Ether compounds for treatment of immune and inflammatory disorders 机翻标题: 暂无翻译,请尝试点击翻译按钮。

公开号/公开日
WO2017035411 A1 2017-03-02 [WO201735411] / 2017-03-02
申请号/申请日
2016WO-US48793 / 2016-08-25
发明人
WILES JASON ALLAN;PHADKE AVINASH S;DESHPANDE MILIND;AGARWAL ATUL;CHEN DAWEI;GADHACHANDA VENKAT RAO;HASHIMOTO AKIHIRO;PAIS GODWIN;WANG QIUPING;WANG XIANGZHU;GREENLEE WILLIAM;
申请人
ACHILLION;
主分类号
IPC分类号
A01N-043/00
摘要
(WO201735411) Compounds, methods of use, and processes for making inhibitors of complement Factor D are provided comprising Formula I, I" and I‴ or a pharmaceutically acceptable salt or composition thereof.  The inhibitors described herein target Factor D and inhibit or regulate the complement cascade.  The inhibitors of Factor D described herein reduces the excessive activation of complement.
机翻摘要
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地址
代理人
代理机构
;
优先权号
2015US-62210258 2015-08-26
主权利要求
(WO201735411) We claim: 1. A compound of Formula I: (I), or a pharmaceutically acceptable salt thereof, wherein A is selected from Al, Α and A2; B is selected from Bl, B l ', B2, B3, and B4; C is selected from CI, CI ', C2, and C3; L is selected from LI, LI ', and L2; L3 is selected from L4 and L5; at least one of A, B, C, L, or L3 is selected from A2, B3, C3, L2, or L5; Al is selected from:   Α is selected from the moieties in Fig. 6; A2 is selected from:  232  233  234  Bl is selected from a monocyclic or bicyclic carbocyclic; a monocyclic or bicyclic carbocyclic-oxy group; a monocyclic, bicyclic, or tricyclic heterocyclic group having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and from 4 to 7 ring atoms per ring; C2- C6alkenyl; C2-C6alkynyl; -(Co-C4alkyl)(aryl); -(Co-C4alkyl)(heteroaryl); or -(Co- C4alkyl)(biphenyl), each of which B l is unsubstituted or substituted with one or more substituents independently chosen from R33and R34, and 0 or 1 substituents chosen from R35and R36; Β is selected from a moiety in Fig. 11A, 11B, 11C and 11D; B2 is selected from a moiety of Fig. 12; B3 is selected from: (i) a monocyclic or bicyclic carbocyclic; a monocyclic or bicyclic carbocyclic-oxy group; a monocyclic, bicyclic, or tricyclic heterocyclic group having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and from 4 to 7 ring atoms per ring; C2-C6alkenyl; C2-C6alkynyl; -(Co-C4alkyl)(aryl); -(Co- C4alkyl)(heteroaryl); or -(Co-C4alkyl)(biphenyl); each of which B3 is substituted with one or more of the following: S(0)= R21, SFs, and JC(R9)= R21; (ii) a monocyclic, bicyclic, or tricyclic heterocyclic group that has at least one boron or silicon atom in the ring or a monocyclic, bicyclic, or tricyclic heteroaryl group that has at least one boron in the ring; (iii) a 6-membered aryl group fused to a 5-membered saturated cyclic group that optionally contains 1 or 2 heteroatoms independently chosen from N and S wherein one of the CH2groups of the 5-membered cyclic group is optionally substituted by oxo, excluding dihydrobenzofuran; (iv) (optionally substituted alkyl)-(optionally substituted cycloalkyl), (optionally substituted alkenyl)-(optionally substituted cycloalkyl), or (optionally substituted alkynyl)-(optionally substituted cycloalkyl); wherein B3 can be further substituted one or more times with the substituents independently selected from R35, R36and R48; B4 is selected from the following: (i) a 4-membered carbocyclic fused to a 5- or 6- membered heteroaryl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S; wherein the 4-5 or 4-6 ring system can be optionally substituted; (ii) a 4-membered carbocyclic fused to a 6-membered aryl ring wherein the 4- 6 ring system can be optionally substituted; (iii) a monocyclic or bicyclic carbocyclic; a monocyclic or bicyclic carbocyclic- oxy group; a monocyclic, bicyclic, or tricyclic heterocyclic group having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and from 4 to 7 ring atoms per ring; C2-C6alkenyl; C2-C6alkynyl; -(Co-C4alkyl)(aryl); -(Co-C4alkyl)(heteroaryl); or -(Co-C4alkyl)(biphenyl); each of which B3 is substituted one or more times with S(0)2OR21; (iv) (cycloalkyl)-(optionally substituted aryl), (cycloalkyl)-(optionally substituted heteroaryl), (cycloalkyl)-(optionally substituted heterocyclic), (alkyl)-alkenyl), cycloalkyl-alkenyl; (v) alkyl, (alkyl)-(alkenyl), alkyl(alkynyl), cycloalkyl-alkenyl each of which can be optionally substituted; (vi) (optionally substituted alkyl)-(optionally substituted cycloalkyl), (alkenyl)- (optionally substituted cycloalkyl), (alkynyl)-(optionally substituted cycloalkyl), (optionally substituted cycloalkyl)-(optionally substituted cycloalkyl); wherein B4 can be substituted 1, 2, 3 or 4 times or more with the substituents independently selected from R33, R34, R35R36and R48;  CI ' is selected from a moiety in Fig 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 21, 2J, 2L and 2M; C2 is selected from:  wherein q is 0, 1, 2 or 3 and r is 1, 2 or 3; C3 is selected from:  LI is a bond or is chosen from the formulas  LI ' is selected from a moiety of Figure 8, wherein a methyl group can optionally be replaced with another alkyl group; L2 is selected from:  or an optionally substituted monocyclic or bicyclic carbocyclic; an optionally substituted monocyclic or bicyclic carbocyclic-oxy group; an optionally substituted monocyclic or bicyclic heterocyclic group having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and from 4 to 7 ring atoms per ring, an optionally substituted -(Co-C4alkyl)(aryl); an optionally substituted -(Co-C4alkyl)(5-membered heteroaryl) selected from pyrrole, furan, thiophene, pyrazole, oxazole, isoxazole, thiazole and isothiazole or a substituted imidazole; an optionally substituted -(Co-C4alkyl)(6-membered heteroaryl); an optionally substituted -(Co-C4alkyl)(8- membered heteroaryl); an optionally substituted -(Co-C4alkyl)(9-membered heteroaryl) selected from isoindole, indazole, purine, indolizine, benzothiophene, benzothiazole, benzoxazole, benzofuran, and furopyridine; and -(Co-C4alkyl)(10-membered heteroaryl); q is 1, 2 or 3; L3 is selected from L4 or L5; L4 is -C(O)-; L5 is -C(S)-, -P(0)OH-, -S(O)-, -S(0)2- or -C(R52)2-; Q1is N(R*) or C^R1'); Q2IS C(R2R2'), C(R2R2')-C(R2R2'), S, 0, N(R2) or C(R2R2')0; Q3is N(R3), S, or C(R3R3'); Q4is N or CH; Q5is N(R47) or C(R46R46'); Q5a is C(R47R47), N(R47), 0, S, SO, or S02; Q6is N(R47), C(R46R46'), S, or 0; Q7is C(R46R46'), S or N(R47); Q8, Q9, Q10, Q11and Q12are each independently C(R2R2'), S, SO, SO2, O, N(R2), B(R50), Si(R49)2, however if X1is N and X2is CH then L and B taken together cannot be anisole substituted in the 4 position; XIand X2are independently N, CH, or CZ, or X1and X2together are C=C; Z is F, CI, H2, CH3, CH2D, CHD2, or CD3; X3is QR!R1'); X4is N or CH; X4ais N, CH or CZ; X5and X6are C^R1') or X4and X5or X5and X6together are C=C; X5ais C(RlRv) or O;  X8is C(R¾r) or N(R43); XIIis N or CR11; X12is N or CR12; X13is N or CR13; X14is N or CR14, and wherein no more than 2 of X11, X12, X13, and X14are N; X15is H, 0, or S; χ16 is CR12; X17is N or CR13; X18is CR12; X19is N or CR13; X20 is NH or 0; X21 is N or CR14; X22 is N or CR13; X23 is CR12; X24 is 0 or S; X26 is N or CR41; X27 is CR12, NH or 0; X28is N or CH; X29 can be 0 or S; X30 is N or CR5; X31is N, C(R54)2or CR54; X32 is NH, C(R54)2or CR54; X33is -CO- or -SO- or -SC - X34is CHR13, NH, 0, or S; s is 1 or 2; R and R' are independently chosen from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl wherein each group can be optionally substituted; R1, R1, R2, R2, R3, and R3are independently chosen at each occurrence from hydrogen, halogen, hydroxyl, nitro, cyano, amino, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, C2-C6alkynyl, C2-C6alkanoyl, Ci-C6thioalkyl, hydroxyCi-Cealkyl, aminoCi-Cealkyl, -Co- C4alkylNR9R10, -C(0)OR9, -OC(0)R9, -NR9C(0)R10, -C(0)NR9R10, -OC(0)NR9R10, - NR9C(0)OR10, Ci-C2haloalkyl, and Ci-C2haloalkoxy; or R1and R2are linked to form a 3- to 6-membered carbocyclic or aryl ring; or R2and R3are linked to form a 3- to 6-membered carbocyclic ring; or R1and R1, or R2and R2, or R3and R3are linked to form a 3 - to 6-membered carbocyclic spiro ring; or R1and R1', R2and R2or R3and R3are linked to form a 3- to 6-membered heterocyclic spiro ring; each of which ring is unsubstituted or substituted with 1 or more substituents independently chosen from halogen, hydroxyl, cyano, -COOH, Ci-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, Ci- C4alkoxy, C2-C4alkanoyl, hydroxyCi-C4alkyl, (mono- and di-Ci-C4alkylamino)Co- C4alkyl, -Co-C4alkyl(C3-C7cycloalkyl), -0-Co-C4alkyl(C3-C7cycloalkyl), Ci-C2haloalkyl, and Ci-C2haloalkoxy; or R1and R1or R2and R2are linked to form a carbonyl group; or R1and R2or R2and R3can be taken together to form a carbon-carbon double bond; R4, R5, and R6are selected from hydrogen, -JCHO, -JC(0) H2, -JC2-C6alkanoyl, - JC(0) H(CH3), -J-COOH, -JP(0)(OR9)2, -JOC(0)R9, -JC(0)OR9, -JC(0)N(CH2CH2R9)(R10), - J R9C(0)R10, -JSO2 H2, -JS(0) H2, -JC(CH2)2F, -JCH(CF3) H2, -JC(0)Co-C2alkyl(C3- C7cycloalkyl), -JNR9(C2-C6alkanoyl), -JNR9C(0) R9R10, -JS02(Ci-C6alkyl), -JS02(Ci- Cehaloalkyl), -JS02R7R7, -J-nitro, -J-halogen, -J-hydroxyl, -J-phenyl, a 5- to 6-membered heteroaryl, -J-cyano, -J-cyanoimino, -J-amino, -J-imino, -Ci-C6alkyl, -Co- -C7heterocycloalkyl), -Co-C4alkyl(C3-C7cycloalkyl),  each of which R4, R5and R6other than hydrogen, nitro, halogen, cyano, cyanoimino, or -CHO, is unsubstituted or substituted with one or more of amino, imino, halogen, hydroxyl, cyano, cyanoimino, Ci-C2alkyl, Ci-C2alkoxy, -Co-C2alkyl(mono- and di-Ci-C4alkylamino), Ci- C2haloalkyl, and Ci-C2haloalkoxy; R6is hydrogen, halogen, hydroxyl, Ci-C4alkyl, -Co-C4alkyl(C3-C7cycloalkyl), or Ci- C4alkoxy; or R6and R6may be taken together to form an oxo, vinyl, or imino group; R7is hydrogen, Ci-C6alkyl, or -Co-C4alkyl(C3-C7cycloalkyl); R8and R8are independently chosen from hydrogen, halogen, hydroxyl, Ci-C6alkyl, -Co- C4alkyl(C3-C7cycloalkyl), Ci-C6alkoxy, and (Ci-C4alkylamino)Co-C2alkyl; or R8and R8are taken together to form an oxo group; or R8and R8can be taken together with the carbon that they are bonded to form a 3-membered carbocyclic ring; R9and R10are independently chosen at each occurrence from hydrogen, Ci-C6alkyl, (C3- C7cycloalkyl)Co-C4alkyl, -Co-C4alkyl(C3-C7cycloalkyl), and -0-Co-C4alkyl(C3-C7cycloalkyl); R11, R14, and R15are independently chosen at each occurrence from hydrogen, halogen, hydroxyl, nitro, cyano, -0(PO)(OR9)2, -(PO)(OR9)2, Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, C2- C6alkenyl(aryl), C2-C6alkenyl(cycloalkyl), C2-C6alkenyl(heterocycle), C2-C6alkenyl(heteroaryl), C2-C6alkynyl, C2-C6alkynyl(aryl), C2-C6alkynyl(cycloalkyl), C2-C6alkynyl(heterocycle), C2- C6alkynyl(heteroaryl), C2-C6alkanoyl, Ci-C6alkoxy, Ci-C6thioalkyl, -Co-C4alkyl(mono- and di-C- i-C6alkylamino), -Co-C4alkyl(C3-C7cycloalkyl), -Co-C4alkoxy(C3-C7cycloalkyl), Ci-C2haloalkyl, and Ci-C2haloalkoxy; one of R12and R13is chosen from R31and the other of R12and R13is chosen from R32or both R12and R13are each independently selected from an R32moiety; R16is absent or selected from halogen, hydroxyl, nitro, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, Ci-C6alkoxy, -Co-C4alkyl(mono- and di-Ci-C6alkylamino), -Co-C4alkyl(C3- C7cycloalkyl), Ci-C2haloalkyl, and Ci-C2haloalkoxy; R17is hydrogen, Ci-C6alkyl, or -Co-C4alkyl(C3-C7cycloalkyl); R18and R18are independently selected from hydrogen, halogen, hydroxymethyl, and methyl; and m is 0, 1, 2, or 3; R19is hydrogen, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, -S02Ci-C6alkyl, (mono- and di- Ci-C6alkylamino)Ci-C4alkyl, -Co-C4alkyl(C3-C7cycloalkyl), -Co-C4alkyl(C3-C7heterocycloalkyl), -Co-C4alkyl(aryl), Co-C4alkyl(heteroaryl), and wherein R19other than hydrogen is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, - COOH, and -C(0)OCi-C4alkyl; R21and R22are independently chosen at each occurrence from hydrogen, hydroxyl, cyano, amino, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6alkoxy, (C3-C7cycloalkyl)Co-C4alkyl, (phenyl)Co- C4alkyl, -Ci-C4alkylOC(0)OCi-C6alkyl, -Ci-C4alkylOC(0)Ci-C6alkyl, -Ci-C4alkylC(0)OCi- C6alkyl, (4- to 7-membered heterocycloalkyl)Co-C4alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S, and (5- or 6- membered unsaturated or aromatic heterocycle)Co-C4alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S, and each R21and R22can be optionally substituted; R is independently chosen at each occurrence from Ci-C6alkyl, Ci-C6haloalkyl, (aiyl)Co- C4alkyl, (C3-C7cycloalkyl)Co-C4alkyl, (phenyl)Co-C4alkyl, (4- to 7-membered heterocycloalkyl)Co-C4alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S, and (5- or 6- membered unsaturated or aromatic heterocycle)Co-C4alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S, and each R23can be optionally substituted; R24and R25are taken together with the nitrogen to which they are attached to form a 4- to 7-membered monocyclic heterocycloalkyl group, or a 6- to 10- membered bicyclic heterocyclic group having fused, spiro, or bridged rings, and each R24and R25can be optionally substituted; R31is chosen from hydrogen, halogen, hydroxyl, nitro, cyano, amino, -COOH, Ci- C2haloalkyl, Ci-C2haloalkoxy, Ci-C6alkyl, -Co-C4alkyl(C3-C7cycloalkyl), C2-C6alkenyl, C2- Cealkanoyl, Ci-Cealkoxy, C2-C6alkenyloxy, -C(0)OR9, Ci-Cethioalkyl, -Co-C4alkyl R9R10, - C(0) R9R10, -SO2R9, -S02R9R10, -OC(0)R9, and -C( R9) R9R10each of which R31other than hydrogen, halogen, hydroxyl, nitro, cyano, Ci-C2haloalkyl, and Ci-C2haloalkoxy is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, -COOH, -CO H2 Ci-C2haloalkyl, and Ci-C2haloalkoxy, and each of which R31is also optionally substituted with one substituent chosen from phenyl and 4- to 7-membered heterocycle containing 1, 2, or 3 heteroatoms independently chosen from N, O, and S; which phenyl or 4- to 7-membered heterocycle is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, Ci-C6alkoxy, (mono- and di-Ci-C6alkylamino)Co-C4alkyl, Ci-C6alkylester, -Co- C4alkyl)(C3-C7cycloalkyl), Ci-C2haloalkyl, and Ci-C2haloalkoxy; R32is chosen from -0(CH2)i-4R23a, -OC2-C4alkenylR23a, -OC2-C4alkynylR23, -0(CH2)i-4paracyclophane, -0(CH2)i-4P(0)R23bR23b, -0(CH2)i-4S(0) R21R22, -0(CH2)i-4S(0) R24R25, - 0(CH2)i-4S02 R21R22, -0(CH2)i-4S02 R24R25, -0(C3-C7cycloalkyl), -O(aiyl), -O(heteroaiyl), and -O(heterocycle) and each group can be optionally substituted; R23ais selected from (C3-C7cycloalkyl), and each R23acan be optionally substituted. R23bis selected from hydroxyl, Ci-C6alkoxy,Ci-C6alkyl, (C3-C7cycloalkyl)Co-C4alkyl, (phenyl)Co-C4alkyl, -0(CH2)2-40(CH2)8-i8, -OC(R23c)2OC(0)OR23d, -OC(R23c)2OC(0)R23d, an N-linked amino acid or an N-linked amino acid ester, and each R23bcan be optionally substituted. Rcis independently selected from hydrogen, Ci-Csalkyl, C2-C8alkenyl, C2-C8alkynyl, (aryl)Co-C4alkyl, (aryl)C2-C8alkenyl- or (aryl)C2-C8alkynyl; or two R23cgroups can be taken together with the carbon that they are bonded to form a 3-6 membered heterocycloalkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S, or a 3-6 membered carbocyclic ring, and each R23ccan be optionally substituted. R23dis independently selected from Ci-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, (aiyl)Co- C4alkyl, (aryl)C2-C8alkenyl or (aryl)C2-C8alkynyl, and each R23dcan be optionally substituted. R33is independently chosen from halogen, hydroxyl, -COOH, cyano, Ci-C6alkyl, C2- Cealkanoyl, Ci-Cealkoxy, -Co-C4alkylNR9R10, -SO2R9, Ci-C2haloalkyl, and Ci-C2haloalkoxy; R34is independently chosen from nitro, C2-C6alkenyl, C2-C6alkynyl, Ci-C6thioalkyl, -JC3- Cvcycloalkyl, -B(OH)2, -JC(0) R9R23,-JOS02OR21, -C(0)(CH2)i-4S(0)R21, -0(CH2)i-4S(0) R21R22-JOP(0)(OR21)(OR22), -JP(0)(OR21)(OR22), -JOP(0)(OR21)R22, -JP(0)(OR21)R22, -JOP(0)R21R22, -JP(0)R21R22, -JSP(0)(OR21)(OR22), -JSP(0)(OR21)(R22), -JSP(0)(R21)(R22), -JNR9P(0)(NHR21)( HR22), -JNR9P(0)(OR21)( HR22), -J R9P(0)(OR21)(OR22), -JC(S)R21, -J R21S02R22, -JNR9S(O) R10R22, -J R9SO2R10R22, -JS02R9COR22, -JS02R9CO R21R22, -J R21S02R22, -JC(0) R21S02R22, -JC( H2)= R22, -JCH( H2) R9S(0)2R22, -JOC(0) R21R22, -J R21C(0)OR22, -J R21OC(0)R22, -(CH2)i-4C(0) R21R22, -JC(0)R24R25, -J R9C(0)R21, -JC(0)R21, -JNR9C(O) R10R22, -CCR21, -(CH2)i-4OC(0)R21, and -JC(0)OR23; each of which R34may be unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, amino, oxo, -B(OH)2, -Si(CH3)3, -COOH, -CO H2, -P(0)(OH)2, Ci-Cealkyl, -Co-C4alkyl(C3-C7cycloalkyl), Ci-C6alkoxy, -Co-C2alkyl(mono- and di-Ci-C4alkylamino), Ci-C6alkylester, Ci-C4alkylamino, Ci- C4hydroxylalkyl, Ci-C2haloalkyl, and Ci-C2haloalkoxy; R35is independently chosen from naphthyl, naphthyloxy, indanyl, (4- to 7-membered heterocycloalkyl)Co-C4alkyl containing 1 or 2 heteroatoms chosen from N, O, and S, and bicyclic heterocycle containing 1, 2, or 3 heteroatoms independently chosen from N, O, and S, and containing 4- to 7- ring atoms in each ring; each of which R35is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, Ci-C6alkoxy, (mono- and di-Ci-C6alkylamino)Co-C4alkyl, Ci- C6alkylester, -Co-C4alkyl(C3-C7cycloalkyl), -SO2R9, Ci-C2haloalkyl, and Ci-C2haloalkoxy; R is independently chosen from tetrazolyl, (phenyl)Co-C2alkyl, (phenyl)Ci-C2alkoxy, phenoxy, and 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently chosen from N, O, B, and S, each of which R36is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, Ci-C6alkyl, C2-C6alkenyl, C2- C6alkanoyl, Ci-C6alkoxy, (mono- and di-Ci-C6alkylamino)Co-C4alkyl, Ci-C6alkylester, -Co- C4alkyl(C3-C7cycloalkyl), -SO2R9, -OSi(CH3)2C(CH3)3, -Si(CH3)2C(CH3)3, Ci-C2haloalkyl, and Ci-C2haloalkoxy; R40is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl wherein each group can be optionally substituted; R41is hydrogen, Ci-Cealkyl, or -(Co-C2alkyl)(C3-C5cycloalkyl); R42is halo, hydroxy, Ci-C6alkoxy, Ci-C6haloalkoxy, -SH, or -S(Ci-C6alkyl); R43is hydrogen, acyl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl wherein each group can be optionally substituted; R44, R44, R45, R45are independently hydrogen, hydroxyl, amino, cyano, halogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; wherein each group can be optionally substituted; R46and R46are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl wherein each group can be optionally substituted and at least one of R46or R46is not hydrogen; R47is hydrogen, acyl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl wherein each group can be optionally substituted; R48is independently chosen from hydrogen, halogen, hydroxyl, nitro, cyano, amino, Ci- C6alkyl, Ci-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6thioalkyl, Ci-C6alkoxy, -JC3- Cvcycloalkyl, -B(OH)2, -JC(0) R9R23,-JOS02OR21, -C(0)(CH2)i-4S(0)R21, -0(CH2)i-4S(0) R21R22-JOP(0)(OR21)(OR22), -JP(0)(OR21)(OR22), -JOP(0)(OR21)R22, -JP(0)(OR21)R22, -JOP(0)R21R22, -JP(0)R21R22, -JSP(0)(OR21)(OR22), -JSP(0)(OR21)(R22), -JSP(0)(R21)(R22), - J R9P(0)( HR21)( HR22), -JNR9P(0)(OR21)( HR22), -J R9P(0)(OR21)(OR22), -JC(S)R21, - J R21S02R22, -J R9S(O) R10R22, -JNR9SO2R10R22, -JS02R9COR22, -JS02R9CO R21R22, -J R21S02R22, -JC(0) R21S02R22, -JC( H2)= R22, - JCH( H2) R9S(0)2R22, -JOC(0) R21R22, -J R21C(0)OR22, -J R21OC(0)R22, -(CH2)i-4C(0) R21R22, -JC(0)R24R25, -J R9C(0)R21, -JC(0)R21, -JNR9C(O) R10R22, -CCR21, -(CH2)i-4OC(0)R21, -JC(0)OR23; each of which R48may be unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, amino, oxo, -B(OH)2, -Si(CH3)3, -COOH, -CO H2, -P(0)(OH)2, Ci-Cealkyl, -Co- C4alkyl(C3-C7cycloalkyl), Ci-Cealkoxy, -Co-C4alkyl(mono- and di-Ci-C4alkyl R9R10), Ci- C6alkylester, Ci-C4alkylamino, Ci-C4hydroxylalkyl, Ci-C2haloalkyl, Ci-C2haloalkoxy, -OC(0)R9, - R9C(0)R10, -C(0) R9R10, -OC(0) R9R10, - R9C(0)OR10, Ci-C2haloalkyl, and Ci- C2haloalkoxy; R48ais R48, S(0)= R21, SFs, or JC(R9)= R21and S02OR21; R49is halo, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl wherein each group can be optionally substituted or two R49groups can be taken together to form a double bond that can be optionally substituted; R50is hydroxy or Ci-C6alkyoxy; R51is CH3, CH2F, CHF2or CF3; R52is independently selected from halo, hydrogen, or optionally substituted Cl-C6alkyl; R53is cyano, nitro, hydroxyl or Ci-C6alkoxy; R54is hydrogen, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, C2-C6alkynyl, C2- C6alkanoyl, Ci-C6thioalkyl, hydroxyCi-Cealkyl, aminoCi-Cealkyl, -Co-C4alkyl(C3-C7cycloalkyl), (phenyl)Co-C4alkyl-, (heterocycloalkyl)Co-C4alkyl and (heteroaryl)Co-C4alkyl- wherein the groups can be optionally substituted; J is independently chosen at each occurrence from a covalent bond, Ci-C4alkylene, -OCi- C4alkylene, C2-C4alkenylene, and C2-C4alkynylene. A compound of Formula I: (I), or a pharmaceutically acceptable salt thereof, wherein A is selected from Al, Α and A2; B is selected from Bl, Bl', B2, B3, and B4; C is selected from CI, CI', C2, C3, and C4; L is selected from LI, LI', L2, and L2'; L3 is selected from L4 and L5; at least one of A, B, C, L, or L3 is selected from A2, B3, C3, (L2 or L2') or L5, and either CisC4 orLisL2'; ' is selected from:   249  R is C1-C4 alkyl; R102is C1-C4 alkyl, Br, CI or F; and wherein Al, Al', A2, Bl, Bl', B2, B3, B4, CI, CI', C2, C3, LI, LI', L2, L4, andL5 are as defined 1. 3. A method for the treatment of a host with a disorder selected from fatty liver and conditions stemming from fatty liver, nonalcoholic steatohepatitis (NASH), liver inflammation, cirrhosis, liver failure; dermatomyocitis; amyotrophic lateral sclerosis; cytokine or inflammatory reactions in response to biotherapeutics, or an inflammatory reaction to CAR T-cell therapy, comprising administering an effective amount of a compound selected from claim 1 or claim 2. 4. A method for the treatment of a host with a disorder selected from paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulonephritis, rheumatoid arthritis, multiple sclerosis, age- related macular degeneration (AMD), retinal degeneration, an ophthalmic disease, a respiratory disease or a cardiovascular disease, comprising administering an effective amount of a compound selected from claim 1 or claim 2. 5. A compound selected from claim 1 or claim 2 for use to treat of a host with a disorder selected from fatty liver and conditions stemming from fatty liver, nonalcoholic steatohepatitis (NASH), liver inflammation, cirrhosis, liver failure; dermatomyocitis; amyotrophic lateral sclerosis; cytokine or inflammatory reactions in response to biotherapeutics, or an inflammatory reaction to CAR T-cell therapy. 6. A compound selected from claim 1 or claim 2 for use to treat a host with a disorder selected from paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulonephritis, rheumatoid arthritis, multiple sclerosis, age-related macular degeneration (AMD), retinal degeneration, an ophthalmic disease, a respiratory disease or a cardiovascular disease. 7. Use of a compound of claim 1 or claim 2 in the manufacture of a medicament to treat a host with a disorder selected from fatty liver and conditions stemming from fatty liver, nonalcoholic steatohepatitis (NASH), liver inflammation, cirrhosis, liver failure; dermatomyocitis; amyotrophic lateral sclerosis; cytokine or inflammatory reactions in response to biotherapeutics, or an inflammatory reaction to CAR T-cell therapy. 8. Use of a compound of claim 1 or claim 2 in the manufacture of a medicament to treat a host with a disorder selected from paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulonephritis, rheumatoid arthritis, multiple sclerosis, age-related macular degeneration (AMD), retinal degeneration, an ophthalmic disease, a respiratory disease or a cardiovascular disease. 9. A compound of claim 1 or claim 2 for use to treat of a host with a disorder selected from fatty liver and conditions stemming from fatty liver, nonalcoholic steatohepatitis (NASH), liver inflammation, cirrhosis, liver failure; dermatomyocitis; amyotrophic lateral sclerosis; cytokine or inflammatory reactions in response to biotherapeutics, or an inflammatory reaction to CAR T-cell therapy. 10. A compound of claim 1 or claim 2 for use to treat a host with a disorder selected from paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulonephritis, rheumatoid arthritis, multiple sclerosis, age-related macular degeneration (AMD), retinal degeneration, an ophthalmic disease, a respiratory disease or a cardiovascular disease. 11. The method of claim 3 or 4, wherein the disorder is NASH, and the host is a human. 12. The method of claim 3 or 4, wherein the disorder is fatty liver, and the host is a human. 13. The method of claim 3 or 4, wherein the disorder is cirrhosis, and the host is a human. 14. The method of claim 3 or 4, wherein the disorder is liver failure, and the host is a human. 15. The method of claim 3 or 4, wherein the disorder amyotrophic lateral sclerosis, and the host is a human. 16. The method of claim 3 or 4, wherein the disorder is cytokine or inflammatory reactions in response to a pharmaceutical or biotherapeutic, or an inflammatory reaction to CAR T- cell therapy, and the host is a human. 17. The compound of claim 5 or 6, wherein the disorder is NASH, and the host is a human. 18. The compound of claim 5 or 6, wherein the disorder is fatty liver, and the host is a human. 19. The compound of claim 5 or 6, wherein the disorder is cirrhosis, and the host is a human. 20. The compound of claim 5 or 6, wherein the disorder is liver failure, and the host is a human. 21. The compound of claim 5 or 6, wherein the disorder amyotrophic lateral sclerosis, and the host is a human. 22. The compound of claim 5 or 6, wherein the disorder is cytokine or inflammatory reactions in response to a pharmaceutical or biotherapeutic, or an inflammatory reaction to CAR T-cell therapy, and the host is a human. 23. The use of claim 7 or 8, wherein the disorder is NASH, and the host is a human. 24. The use of claim 7 or 8, wherein the disorder is fatty liver, and the host is a human. 25. The use of claim 7 or 8, wherein the disorder is cirrhosis, and the host is a human. 26. The compound of claim 7 or 8, wherein the disorder is liver failure, and the host is a human. 27. The compound of claim 7 or 8, wherein the disorder amyotrophic lateral sclerosis, and the host is a human. 28. The compound of claim 7 or 8, wherein the disorder is cytokine or inflammatory reactions in response to biotherapeutics, or an inflammatory reaction to CAR T-cell therapy, and the host is a human.
法律状态
(WO201735411) LEGAL DETAILS FOR WO2017035411  Actual or expected expiration date=2019-02-26    Legal state=ALIVE    Status=PENDING     Event publication date=2016-08-25  Event code=WO/APP  Event indicator=Pos  Event type=Examination events  Application details  Application country=WO WOUS2016048793  Application date=2016-08-25  Standardized application number=2016WO-US48793     Event publication date=2017-03-02  Event code=WO/A1  Event type=Examination events  Published application with search report  Publication country=WO  Publication number=WO2017035411  Publication stage Code=A1  Publication date=2017-03-02  Standardized publication number=WO201735411  LEGAL DETAILS FOR DESIGNATED STATE DE  Actual or expected expiration date=2018-02-27    Legal state=DEAD    Status=LAPSED   Corresponding cc:  Designated or member state=DE     Event publication date=2018-02-27  Event code=WO/NENP  Event type=Event indicating Not In Force  Non-entry into the national phase in: Corresponding cc:  Designated or member state=DE  LEGAL DETAILS FOR DESIGNATED STATE EP  Actual or expected expiration date=2036-08-25    Legal state=ALIVE    Status=PENDING   Corresponding cc:  Designated or member state=EP Corresponding appl: EP16840167    Event publication date=2017-04-19  Event code=WO/121  Event type=Designated states  EP: The EPO has been informed by wipo that ep was designated in this application Corresponding cc:  Designated or member state=EP
专利类型码
A1
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