1〇-2-amino-3-(2,4-dichlorophenyl)propanyl]-5-[3-(2-aminoethylamino)propyl]-2 -曱基旅_-1-yl}-3-(2,4-diphenyl)-1-propan-1-one; (14) (R)-2-Amino-l-{(2R,5S)- 4-[(R)-2-amino-3-(2,4-didecylphenyl)propanyl]-5-[3-(2-aminoethylamino)propyl]-2- Methylpiperidine-1-yl}_3-(2,4-dimethylphenyl)propan-1-one; (15) (11)-2-amino-1-[(211,5 8)- 5-[3-(2-Aminoethylamino)propyl]-4-((R)-2-amino-3-na-2-yl-propyl-)-methyl-branol- 1-yl]-3-cai-2_yl-propan-1-indole, and (16) (R)_2-amino-1_{(2,58)-4-[(11)-2-amino -3-(3,4-diphenylphenyl)propsyl]-5-[3-(2-aminoethylamino)propyl]-2-methyl brace 0 well-1-yl}·122698 .doc 200817341 3-(3,4-dichlorophenyl)-acetone, or its pharmaceutically acceptable salt. The compound according to any one of claims 1 to 2, wherein the compound is selected from the group consisting of: (1 7) (R)-2-amino-l-{(2S,5R)-4-[( R)-2-Amino-3-(3,4-dichlorophenyl)propane Si&yl]-2-[4-(2-aminoethylamino)butyl]-5-methyl oxime- 1_yl 3-(3,4-dichlorophenyl)-propyl·ι·_ ; (18) (R)-2-Amino-l-{(2S,5R)-4-[(R)- 2-Amino-3-(2,4-dimethylbasinyl)propyl]2-[4-(2-aminoethylamino)butyl]-5-methyl british base}-3 -(2,4·dimethylphenyl)-propan-1-one; (19) (11)_2-amino-1-{(28,51〇-2-[4-(2-amino) Amino)butyl]-4-[(R)-2-amino-3-(4-trifluoromethylphenyl)propanyl]-5-isobutylpiped-1-yl}-3 -(4-Trifluoromethyl-phenyl)propan-1-one; (20) (R)-2-Amino-l-{(2S,5R)-4-[(R)-2-amino group -3-(4-Phenylphenyl)propanyl]-2-[4-(2-aminoethylamino)butyl]-5-isobutyl brigade p-kib 3 - (4-gas benzene ()) (1)-2-amino-1-((211,58)-5-[4-(2-aminoethylamino)butyl]_4-[ (R)-2.Amino-3-(3-trifluoromethylphenyl)propanyl]-2-isobutylpiperone-1-yl}-3-(3-trifluoromethyl-benzene Base) propan-1-one; (22) l-{(2 R,5S)-5-[4-(2-Aminoethylamino)butyl]_4·[3-(3,4-diphenyl)-propenyl]-2-isobutylpiperene- L-yl}-3_(3,4-diphenyl)propyl-1 -indole; (23) &gt;^-(4-{(28,5 ft)-1,4-bis-[3-( 3,4·dichlorophenyl)propyl]_5-isobutylpiped-2-yl} butyl)ethane-1,2-diamine; 122698.doc 200817341 (24) (11)-3- Amino-1-{(211,58)-4-[(11)-3-amino-4-(2,4-dichlorophenyl)butanoic acid]-5-[4-(2-amine Ethylamino)butyl]-2-isobutyl brigade p-1-yl}_4-(2,4-dichlorophenyl)butan-1-one; (25) (R)-3-amine -1{(28,511)-4-[(11)-3-amino-3-(2,4-dichlorophenyl)propanyl]-2-[4-(2-aminoethylamine) Butyl]-5-isobutylpiped-1-yl}-3-(2,4-diphenyl)-propan-1-one; (26) (R)-2-amino- L-{(2S,5R)-4-[(R)-2-Amino-3((4-chloro-2-indolylphenyl)-propyl]-2_[4-(2-amino) Ethyl)butyl]-5-isobutyl brigade '2 well-1-yl}-3-(4-chloro-2-indolyl-phenyl)prop-1--; (27) (R) 2-Amino- l-{(2S,5R)-4-[(R)-2-amino-3-(2-a-4-methylphenyl)-propenyl]-2. 4-(2-Aminoethylamino)butyl]-5-isobutylpiperidin-1-yl}-3_(2-chloro-4-methyl (-phenyl)propan-1-one; (28) (R)-2-aminol-1-{(28,51〇-4-[(11)-2-amino-3-(3,4) -difluorophenyl)propanyl]-2-[4-(2-aminoethylamino)butyl]-5-isobutylpiped-1-yl}-3-(3,4-di Fluorophenyl)propan-1-one; (29) (R)-2-Amino-l-[(2R,5S)-5-[4-(2-aminoethylamino)butyl]-4 -((R)-2-amino-4-phenyl-butanyl)-2-isobutylpiped-1-yl]-4-phenylbutan-1-one; (30) (R)-2 -amino-1_{(211,58)-4-[(11)-2-amino-3-(4-indolylbutyl)propenyl]-5-[4-(2-amine Ethylamino)butyl]-2-isobutylpiped-1-yl}-3-(4-indenyltributylphenyl)propan-1-one; (31) 1-{(211,5 8)-5-[4-(2-Aminoethylamino)butyl]-4-[3_(3,4-dimethylphenyl)-propenyl]-2-isobutyl piperidine-l -3}(3,4-dimethylphenyl)propan-1-one; 122698.doc 200817341 (32) (R)-2-Amino-l-{(2R,5S)-4- ((R)-2-amino-3-naphthalen-2-yl-propenyl)-2·isobutyl-5·[3-([1,3,4]thiadiazol-2-ylamine Base) propyl] piperidine. Well-1 -yl}-3 -na-2-yl-propan-1 -copper; (33) (R)-2-amino-1-{(28,511)-4-[(11)-2-amine 3-(3,4-dimethylphenyl)propanyl]-2-[4-(2-aminoethylamino)butyl]-5-isobutylpiperin-1-yl} -3-(3,4-dimethylphenyl)-propan-1-indole; (34) (R)-2-amino-l-{(2S,5R)-4-[(R)-2 -amino-3-(4-chloro-3-indolylphenyl)-propenyl]-2-[4-(2-aminoethylamino)butyl]-5-isobutylperazine- 1-(yl)}-3-(4-chloro-3-methyl-phenyl)propan-1-indole; (35) (R)-2-amino-l-{(2R,5S)-5-[ 4-(2-Aminoethylamino)butyl]-4-[(R)-2-amino-3-(4-decyloxyphenyl)propanyl]-2-isobutyl brace Well--1-yl}-3-(4-methoxyphenyl)propan-1-indole; (36) (R)-2-amino-l_{(2R,5S)-4-((R) 2-amino-3-biphenyl-4-yl-propenyl)-5-[4-(2-amino-ethylamino)butyl]-2-isobutylpiperin-1-yl 3 -biphenyl·4-yl-propan-1 -indole; (37) (R)-2-aminol_l-[(2R,5S)-4-((R)-2-amino-3 -naphthalen-2-ylpropenyl)_2-isobutyl-5_[3-([1,2,4]tris.sodium-1-yl-propyl) ·C1--1, (3 8) (R)-2-Amino-1_{(215 8)-4-(()-2-amino-3-3-naphthalene-2-yl-propyl ))-2-isobutyl- 5·[3-([1,2,4]tris-7-ylamino)propyl]σ辰呼_1_ base} - 3 · Qin-2 -yl- Propane-1 -嗣, (39) (R)_2-Amino small {(2R,5S)-4-((R)-2-amino3-3-naphthalen-2-yl-propenyl)-2- Isobutyl-5-[3-(嗟 -2--2-ylamino)propyl] 旅呼_1_基卜3_茶-2-基-丙-1 -嗣, 122698.doc 200817341 (40) ( R)-2-Amino-l-{(2R,5S)-4-((R)-2-amino-3-naphthalen-2-yl-propenyl)-2-isobutyl-5- [3-(5-Methylthiazol-2-ylamino)propyl]piperazin-1 -yl}-3-n-2-yl-propan-1 -S, (41) (R)-2 -amino-l-{(2R,5S)-4-((R)-2-amino-3-naphthalen-2-yl-propenyl)-2-isobutyl-5-[3-( 4-methylthiazol-2-ylamino)propyl]piped-1_yl}-3-n-2-yl-propan-1-yl, (42) (R)-2-amino-l- {(2R,5S)-4-((R)-2-amino-3_cain-2-yl-propyl)-2-isobutyl-5- [3-(5-methyl-[1 ,3,4]ϋ塞二二-2-ylamino)propyl] Well ► p-well-1 -yl} - 3 -na-2-yl-propan-1 -阙, (43) N-{( R)-2-[(2S,5R)-4-((R)_2-acetamido-3-naphthalen-2-yl-propenyl)-5-isobutyl-2-(3-[ 1,2,4]triazol-1-yl-propyl)piped-1-yl]_ 1-na-2- Methyl-2-oxo-ethyl}-ethinamine, (44) (R)-2-amino-l-{(2R,5S)-4-((R)_2-amino-3 -naphthalen-2-yl-propyl aryl)-2-isobutyl-5- [3-(3-indolyliso- oxime-5-ylamino)propyl]α bottom ρ well · 1 - }} - 3 -na 2 -yl-propan-1 - fluorene, (45) (R)-2 -amino-1-{(2R,5S)-4-((R)-2-amino- 3-naphthalen-2-yl-propenyl)-2-isobutyl-5-[3-(5-methylisoxazol-3-ylamino)propyl]piperazine-1 _yl} _ 3 -Ny-2-yl-propyl-1-anthracene, (46) (R)-2-Amino- l-{(2R,5S)-4-((R)-2.Amino-3- Naphthalen-2-yl-propionyl)-2-isobutyl-5-[3-(pyrimidin-4-ylamino)propyl]piped_1_yl}_3_na-2-yl-propyl- 1 -嗣, (47) (R)-2-Amino-l-{(2R,5S)-4-((R)-2-amino-3-3-naphthalen-2-yl-propanyl)- 2-isobutyl-5-[3-(isooxato-3-ylamino)propyl]p-p--1_yl}_ 3 -na-2-yl-propan-1 -嗣; 122698 .doc -10· 200817341 (48) (1〇-2-Amino-1-{(211,5 8)-4-((11)-2-amino-3-naphthalen-2-yl-propionate 2-isobutyl-5-[3-(pyrimidin-2-ylamino)propyl]piped-1-yl-3-naphthalen-2-yl-propan-1-one; (49) (R)-2-aminol-l-{(2R,5S)-4-((R)-2-amino}_3_ -2-yl-propionyl)-5-[2-(1Η-imidazol-2-yl)ethyl]-2-isobutylpiped-1-yl}_3_na-2-yl-propan-1 - reward, (50) (S)-2-Amineyl small {(2R,5S)_4-[(R)-2-amino3·(2,4-dichlorophenyl)propanyl]-2-iso Butyl-5-[3-([1,3,4]thiadiazol-2-ylamino)propyl]piped-1-yl}-3-(2,4-dichloro-phenyl)丙_ι_ ketone; and (51) (R)-2-aminol_l-[(2R,5S)-5-[4-(2-aminoethylamino)butyl]_4_ ((R)- 2-Amino-3-#-phenylpropanyl)_2-isobutylpipekib 3_potential tolyl-propan-1-one; or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier 0. 11. The medicament of claim H) The composition is used for transmucosal administration, oral administration of 16 drugs, dermal administration, inhalation administration or nasal administration. 12. A compound according to claim 2 and 7 or a pharmaceutically acceptable salt thereof for use as a pharmaceutical. 13. A compound according to any one of claims i, 2 and 7 or a pharmaceutically acceptable salt thereof for use in the treatment of melanocortin receptor function in a human or non-human mammal Change the condition of the reaction. 14. The compound of claim 13, wherein the condition is selected from the group consisting of male sexual function 122698.doc 200817341 disorder, female sexual dysfunction, eating disorder, excess body weight, fat, suboptimal body weight and cachexia composition. group. 15. The use of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof for use in the manufacture of a melanocortin for treatment of a human or non-human mammal A drug that responds to changes in receptor function. . C. The use of claim 15 wherein the condition is selected from the group consisting of male sexual dysfunction, female sexual dysfunction, eating disorder, excess body weight, obesity, suboptimal body weight, and cachexia. A compound according to any one of the items 1 to 9 or a pharmaceutically acceptable salt thereof for use in the manufacture of a disorder or condition associated with melanocortin receptor activity The drug. 18. The use of claim 17, wherein the condition or condition is an eating disorder, obesity, and a dysfunction associated with energy balance or sexual dysfunction. 122698.doc 12- 200817341 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please reveal the best display invention. Characteristic chemical formula: U 122698.doc