根據一方面，本發明提供具有化學式(I)之結構的化合物，其中， R1
係選自鹵素、取代的或未被取代的烷基、取代的或未被取代的鹵烷基、取代的或未被取代的環烷基、取代的或未被取代的烷氧基、取代的或未被取代的鹵烷氧基、-(CRa
Rb
)1-3
OH、-C(O)NH-烷基、-S(O)2
-烷基、-S(O)2
NH-烷基、-C(O)OH、-C(O)O-烷基、-(CRa
Rb
)1-3C(O)OH
與 -(CRa
Rb
)1-3C(O)O-
烷基； R2
為取代的或未被取代的苯基或取代的或未被取代的萘基，其中該等取代基可能為一或更多個並且獨立地選自鹵素、取代的或未被取代的烷基、取代的或未被取代的鹵烷基、-OR4
、-NR5
R6
以及取代的或未被取代的環烷基； X係選自-C(O)OH、-C(O)O烷基、-C(O)NR5
R6
、-(CRa
Rb
)1-3C(O)OH
、-(CRa
Rb
)1-3C(O)O-
烷基、-O-(CRa
Rb
)1-3C(O)OH
、-O-(CRa
Rb
)1-3C(O)O-
烷基、-CRc
=CRc
-C(O)OH、鹵素、取代的或未被取代的烷基、取代的或未被取代的鹵烷基、OR4
以及-S(O)2
-烷基； Ra
與 Rb
係獨立地選自氫、鹵素、羥基、取代的或未被取代的烷基、取代的或未被取代的鹵烷基以及取代的或未被取代的環烷基；或Ra
與 Rb
可與它們所連接的碳原子共同形成一取代的或未被取代的3 至 6元飽和碳環之環； Rc
係獨立地選自氫、鹵素以及取代的或未被取代的烷基； 在每個情況下可能是相同或不同地R3
係獨立地選自 鹵素、氰基、取代的或未被取代的烷基、取代的或未被取代的鹵烷基與-OR4
； R4
係選自氫、取代的或未被取代的烷基、取代的或未被取代的鹵烷基與取代的或未被取代的環烷基； R5
與 R6
係獨立地選自氫、取代的或未被取代的烷基與取代的或未被取代的環烷基；以及 ‘n’為在0至2包含兩端點的一整數； 或其藥學上可接受之鹽類。 應了解化學式(I)在結構上包含所有適用的互變異構物、立體異構物、鏡像異構物以及非鏡像異構物以及可能由本文描述的種類之化學結構考量到的藥學上可接受的鹽類。 根據一具體實施例，提供了具有化學式(II)之結構的化合物：其中， R1
係選自鹵素、取代的或未被取代的烷基、取代的或未被取代的鹵烷基、取代的或未被取代的烷氧基、取代的或未被取代的鹵烷氧基、-(CRa
Rb
)1-3
OH、-C(O)NH-烷基、-C(O)OH與 -(CRa
Rb
)1-3C(O)OH
； X 係選自-C(O)OH、-C(O)O烷基、-(CRa
Rb
)1-3C(O)OH
、-(CRa
Rb
)1-3C(O)O-
烷基、-O-(CRa
Rb
)1-3C(O)OH
、-CRc
=CRc
-C(O)OH、鹵素、取代的或未被取代的烷基、取代的或未被取代的鹵烷基、OR4
以及-S(O)2
-烷基； 在每個情況下可能是相同或不同的R3
係獨立地選自鹵素、取代的或未被取代的烷基、取代的或未被取代的鹵烷基與-OR4
； 在每個情況下可能是相同或不同的R7
係獨立地選自鹵素、取代的或未被取代的烷基、取代的或未被取代的鹵烷基、-OR4
以及取代的或未被取代的環烷基； R4
係選自氫、取代的或未被取代的烷基與取代的或未被取代的鹵烷基； Ra
與Rb
係獨立地選自氫、鹵素、取代的或未被取代的烷基； Rc
係獨立地為氫或取代的或未被取代的烷基； ‘n’ 為在0至2包含兩端點的一整數；以及 ‘p’ 為在0至2包含兩端點的一整數； 或其藥學上可接受之鹽類。 根據另一具體實施例，提供了具有化學式(III)的結構之化合物：其中， R1
係選自鹵素、取代的或未被取代的烷基、取代的或未被取代的鹵烷基、取代的或未被取代的烷氧基、取代的或未被取代的鹵烷氧基、-(CRa
Rb
)1-3
OH、-C(O)NH-烷基、-C(O)OH 與 -(CRa
Rb
)1-3C(O)OH
； X係選自-C(O)OH、-C(O)O烷基、-(CRa
Rb
)1-3C(O)OH
、-(CRa
Rb
)1-3C(O)O-
烷基、-O-(CRa
Rb
)1-3C(O)OH
、-CRc
=CRc
-C(O)OH、鹵素、取代的或未被取代的烷基、取代的或未被取代的鹵烷基、OR4
以及 -S(O)2
-烷基； 在每個情況下可能是相同或不同的R3
係獨立地選自鹵素、取代的或未被取代的烷基、取代的或未被取代的鹵烷基與 -OR4
； R4
係選自氫、取代的或未被取代的烷基與取代的或未被取代的鹵烷基； Ra
與 Rb
係獨立地選自氫、鹵素、取代的或未被取代的烷基； Rc
係獨立地為氫或取代的或未被取代的烷基；以及 ‘n’ 為在0至2包含兩端點的一整數； 或其藥學上可接受之鹽類。 根據另一具體實施例，提供了具有化學式(IV)之結構的化合物：其中， R1
係選自鹵素、取代的或未被取代的烷基、取代的或未被取代的鹵烷基、取代的或未被取代的烷氧基、取代的或未被取代的鹵烷氧基、-(CRa
Rb
)1-3
OH、-C(O)NH-烷基、-C(O)OH 以及 -(CRa
Rb
)1-3C(O)OH
； X係選自-C(O)OH、-C(O)O烷基、-(CRa
Rb
)1-3C(O)OH
、-(CRa
Rb
)1-3C(O)O-
烷基、-O-(CRa
Rb
)1-3C(O)OH
、-CRc
=CRc
-C(O)OH、鹵素、取代的或未被取代的烷基、取代的或未被取代的鹵烷基、OR4
以及-S(O)2
-烷基； R2
為取代的或未被取代的苯基或取代的或未被取代的萘基，其中該等取代基可能為一或更多個，並且係獨立地選自鹵素、取代的或未被取代的烷基、取代的或未被取代的鹵烷基、-OR4
以及取代的或未被取代的環烷基； 在每個情況下可能是相同或不同的R3
係獨立地選自鹵素、取代的或未被取代的烷基、取代的或未被取代的鹵烷基與-OR4
； R4
係選自氫、取代的或未被取代的烷基與取代的或未被取代的鹵烷基； Ra
與 Rb
係獨立地選自氫、鹵素、取代的或未被取代的烷基； Rc
係獨立地為氫或取代的或未被取代的烷基；以及 ‘n’ 為在0至2包含兩端點的一整數； 或其藥學上可接受之鹽類。 應了解化學式(I)、化學式(II)、化學式(III)及/或化學式(IV)在結構上包含所有適用的互變異構物、立體異構物、鏡像異構物以及非鏡像異構物，包括同位素，以及可能由本文描述的種類之化學結構考量到的藥學上可接受的鹽類。 闡述於下文之本發明的一或更多具體實施例的細節在本質上僅為說明性的，並且不意圖限制本發明的範圍。本發明的其他特徵、目標與優勢由描述與申請專利範圍來看是清楚的。 根據另一具體實施例，提供了化學式(I)之化合物，其中R1
係選自鹵素、取代的或未被取代的烷基、取代的或未被取代的鹵烷基、取代的或未被取代的烷氧基、取代的或未被取代的鹵烷氧基、-(CRa
Rb
)1-3
OH、-C(O)NH-烷基、-C(O)OH與-(CRa
Rb
)1-3C(O)OH
；其中Ra
與Rb
係獨立地為氫或取代的或未被取代的烷基。 根據另一具體實施例，提供了化學式(I)之化合物，其中X係選自-C(O)OH、-(CRa
Rb
)1-3C(O)OH
、-O-(CRa
Rb
)1-3C(O)OH
、-CRc
=CRc
-C(O)OH、鹵素、取代的或未被取代的烷基、取代的或未被取代的鹵烷基、OR4
與 -S(O)2
-烷基；其中Ra
、Rb
與Rc
係獨立地為氫或取代的或未被取代的烷基。 根據另一具體實施例，提供了化學式(I)之化合物，其中R2
為被取代的或未被取代的苯基或取代的或未被取代的萘基，其中該等取代基可能為一或兩個，並且係獨立地選自鹵素、取代的或未被取代的烷基、取代的或未被取代的鹵烷基、-O-烷基以及取代的或未被取代的環烷基； 根據另一具體實施例，提供了化學式(I)之化合物，其中R3
為鹵素、取代的或未被取代的烷基、取代的或未被取代的鹵烷基與–O-烷基並且 ‘n’為0、1或2； 在本發明另一方面，提供了在治療、管理或減輕與鈣敏感受體（CaSR）調節劑相關聯的疾病、病症、病徵或症狀之嚴重性有效用的化學式(I)之化合物。 在另一方面，本發明提供了包含至少一個化學式(I)之化合物以及至少一藥學上可接受的賦形劑之藥學組成物。 在另一方面，本發明將在治療、管理或減輕與鈣敏感受體（CaSR）調節劑相關聯的疾病、病症、病徵或症狀之嚴重性有效用的化學式(I)之化合物的藥學組成物於對其有需要的受試者中經由給藥予受試者治療有效量的一或更多個本文所描述的化合物而提供，以造成此類受體之調節。 在另一方面，提供了化學式(IV)之化合物的製備程序其中 R1
、R2
、R3
、X與‘n’為如同本文上述所定義者； 該程序係包含步驟： (a)將化學式(1)之化合物與化學式(1a)反應，以提供化學式(2)之化合物(b) 在合適的溶劑中之DIPEA的存在下，將化學式(2)的化合物與甲基磺醯氯反應，以生成化學式(3)的化合物(c) 在碳酸鈉的存在下將化學式(3)的化合物與化學式(3b)的化合物反應，以生成化學式(5)的化合物(d) 經由使用碳酸鈉與PdCl2
(dppf)，將化學式(5)的化合物伴隨化學式(4a)的硼酸耦合 ，以生成化學式(IV)之化合物(e) 經由使用合適的溶劑，將化學式(IV)伴隨LiOH 水解（當X或R1
代表一酯類時），以生成化學式(IV)的酸類化合物。According to one aspect, the present invention provides a compound having the structure of formula (I), Wherein R 1 is selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy Alkyl, substituted or unsubstituted haloalkoxy, -(CR a R b ) 1-3 OH, -C(O)NH-alkyl, -S(O) 2 -alkyl, -S(O 2 NH-alkyl, -C(O)OH, -C(O)O-alkyl, -(CR a R b ) 1-3C(O)OH and -(CR a R b ) 1-3C( O) O- alkyl; R 2 is a substituted or unsubstituted phenyl group or a substituted or unsubstituted naphthyl group, wherein the substituents may be one or more and independently selected from halogen, substituted Or unsubstituted alkyl, substituted or unsubstituted haloalkyl, -OR 4 , -NR 5 R 6 and substituted or unsubstituted cycloalkyl; X is selected from -C(O) OH, -C(O)Oalkyl, -C(O)NR 5 R 6 , -(CR a R b ) 1-3C(O)OH , -(CR a R b ) 1-3C(O)O - alkyl, -O- (CR a R b) 1-3C (O) OH, -O- (CR a R b) 1-3C (O) O- alkyl, -CR c = CR c -C ( O) OH, a halogen, a substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, oR 4 and -S (O) 2 - alkyl; R a and R b Department alone Selected from hydrogen, halogen, hydroxy, a substituted or unsubstituted alkyl, substituted or unsubstituted alkyl group and a halogen substituted or unsubstituted cycloalkyl group; or R a and R b may be with them The attached carbon atoms together form a substituted or unsubstituted 3 to 6 membered saturated carbocyclic ring; R c is independently selected from the group consisting of hydrogen, halogen, and substituted or unsubstituted alkyl; The R 3 groups which may be the same or different are independently selected from halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and -OR 4 ; R 4 is selected from hydrogen , substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and substituted or unsubstituted cycloalkyl; R 5 and R 6 are independently selected from hydrogen, substituted or unsubstituted a substituted alkyl group and a substituted or unsubstituted cycloalkyl group; and 'n' is an integer comprising a point at both ends from 0 to 2; or a pharmaceutically acceptable salt thereof. It is to be understood that the chemical formula (I) structurally comprises all suitable tautomers, stereoisomers, mirror image isomers and non-image isomers as well as pharmaceutically acceptable substances which may be considered by the chemical structure of the species described herein. Salt. According to a specific embodiment, a compound having the structure of formula (II) is provided: Wherein R 1 is selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkyl Oxygen, -(CR a R b ) 1-3 OH, -C(O)NH-alkyl, -C(O)OH and -(CR a R b ) 1-3C(O)OH ; From -C(O)OH, -C(O)Oalkyl, -(CR a R b ) 1-3C(O)OH , -(CR a R b ) 1-3C(O)O- alkyl, -O-(CR a R b ) 1-3C(O)OH , -CR c =CR c -C(O)OH, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted halogen Alkyl, OR 4 and -S(O) 2 -alkyl; R 3 which may be the same or different in each case are independently selected from halogen, substituted or unsubstituted alkyl, substituted or not Substituted haloalkyl and -OR 4 ; in each case may be the same or different R 7 is independently selected from halo, substituted or unsubstituted alkyl, substituted or unsubstituted halo a group, -OR 4 and a substituted or unsubstituted cycloalkyl group; R 4 is selected from hydrogen, a substituted or unsubstituted alkyl group and a substituted or unsubstituted haloalkyl group; R a and R b Independently selected Hydrogen, halogen, a substituted or unsubstituted alkyl group; R c is independently hydrogen-based or a substituted or unsubstituted alkyl; 'n-' is an integer in both inclusive 0 to 2; and 'p' is an integer comprising a point at both ends from 0 to 2; or a pharmaceutically acceptable salt thereof. According to another specific embodiment, a compound having the structure of formula (III) is provided: Wherein R 1 is selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkyl Oxygen, -(CR a R b ) 1-3 OH, -C(O)NH-alkyl, -C(O)OH and -(CR a R b ) 1-3C(O)OH ; From -C(O)OH, -C(O)Oalkyl, -(CR a R b ) 1-3C(O)OH , -(CR a R b ) 1-3C(O)O- alkyl, -O-(CR a R b ) 1-3C(O)OH , -CR c =CR c -C(O)OH, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted halogen Alkyl, OR 4 and -S(O) 2 -alkyl; R 3 which may be the same or different in each case are independently selected from halogen, substituted or unsubstituted alkyl, substituted or not Substituted haloalkyl and -OR 4 ; R 4 is selected from hydrogen, substituted or unsubstituted alkyl and substituted or unsubstituted halo; R a and R b are independently selected from hydrogen a halogen, a substituted or unsubstituted alkyl group; R c is independently hydrogen or a substituted or unsubstituted alkyl group; and 'n' is an integer comprising a point at both ends from 0 to 2; A pharmaceutically acceptable salt. According to another specific embodiment, a compound having the structure of formula (IV) is provided: Wherein R 1 is selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkyl Oxyl, -(CR a R b ) 1-3 OH, -C(O)NH-alkyl, -C(O)OH and -(CR a R b ) 1-3C(O)OH ; From -C(O)OH, -C(O)Oalkyl, -(CR a R b ) 1-3C(O)OH , -(CR a R b ) 1-3C(O)O- alkyl, -O-(CR a R b ) 1-3C(O)OH , -CR c =CR c -C(O)OH, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted halogen Alkyl, OR 4 and -S(O) 2 -alkyl; R 2 is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl, wherein the substituents may be one or more And independently selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, -OR 4 and substituted or unsubstituted cycloalkyl; in each case The R 3 groups which may be the same or different are independently selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and -OR 4 ; R 4 is selected from hydrogen, substituted Or not a substituted alkyl group and a substituted or unsubstituted haloalkyl group; R a and R b are independently selected from hydrogen, halogen, substituted or unsubstituted alkyl; R c is independently hydrogen or substituted Or an unsubstituted alkyl group; and 'n' is an integer comprising a point at both ends from 0 to 2; or a pharmaceutically acceptable salt thereof. It is to be understood that the chemical formula (I), the chemical formula (II), the chemical formula (III) and/or the chemical formula (IV) structurally comprise all suitable tautomers, stereoisomers, mirror image isomers and non-image isomers. , including isotopes, and pharmaceutically acceptable salts that may be considered by the chemical structure of the species described herein. The details of one or more embodiments of the invention set forth below are merely illustrative in nature and are not intended to limit the scope of the invention. Other features, objects, and advantages of the invention will be apparent from the description and appended claims. According to another embodiment, there is provided a compound of formula (I), wherein R 1 is selected from halo, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted Substituted alkoxy, substituted or unsubstituted haloalkoxy, -(CR a R b ) 1-3 OH, -C(O)NH-alkyl, -C(O)OH and -(CR a R b ) 1-3C(O)OH ; wherein R a and R b are independently hydrogen or a substituted or unsubstituted alkyl group. According to another specific embodiment, there is provided a compound of formula (I), wherein X is selected from the group consisting of -C(O)OH, -(CR a R b ) 1-3C(O)OH , -O-(CR a R b ) 1-3C(O)OH , -CR c =CR c -C(O)OH, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, OR 4 and - S(O) 2 -alkyl; wherein R a , R b and R c are independently hydrogen or substituted or unsubstituted alkyl. According to another embodiment, there is provided a compound of formula (I), wherein R 2 is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl, wherein the substituents may be one or Two, and independently selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, -O-alkyl, and substituted or unsubstituted cycloalkyl; In another embodiment, there is provided a compound of formula (I), wherein R 3 is halo, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and —O-alkyl and 'n ' is 0, 1 or 2; in another aspect of the invention, there is provided a chemical formula effective for treating, managing or ameliorating the severity of a disease, disorder, symptom or symptom associated with a calcium sensitive receptor (CaSR) modulator Compound of (I). In another aspect, the invention provides a pharmaceutical composition comprising at least one compound of formula (I) and at least one pharmaceutically acceptable excipient. In another aspect, the invention provides a pharmaceutical composition of a compound of formula (I) effective for treating, managing or ameliorating the severity of a disease, disorder, condition or symptom associated with a calcium sensitive receptor (CaSR) modulator Provided to a subject in need thereof by administering to the subject a therapeutically effective amount of one or more of the compounds described herein to effect modulation of such receptors. In another aspect, a preparation procedure for a compound of formula (IV) is provided Wherein R 1 , R 2 , R 3 , X and 'n' are as defined above; the procedure comprises the steps of: (a) reacting a compound of formula (1) with formula (1a) to provide a chemical formula ( 2) Compound (b) reacting a compound of formula (2) with methylsulfonium chloride in the presence of DIPEA in a suitable solvent to form a compound of formula (3) (c) reacting a compound of formula (3) with a compound of formula (3b) in the presence of sodium carbonate to form a compound of formula (5) (d) coupling a compound of formula (5) with boric acid of formula (4a) by using sodium carbonate with PdCl 2 (dppf) to form a compound of formula (IV) (e) Hydrolysis of chemical formula (IV) with LiOH (when X or R 1 represents an ester) by using a suitable solvent to form an acid compound of formula (IV) .
定義與縮寫： 除非另外指明，在本說明書與申請專利範圍中所使用的下列用語具有以下所提供的意義。 為了解釋本說明書的目的，將應用下列定義，並且在適當時候下，以單數使用的用語亦將包括複數，反之亦然。 此用語「鹵素（halogen）」或「鹵基（halo）」意指氟、氯、溴或碘。 除非另外指明，在本申請書中「 側氧基（oxo）」意指C(=O)基團。此類側氧基基團可為本發明之化合物中的任何環或鏈的一部分。 此用語「烷基（alkyl）」意指烷類衍生的碳氫化合物自由基，其骨架中僅包括碳與氫原子，不包含不飽和碳，具有一至六個碳原子，並且以單鍵連接至分子的其餘部分，例如甲基、乙基、正丙基、1-甲基乙基（異丙基）、正丁基、正戊基、1,1-二甲基乙基（叔丁基）以及諸如此類。除非闡述或敘述相反，本文中所描述或主張的所有烷基基團可為直鏈或支鏈的。 此用語「烯基（alkenyl）」意指包含2至10個碳原子並且包括至少一個碳碳雙鍵的碳氫化合物自由基。烯基基團的非限制性範例包括乙烯基、1-丙烯基、2-丙烯基（烯丙基）、異丙烯基、2-甲基-l-丙烯基、1-丁烯基、2-丁烯基以及諸如此類。除非闡述或敘述相反，本文中所描述或主張的所有烯基基團可為直鏈或支鏈的。 此用語「炔基（alkynyl）」意指包含2至10個碳原子並且包括至少一個碳碳三鍵的碳氫化合物自由基。炔基基團的非限制性範例包括乙炔基、丙炔基、丁炔基以及諸如此類。除非闡述或敘述相反，本文中所描述或主張的所有炔基基團可為直鏈或支鏈的。 此用語「烷氧基（alkoxy）」意指藉由氧鍵結連接的烷基基團。此類基團的非限制性範例為甲氧基、乙氧基與丙氧基以及諸如此類。除非闡述或敘述相反，本文中所描述或主張的所有烷氧基基團可為直鏈或支鏈的。 此用語「鹵烷基（haloalkyl）」意指以一或更多個如上述定義的鹵素原子替代之如上述定義的烷基基團。優選地，鹵烷基可為單鹵烷基、雙鹵烷基或多鹵烷基(包括過鹵烷基。單鹵烷基可具有一個碘、溴、氯或氟原子)。雙鹵烷基與多鹵烷基基團可被二或更多個相同的鹵素原子或不同的鹵素原子的組合所替代。優選地，多鹵烷基被多達12個鹵素原子替代。鹵烷基的非限制性範例包括氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、三氯甲基、五氟乙基、七氟丙基、二氟氯甲基、二氯氟甲基、二氟乙基、二氟丙基、二氯乙基、二氯丙基以及諸如此類。過鹵烷基意指所有氫原子被鹵素原子取代的烷基。除非闡述或敘述相反，本文中所描述或主張的所有鹵烷基基團可為直鏈或支鏈的。 此用語「鹵烷氧基（haloalkoxy）」意指本文所定義的鹵烷基，基團藉由氧鍵連結。此類基團的非限制性範例為單鹵烷氧基、雙鹵烷氧基、或多鹵烷氧基(包括過鹵烷氧基)。除非闡述或敘述相反，本文中所描述或主張的所有鹵烷氧基基團可為直鏈或支鏈的。 此用語「環烷基（cycloalkyl）」意指具有3至12個碳原子之非芳香族的單或多環之環系統，例如環丙基、環丁基、環戊基、環己基以及諸如此類。多環的環烷基基團的範例包括但不限於全氫化萘基（perhydro naphththyl）、金剛烷基（adamantyl）與降莰基（norbornyl）基團、橋接的環基團或螺雙環基團(例如螺(4,4)壬-2-基以及諸如此類)。 此用語「環烷基烷基（cycloalkylalkyl）」意指直接鍵結至如同上述定義的烷基基團之如同上述定義的環烷基基團，例如環丙基甲基、環丁基甲基、環戊基甲基、環己基甲基、環己基乙基等等。 此用語「芳基（aryl）」意指具有6-至14-碳原子的芳香族自由基，其包括單環、雙環與三環的芳香族系統，例如苯基、萘基、四氫萘基、二氫茚基與聯苯基以及諸如此類。 此用語「芳基烷基（arylalkyl）」意指直接鍵結至如同上述定義的烷基基團之如同上述定義的芳基基團，例如-CH2
C6
H5
與-C2
H4
C6
H5
。 「3至6元飽和碳環之環」意指為單環的碳環之環以及如同本文定義之非芳香族的碳環之環。 如同本文中所使用的「碳環之環（carbocyclic ring）」或「碳環（carbocycle）」意指3至6元飽和或部分未飽和的、單環、稠合雙環、包含碳原子的螺環之環，其可隨選地被替代，舉例來說，碳環之環包括但不限於環丙基、環丁基、環戊基、環己基、伸環丙基、環己酮等等。 此用語「雜環之環（heterocyclic ring）」或「雜環基環（heterocyclyl ring）」或「雜環基（heterocyclyl）」除非另外指明，意指經取代的或未被取代的非芳香族3至15元環，該環由碳原子組成以及有一或更多個獨立地選自N、O或S的雜原子。雜環之環可為單、雙或三環的環系統，該環系統可包括稠合、橋接或螺環系統，並且在雜環之環中的氮、碳、氧或硫原子可被隨選地氧化成各種氧化態。此外，氮原子可隨選地被季銨化（quaternized），雜環或雜環基可隨選地包含一或更多烯鍵，且雜環之環或雜環基中的一或兩個碳原子可被-CF2
-、-C(O)-、-S(O)-、S(O)2
、-C(=N-烷基)-或 –C(=N-環烷基)等等中斷。此外雜環之環亦可與芳香環稠合。雜環之環的非限制性範例包括氮雜環丁烷基（azetidinyl）、苯並哌喃基（benzopyranyl）、苯并二氫哌喃基（chromanyl）、十氫異喹啉基（decahydroisoquinolyl）、二氫茚基（indanyl）、二氫吲哚基（indolinyl）、異二氫吲哚基（isoindolinyl）、異苯并二氫哌喃基（isochromanyl）、異四氫噻唑基（isothiazolidinyl）、異噁唑啶基（isoxazolidinyl）、嗎啉基（morpholinyl）、噁唑啉基（oxazolinyl）、噁唑啶基（oxazolidinyl）、2 - 氧代哌嗪基（2-oxopiperazinyl）、2-氧代哌啶基（2-oxopiperidinyl）、2-氧代吡咯啶基（2-oxopyrrolidinyl）、2-氧代氮呯基（2-oxoazepinyl）、八氫吲哚基（octahydroindolyl）、八氫異吲哚基（octahydro isoindolyl）、全氫氮呯基（perhydroazepinyl）、哌嗪基（piperazinyl）、4-哌啶酮基（4-piperidonyl）、吡咯啶基（pyrrolidinyl）、哌啶基（piperidinyl）、吩噻嗪基（phenothiazinyl）、吩噁嗪基（phenoxazinyl）、奎寧環基（quinuclidinyl）、四氫異喹啉基（tetrahydroisoquinolyl）、四氫呋喃基（tetrahydrofuryl）、四氫吡喃基（tetrahydropyranyl）、噻唑啉基（thiazolinyl）、噻唑烷基（thiazolidinyl）、硫代嗎啉基（thiamorpholinyl）、硫代嗎啉基亞碸（thiamorpholinylsulfoxide）、硫代嗎啉基碸吲哚啉（thiamorpholinylsulfoneindoline）、苯并二噁唑（benzodioxole）、四氫喹啉（tetrahydroquinoline）、四氫苯并吡喃（tetrahydrobenzopyran）以及諸如此類。雜環之環可經由雜環之環的任何原子連接，其導致穩定結構的形成。 此用語「雜芳基（heteroaryl）」除非另外指明，意指取代的或未被取代的5至14元芳香族雜環之環，該環帶有一或更多個獨立地選自N、O或S的雜原子。雜芳香可為單、雙或三環的系統。雜芳基環可經由雜芳基環的任何原子連接以導致穩定結構的形成。雜芳基環的的非限制性範例包括噁唑基（oxazolyl）、異噁唑基（isoxazolyl）、咪唑基（imidazolyl）、呋喃基（furyl）、吲哚基（indolyl）、異吲哚基（isoindolyl）、吡咯基（pyrrolyl）、***基（triazolyl）、三嗪基（triazinyl）、四唑基（tetrazolyl）、噻吩基（thienyl）、噻唑基（thiazolyl）、異噻唑基（isothiazolyl）、吡啶基（pyridyl）、嘧啶基（pyrimidinyl）、吡嗪基（pyrazinyl）、噠嗪基（pyridazinyl）、苯並呋喃基（benzofuranyl）、苯並噻唑基（benzothiazolyl）、苯並噁唑基（benzoxazolyl）、苯並咪唑基（benzimidazolyl）、苯並噻吩基（benzothienyl）、咔唑基（carbazolyl）、喹啉基（quinolinyl）、異喹啉基（isoquinolinyl）、喹唑啉基（quinazolinyl）、噌啉基（cinnolinyl）、萘啶基（naphthyridinyl）、蝶啶基（pteridinyl）、嘌呤基（purinyl）、喹喔啉基（quinoxalinyl）、喹啉基（quinolyl）、異喹啉基（isoquinolyl）、噻二唑基（thiadiazolyl）、吲哚嗪基（indolizinyl）、吖啶基（acridinyl）、啡嗪基（phenazinyl）、呔嗪基（phthalazinyl）以及諸如此類。 此用語「雜環基烷基」意指直接鏈結至烷基基團的雜環之環自由基。雜環基烷基自由基可於烷基基團的任何碳原子連接至主要的結構，其導致穩定結構的形成。 此用語「雜芳基烷基」意指直接鏈結至烷基基團的雜芳基環自由基。雜芳基烷基自由基可於烷基基團的任何碳原子連接至主要的結構，其導致穩定結構的形成。 除非另外指明，此用語「被替代的」如同本文中所使用地意指具有一或更多個取代基連接至基團或基元的結構骨架上之基團或基元。此類取代基包括但不限於羥基、鹵素、羧基、氰基、硝基、側氧基（=O）、硫基（=S）、烷基、鹵烷基、烯基、炔基、芳基、芳基烷基、環烷基、環烷基烷基、雜芳基、雜環之環、雜環基烷基、雜芳基烷基、-C(O)ORx
、-C(O)Rx
、-C(S)Rx
、-C(O)NRx
Ry
、 -NRx
C(O)NRy
Rz
、-N(Rx
)S(O)Ry
、-N(Rx
)S(O)2
Ry
、-NRx
Ry
、-NRx
C(O)Ry
、-NRx
C(S)Ry
、-NRx
C(S)NRy
Rz
、- S(O)2
NRx
Ry
、-ORx
、-OC(O)Rx
、-OC(O)NRx
Ry
、-Rx
C(O)ORy
、-Rx
C(O)NRy
Rz
、-Rx
C(O)Ry
、-SRx
以及-S(O)2
Rx
；其中的每個情況下Rx
、Ry
與Rz
係獨立地選自氫、鹵素、烷基、鹵烷基、烯基、炔基、環烷基與芳基。上述「被替代的」基團不能進一步地被替代。舉例來說，當「被替代的烷基」上的取代基為「芳基」或「烯基」時，此芳基或烯基不能分別是被替代的芳基或被替代的烯基。 本發明之化合物可具有一或更多個掌性中心。每個掌性中心的絕對立體化學可為‘R’或‘S’。本發明之化合物包括所有非鏡像異構物與鏡像異構物以及其混合物。除非另外特別指明，一立體異構物的參考適用至可能的立體異構物中的任一者。每當無具體說明立體異構組成物時，應了解的是包含所有可能的立體異構物。 此用語「立體異構物（stereoisomer）」意指由相同原子組成，經由相同鍵鍵結但具有不能互換的不同三度空間結構之化合物 。此三度空間結構稱為組態。如同本文所使用的，此用語「鏡像異構物（enantiomer）」意指分子為彼此的不可重疊的鏡像之兩立體異構物。此用語「掌性中心（chiral center）」意指四個不同基團所連接的碳原子。如同本文所使用的，此用語「非鏡像異構物（diastereomers）」意指不是鏡像異構物的立體異構物。此用語「消旋物（racemate）」或「消旋混合物（racemic mixture）」意指鏡像異構物的相等部分之混合物。 「互變異構物（tautomer）」意指經歷由化合物的一原子至化合物的另一原子之快速質子轉移的化合物。本文所描述的化合物中的一些者可以不同的氫連接點之互變異構物存在。個別的互變異構物以及其混合物隨化學式(I)之化合物而被包含。 此用語狀態、病症或症狀的「治療」包括：(a)延遲在可能患有或傾向患有此狀態、病症或症狀，但還沒有經歷或顯現此狀態、病症或症狀的臨床或亞臨床病徵的受試者發展之狀態、病症或症狀的臨床症狀出現；(b)抑制此狀態、病症或症狀，即，阻止或降低疾病或至少一個其臨床或亞臨床病徵的發展；c) 減輕疾病病症或症狀或至少一個其臨床或亞臨床病徵的嚴重性或(d) 緩解疾病，即，造成狀態、病症或症狀或至少一個其臨床或亞臨床病徵的復原。 此用語「調節」或「調節作用（modulation）」或「調節劑（modulator）」意指受體的量、質或特定活性或功能之效果的增加。以說明而非限制的方式，它包括本發明之鈣敏感受體（CaSR）的促效劑（agonist）、部分促效劑（partial agonist）、異位調節劑（allosteric modulator）。此類調節作用可能在特定事件的發生下，例如訊息傳遞路徑的活化而偶然發生。 此用語「鈣敏感受體異位調節劑（allosteric modulators of calcium-sensing receptor）」意指化合物結合至鈣敏感受體，並誘發經由內源性配基Ca2+
降低鈣敏感受體活化之閾值的構形改變(其視暴露於鈣敏感受體之化合物濃度而定)之能力。 此用語「受試者」包括哺乳動物（特別是人類）與其他動物，例如家畜（例如，家庭寵物包括貓與狗）與非家畜（例如野生動物）。 「治療有效量」意指當給藥予受試者用於治療疾病、病症、病徵或症狀時，足以在受試者造成給藥目的之效果的化合物的量。此「治療有效量」將視化合物、疾病與其嚴重性，以及待治療受試者的年齡、體重、身體狀況與反應而定。 藥學上可接受的鹽類： 本發明之化合物可與酸類或鹼類生成鹽類。本發明之化合物可能為足夠酸或鹼以生成穩定的無毒性酸性或鹼性鹽類，以藥學上可接受之鹽類的化合物給藥可能是合適的。藥學上可接受之鹽類的非限制性範例為經由酸類的加入而生成的無機、有機酸加成鹽，包括鹽酸鹽。藥學上可接受之鹽類的非限制性範例為經由鹼類的加入而生成的無機、有機鹼加成鹽。本發明之化合物亦可能與胺基酸形成鹽類。可使用本領域已熟知的標準程序，舉例來說，經由將足量的鹼性化合物例如(胺類)伴隨提供生理上可接受之陰離子的合適酸類反應而獲得藥學上可接受之鹽類。 關於以化學式(I)描述的整體化合物，本發明延伸至這些立體異構物形式及其混合物。在一定程度上先前技藝教導特定立體異構物的合成或分離，本發明的不同立體異構物形式可經由本領域已知的方法與彼此分離，或可經由立體結構上特異的或不對稱合成或掌性HPLC（高效液相層析法）獲得所給定的異構物。亦考慮本文所描述之化合物的互變異構物形式與混合物。 可經由使用下文所提及的各種體外與體內計劃書或本領域已知的方法實現鈣敏感受體（CaSR）調節活性的本發明之化合物的篩選。 藥學組成物 本發明係相關於包含本文所揭露之化學式(I)的化合物的藥學組成物。特別地，包含治療有效量的至少一個本文所描述之化學式(I)的化合物以及至少一個藥學上可接受之賦形劑（例如載體或稀釋劑）的藥學組成物。優選地，考量的藥學組成物包括當給藥予受試者時足以調節本文描述的鈣敏感受體（CaSR）媒介的疾病之量的本文所述之化合物。 考量的受試者包括，舉例來說，活細胞與哺乳動物，包括人類的哺乳動物。本發明之化合物可與藥學上可接受的賦形劑關聯（例如載體或稀釋劑）或以載體稀釋，或密封於可以是膠囊、小袋、紙包或其他容器之形式的載體內。藥學上可接受的賦形劑包括本身不誘發對接受組成物的個體有害的抗體產生，並且可將其給藥而無不當毒性的藥劑。 適合的載體或賦形劑的範例包括但不限於水、鹽類溶液、酒精、聚乙二醇類、多羥基蓖麻油、花生油、橄欖油、明膠、乳糖、白土、蔗糖、糊精、碳酸鎂、糖、環糊精、直鏈澱粉、硬脂酸鎂、滑石、明膠、瓊脂、果膠、***膠、硬脂酸或纖維素低烷基醚、水楊酸、脂肪酸、脂肪酸胺、脂肪酸單甘油酯和雙甘油酯、新戊四醇脂肪酸酯、聚氧乙烯、羥甲基纖維素與聚乙烯吡咯啶酮。 藥學組成物亦可包括一或更多藥學上可接受的輔劑、溼潤劑、乳化劑、懸浮劑、防腐劑、影響滲透壓的鹽類、緩衝液、甜味劑、調味劑、著色劑或任何前述物質的組合物。可經由採用本領域已知的程序配製本發明之藥學組成物，以便提供於給藥予受試者後活性成分的迅速、持續或延遲釋放。 本文所描述的藥學組成物可經由本領域已知的傳統技術製備。舉例來說，可將活性化合物與載體混合，或以載體稀釋，或密封於可以是安瓿、膠囊、小袋、紙包或其他容器的形式之載體內。當載體作為稀釋劑時，其可能是作為活性化合物的載具、賦形劑或介質的固體、半固體或液體材料。可將活性化合物吸附於顆粒狀固體容器上，舉例來說，於小袋中。 藥學組成物可能是傳統形式，舉例來說，膠囊、片劑、膠囊狀片劑、口服崩解片劑、噴霧劑、溶液、懸浮液或局部應用的產品。 給藥路徑可為任何有效將本發明之活性化合物運輸至適當或需要的作用位置之路徑。適合的給藥路徑包括但不限於口服、鼻吸、肺部、口腔、表皮下（subdermal）、皮內、經皮、腸胃外、直腸、儲庫式（depot）、皮下（subcutaneous）、靜脈、尿道、肌肉內、鼻腔內、眼用（例如以眼用溶液）或局部（例如以局部軟膏）。 固體口服製劑包括但不限於片劑、膠囊狀片劑、膠囊（軟或硬明膠）、口服崩解片劑、糖衣錠（在粉末或顆粒形式中包含活性成分）、喉錠及錠劑。具有滑石及/或碳水化合物的載體或結合劑或類似物的片劑、糖衣錠或膠囊為特別適合用於口服應用者。液體製劑包括但不限於糖漿、乳劑、懸浮液、溶液、軟明膠與無菌可注射液體，例如水性或非水性液體懸浮液或溶液。對於腸胃外應用，特別適合者為可注射溶液或懸浮液，優選地為伴隨活性化合物溶解於多羥基蓖麻油（polyhydroxylated castor oil）的水性溶液。 藥物製備係優選地以單位劑量形式。在此類形式中，將製劑細分為包含適當量的活性成分之單位劑量。單位劑量形式可為包裝的製劑，其包含個別數量製劑的包裝，例如袋裝片劑、膠囊以及小瓶或安瓿中的粉末。此外，單位劑量形式可能本身為膠囊、片劑、膠囊狀片劑、小袋或錠劑，或它可能為包裝形式中適當數目的任何這些者。 對於給藥予受試者病患，本發明的化合物之每日總劑量當然取決於給藥的模式。舉例來說，口服給藥可需要比起靜脈內（直接至血液）較高的每日總劑量。在單位劑量製劑中活性成分的量可能根據活性成分的效力或者給藥的模式由0.1 mg至10000 mg變化或調整。 用於治療本文所描述的疾病與病症之合適的化合物劑量可由相關領域的技術人員決定。治療劑量一般係經由基於來自動物研究得到的初步證據之受試者劑量範圍研究而確定。劑量必須足以對病人造成想要的治療益處而不引起不希望的副作用。舉例來說，CaSR 調節劑的每日劑量範圍可由大約0.1至大約30.0 mg/kg。給藥模式、劑量形式、適合的藥學賦形劑、稀釋劑或載體亦可被善加使用並且由本領域的技術人員調整。所有變化與修改係設想於本發明的範圍內。 治療方法 在另一方面，本發明提供在治療、管理及/或減輕由鈣敏感受體（CaSR）調節之疾病、病症、病徵或症狀之嚴重性有效用的化合物及其藥學組成物。本發明進一步地提供在對其有需要的受試者治療由CaSR調節之疾病、病症、病徵或症狀的方法，該方法係經由給藥予受試者一治療有效量之本發明的化合物或藥學組成物。 在本發明的另一方面，所提供的方法對於可經由調節CaSR來治療的症狀之診斷是有效用的，以用於判斷病患將對治療劑有沒有反應。 在另一方面，本發明提供了經由調節CaSR的疾病、病症或症狀治療的方法。在此方法中，將需要此類治療的受試者以治療有效量之本文所描述的化學式(I)之化合物給藥。 本發明之化合物與藥學組成物對具有以下列一或更多者為特徵之疾病、病症、病徵或症狀需要治療的受試者而言是有效的： (a) 異常鈣離子平衡， (b) 生成或分泌受到鈣敏感受體（CaSR）活性影響的傳訊者之量異常或 (c) 功能受鈣敏感受體活性影響的傳訊者活性程度異常。在一方面，病患具有以一或更多鈣敏感受體調節的成分之量異常為特徵的疾病、病症、病徵或症狀，並且該化合物在細胞的CaSR為具活性的，該細胞包括副甲狀腺細胞、骨細胞（前破骨細胞、破骨細胞、前成骨細胞、成骨細胞）、近腎小球腎細胞、腎小球環間膜細胞、腎小球腎細胞、近端小管腎細胞、遠端小管腎細胞、亨氏環升支粗段細胞（cell of the thick ascending limb of Henle's loop ）及/或腎集合小管、甲狀腺濾泡旁細胞（C-cell）、腸細胞、血小板、血管平滑肌細胞、胃腸道細胞、腦下垂體細胞或下視丘細胞。鈣敏感受體的傳訊者為鈣。 作為CaSR的調節劑之化學式(I)之化合物在治療、管理及/或減輕疾病、病症、病徵或症狀的嚴重性、發病率/死亡率或併發症上是潛在有效用的，該疾病、病症、病徵或症狀包括但不限於原發性副甲狀腺機能亢進、次發性副甲狀腺機能亢進、第三級副甲狀腺機能亢進、慢性腎功能衰竭（具有或不具透析）、慢性腎臟病（具有或不具透析）、副甲狀腺腺瘤、副甲狀腺增生、副甲狀腺癌、血管和心瓣膜鈣化、異常的鈣平衡例如高鈣血症、異常的磷平衡例如低磷血症、因副甲狀腺機能亢進、慢性腎病或副甲狀腺癌引發的骨相關疾病或併發症、腎移植後之骨質流失、囊性纖維性骨炎、衰弱性骨疾病、腎性骨疾病、由於副甲狀腺機能亢進或慢性腎臟疾病引發的心血管併發症、(Ca2+
)e
離子異常高的某些惡性腫瘤、心臟、腎臟或腸道功能障礙、足細胞（podocyte）相關的疾病、不正常的腸道蠕動、腹瀉、胃泌素和胃酸分泌增強而直接或間接益於萎縮性胃炎，或經由增加胃液酸度改善藥學化合物、藥物或營養補充品從胃腸道的吸收。 原發性副甲狀腺機能亢進為副甲狀腺的一或更多病症，其起因於副甲狀腺本身的機能亢進（偶發獲得或家族性的），這造成可能是由於單一或雙重的腺瘤、增生、多腺體疾病或罕見地因副甲狀腺癌的PTH過量分泌。因此，血鈣升高到高於正常的量（稱為高鈣血症）。此升高的鈣量可能導致許多短期與長期的併發症。 當Ca2+
水平的循環量減少而刺激PTH分泌時，即發生次發性副甲狀腺機能亢進。次發性副甲狀腺機能亢進的一個原因為慢性腎功能不全（亦稱為慢性腎病或CKD），例如腎多囊性疾病或慢性腎盂腎炎的次發性副甲狀腺機能亢進，或慢性腎功能衰竭，例如血液透析的患者（也稱為晚期腎病或ESRD）的次發性副甲狀腺機能亢進。對起因於低鈣攝取、腸胃道疾病、腎功能不全、維生素D缺乏、鎂缺乏以及腎性高鈣尿症（renal hypercalciuria）的低鈣之反應可能產生過量 PTH 。第三級副甲狀腺機能亢進可能在長期的次發性副甲狀腺機能亢進與高鈣血症後發生。 在一方面，可使用本發明之化合物與組成物以治療、管理及/或減輕受試者的血管或瓣膜鈣化。在一方面，本發明之化合物的給藥延緩或逆轉細胞外基質羥磷石灰結晶沉積的形成、成長或沉積。在本發明的另一方面，本發明的化合物之給藥防止細胞外基質羥磷石灰結晶沉積的形成、成長或沉積。在一方面，亦可使用本發明之化合物防止或治療動脈粥樣硬化的鈣化以及內側鈣化與以血管鈣化為特徵的其他症狀。在一方面，血管鈣化可能與慢性腎功能不全或末期腎病或過量的鈣或PTH本身有關聯。在另一方面，血管鈣化可能與前或後透析或***有關聯。在進一步的方面，血管鈣化可能與糖尿病第I或第II型相關聯。在又一方面，血管鈣化可能與心血管疾病有關聯。 異常鈣平衡例如副甲狀腺機能亢進相關疾病的特徵可如同標準醫學教科書但不限於Harrison's Principles of Internal Medicine中所描述。特別是，可使用本發明之化合物與組成物來參與在稱為PTH之副甲狀腺素的血清量的減少：這些產物因而對疾病例如副甲狀腺機能亢進的治療可能是有效用的。 異常磷平衡例如低磷血症的特徵可如同標準醫學教科書，但不限於Harrison's Principles of Internal Medicine中所描述。特別是，可使用本發明之化合物與組成物來參與在稱為PTH之副甲狀腺素的血清量的減少：這些產物因而對疾病例如低磷血症的治療可能是有效用的。 在一方面，由本發明的方法治療之足細胞疾病或病症起因於足細胞的一或更多功能的擾動。這些足細胞的功能包括：(i) 對蛋白質的大小障礙；(ii) 對蛋白質的電荷障礙；(iii) 毛細管環狀的維持；(iv) 抵消腎小球內壓力；(v) 腎小球基底膜（GMB）的合成與維持；(vi) 腎小球內皮細胞（GEN）完整性所需要的血管內皮生長因子（VEGF）的產生與分泌。此類病症或疾病包括但不限於足細胞喪失（足細胞減少，podocytopenia）、足細胞突變、足突寬度增加或裂孔隔膜長度減少。在一方面，足細胞相關疾病或病症可能為足細胞密度的消失或縮減。在一方面，足細胞密度縮減可能由於足細胞數目的減少，舉例來說，由於細胞凋亡、脫離、增生缺乏、DNA損傷或肥大。 在一方面，足細胞相關疾病或病症可能由於足細胞損傷。在一方面，足細胞損傷可能由於機械性應力(例如高血壓（high blood pressure）、高血壓（hypertension）或局部缺血（ischemia）)、氧氣供應缺乏、毒性物質、內分泌失調、感染、對比劑、機械損傷、細胞毒性劑（順鉑、阿黴素、嘌呤黴素）、鈣調神經磷酸酶抑制劑、發炎作用（例如，由於感染、外傷、缺氧、阻塞或局部缺血）、輻射、感染（例如細菌性、真菌性或病毒性）、免疫系統功能不全（例如自體免疫疾病、系統性疾病、或IgA腎病）、遺傳性病症、藥物（例如，抗細菌劑、抗病毒劑、抗真菌劑、免疫抑制劑、抗發炎劑、鎮痛或抗癌劑）、器官衰竭、器官移植或尿路病變。在一方面，局部缺血可為鐮形血球性貧血、血栓形成、移植、阻塞、休克或失血。在一方面，遺傳性病症可包括芬蘭型先天性腎病症候群（congenital nephritic syndrome of the Finnish type）、胎兒膜性腎病（fetal membranous nephropathy）或足細胞特異性蛋白突變。 在一方面，可使用本發明之化合物以治療異常腸蠕動病症，例如腹瀉。本發明的方法包含給藥予受試者治療有效量之化學式I的化合物。在進一步的方面，腹瀉可能為滲出性腹瀉，即，起因於小或大腸黏膜的直接損傷。此類型腹瀉可由腸的感染性或發炎性病症所造成。在一方面，滲出性腹瀉可與胃腸或腹腔手術、化療、放射線治療、發炎作用或毒性外傷相關聯。在另一方面，腹瀉可為分泌性的，意味著有活性分泌的增加，或有吸收的抑制。很少或沒有結構的損傷。此類型腹瀉最常見的原因為霍亂。在另一方面，腹瀉可由於腸道運輸的加速（高速運輸的腹瀉）。因為快速流過而損害腸道吸收水分的能力而可能發生此類情況。 可使用本發明之化合物與組成物，特別是參與提高胃泌素或胃酸分泌，以直接或間接有益於某些例如但不限於萎縮性胃炎的醫療狀況，或經由提高胃酸酸性以改善藥物化合物、藥物或營養補充品由腸胃道的吸收。 將此說明書中提及的專利、專利申請書以及非專利出版物其整體以引用的方式併入本文。 製備的一般方法 本文所描述的化合物可經由本領域已知的技術製備。此外，本文所描述的化合物可經由按照方案1至2中描述的反應次序製備。進一步地，在下列方案中，其中提及的特定鹼類、酸類、試劑、溶劑、耦合劑等，要了解亦可使用本領域已知的其他鹼類、酸類、試劑、溶劑、耦合劑等，因而其包含於本發明之範圍中。反應條件的變化，舉例來說，如同本領域已知而可使用的溫度及/或反應持續時間，亦包含在本發明的範圍內。在這些方案中描述的化合物之異構物，除非另有指明，亦包含於本發明的範圍內。方案 -1 結構式化學式(I)之化合物(其中X、R1
、R2
、R3
與‘n’為如同本文上述者)可經由依照如同方案1描述的連續轉化來製備。可從化學式(1)的化合物製備化學式(2)的化合物，其經由在適合溶劑中之Cs2
CO3
的存在下與適當的溴乙醇(1a)反應。將化學式(2)的化合物在適合的溶劑中之DIPEA的存在下與甲烷磺醯氯反應，以提供化學式(3)之化合物，其進一步地在適合的溶劑中之Na2
CO3
的存在下與化學式(3a)反應，以提供化學式(4)之化合物。將此化學式(4)之化合物在Na2
CO3
與PdCl2
（dppf）的存在下與化學式(4a)的硼酸耦合，以生成化學式(I)（異構物的混合物），將其進一步地經由管柱層析法分離，以獲得單一異構物。化學式(I)之化合物（酯類）可以在適合的溶劑中之LiOH（或任何適合的鹼類）處理，以生成化學式(IV)的酸類化合物。 替代地，化學式(IV)之化合物可經由依照如同方案2描述的程序來製備。方案 -2 將化學式(3)之化合物在適合的溶劑中之碳酸鈉的存在下與化學式(3b)的特定胺類反應，以提供化學式(5)之化合物。將此化學式(5)之化合物在碳酸鈉與PdCl2
(dppf)的存在下與化學式(4a)的硼酸耦合，以提供化學式(IV)之化合物。可將化學式(IV)之化合物（當為酯類時）以在適合的溶劑中之LiOH（或任何適合的鹼類）處理，以提供相對應的化學式(IV)的酸類化合物。 實驗 以下列範例進一步地說明本發明，此範例僅為本發明的示範性提供而不限制本發明的範圍。下列闡述的範例示範代表性的化合物製備的合成程序。對本領域的技術人員而言某些修改與等效物將是明顯的，並且意圖包括於本發明的範圍之內。將上述專利與專利申請書併入本文以作為參考。 中間產物 中間產物-1：羥基中間產物：將Cs2
CO3
（2當量）加至充分攪拌的DMF中之相對應的苯酚（1當量）溶液中，並且將混合物加熱至50°C 30分鐘。將其冷卻至室溫並且加入溴醇（2-溴乙醇或3-溴丙-1-醇）（1.1當量）至上述溶液。將反應混合物進一步地加熱至50°C隔夜。在反應完成之後（以TLC確認），其以水淬冷，用醋酸乙酯萃取，再以水沖洗，乾燥（Na2
SO4
）並濃縮，以提供粗製的產物，其以管柱層析法純化，以提供想要的化合物（45-65%）。使用類似的程序製備以下表格1中提及的中間產物-1a至中間產物-1i。表格 -1 ：
中間產物-2：O-甲磺酸酯中間產物於0ºC下將DIPEA（4當量）加至無水DCM中之羥基中間產物（來自中間產物-1a-1l）（1當量）的溶液，並且將混合物攪拌10 min。將甲基磺醯氯（1.5當量）加於此中，並且將反應於室溫下攪拌2h。TLC顯示起始材料的完全轉變。其以水淬冷並且以DCM萃取。有機層以水沖洗，乾燥（Na2
SO4
）並濃縮，以提供這樣使用的所需化合物（80-90%）。使用類似的程序製備以下表格2中提及的中間產物-2a至2l。表格 -2 ：
中間產物-3:將甲磺酸酯衍生物（來自中間產物2a-2l）（1當量）、相對應的掌性胺類（2當量）（(R)
-1-(萘-1-基) 乙胺或(R)
-1-(3-甲氧基苯基)乙胺）以及Na2
CO3
（1.3當量）的混合物加熱至110ºC隔夜。在反應完成之後（經由TLC確認），反應以水淬冷並且以醋酸乙酯萃取。有機層以水沖洗，乾燥（Na2
SO4
）並濃縮，以提供所需化合物（50-60%）。使用類似的程序製備以下表格3中提及的中間產物-3a至3 r。表格 -3: 範例
範例-1(R)
-N
-甲基-5-(2-((1-(萘-1-基)乙基)胺基)乙氧基)-3'-(三氟甲基)-[1,1'-聯苯基]-3-甲醯胺將3-(三氟甲基)苯硼酸（1.2當量）、Na2
CO3
（2當量）與H2
O加至二噁烷中之中間產物-3a（1當量）的溶液中。將混合物脫氣15分鐘，然後加入PdCl2
(dppf)（5 mol%）。將反應混合物加熱至80°C隔夜。TLC顯示起始材料的完全轉換，因而其被通過矽藻土墊過濾，並濃縮，以提供粗製的產物，其以管柱層析法純化（10%醋酸乙酯-己烷）以提供所需化合物（產率：50-60%）；質量：m/z：493 (M+1)+
。1
H NMR (400 MHz, DMSO-d 6
) 8.30 (d,J
= 8 Hz, 1H), 8.07(d,J
=8 Hz 1H), 7.96– 7.91 (m, 2H), 7.67 – 7.61 (m, 6H), 7.59-7.52 (m, 3H), 7.01– 6.96 (m, 2H), 5.42 (m, 1H), 4.50 – 4.36 (m, 2H), 3.50 – 3.48(m, 1H), 3.25 – 3.03 (m, 4H), 2.1 (d,J
= 5.6 Hz, 3H) ；m/z：493 (M+1)+
將表格4中的範例2至範例27經由採用來自中間產物3a-3r的適當中間產物與相對應的苯基硼酸，依照範例1中描述的類似程序製備。表格 -4 ： 範例 -28 (R)
-4-甲基-3'-(甲基胺甲醯基)-5'-(2-((1-(萘-1-基)乙基)胺基)乙氧基)-[1,1'-聯苯基]-3-羧酸 步驟 -1
:(R)
-甲基 4-甲基-3'-(甲基胺甲醯基)-5'-(2-((1-(萘-1-基)乙基)胺基)乙氧基)-[1,1'-聯苯基]-3-羧酸酯 將(3-(甲氧基羰基)-4-甲基苯基)硼酸（1.2 當量）、Na2
CO3
（2當量）與水加至二噁烷中的(R)
-3-溴-N
-甲基-5-(2-((1-(萘-1-基)乙基)胺基)乙氧基)苯甲醯胺（中間產物-3a）（1當量）之溶液。將混合物脫氣15分鐘，然後加入PdCl2
(dppf)（5 mol%）。將反應混合物加熱至80°C隔夜。TLC顯示起始材料的完全轉換，因而其被通過矽藻土墊過濾，並濃縮，以提供粗製的產物，其以管柱層析法純化（10%醋酸乙酯-己烷）以提供所需化合物（產率：50-60%）。步驟 -2
:(R)
-4-甲基-3'-(甲基胺甲醯基)-5'-(2-((1-(萘-1-基)乙基)胺基)乙氧基)-[1,1'-聯苯基]-3-羧酸 將水中的LiOH（2當量）加至THF中的上述步驟1中間產物（1當量），並且將反應混合物於室溫下攪拌隔夜。在完成之後（TLC），其被濃縮，以醋酸乙酯沖洗並且酸化（10%檸檬酸），以提供固體化合物，其於真空的情況下過濾並乾燥（60-70%）； m/z：483 (M+1)+
.1
H NMR (400 MHz, DMSO-d6) δ 8.58-8.57 (d,J
= 4.8 Hz, 1H), 8.29-8.27 (d,J
= 8 Hz, 1H), 7.98 (s, 1H), 7.93-7.91 (m, 1H), 7.79-7.63 (m 3H), 7.53 - 7.47 (m, 3H), 7.36 (s, 1H), 7.31 - 7.29 (m, 2H), 4.69-4.67 (m, 1H), 4.16-4.14 (m, 2H), 2.80-2.79 (m, 5H), 2.50(s, 3H), 1.41-1.39 (d, J = 6.4Hz, 3H)；m/z：483 (M+1)+
經由使用適當的被替代的芳基硼酸酯以及適當的中間產物（來自中間產物-3a至3r），依照如同範例28之步驟1中所描述的類似耦合反應程序製備表格5中提供的範例29至116。再對此酯類化合物經由依照如同範例28之步驟2中所描述的類似酯水解程序，使用LiOH進行酯水解。表格 -5 ：
將表格6中所提供的範例112至117經由依照如同範例28的步驟1接著步驟2中所描述的類似程序製備。表格 -6:
體外藥理活性 將在本發明的範圍內之某些說明性的化合物根據以下提供的程序篩選CaSR活性。亦可經由本領域的技術人員已知的其他方法與程序進行化合物的篩選。 經由鈣敏感受體（CaSR）之調節的鈣模仿劑之體外試驗方法： 化合物調節鈣敏感受體的能力係經由測量細胞內鈣 [Ca2+
]i的增加而測定。發展表達hCaSR_pTriEx-3 hygro載體之穩定轉染的HEK293細胞被發展。將細胞於包含20% FBS的Ham’s F12之96孔盤中，在37°C、5% CO2
下生長隔夜至80%滿盤（confluency）。隨後將細胞以包含126 mM NaCl2
、1 mM MgCl2
與4 mM KCl 的20mM HEPES緩衝液廣泛地沖洗，以移除可能干擾試驗的血清成分。將包含0.1% BSA與1mg/ml葡萄糖的HEPES鹼基緩衝液中的鈣敏感Fluo4NW染劑載入細胞30分鐘，以測量細胞內鈣的變化。 於FLIPR使用20 mM HEPES鹼基緩衝液中之0.3 mM CaCl2
測量化合物的活性。化合物調節受體活性的效力經由計算8點試驗中化合物的EC50
反應被測定，並且使用GraphPad Prism 5被繪製成圖。 使用上述試驗步驟測試所製備的化合物，並且將獲得的結果提供於下。將幾個代表性的化合物之EC50
（nM）數值敘述於表格7。 已於表格7提供代表性化合物的體外活性數據。 表格-7：
因此，上述的體外試驗方法顯示發現本發明之化合物表現CaSR的促效活性，從而顯示治療與CaSR調節相關聯的疾病、病症的效用。CKD Wistar 大鼠的體內活性：
將動物以0.75%腺嘌呤飲食餵養28天的一段時間，以供慢性腎病（CKD）的發展。在第28日血漿PTH的測量之後，將動物在牠們用於研究之前根據血漿PTH（完整PTH）程度隨機分組。將隔夜禁食的動物以眼窩放血的方式採集基礎血液樣本（0.5 ml）。將大鼠以載體與測試化合物口服給劑，其中它們係以PEG 300：PG：Captisol（20：15：65）調製。每個群組中使用6至8隻動物，再以1 mg/kg的劑量給藥本發明之化合物。在2 h後將口服給劑的動物以食物與水任意餵養。於血漿PTH評估的不同時間點，在輕微***麻醉的情況下以眼窩放血的方式採集治療後的血液樣本。使用三明治ELISA套組（Immunotopics, USA）測量血漿PTH。將血漿PTH抑制百分率相針對個體基礎未經處理數值經由使用下列公式計算 抑制百分比 = （治療前個體數值 – 治療後個體數值 / 治療前個體數值 ）X 100 因此，上述體內方法顯示發現本發明之化合物表現抑制血漿PTH量，從而顯示治療與CaSR調節相關聯的疾病、病症的效用。腎切除 SD 大鼠的體內活性：
本研究使用重量200-270 g的雄性、Sprague Dawley大鼠。在5/6腎切除的CKD大鼠模型中，原始腎功能質量係經由兩步驟手術而減少至六分之五（5/6）。在第一次手術中，麻醉狀態下切開腹腔並且將左腎去腎囊。將腎臟兩端1/3的部分切除，並且封閉腹部切口。在第一次手術後的一週，經由橫切血管與輸尿管完全移除右腎。在第二次手術之後，將所有腎切除的動物以1.2%含磷飲食餵養，且將假手術控制組動物以正常控制組飲食餵養，直到研究終止。第二次手術的三週後，將動物以眼窩放血的方式採集血液，用於全血中離子化的鈣以及生化參數像是磷、尿素、BUN、肌酐與血漿中完整PTH的評估。使用Rat Bioactive intact PTH ELISA套組以三明治ELISA方法來測量血漿iPTH。在所需的iPTH程度確認之後，將動物根據iPTH程度隨機分組成不同治療與載具控制群組，每群組中8-10隻動物，且維持8隻動物在假手術控制群組中。在隨機分組後，立刻開始以測試與參考物治療27天，伴隨體重的每日記錄。在治療期間，於第14日與第27日的最末給劑後24 h，將所有動物以眼窩放血的方式採血以供上述提及的生化參數之評估。為了評估急性的效果，於第27日的最末給劑後2 h測量血漿iPTH。 經由使用下列公式計算血漿 iPTH 的抑制百分率： 抑制百分比 = ((載具平均值 – 治療後個體數值) / (載具平均值)) X 100 因此，上述的體內方法顯示發現本發明之化合物表現抑制血漿iPTH量，從而顯示治療與CaSR的調節相關聯的疾病、病症之效用。 雖然上述已詳細描述特定具體實施例與範例，本領域具一般技藝的技術人員將清楚地了解具體實施例與範例中許多修改是可能的而不脫離其教示。所有此類修改係意圖包含於本發明下述的申請專利範圍中。Definitions and Abbreviations: Unless otherwise indicated, the following terms used in the specification and patent claims have the meanings provided below. For the purposes of this description, the following definitions will apply, and where appropriate, the terms used in the singular will also include the plural and vice versa. The term "halogen" or "halo" means fluoro, chloro, bromo or iodo. Unless otherwise indicated, "oxo" in this application means a C(=O) group. Such pendant oxy groups can be part of any of the rings or chains of the compounds of the invention. The term "alkyl" means an alkane-derived hydrocarbon radical having only carbon and hydrogen atoms in its skeleton, no unsaturated carbon, one to six carbon atoms, and is bonded to the single bond. The remainder of the molecule, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl) And so on. Unless stated or recited to the contrary, all alkyl groups described or claimed herein may be straight or branched. The term "alkenyl" means a hydrocarbon radical containing from 2 to 10 carbon atoms and including at least one carbon-carbon double bond. Non-limiting examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-l-propenyl, 1-butenyl, 2- Butenyl and the like. Unless stated or recited to the contrary, all alkenyl groups described or claimed herein may be straight or branched. The term "alkynyl" means a hydrocarbon radical comprising from 2 to 10 carbon atoms and comprising at least one carbon-carbon triple bond. Non-limiting examples of alkynyl groups include ethynyl, propynyl, butynyl, and the like. All alkynyl groups described or claimed herein may be straight or branched unless stated or stated to the contrary. The term "alkoxy" means an alkyl group bonded by oxygen bonding. Non-limiting examples of such groups are methoxy, ethoxy and propoxy, and the like. Unless stated or recited to the contrary, all alkoxy groups described or claimed herein may be straight or branched. The phrase "haloalkyl" means an alkyl group as defined above substituted with one or more halogen atoms as defined above. Preferably, the haloalkyl group can be a monohaloalkyl group, a dihaloalkyl group or a polyhaloalkyl group (including a perhaloalkyl group. The monohaloalkyl group can have one iodine, bromine, chlorine or fluorine atom). The dihaloalkyl group and the polyhaloalkyl group may be replaced by two or more of the same halogen atoms or a combination of different halogen atoms. Preferably, the polyhaloalkyl group is replaced by up to 12 halogen atoms. Non-limiting examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloro Methyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, and the like. A perhaloalkyl group means an alkyl group in which all hydrogen atoms are replaced by a halogen atom. Unless stated or recited to the contrary, all haloalkyl groups described or claimed herein may be straight or branched. The term "haloalkoxy" means a haloalkyl group as defined herein, the group being bonded by an oxygen bond. Non-limiting examples of such groups are monohaloalkoxy, dihaloalkoxy, or polyhaloalkoxy (including perhaloalkoxy). Unless otherwise stated or recited, all haloalkoxy groups described or claimed herein may be straight or branched. The term "cycloalkyl" means a non-aromatic mono- or polycyclic ring system having 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Examples of polycyclic cycloalkyl groups include, but are not limited to, perhydro naphththyl, adamantyl and norbornyl groups, bridged ring groups or spiro bicyclic groups ( For example, spiro (4,4) inden-2-yl and the like). The term "cycloalkylalkyl" means a cycloalkyl group as defined above, which is directly bonded to an alkyl group as defined above, such as cyclopropylmethyl, cyclobutylmethyl, cyclopentane. Methyl, cyclohexylmethyl, cyclohexylethyl and the like. The term "aryl" means an aromatic radical having 6 to 14 carbon atoms, which includes monocyclic, bicyclic and tricyclic aromatic systems such as phenyl, naphthyl, tetrahydronaphthyl. , indanyl and biphenyl, and the like. The term "arylalkyl" means an aryl group as defined above, directly bonded to an alkyl group as defined above, for example -CH2
C6
H5
With -C2
H4
C6
H5
. "A ring of a 3 to 6 membered saturated carbocyclic ring" means a ring of a monocyclic carbocyclic ring and a ring of a non-aromatic carbocyclic ring as defined herein. As used herein, "carbocyclic ring" or "carbocycle" means a 3 to 6 membered saturated or partially unsaturated, monocyclic, fused bicyclic, spiro ring containing carbon atoms. Rings, which may alternatively be substituted, for example, ring of carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl, cyclohexanone, and the like. The phrase "heterocyclic ring" or "heterocyclyl ring" or "heterocyclyl" means substituted or unsubstituted non-aromatic 3 unless otherwise specified. To a 15-membered ring, the ring consists of carbon atoms and one or more heteroatoms independently selected from N, O or S. The heterocyclic ring may be a mono-, bi- or tricyclic ring system which may include a fused, bridged or spiro ring system, and the nitrogen, carbon, oxygen or sulfur atom in the heterocyclic ring may be selected Oxidation to various oxidation states. Further, the nitrogen atom may be optionally quaternized, and the heterocyclic or heterocyclic group may optionally contain one or more olefinic bonds, and one or two carbons of the heterocyclic ring or heterocyclic group. Atom can be -CF2
-, -C(O)-, -S(O)-, S(O)2
, -C(=N-alkyl)- or -C(=N-cycloalkyl) and the like are interrupted. Further, the heterocyclic ring may be fused to the aromatic ring. Non-limiting examples of heterocyclic rings include azetidinyl, benzopyranyl, chromanyl, decahydroisoquinolyl, Indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, heterosexual Isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2-oxopiperidinyl (2-oxopiperidinyl), 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl ), perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl Phenoxyzinyl Inyl), quinuclidinyl, tetrahydroisoquinolyl, tetrahydrofuryl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, Thiomorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfoneindoline, benzodioxole, tetrahydroquinoline, Tetrahydrobenzopyran and the like. The ring of the heterocyclic ring can be attached via any atom of the ring of the heterocyclic ring which results in the formation of a stable structure. The term "heteroaryl", unless otherwise indicated, means a substituted or unsubstituted ring of a 5 to 14 membered aromatic heterocyclic ring having one or more independently selected from N, O or The hetero atom of S. Heteroaromatics can be single, double or triple ring systems. The heteroaryl ring can be attached via any atom of the heteroaryl ring to result in the formation of a stable structure. Non-limiting examples of heteroaryl rings include oxazolyl, isoxixyllyl, imidazolyl, furyl, indolyl, isodecyl ( Isoindolyl), pyrrolyl, triazolyl, triazinyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, pyridine Pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, Benzimidazolyl, benzothienyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, porphyrin Cinnolinyl), naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolinyl (isoquinolyl), thiadiazolyl, indolizinyl, acridinyl, phenazinyl, phthalazinyl and the like. The term "heterocyclylalkyl" means a ring radical of a heterocyclic ring directly bonded to an alkyl group. A heterocyclylalkyl radical can be attached to the primary structure at any carbon atom of the alkyl group, which results in the formation of a stable structure. The term "heteroarylalkyl" means a heteroaryl ring radical that is directly attached to an alkyl group. A heteroarylalkyl radical can be attached to the main structure at any carbon atom of the alkyl group, which results in the formation of a stable structure. The term "substituted" as used herein, unless otherwise indicated, means a group or moiety having one or more substituents attached to the structural backbone of a group or moiety. Such substituents include, but are not limited to, hydroxy, halo, carboxy, cyano, nitro, pendant oxy (=O), thio (=S), alkyl, haloalkyl, alkenyl, alkynyl, aryl , arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclic ring, heterocyclylalkyl, heteroarylalkyl, -C(O)ORx
, -C(O)Rx
, -C(S)Rx
,-C(O)NRx
Ry
, -NRx
C(O)NRy
Rz
, -N(Rx
)S(O)Ry
, -N(Rx
)S(O)2
Ry
, -NRx
Ry
, -NRx
C(O)Ry
, -NRx
C(S)Ry
, -NRx
C(S)NRy
Rz
, - S(O)2
NRx
Ry
, -ORx
, -OC(O)Rx
, -OC(O)NRx
Ry
, -Rx
C(O)ORy
, -Rx
C(O)NRy
Rz
, -Rx
C(O)Ry
, -SRx
And -S(O)2
Rx
; in each case Rx
, Ry
With Rz
They are independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl and aryl. The above "substituted" group cannot be further replaced. For example, when the substituent on the "substituted alkyl group" is "aryl" or "alkenyl", the aryl or alkenyl group cannot be an substituted aryl group or an substituted alkenyl group, respectively. The compounds of the invention may have one or more palmitic centers. The absolute stereochemistry of each palm center can be 'R' or 'S'. The compounds of the invention include all non-image isomers and mirror image isomers as well as mixtures thereof. Unless otherwise specified, a reference to a stereoisomer applies to any of the possible stereoisomers. Whenever a stereoisomeric composition is not specified, it should be understood that all possible stereoisomers are included. The term "stereoisomer" means a compound composed of the same atom, bonded via the same bond but having different three-dimensional structures that are not interchangeable. This three-dimensional structure is called a configuration. As used herein, the term "enantiomer" means that the molecules are two stereoisomers of non-superimposable mirror images of each other. The term "chiral center" means a carbon atom to which four different groups are attached. As used herein, the term "diastereomers" means a stereoisomer that is not a mirror image isomer. The term "racemate" or "racemic mixture" means a mixture of equal parts of the mirror image isomer. "Tautomer" means a compound that undergoes rapid proton transfer from one atom of a compound to another atom of the compound. Some of the compounds described herein may exist as tautomers of different hydrogen attachment points. Individual tautomers and mixtures thereof are included with the compounds of formula (I). "Treatment" of the state, disorder or symptom of this term includes: (a) delaying the clinical or subclinical symptoms of a condition, disorder or symptom that may or may not have or manifested in the state, condition or symptom The clinical symptoms of the state, condition or symptom of the development of the subject; (b) inhibition of the condition, disorder or symptom, ie, preventing or reducing the progression of the disease or at least one of its clinical or subclinical signs; c) alleviating the disease condition Or the severity of the symptoms or at least one of its clinical or subclinical signs or (d) alleviating the disease, ie, causing a recovery of the condition, disorder or symptom or at least one of its clinical or subclinical signs. The phrase "modulate" or "modulation" or "modulator" means an increase in the effect of the amount, quality or specific activity or function of the receptor. By way of illustration and not limitation, it includes a agonist, a partial agonist, an allosteric modulator of the calcium sensitive receptor (CaSR) of the invention. Such modulation may occur by chance of a specific event, such as activation of a message delivery pathway. The term "allosteric modulators of calcium-sensing receptor" means that a compound binds to a calcium-sensitive receptor and induces via an endogenous ligand Ca.2+
The ability to reduce the conformational change in the threshold of calcium-sensitive receptor activation, depending on the concentration of the compound exposed to the calcium-sensitive receptor. The term "subject" includes mammals (especially humans) and other animals, such as livestock (eg, domestic pets including cats and dogs) and non-live animals (eg, wild animals). By "therapeutically effective amount" is meant an amount of a compound that, when administered to a subject for the treatment of a disease, disorder, condition or symptom, is sufficient to cause an effect of administration for the purpose of administration. This "therapeutically effective amount" will depend on the compound, the disease and its severity, and the age, weight, physical condition and response of the subject to be treated. Pharmaceutically Acceptable Salts: The compounds of the invention may form salts with acids or bases. The compounds of the invention may be sufficiently acidic or base to form stable non-toxic acidic or basic salts, and administration of a compound of a pharmaceutically acceptable salt may be suitable. A non-limiting example of a pharmaceutically acceptable salt is an inorganic, organic acid addition salt formed via the addition of an acid, including the hydrochloride salt. A non-limiting example of a pharmaceutically acceptable salt is an inorganic, organic base addition salt formed by the addition of a base. The compounds of the invention may also form salts with amino acids. Pharmaceutically acceptable salts can be obtained, for example, by reacting a sufficient amount of a basic compound such as an amine with a suitable acid which provides a physiologically acceptable anion, using standard procedures well known in the art. With regard to the monolithic compounds described by formula (I), the invention extends to these stereoisomeric forms and mixtures thereof. To the extent that prior art teaches the synthesis or isolation of specific stereoisomers, the different stereoisomeric forms of the invention may be separated from each other via methods known in the art, or may be specifically or asymmetrically synthesized via stereostructures. Or palmitic HPLC (high performance liquid chromatography) to obtain the given isomer. The tautomeric forms and mixtures of the compounds described herein are also contemplated. Screening of compounds of the invention that achieve calcium sensitive receptor (CaSR) modulating activity can be accomplished via the use of various in vitro and in vivo protocols mentioned below or methods known in the art. Pharmaceutical Compositions The present invention relates to pharmaceutical compositions comprising a compound of formula (I) as disclosed herein. In particular, a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula (I) described herein and at least one pharmaceutically acceptable excipient (e.g., carrier or diluent). Preferably, the pharmaceutically acceptable composition comprises a compound described herein in an amount sufficient to modulate a calcium sensitive receptor (CaSR) vector described herein when administered to a subject. Subjects considered include, for example, living cells and mammals, including human mammals. The compounds of the present invention may be associated with a pharmaceutically acceptable excipient (e.g., a carrier or diluent) or diluted with a carrier, or enclosed in a carrier which may be in the form of a capsule, sachet, paper, or other container. Pharmaceutically acceptable excipients include those which do not themselves induce the production of antibodies which are harmful to the individual receiving the composition, and which can be administered without undue toxicity. Examples of suitable carriers or excipients include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxy castor oil, peanut oil, olive oil, gelatin, lactose, white clay, sucrose, dextrin, magnesium carbonate. , sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or cellulose low alkyl ether, salicylic acid, fatty acid, fatty acid amine, fatty acid single Glycerides and diglycerides, neopentyl glycol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. The pharmaceutical composition may also include one or more pharmaceutically acceptable adjuvants, wetting agents, emulsifying agents, suspending agents, preservatives, salts which affect osmotic pressure, buffers, sweeteners, flavoring agents, coloring agents or A composition of any of the foregoing. The pharmaceutical compositions of the present invention can be formulated by procedures known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a subject. The pharmaceutical compositions described herein can be prepared via conventional techniques known in the art. For example, the active compound may be mixed with the carrier, or diluted in a carrier, or enclosed in a carrier which may be in the form of an ampule, capsule, sachet, paper packet or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which is a carrier, excipient or medium for the active compound. The active compound can be adsorbed onto a particulate solid container, for example, in a sachet. The pharmaceutical composition may be in a conventional form, for example, a capsule, a tablet, a capsular tablet, an orally disintegrating tablet, a spray, a solution, a suspension or a topical application. The route of administration can be any route effective to transport the active compound of the invention to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, Urethral, intramuscular, intranasal, ophthalmic (eg, in ophthalmic solutions) or topical (eg, in topical ointments). Solid oral preparations include, but are not limited to, tablets, capsulated tablets, capsules (soft or hard gelatin), orally disintegrating tablets, dragees (containing active ingredients in powder or granule form), throat lozenges and lozenges. Tablets, dragees or capsules having a carrier or binder or talc of talc and/or carbohydrate are particularly suitable for oral use. Liquid preparations include, but are not limited to, syrups, emulsions, suspensions, solutions, soft gelatin, and sterile injectable liquids such as aqueous or nonaqueous liquid suspensions or solutions. For parenteral use, it is especially suitable as an injectable solution or suspension, preferably an aqueous solution with the active compound dissolved in the polyhydroxylated castor oil. The drug preparation is preferably in unit dosage form. In such forms, the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a packaged preparation which contains a package of the individual quantities of the preparation, such as a packaged tablet, a capsule, and a powder in a vial or ampule. Furthermore, the unit dosage form may itself be a capsule, tablet, capsular tablet, sachet or lozenge, or it may be any of the appropriate number in the packaged form. For administration to a subject, the total daily dose of the compound of the invention will of course depend on the mode of administration. For example, oral administration may require a higher total daily dose than intravenous (direct to blood). The amount of active ingredient in a unit dosage formulation may vary or be adjusted from 0.1 mg to 10000 mg depending on the potency of the active ingredient or the mode of administration. Suitable compound dosages for the treatment of the diseases and conditions described herein can be determined by those skilled in the relevant art. Therapeutic doses are generally determined via a subject dose range study based on prima facie evidence from animal studies. The dose must be sufficient to cause the desired therapeutic benefit to the patient without causing undesirable side effects. For example, the daily dose of the CaSR modulator can range from about 0.1 to about 30.0 mg/kg. The mode of administration, dosage form, suitable pharmaceutical excipients, diluents or carriers can also be used well and adjusted by those skilled in the art. All changes and modifications are contemplated as being within the scope of the invention. Methods of Treatment In another aspect, the invention provides a compound and a pharmaceutical composition thereof useful for treating, managing, and/or alleviating the severity of a disease, disorder, condition, or symptom modulated by a calcium sensitive receptor (CaSR). The invention further provides a method of treating a disease, disorder, condition or symptom modulated by CaSR in a subject in need thereof, by administering to the subject a therapeutically effective amount of a compound or pharmacy of the invention Composition. In another aspect of the invention, the provided methods are effective for the diagnosis of symptoms that can be treated via modulation of CaSR for use in determining whether a patient will respond to a therapeutic agent. In another aspect, the invention provides methods of treatment via a disease, disorder or condition that modulates CaSR. In this method, a subject in need of such treatment is administered in a therapeutically effective amount of a compound of formula (I) as described herein. The compounds of the present invention and pharmaceutical compositions are effective for subjects having a disease, disorder, condition or symptom characterized by one or more of the following: (a) abnormal calcium ion balance, (b) The amount of courier that produces or secretes an effect of calcium-sensitive receptor (CaSR) activity is abnormal or (c) the degree of activity of the courier affected by the activity of the calcium-sensitive receptor is abnormal. In one aspect, the patient has a disease, disorder, symptom or symptom characterized by an abnormal amount of a component modulated by one or more calcium sensitive receptors, and the compound is active in the CaSR of the cell, the cell including the parathyroid gland Cells, bone cells (pre-osteoclasts, osteoclasts, pre-osteoblasts, osteoblasts), proximal glomerular kidney cells, glomerular ring mesangial cells, glomerular kidney cells, proximal tubule kidney cells , distal tubule kidney cells, cell of the thick ascending limb of Henle's loop and/or renal tubules, thyroid follicular cells (C-cell), intestinal cells, platelets, vascular smooth muscle Cells, gastrointestinal cells, pituitary cells, or hypothalamic cells. The courier of calcium-sensitive receptors is calcium. A compound of formula (I) which is a modulator of CaSR is potentially effective in treating, managing and/or alleviating the severity, morbidity/mortality or complications of a disease, disorder, symptom or symptom, the disease, condition , symptoms or symptoms including, but not limited to, primary parathyroid hyperfunction, secondary hyperthyroidism, tertiary parathyroid hyperactivity, chronic renal failure (with or without dialysis), chronic kidney disease (with or without Dialysis), parathyroid adenoma, parathyroid hyperplasia, parathyroid carcinoma, vascular and heart valve calcification, abnormal calcium balance such as hypercalcemia, abnormal phosphorus balance such as hypophosphatemia, hyperparathyroidism, chronic kidney disease Or bone-related diseases or complications caused by parathyroid cancer, bone loss after kidney transplantation, cystic fibrosis, debilitating bone disease, renal bone disease, cardiovascular disease caused by parathyroid hyperactivity or chronic kidney disease Complications, (Ca2+
)e
Some malignant tumors with abnormally high levels of ions, heart, kidney or intestinal dysfunction, podocyte-related diseases, abnormal intestinal peristalsis, diarrhea, gastrin and gastric acid secretion, directly or indirectly benefit from atrophy Gastritis, or the absorption of pharmaceutical compounds, drugs or nutritional supplements from the gastrointestinal tract by increasing the acidity of the gastric juice. Primary hyperparathyroidism is one or more conditions of the parathyroid gland, which is caused by hyperactivity of the parathyroid gland itself (occasional or familial), which may be due to single or double adenomas, hyperplasia, and more Glandular disease or rare excretion of PTH due to parathyroid cancer. Therefore, blood calcium is elevated to a higher than normal amount (referred to as hypercalcemia). This elevated calcium may cause many short-term and long-term complications. When Ca2+
When the level of circulation is reduced and the secretion of PTH is stimulated, secondary hyperparathyroidism occurs. One cause of secondary hyperparathyroidism is chronic renal insufficiency (also known as chronic kidney disease or CKD), such as renal polycystic disease or chronic pyelonephritis secondary hyperthyroidism, or chronic renal failure, For example, hemodialysis patients (also known as end stage renal disease or ESRD) have secondary hyperparathyroidism. Excessive PTH may be produced by low calcium responses resulting from low calcium intake, gastrointestinal disorders, renal insufficiency, vitamin D deficiency, magnesium deficiency, and renal hypercalciuria. Tertiary hyperparathyroidism may occur after long-term secondary hyperthyroidism and hypercalcemia. In one aspect, the compounds and compositions of the invention can be used to treat, manage, and/or alleviate vascular or valve calcification in a subject. In one aspect, administration of a compound of the invention delays or reverses the formation, growth or deposition of extracellular matrix hydroxyphosphorus lime crystal deposition. In another aspect of the invention, administration of a compound of the invention prevents the formation, growth or deposition of extracellular matrix hydroxyphosphorus lime crystal deposition. In one aspect, the compounds of the invention may also be used to prevent or treat calcification of the atherosclerosis as well as medial calcification and other symptoms characterized by vascular calcification. In one aspect, vascular calcification may be associated with chronic renal insufficiency or end stage renal disease or excessive calcium or PTH itself. On the other hand, vascular calcification may be associated with pre- or post-dialysis or uremia. In a further aspect, vascular calcification may be associated with Type I or Type II diabetes. In yet another aspect, vascular calcification may be associated with cardiovascular disease. Abnormal calcium balance, such as parathyroid hyperactivity-related diseases, can be characterized as described in standard medical textbooks but not limited to Harrison's Principles of Internal Medicine. In particular, the compounds and compositions of the present invention can be used to participate in the reduction in the amount of serum in a parathyroid hormone known as PTH: these products may thus be effective for the treatment of diseases such as hyperparathyroidism. The abnormal phosphorus balance, such as hypophosphatemia, can be characterized as standard medical textbooks, but is not limited to those described in Harrison's Principles of Internal Medicine. In particular, the compounds and compositions of the present invention can be used to participate in the reduction in the amount of serum in a parathyroid hormone known as PTH: these products may thus be effective for the treatment of diseases such as hypophosphatemia. In one aspect, the podocyte disease or condition treated by the methods of the invention results from a disturbance in one or more functions of the podocyte. The functions of these podocytes include: (i) size disorders to proteins; (ii) charge trapping of proteins; (iii) maintenance of capillary loops; (iv) counteracting intraglomerular pressure; (v) glomeruli Synthesis and maintenance of the basement membrane (GMB); (vi) Production and secretion of vascular endothelial growth factor (VEGF) required for glomerular endothelial cell (GEN) integrity. Such conditions or diseases include, but are not limited to, podocyte loss (podocyte reduction, podocytopenia), podocyte mutation, increased foot process width, or reduced slit membrane length. In one aspect, a podocyte-associated disease or condition may be the disappearance or reduction of podocyte density. In one aspect, podocyte density reduction may be due to a decrease in the number of podocytes, for example, due to apoptosis, detachment, lack of proliferation, DNA damage, or hypertrophy. In one aspect, a podocyte-associated disease or condition may be due to podocyte damage. In one aspect, podocyte injury may be due to mechanical stress (such as high blood pressure, hypertension or ischemia), lack of oxygen supply, toxic substances, endocrine disorders, infection, contrast agents. , mechanical damage, cytotoxic agents (cisplatin, doxorubicin, puromycin), calcineurin inhibitors, inflammatory effects (eg, due to infection, trauma, hypoxia, obstruction or ischemia), radiation, Infection (eg bacterial, fungal or viral), immune system insufficiency (eg autoimmune disease, systemic disease, or IgA nephropathy), hereditary disorder, drugs (eg antibacterial, antiviral, antibiotic Fungal agents, immunosuppressants, anti-inflammatory agents, analgesic or anticancer agents), organ failure, organ transplantation or urinary tract disease. In one aspect, the ischemia can be sickle cell anemia, thrombosis, transplantation, obstruction, shock, or blood loss. In one aspect, the hereditary condition can include a congenital nephritic syndrome of the Finnish type, a fetal membranous nephropathy, or a podocyte-specific protein mutation. In one aspect, the compounds of the invention can be used to treat abnormal intestinal peristalsis conditions, such as diarrhea. The methods of the invention comprise administering to the subject a therapeutically effective amount of a compound of Formula I. In a further aspect, the diarrhea may be exudative diarrhea, ie, direct damage resulting from small or large intestinal mucosa. This type of diarrhea can be caused by an infectious or inflammatory condition of the intestine. In one aspect, exudative diarrhea can be associated with gastrointestinal or abdominal surgery, chemotherapy, radiation therapy, inflammatory effects, or toxic trauma. On the other hand, diarrhea can be secretory, meaning an increase in active secretion, or inhibition of absorption. Little or no structural damage. The most common cause of this type of diarrhea is cholera. On the other hand, diarrhea can be accelerated by intestinal transport (high-speed transport of diarrhea). This can happen because of the rapid flow through and the ability of the intestine to absorb moisture. The compounds and compositions of the present invention may be used, particularly to increase gastrin or gastric acid secretion, to directly or indirectly benefit certain medical conditions such as, but not limited to, atrophic gastritis, or to improve drug compounds by increasing gastric acidity, Drugs or nutritional supplements are absorbed by the gastrointestinal tract. The patents, patent applications, and non-patent publications referred to in this specification are hereby incorporated by reference in their entirety. General Methods of Preparation The compounds described herein can be prepared via techniques known in the art. Furthermore, the compounds described herein can be prepared via the reaction sequence as described in Schemes 1 to 2. Further, in the following schemes, specific bases, acids, reagents, solvents, coupling agents and the like mentioned therein, it is understood that other bases, acids, reagents, solvents, coupling agents, etc. known in the art may also be used. It is therefore included in the scope of the invention. Variations in the reaction conditions, for example, temperatures and/or reaction durations as may be known in the art are also included within the scope of the invention. Isomers of the compounds described in these schemes are included within the scope of the invention unless otherwise indicated.Program -1 a compound of formula (I) (wherein X, R1
, R2
, R3
And 'n' as described herein above) can be prepared via continuous transformation as described in Scheme 1. A compound of formula (2) can be prepared from a compound of formula (1) via a Cs in a suitable solvent2
CO3
In the presence of the reaction with the appropriate bromoethanol (1a). The compound of formula (2) is reacted with methanesulfonyl chloride in the presence of DIPEA in a suitable solvent to provide a compound of formula (3) which is further Na in a suitable solvent2
CO3
It is reacted with the chemical formula (3a) in the presence of a compound of the formula (4). This compound of formula (4) is in Na2
CO3
With PdCl2
The boronic acid of formula (4a) is coupled in the presence of (dppf) to form formula (I) (a mixture of isomers) which is further separated by column chromatography to obtain a single isomer. The compound of formula (I) (ester) can be treated with LiOH (or any suitable base) in a suitable solvent to form an acid compound of formula (IV). Alternatively, a compound of formula (IV) can be prepared via a procedure as described in Scheme 2.Program -2 The compound of formula (3) is reacted with a specific amine of formula (3b) in the presence of sodium carbonate in a suitable solvent to provide a compound of formula (5). The compound of the formula (5) is in sodium carbonate and PdCl2
The boronic acid of formula (4a) is coupled in the presence of (dppf) to provide a compound of formula (IV). The compound of formula (IV) (when it is an ester) can be treated with LiOH (or any suitable base) in a suitable solvent to provide the corresponding acid compound of formula (IV). The invention is further illustrated by the following examples, which are merely exemplary of the invention and are not intended to limit the scope of the invention. The examples set forth below demonstrate synthetic procedures for the preparation of representative compounds. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention. The above patents and patent applications are incorporated herein by reference. Intermediate product Intermediate-1: Hydroxyl intermediate:Will Cs2
CO3
(2 eq.) was added to a corresponding solution of phenol (1 eq.) in well-stirred DMF, and the mixture was heated to 50 ° C for 30 minutes. It was cooled to room temperature and bromohydrin (2-bromoethanol or 3-bromopropan-1-ol) (1.1 eq.) was added to the above solution. The reaction mixture was further heated to 50 ° C overnight. After completion of the reaction (confirmed by TLC), it was quenched with water, extracted with ethyl acetate, rinsed with water and dried (Na2
SO4
And concentrated to provide the crude product which was purified by column chromatography to afford the desired compound (45-65%). Intermediate product-1a to intermediate-1i mentioned in Table 1 below were prepared using a similar procedure.form -1 :
Intermediate-2: O-mesylate intermediateDIPEA (4 equivalents) was added to a solution of the hydroxy intermediate (from intermediate-1a-1l) (1 eq.) in dry DCM at 0 °C and the mixture was stirred for 10 min. Methylsulfonium chloride (1.5 equivalents) was added thereto, and the reaction was stirred at room temperature for 2 h. TLC shows a complete transition of the starting material. It was quenched with water and extracted with DCM. The organic layer is rinsed with water and dried (Na2
SO4
And concentrated to provide the desired compound (80-90%) for use as such. The intermediates - 2a to 2l mentioned in Table 2 below were prepared using a similar procedure.form -2 :
Intermediate-3:The mesylate derivative (from the intermediate product 2a-2l) (1 equivalent), the corresponding palmitic amine (2 equivalents)(R)
-1-(naphthalen-1-yl)ethylamine or(R)
-1-(3-methoxyphenyl)ethylamine) and Na2
CO3
The mixture (1.3 eq.) was heated to 110 ° C overnight. After completion of the reaction (confirmed via TLC), the reaction was quenched with water and extracted with ethyl acetate. The organic layer is rinsed with water and dried (Na2
SO4
And concentrated to provide the desired compound (50-60%). The intermediates -3a to 3r mentioned in Table 3 below were prepared using a similar procedure.form -3: example
Example-1(R)
-N
-Methyl-5-(2-((1-(naphthalen-1-yl)ethyl)amino)ethoxy)-3'-(trifluoromethyl)-[1,1'-biphenyl --3-carboxamide3-(Trifluoromethyl)benzeneboronic acid (1.2 equivalents), Na2
CO3
(2 equivalents) and H2
O is added to a solution of the intermediate product -3a (1 equivalent) in dioxane. Degas the mixture for 15 minutes, then add PdCl2
(dppf) (5 mol%). The reaction mixture was heated to 80 ° C overnight. TLC showed complete conversion of the starting material, which was then filtered through a pad of Celite and concentrated to afford crude product which was purified by column chromatography (10% ethyl acetate-hexane) Compound (yield: 50-60%); mass: m/z: 493 (M+1)+
.1
H NMR (400 MHz, DMSO-d 6
) 8.30 (d,J
= 8 Hz, 1H), 8.07(d,J
=8 Hz 1H), 7.96– 7.91 (m, 2H), 7.67 – 7.61 (m, 6H), 7.59-7.52 (m, 3H), 7.01– 6.96 (m, 2H), 5.42 (m, 1H), 4.50 – 4.36 (m, 2H), 3.50 – 3.48(m, 1H), 3.25 – 3.03 (m, 4H), 2.1 (d,J
= 5.6 Hz, 3H) ;m/z: 493 (M+1)+
Examples 2 through 27 of Table 4 were prepared according to a similar procedure as described in Example 1, using the appropriate intermediate from intermediates 3a-3r and the corresponding phenylboronic acid.form -4 : example -28 (R)
4-methyl-3'-(methylamine-mercapto)-5'-(2-((1-(naphthalen-1-yl)ethyl)amino)ethoxy)-[1,1 '-biphenyl]-3-carboxylic acid step -1
:(R)
-methyl 4-methyl-3'-(methylamine-mercapto)-5'-(2-((1-(naphthalen-1-yl)ethyl)amino)ethoxy)-[1 ,1'-biphenyl]-3-carboxylate (3-(methoxycarbonyl)-4-methylphenyl)boronic acid (1.2 eq.), Na2
CO3
(2 equivalents) with water added to dioxane(R)
-3-bromo-N
A solution of methyl-5-(2-((1-(naphthalen-1-yl)ethyl)amino)ethoxy)benzamide (intermediate-3a) (1 eq.). Degas the mixture for 15 minutes, then add PdCl2
(dppf) (5 mol%). The reaction mixture was heated to 80 ° C overnight. TLC showed complete conversion of the starting material, which was then filtered through a pad of Celite and concentrated to afford crude product which was purified by column chromatography (10% ethyl acetate-hexane) Compound (yield: 50-60%).step -2
:(R)
4-methyl-3'-(methylamine-mercapto)-5'-(2-((1-(naphthalen-1-yl)ethyl)amino)ethoxy)-[1,1 '-Biphenyl]-3-carboxylic acid LiOH (2 eq.) in water was added to the above intermediate product (1 eq.) in THF, and the mixture was stirred overnight at room temperature. After completion (TLC), it was concentrated, washed with ethyl acetate and acidified (10% citric acid) to provide a solid compound which was filtered and dried under vacuum (60-70%); m/z: 483 (M+1)+
.1
H NMR (400 MHz, DMSO-d6) δ 8.58-8.57 (d,J
= 4.8 Hz, 1H), 8.29-8.27 (d,J
= 8 Hz, 1H), 7.98 (s, 1H), 7.93-7.91 (m, 1H), 7.79-7.63 (m 3H), 7.53 - 7.47 (m, 3H), 7.36 (s, 1H), 7.31 - 7.29 (m, 2H), 4.69-4.67 (m, 1H), 4.16-4.14 (m, 2H), 2.80-2.79 (m, 5H), 2.50(s, 3H), 1.41-1.39 (d, J = 6.4Hz) , 3H);m/z:483 (M+1)+
Prepare Example 29 provided in Table 5 by using a suitable substituted aryl boronate and appropriate intermediates (from intermediates -3a to 3r) according to a similar coupling reaction procedure as described in Step 1 of Example 28. To 116. This ester compound was then subjected to ester hydrolysis using LiOH via a similar ester hydrolysis procedure as described in Step 2 of Example 28.form -5 :
The examples 112 to 117 provided in Table 6 were prepared via a similar procedure as described in Step 1 of Example 28 followed by Step 2.form -6:
In Vitro Pharmacological Activity Certain illustrative compounds within the scope of the invention are screened for CaSR activity according to the procedures provided below. Screening of compounds can also be carried out by other methods and procedures known to those skilled in the art. In vitro test for calcium-modulated agents mediated by calcium-sensitive receptors (CaSR): The ability of compounds to modulate calcium-sensitive receptors is measured by intracellular calcium [Ca2+
It is measured by the increase of i. Development of stably transfected HEK293 cells expressing the hCaSR_pTriEx-3 hygro vector was developed. Cells were plated in 96-well plates of Ham's F12 containing 20% FBS at 37 ° C, 5% CO2
It grows overnight to 80% confluency. The cells are then contained in 126 mM NaCl2
, 1 mM MgCl2
Flush extensively with 4 mM KCl in 20 mM HEPES buffer to remove serum components that may interfere with the assay. Calcium-sensitive Fluo4NW stain in HEPES base buffer containing 0.1% BSA and 1 mg/ml glucose was loaded into the cells for 30 minutes to measure changes in intracellular calcium. Use 0.3 mM CaCl in 20 mM HEPES base buffer for FLIPR2
The activity of the compound was measured. The potency of a compound to modulate receptor activity by calculating the EC of a compound in an 8-point assay50
The reaction was determined and plotted as a graph using GraphPad Prism 5. The prepared compound was tested using the above test procedure, and the results obtained were provided below. EC of several representative compounds50
The (nM) values are given in Table 7. In vitro activity data for representative compounds are provided in Table 7. Form-7:
Thus, the above in vitro assays have shown that the compounds of the invention exhibit agonistic activity of CaSR, thereby demonstrating the utility of treating diseases and conditions associated with CaSR modulation.CKD Wistar In vivo activity of rats:
Animals were fed a 0.75% adenine diet for a period of 28 days for the development of chronic kidney disease (CKD). After the measurement of plasma PTH on day 28, animals were randomized according to the extent of plasma PTH (intact PTH) before they were used for the study. Animals that were fasted overnight were given a basal blood sample (0.5 ml) by bloodletting from the orbit. Rats were orally administered with vehicle and test compound, wherein they were formulated with PEG 300:PG:Captisol (20:15:65). Six to eight animals were used in each group, and the compound of the present invention was administered at a dose of 1 mg/kg. Oral administration of the animals was arbitrarily fed with food and water after 2 h. At various time points of plasma PTH assessment, post-treatment blood samples were collected by eye socket bleeding under mild ether anesthesia. Plasma PTH was measured using a sandwich ELISA kit (Immunotopics, USA). Percentage of plasma PTH inhibition was calculated for individual untreated values. Percent inhibition was calculated by using the following formula = (pre-treatment individual value - post-treatment individual value / pre-treatment individual value) X 100 Therefore, the above in vivo method revealed the discovery of the compound of the present invention. The performance inhibits the amount of plasma PTH, thereby showing the utility of treating diseases and conditions associated with CaSR regulation.Nephrectomy SD In vivo activity of rats:
Male, Sprague Dawley rats weighing 200-270 g were used in this study. In the 5/6 nephrectomized CKD rat model, the original renal function quality was reduced to five-fifths (5/6) via two-step surgery. In the first operation, the abdominal cavity was cut under anesthesia and the left kidney was removed from the kidney capsule. Cut a third of the ends of the kidney and close the abdominal incision. One week after the first surgery, the right kidney was completely removed via transection of blood vessels and ureters. After the second surgery, all nephrectomized animals were fed a 1.2% phosphorus-containing diet and sham-controlled animals were fed a normal control group diet until the study was terminated. Three weeks after the second surgery, the animals were harvested by bloodletting from the orbital fossa for calcium ionization in whole blood and biochemical parameters such as phosphorus, urea, BUN, creatinine and plasma PTH. Plasma iPTH was measured by a sandwich ELISA method using a Rat Bioactive intact PTH ELISA kit. After confirmation of the required degree of iPTH, animals were randomly assigned to different treatment and vehicle control groups according to the degree of iPTH, 8-10 animals per group, and 8 animals were maintained in the sham control group. Immediately after randomization, the test and reference materials were started for 27 days, with daily recording of body weight. During the treatment period, all animals were bled in the orbital fossa 24 hours after the last dose on the 14th and 27th days for the evaluation of the biochemical parameters mentioned above. To assess the acute effect, plasma iPTH was measured 2 h after the last dose on day 27. Percent inhibition of plasma iPTH was calculated by using the following formula: % inhibition = ((average of vehicle - individual value after treatment) / (average of vehicle)) X 100 Therefore, the above in vivo method showed inhibition of the expression of the compound of the present invention. The amount of plasma iPTH, thereby showing the utility of the disease or condition associated with the modulation of CaSR. While the invention has been described with respect to the specific embodiments and embodiments illustrated in the embodiments All such modifications are intended to be included within the scope of the following claims.