CFTR REGULATORS AND METHODS OF USE THEREOFMethod provided herein is the compound of activation CFTR and for treating constipation, xerophthalmia obstacle or other diseases and obstacle.Pharmaceutical composition, it includes the compounds of pharmaceutically acceptable excipient and formulas i:or its pharmaceutically acceptable salt,wherein:ar is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;l1and l2it is independently substituted or unsubstituted c1-c3alkylidene;n1, n2, n3, n4 and n5 are independently 0 to 4 integers;m1, m2, m3, m4, m5, v1, v2, v3, v4 and v5 are independently 1 or 2;r1it is hydrogen, halogen ,-cx1.13,-chx1.12,-ch2x1.1,-cn,-son1r1a,-sov1nr1br1c,-nhnr1br1c,- onr1br1c,-nhc(o)nhnr1br1c,-nhc(o)nr1br1c,-n(o)m1,-nr1br1c,-c(o)r1d,-c(o)or1d,-c(o) nr1br1c,-or1a,-nr1bso2r1a,-nr1bc(o)r1d,-nr1bc(o)or1d,-nr1bor1d,-ocx1.13,-ochx1.12, taken generation or unsubstituted alkyl, substituted or unsubstituted miscellaneous alkyl, substituted or unsubstituted naphthenic base, quilt substitution or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl or substituted or unsubstituted miscellaneous aryl;r2it is hydrogen, halogen ,-cx2.13,-chx2.12,-ch2x2.1,-cn,-son2r2a,-sov2nr2br2c,-nhnr2br2c,- onr2br2c,-nhc(o)nhnr2br2c,-nhc(o)nr2br2c,-n(o)m2,-nr2br2c,-c(o)r2d,-c(o)or2d,-c(o) nr2br2c,-or2a,-nr2bso2r2a,-nr2bc(o)r2d,-nr2bc(o)or2d,-nr2bor2d,-ocx2.13,-ochx2.12, taken generation or unsubstituted alkyl, substituted or unsubstituted miscellaneous alkyl, substituted or unsubstituted naphthenic base, quilt substitution or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl or substituted or unsubstituted miscellaneous aryl;r3it is hydrogen, halogen ,-cx3.13,-chx3.12,-ch2x3.1,-cn,-son3r3a,-sov3nr3br3c,-nhnr3br3c,- onr3br3c,-nhc(o)nhnr3br3c,-nhc(o)nr3br3c,-n(o)m3,-nr3br3c,-c(o)r3d,-c(o)or3d,-c(o) nr3br3c,-or3a,-nr3bso2r3a,-nr3bc(o)r3d,-nr3bc(o)or3d,-nr3bor3d,-ocx3.13,-ochx3.12, taken generation or unsubstituted alkyl, substituted or unsubstituted miscellaneous alkyl, substituted or unsubstituted naphthenic base, quilt substitution or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl or substituted or unsubstituted miscellaneous aryl;r4it is hydrogen, halogen ,-cx4.13,-chx4.12,-ch2x4.1,-cn,-son4r4a,-sov4nr4br4c,-nhnr4br4c,- onr4br4c,-nhc(o)nhnr4br4c,-nhc(o)nr4br4c,-n(o)m4,-nr4br4c,-c(o)r4d,-c(o)or4d,-c(o) nr4br4c,-or4a,-nr4bso2r4a,-nr4bc(o)r4d,-nr4bc(o)or4d,-nr4bor4d,-ocx4.13,-ochx4.12, taken generation or unsubstituted alkyl, substituted or unsubstituted miscellaneous alkyl, substituted or unsubstituted naphthenic base, quilt substitution or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl or substituted or unsubstituted miscellaneous aryl;r5it is hydrogen, halogen ,-cx5.13,-chx5.12,-ch2x5.1,-cn,-son5r5a,-sov5nr5br5c,-nhnr5br5c,- onr5br5c,-nhc(o)nhnr5br5c,-nhc(o)nr5br5c,-n(o)m5,-nr5br5c,-c(o)r5d,-c(o)or5d,-c(o) nr5br5c,-or5a,-nr5bso2r5a,-nr5bc(o)r5d,-nr5bc(o)or5d,-nr5bor5d,-ocx5.13,-ochx5.12, taken generation or unsubstituted alkyl, substituted or unsubstituted miscellaneous alkyl, substituted or unsubstituted naphthenic base, quilt substitution or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl or substituted or unsubstituted miscellaneous aryl;r1a,r1b,r1c,r1d,r2a,r2b,r2c,r2d,r3a,r3b,r3c,r3d,r4a,r4b,r4c,r4d,r5a,r5b,r5cand r5dindependently it is hydrogen, halogen ,-cf3,-ccl3,-cbr3,-ci3,-oh,-nh2,-cooh,-conh2,-no2,-sh,-so3h,-so4h,- so2nh2,-nhnh2,-onh2,-nhc(o)nhnh2,-nhc(o)nh2,-nhso2h,-nhc(o)h,-nhc(o)-oh,-nhoh,- ocf3,-occl3,-ocbr3,-oci3,-ochf2,-ochcl2,-ochbr2,-ochi2, substituted or unsubstituted alkyl, it is substituted or unsubstituted miscellaneous alkyl, substituted or unsubstituted naphthenic base, substituted or unsubstituted miscellaneous naphthenic base, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;with identical nitrogen-atoms key the r of conjunction1b,r1c,r2b,r2c,r3b,r3c,r4b,r4c,r5band r5csubstituent group optionally connect formed it is substituted or unsubstituted heterocyclylalkyl or substituted or unsubstituted heteroaryl;andx1.1,x2.1,x3.1,x4.1and x5.1it is independently-cl ,-br ,-i or-f.
CFTR 조절제 및 이의 사용 방법본원에서는 CFTR을 활성화시키는 화합물, 및 변비, 안구건조증 장애, 또는 다른 질환 및 장애를 치료하는 방법을 제공한다.약학적으로 허용되는 부형제, 및 하기 화학식 I의 화합물, 또는 이의 약학적으로 허용되는 염을 포함하는 약학 조성물:[이미지]상기 식에서,Ar은 치환된 또는 비치환된 아릴, 또는 치환된 또는 비치환된 헤테로아릴이고;L1 및 L2는 독립적으로 치환된 또는 비치환된 C1-C3 알킬렌이고;n1, n2, n3, n4 및 n5는 독립적으로 정수 0 내지 4이고;m1, m2, m3, m4, m5, v1, v2, v3, v4 및 v5는 독립적으로 1 또는 2이고;R1은 수소, 할로겐, -CX1.13, -CHX1.12, -CH2X1.1, -CN, -SOn1R1A, -SOv1NR1BR1C, -NHNR1BR1C, -ONR1BR1C, -NHC(O)NHNR1BR1C, -NHC(O)NR1BR1C, -N(O)m1, -NR1BR1C, -C(O)R1D, -C(O)OR1D, -C(O)NR1BR1C, -OR1A, -NR1BSO2R1A, -NR1BC(O)R1D, -NR1BC(O)OR1D, -NR1BOR1D, -OCX1.13, -OCHX1.12, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 헤테로알킬, 치환된 또는 비치환된 사이클로알킬, 치환된 또는 비치환된 헤테로사이클로알킬, 치환된 또는 비치환된 아릴, 또는 치환된 또는 비치환된 헤테로아릴이고; R2는 수소, 할로겐, -CX2.13, -CHX2.12, -CH2X2.1, -CN, -SOn2R2A, -SOv2NR2BR2C, -NHNR2BR2C, -ONR2BR2C, -NHC(O)NHNR2BR2C, -NHC(O)NR2BR2C, -N(O)m2, -NR2BR2C, -C(O)R2D, -C(O)OR2D, -C(O)NR2BR2C, -OR2A, -NR2BSO2R2A, -NR2BC(O)R2D, -NR2BC(O)OR2D, -NR2BOR2D, -OCX2.13, -OCHX2.12, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 헤테로알킬, 치환된 또는 비치환된 사이클로알킬, 치환된 또는 비치환된 헤테로사이클로알킬, 치환된 또는 비치환된 아릴, 또는 치환된 또는 비치환된 헤테로아릴이고; R3은 수소, 할로겐, -CX3.13, -CHX3.12, -CH2X3.1, -CN, -SOn3R3A, -SOv3NR3BR3C, -NHNR3BR3C, -ONR3BR3C, -NHC(O)NHNR3BR3C, -NHC(O)NR3BR3C, -N(O)m3, -NR3BR3C, -C(O)R3D, -C(O)OR3D, -C(O)NR3BR3C, -OR3A, -NR3BSO2R3A, -NR3BC(O)R3D, -NR3BC(O)OR3D, -NR3BOR3D, -OCX3.13, -OCHX3.12, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 헤테로알킬, 치환된 또는 비치환된 사이클로알킬, 치환된 또는 비치환된 헤테로사이클로알킬, 치환된 또는 비치환된 아릴, 또는 치환된 또는 비치환된 헤테로아릴이고; R4는 수소, 할로겐, -CX4.13, -CHX4.12, -CH2X4.1, -CN, -SOn4R4A, -SOv4NR4BR4C, -NHNR4BR4C, -ONR4BR4C, -NHC(O)NHNR4BR4C, -NHC(O)NR4BR4C, -N(O)m4, -NR4BR4C, -C(O)R4D, -C(O)OR4D, -C(O)NR4BR4C, -OR4A, -NR4BSO2R4A, -NR4BC(O)R4D, -NR4BC(O)OR4D, -NR4BOR4D, -OCX4.13, -OCHX4.12, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 헤테로알킬, 치환된 또는 비치환된 사이클로알킬, 치환된 또는 비치환된 헤테로사이클로알킬, 치환된 또는 비치환된 아릴, 또는 치환된 또는 비치환된 헤테로아릴이고; R5는 수소, 할로겐, -CX5.13, -CHX5.12, -CH2X5.1, -CN, -SOn5R5A, -SOv5NR5BR5C, -NHNR5BR5C, -ONR5BR5C, -NHC(O)NHNR5BR5C, -NHC(O)NR5BR5C, -N(O)m5, -NR5BR5C, -C(O)R5D, -C(O)OR5D, -C(O)NR5BR5C, -OR5A, -NR5BSO2R5A, -NR5BC(O)R5D, -NR5BC(O)OR5D, -NR5BOR5D, -OCX5.13, -OCHX5.12, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 헤테로알킬, 치환된 또는 비치환된 사이클로알킬, 치환된 또는 비치환된 헤테로사이클로알킬, 치환된 또는 비치환된 아릴, 또는 치환된 또는 비치환된 헤테로아릴이고; R1A,R1B, R1C, R1D, R2A,R2B, R2C, R2D, R3A,R3B, R3C, R3D, R4A,R4B, R4C, R4D, R5A,R5B, R5C 및 R5D는 독립적으로 수소, 할로겐, -CF3, -CCl3,-CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 헤테로알킬, 치환된 또는 비치환된 사이클로알킬, 치환된 또는 비치환된 헤테로사이클로알킬, 치환된 또는 비치환된 아릴, 또는 치환된 또는 비치환된 헤테로아릴이고; 동일한 질소 원자에 결합된 R1B, R1C, R2B, R2C, R3B, R3C,R4B, R4C, R5B 및 R5C 치환기는 임의적으로 연결되어 치환된 또는 비치환된 헤테로사이클로알킬, 또는 치환된 또는 비치환된 헤테로아릴을 형성할 수 있고; X1.1, X2.1, X3.1, X4.1 및 X5.1은 독립적으로 -Cl, -Br, -I 또는 -F이다.