Substituted indole ether compounds
阅读说明：本技术 取代的吲哚醚化合物 (Substituted indole ether compounds ) 是由 A·J·迪克曼 B·K·怀特利 D·S·多德 T·S·哈克 于 2018-12-14 设计创作，主要内容包括：公开式(I)化合物、其N-氧化物或盐,其中R<Sub>1</Sub>、G、A、R<Sub>5</Sub>和n为本申请所定义。还公开使用这种化合物作为通过Toll样受体7或8或9的信号传导抑制剂的方法,以及包含这种化合物的药物组合物。这些化合物可用于治疗炎性和自身免疫性疾病。<Image he="290" wi="520" file="DDA0002537397060000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(Disclosed are compounds of formula (I), N-oxides, or salts thereof, wherein R 1 、G、A、R 5 And n is as defined herein. Also disclosed are methods of using such compounds as inhibitors of signaling through Toll-like receptors 7 or 8 or 9, and pharmaceutical compositions comprising such compounds. These compounds are useful for the treatment of inflammatory and autoimmune diseases.)
1. A compound of formula (I)
An N-oxide or salt thereof, wherein:
g is:
(i)
(ii)
(iii)
(iv) a 9-membered heterocycle selected from:
or
(v) A 10-membered heterocycle selected from:
a is-L-R6；
L is a bond, - (CR)xRx)1-2-、-(CRxRx)1-2CRx(OH)-、-(CRxRx)1-2O-、-CRxRxC(O)-、-CRxRxC(O)NRx(CRxRx)0-4-、-CRxRxNRxC(O)(CRxRx)0-4-or-CRxRxNRxC(O)(CRxRx)0-4-；
R1Is H, Cl, -CN, C1-4Alkyl radical, C1-3Fluoroalkyl radical, C1-3Hydroxyalkyl radical, C1-3Hydroxy-fluoroalkyl, -CRv＝CH2、C3-6Cycloalkyl, -CH2(C3-6Cycloalkyl), -C (O) O (C)1-3Alkyl) or tetrahydropyranyl;
each R2Independently halogen, -CN, -OH, -NO2、C1-4Alkyl radical, C1-2Fluoroalkyl radical, C1-2Cyanoalkyl, C1-3Hydroxyalkyl radical, C1-3Aminoalkyl, -O (CH)2)1-2OH、-(CH2)0-4O(C1-4Alkyl group), C1-3Fluoroalkoxy, - (CH)2)1-4O(C1-3Alkyl), -O (CH)2)1-2OC(O)(C1-3Alkyl), -O (CH)2)1-2NRxRx、-C(O)O(C1-3Alkyl), - (CH)2)0-2C(O)NRyRy、-C(O)NRx(C1-5Hydroxyalkyl), -C (O) NRx(C2-6Alkoxyalkyl), -C (O) NRx(C3-6Cycloalkyl), -NR-yRy、-NRy(C1-3Fluoroalkyl group), -NRy(C1-4Hydroxyalkyl), -NR)xCH2(phenyl), -NRxS(O)2(C3-6Cycloalkyl), -NR-xC(O)(C1-3Alkyl), -NR-xCH2(C3-6Cycloalkyl), - (CH)2)0-2S(O)2(C1-3Alkyl), - (CH)2)0-2(C3-6Cycloalkyl), - (CH)2)0-2(phenyl), morpholinyl, dioxothiomorpholinyl, dimethylpyrazolyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl or-c (o) (thiazolyl);
R2ais C1-6Alkyl radical, C1-3Fluoroalkyl radical, C1-6Hydroxyalkyl radical, C1-3Aminoalkyl, - (CH)2)0-4O(C1-3Alkyl group), C3-6Cycloalkyl, - (CH)2)1-3C(O)NRxRx、-CH2(C3-6Cycloalkyl), -CH2(phenyl), tetrahydrofuranyl, tetrahydropyranyl or phenyl;
each R2bIndependently H, halogen, -CN, -NRxRx、C1-6Alkyl radical, C1-3Fluoroalkyl radical, C1-3Hydroxyalkyl radical, C1-3Fluoroalkoxy, - (CH)2)0-2O(C1-3Alkyl), - (CH)2)0-3C(O)NRxRx、-(CH2)1-3(C3-6Cycloalkyl), -C (O) O (C)1-3Alkyl), -C (O) NRx(C1-3Alkyl), -CRx＝CRxRxor-CRx＝CH(C3-6Cycloalkyl groups);
R2cis R2aOr R2b；
R2dIs R2aOr R2b(ii) a With the proviso that R2cAnd R2dOne is R2aAnd R is2cAnd R2dAnother of (A) is R2b；
Each R5Independently F, Cl, -CN, C1-3Alkyl radical, C1-2Fluoroalkyl or-OCH3；
R6Comprises the following steps:
(i)-NRxRx、-CRxRxC(O)NRx(CRxRx)1-3OH、-CRxRxC(O)NRx(CRxRx)1-2NRxRxor-CRxRxC(O)NRx(CRxRx)1-2CHFCRxRxOH; or
(ii) Azabicyclo [3.2.1]Octyl, azaspiro [5.5]]Undecyl, azetidinyl, C3-6Cycloalkyl, diazabicyclo [2.2.1]Heptyl, diazaspiro [3.5]Nonyl, imidazolyl, morpholinyl, tetrahydrofuryl, tetrahydropyranyl, octahydrocyclopenta [ c ]]Pyrrolyl, phenyl, piperazinyl, piperidinyl, pyrrolidinyl, pyridinyl or quinuclidinyl, each substituted with 0 to 3R6a；
Each R6aIndependently F, Cl, -OH, -CN, C1-6Alkyl radical, C1-4Fluoroalkyl radical, C1-6Hydroxyalkyl, - (CH)2)1-2O(C1-3Alkyl), -NR-xRx、-(CH2)1-2NRxRx、-(CRxRx)1-2S(O)2(C1-3Alkyl), - (CR)xRx)1-2C(O)ORy、-(CRxRx)1-2C(O)NRxRx、-C(O)(CRxRx)1-2NRxRx、-(CRxRx)1-2(phenyl), oxetanyl, morpholinyl, tetrahydrofuryl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, isopropylpiperidinyl, isobutylpiperidinyl, piperazinyl, or-O (piperidinyl);
Rvis H, C1-2Alkyl or C1-2A fluoroalkyl group;
each RxIndependently is H or-CH3；
Each RyIndependently is H or C1-6An alkyl group;
n is 0, 1 or 2; and
p is 0, 1,2, 3 or 4.
2. A compound, N-oxide or salt thereof according to claim 1, wherein:
l is a bond, - (CR)xRx)1-2-、-CH2C(O)-、-CH2C(O)NRx(CRxRx)0-2-、-CH2NRxC (O) -or-CH2NRxC(O)CH2-；
R1Is H, Cl, -CN, C1-4Alkyl radical, C1-2Fluoroalkyl radical, C1-2Hydroxyalkyl or-C (O) O (C)1-2Alkyl groups);
each R2Independently F, Cl, -CN, -OH, C1-4Alkyl radical, C1-2Fluoroalkyl radical, C1-2Cyanoalkyl, C1-3Hydroxyalkyl radical, C1-3Aminoalkyl, - (CH)2)0-2O(C1-4Alkyl), -NR-yRy、-(CH2)0-2C(O)NRyRy、-C(O)NRx(C1-4Hydroxyalkyl), -C (O) NRx(C2-4Alkoxyalkyl), -C (O) NRx(C3-6Cycloalkyl), - (CH)2)0-2S(O)2(C1-3Alkyl), - (CH)2)0-1(C3-6Cycloalkyl), morpholinyl, - (CH)2)0-1(phenyl) or dimethylpyrazolyl;
R2ais C1-4Alkyl radical, C1-2Fluoroalkyl radical, C1-4Hydroxyalkyl, - (CH)2)1-3OCH3、C3-6Cycloalkyl, -CH2C(O)NRxRx、-CH2(C3-6Cycloalkyl), -CH2(phenyl), tetrahydrofuranyl or phenyl;
each R2bIndependently H, F, Cl, -CN, -NRxRx、C1-6Alkyl radical, C1-2Fluoroalkyl radical, C1-3Hydroxyalkyl, - (CH)2)0-2O(C1-2Alkyl), - (CH)2)0-2C(O)NRxRx、-(CH2)1-3(cyclopropyl), -C (O) O (C)1-2Alkyl), -C (O) NRx(C1-3Alkyl), -CRx＝CH2or-CH ═ CH (C)3-6Cycloalkyl groups);
each R5Independently F, Cl, -CN, C1-2Alkyl or-OCH3；
R6Comprises the following steps:
(i)-NRxRx、-CH2C(O)NHCH2CRxRxOH、-CH2C(O)NHCH2CH2CRxRxOH、-CH2C(O)NHCH2CH2NRxRxor-CH2C(O)NHCH2CHFCRxRxOH; or
(ii) Azabicyclo [3.2.1]Octyl, azaspiro [5.5]]Undecyl, azetidinyl, C3-6Cycloalkyl, diazabicyclo [2.2.1]Heptyl, diazaspiro [3.5]Nonyl, imidazolyl, morpholinyl, tetrahydrofuryl, tetrahydropyranyl, octahydrocyclopenta [ c ]]Pyrrolyl, phenyl, piperazinyl, piperidinyl, pyrrolidinyl, pyridinyl or quinuclidinyl, each substituted with 0 to 3R6a；
Each R6aIndependently F, -OH, C1-4Alkyl radical, C1-4Fluoroalkyl radical, C1-4Hydroxyalkyl, - (CH)2)1-2OCH3、-NRxRx、-(CH2)1-2NRxRx、-(CH2)1-2S(O)2(C1-2Alkyl), - (CR)xRx)1-2C(O)ORx、-(CH2)1-2C(O)NRxRx、-C(O)CH2NRxRx、-CRxRx(phenyl), oxetanyl, morpholinyl, tetrahydrofuryl, tetrahydropyranyl, piperidinyl, isopropylpiperidinyl, isobutylpiperidinyl, piperazinyl or-O (piperidinyl);
and p is 0, 1,2 or 3.
3. A compound, N-oxide or salt thereof according to claim 1, wherein:
g is:
(i)
(ii)
(iii)or
(iv) A 9-membered heterocycle selected from:
l is a bond, -CH2-、-CH2CH2-、-CH2C(O)-、-CH2C(O)NH-、-CH2C(O)N(CH3)-、-CH2C(O)NHCH2-or-CH2C(O)NHCH2CH2-；
R1is-CH2CH3or-CH (CH)3)2；
Each R2Independently is-CH3or-OCH3；
R2ais-CH3；
Each R2bIndependently H, Cl or-CH3；
R6Comprises the following steps:
(i)-NH(CH3)、-N(CH3)2、-CH2C(O)NHCH2C(CH3)2OH、-CH2C(O)NHCH2CH2C(CH3)2OH、-CH2C(O)NHCH2CH2NH2or-CH2C(O)NHCH2CHFC(CH3)2OH; or
(ii) Azabicyclo [3.2.1]Octyl, azaspiro [5.5]]Undecyl, azetidinyl, cyclohexyl, diazabicyclo [2.2.1]Heptyl, diazaspiro [3.5]Nonyl, imidazolyl, morpholinyl, octahydrocyclopenta [ c]Pyrrolyl, phenyl, piperazinyl, piperidinyl, pyrrolidinyl, pyridinyl or quinuclidinyl, each substituted with 0 to 2R6a；
Each R6aIndependently F, -OH, -CH3、-CH2CH2CH3、-C(CH3)2、-CH2CH(CH3)2、-CH2CH2CF3、-CH2CH2CH2CF3、-CH2CH2OH、-CH2CH2CH2OH、-CH2CH(CH3)OH、-CH2C(CH3)2OH、-CH2CH2OCH3、-NH2、-N(CH3)2、-CH2NH2、-CH2CH2NH2、-CH2CH2S(O)2CH3、-CH2C(O)OH、-CH2C(O)N(CH3)2、-C(O)CH2N(CH3)2、-CH2(phenyl), morpholinyl, oxetanyl, tetrahydropyranyl, piperidinyl, isopropylpiperidinyl, isobutylpiperidinyl or-O (piperidinyl);
n is 0; and
p is 0.
4. The compound, N-oxide or salt thereof according to claim 1, wherein G is:
(i)
(ii)or
(iii)
5. The compound according to claim 1, or a salt thereof, wherein G is the 9-membered heterocyclic ring.
6. The compound according to claim 1, or a salt thereof, wherein G is the 10-membered heterocyclic ring.
7. A compound, N-oxide or salt thereof according to claim 1, wherein R6Is azetidinyl, cyclohexyl, imidazolyl, morpholinyl, phenyl, piperazinyl, piperidinyl, pyrrolidinyl, pyridinyl or quinuclidinyl, each substituted with 0 to 2R6a。
8. A compound, N-oxide or salt thereof according to claim 1 wherein the compound is selected from 2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-5- (piperidin-4-yloxy) -1H-indole (1); 6- (3-isopropyl-5- (2- (pyrrolidin-1-yl) ethoxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (2); 6- (5- (2- (4, 4-difluoropiperidin-1-yl) ethoxy) -3-isopropyl-1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (3); 6- (5- (2- (3-fluoropiperidin-1-yl) ethoxy) -3-isopropyl-1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (4); 4- (2- ((3-isopropyl-2- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -1H-indol-5-yl) oxy) ethyl) morpholine (5); 2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-5- (piperidin-4-ylmethoxy) -1H-indole (6); 5- (3-isopropyl-5- (piperidin-4-ylmethoxy) -1H-indol-2-yl) -1, 3-dimethylpyridin-2 (1H) -one (7); (S) -5- (3-isopropyl-5- (piperidin-3-yloxy) -1H-indol-2-yl) -1, 3-dimethylpyridin-2 (1H) -one (8); (S) -6- (3-isopropyl-5- (piperidin-3-yloxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (9); 6- (3-isopropyl-5- (piperidin-4-yloxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (10); 5- (3-isopropyl-5- (piperidin-4-yloxy) -1H-indol-2-yl) -1, 3-dimethylpyridin-2 (1H) -one (11); 6- (3-isopropyl-5- (piperidin-4-ylmethoxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (12); 3-chloro-5- (3-isopropyl-5- (piperidin-4-yloxy) -1H-indol-2-yl) -1, 4-dimethylpyridin-2 (1H) -one (13); 5- (3-isopropyl-5- (piperidin-4-yloxy) -1H-indol-2-yl) -1,3, 4-trimethylpyridin-2 (1H) -one (14); 5- (3-isopropyl-5- (piperidin-4-ylmethoxy) -1H-indol-2-yl) -1,3, 4-trimethylpyridin-2 (1H) -one (15); 6- (3-isopropyl-5- (piperidin-4-ylmethoxy) -1H-indol-2-yl) -7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridine (16); 6- (3-isopropyl-5- (piperidin-4-yloxy) -1H-indol-2-yl) -7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridine (17); 6- (5- (azetidin-3-ylmethoxy) -3-isopropyl-1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (18); 6- (5- (azetidin-3-ylmethoxy) -3-isopropyl-1H-indol-2-yl) -7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridine (19); 6- (3-isopropyl-5- (piperidin-4-yloxy) -1H-indol-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridine (20); 1- (4- ((2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-1H-indol-5-yl) oxy) piperidin-1-yl) -2-methylpropan-2-ol (21); 1- (4- ((3-isopropyl-2- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -1H-indol-5-yl) oxy) piperidin-1-yl) -2-methylpropan-2-ol (22); 1- (3- (((2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-1H-indol-5-yl) oxy) methyl) piperidin-1-yl) -2-methylpropan-2-ol (23); 1- (4- (((2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-1H-indol-5-yl) oxy) methyl) piperidin-1-yl) -2-methylpropan-2-ol (24); 5- (5- ((1- (2-hydroxy-2-methylpropyl) piperidin-4-yl) methoxy) -3-isopropyl-1H-indol-2-yl) -1, 3-dimethylpyridin-2 (1H) -one (25); 1- (3- (((3-isopropyl-2- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -1H-indol-5-yl) oxy) methyl) azetidin-1-yl) -2-methylpropan-2-ol (26); 1- (4- (((3-isopropyl-2- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -1H-indol-5-yl) oxy) methyl) piperidin-1-yl) -2-methylpropan-2-ol (27); 1- (3- (((2- (7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) oxy) methyl) azetidin-1-yl) -2-methylpropan-2-ol (28); 2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-5- ((1-methylpiperidin-4-yl) oxy) -1H-indole (29); 2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-5- ((1-methylpiperidin-3-yl) methoxy) -1H-indole (30); 2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-5- ((1-isopropylpiperidin-4-yl) oxy) -1H-indole (31); 6- (3-isopropyl-5- ((1-methylpiperidin-4-yl) oxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (32); 2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-5- ((1-methylpiperidin-4-yl) methoxy) -1H-indole (33); 5- (3-isopropyl-5- ((1-methylpiperidin-4-yl) methoxy) -1H-indol-2-yl) -1, 3-dimethylpyridin-2 (1H) -one (34); 2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-5- ((1-isopropylpiperidin-4-yl) methoxy) -1H-indole (35); 5- (3-isopropyl-5- ((1-isopropylpiperidin-4-yl) methoxy) -1H-indol-2-yl) -1, 3-dimethylpyridin-2 (1H) -one (36); (S) -5- (3-isopropyl-5- ((1-methylpiperidin-3-yl) oxy) -1H-indol-2-yl) -1, 3-dimethylpyridin-2 (1H) -one (37); (S) -6- (3-isopropyl-5- ((1-methylpiperidin-3-yl) oxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (38); 5- (3-isopropyl-5- ((1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) oxy) -1H-indol-2-yl) -1, 3-dimethylpyridin-2 (1H) -one (39); (S) -5- (3-isopropyl-5- ((1- (tetrahydro-2H-pyran-4-yl) piperidin-3-yl) oxy) -1H-indol-2-yl) -1, 3-dimethylpyridin-2 (1H) -one (40); 6- (3-isopropyl-5- ((1-methylpiperidin-4-yl) methoxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (41); 6- (3-isopropyl-5- ((1-isopropylpiperidin-4-yl) methoxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (42); 6- (3-isopropyl-5- ((1- (oxetan-3-yl) piperidin-4-yl) methoxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (43); 6- (3-isopropyl-5- ((1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) methoxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (44); 5- (3-isopropyl-5- ((1-isopropylpiperidin-4-yl) oxy) -1H-indol-2-yl) -1,3, 4-trimethylpyridin-2 (1H) -one (45); 3-chloro-5- (3-isopropyl-5- ((1-methylpiperidin-4-yl) oxy) -1H-indol-2-yl) -1, 4-dimethylpyridin-2 (1H) -one (46); 6- (3-isopropyl-5- ((1-isopropylpiperidin-4-yl) oxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (47); 5- (3-isopropyl-5- ((1-isopropylpiperidin-4-yl) oxy) -1H-indol-2-yl) -1,3, 4-trimethylpyridin-2 (1H) -one (48); 5- (3-isopropyl-5- ((1-isopropylpiperidin-4-yl) methoxy) -1H-indol-2-yl) -1,3, 4-trimethylpyridin-2 (1H) -one (49); 5- (3-isopropyl-5- ((1- (oxetan-3-yl) piperidin-4-yl) oxy) -1H-indol-2-yl) -1,3, 4-trimethylpyridin-2 (1H) -one (50); 5- (3-isopropyl-5- ((1- (oxetan-3-yl) piperidin-4-yl) methoxy) -1H-indol-2-yl) -1,3, 4-trimethylpyridin-2 (1H) -one (51); 6- (3-isopropyl-5- ((1- (oxetan-3-yl) piperidin-4-yl) methoxy) -1H-indol-2-yl) -7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridine (52); 6- (3-isopropyl-5- ((1-methylpiperidin-4-yl) oxy) -1H-indol-2-yl) -7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridine (53); 6- (3-isopropyl-5- ((1-methylpiperidin-4-yl) methoxy) -1H-indol-2-yl) -7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridine (54); 6- (3-isopropyl-5- ((1-isopropylpiperidin-4-yl) methoxy) -1H-indol-2-yl) -7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridine (55); 6- (3-isopropyl-5- ((1- (oxetan-3-yl) piperidin-4-yl) oxy) -1H-indol-2-yl) -7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridine (56); 6- (3-isopropyl-5- ((1-isopropylpiperidin-4-yl) oxy) -1H-indol-2-yl) -7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridine (57); 6- (3-isopropyl-5- ((1-isopropylazetidin-3-yl) methoxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (58); 6- (3-isopropyl-5- ((1-methylazetidin-3-yl) methoxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (59); 6- (3-isopropyl-5- ((1- (oxetan-3-yl) azetidin-3-yl) methoxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (60); 6- (3-isopropyl-5- ((1-methylazetidin-3-yl) methoxy) -1H-indol-2-yl) -7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridine (61); 6- (3-isopropyl-5- ((1-propylpiperidin-4-yl) methoxy) -1H-indol-2-yl) -7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridine (62); 6- (3-isopropyl-5- ((1-propylpiperidin-4-yl) oxy) -1H-indol-2-yl) -7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridine (63); 4- ((3-isopropyl-2- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -1H-indol-5-yl) oxy) -N, N-dimethylcyclohex-1-amine (64); 6- (3-isopropyl-5- ((1-methylpiperidin-4-yl) oxy) -1H-indol-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridine (65); 6- (3-isopropyl-5- ((1-isopropylpiperidin-4-yl) oxy) -1H-indol-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridine (66); 6- (3-isopropyl-5- ((1-propylpiperidin-4-yl) oxy) -1H-indol-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridine (67); 6- (3-isopropyl-5- ((1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) oxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (68); 1- (4- ((2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-1H-indol-5-yl) oxy) piperidin-1-yl) propan-2-ol (69); 2- (4- ((2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-1H-indol-5-yl) oxy) piperidin-1-yl) ethan-1-ol (70); 2- (4- (((2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-1H-indol-5-yl) oxy) methyl) piperidin-1-yl) ethan-1-ol (71); 3- (4- ((2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-1H-indol-5-yl) oxy) piperidin-1-yl) propan-1-ol (72); 2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-5- ((1- (2-methoxyethyl) piperidin-4-yl) methoxy) -1H-indole (73); 5- (3-isopropyl-5- ((1- (2-methoxyethyl) piperidin-4-yl) methoxy) -1H-indol-2-yl) -1, 3-dimethylpyridin-2 (1H) -one (74); 2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-5- ((1- (2-methoxyethyl) piperidin-4-yl) oxy) -1H-indole (75); 5- (5- ((1-isobutylpiperidin-4-yl) oxy) -3-isopropyl-1H-indol-2-yl) -1, 3-dimethylpyridin-2 (1H) -one (76); 6- (5- ((1-isobutylpiperidin-4-yl) oxy) -3-isopropyl-1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (77); 5- (3-isopropyl-5- ((1- (4,4, 4-trifluorobutyl) piperidin-4-yl) oxy) -1H-indol-2-yl) -1, 3-dimethylpyridin-2 (1H) -one (78); 2- (4- ((2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-1H-indol-5-yl) oxy) piperidin-1-yl) -N, N-dimethylacetamide (79); 2- (4- (((2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-1H-indol-5-yl) oxy) methyl) piperidin-1-yl) -N, N-dimethylacetamide (80); 2- (4- (((2- (1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -3-isopropyl-1H-indol-5-yl) oxy) methyl) piperidin-1-yl) -N, N-dimethylacetamide (81); (S) -2- (3- ((2- (1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -3-isopropyl-1H-indol-5-yl) oxy) piperidin-1-yl) -N, N-dimethylacetamide (82); (S) -2- (3- ((3-isopropyl-2- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -1H-indol-5-yl) oxy) piperidin-1-yl) -N, N-dimethylacetamide (83); 2- (3- ((2- (1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -3-isopropyl-1H-indol-5-yl) oxy) piperidin-1-yl) -N, N-dimethylacetamide (84); 2- (4- ((3-isopropyl-2- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -1H-indol-5-yl) oxy) piperidin-1-yl) -N, N-dimethylacetamide (85); 2- (4- (((3-isopropyl-2- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -1H-indol-5-yl) oxy) methyl) piperidin-1-yl) -N, N-dimethylacetamide (86); 2- (4- ((3-isopropyl-2- (1,4, 5-trimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -1H-indol-5-yl) oxy) piperidin-1-yl) -N, N-dimethylacetamide (87); 2- (4- (((3-isopropyl-2- (1,4, 5-trimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -1H-indol-5-yl) oxy) methyl) piperidin-1-yl) -N, N-dimethylacetamide (88); 2- (4- (((2- (7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) oxy) methyl) piperidin-1-yl) -N, N-dimethylacetamide (89); 2- (4- ((2- (7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) oxy) piperidin-1-yl) -N, N-dimethylacetamide (90); 6- (3-isopropyl-5- ((1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) methoxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (91); 6- (3-isopropyl-5- ((1- (2- (methylsulfonyl) ethyl) azetidin-3-yl) methoxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (92); 2- (4- ((3-isopropyl-2- (8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -1H-indol-5-yl) oxy) piperidin-1-yl) -N, N-dimethylacetamide (93); 2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-5- (piperidin-3-ylmethoxy) -1H-indole, 2TFA (94); 2- (dimethylamino) -1- (4- ((2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-1H-indol-5-yl) oxy) piperidin-1-yl) ethanone (95); 2- (dimethylamino) -1- (4- (((2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-1H-indol-5-yl) oxy) methyl) piperidin-1-yl) ethan-1-one (96); 5- (5- ((1- (dimethylglycyl) piperidin-4-yl) methoxy) -3-isopropyl-1H-indol-2-yl) -1, 3-dimethylpyridin-2 (1H) -one (97); (S) -5- (5- ((1- (dimethylglycyl) piperidin-3-yl) oxy) -3-isopropyl-1H-indol-2-yl) -1, 3-dimethylpyridin-2 (1H) -one (98); (S) -2- (dimethylamino) -1- (3- ((3-isopropyl-2- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -1H-indol-5-yl) oxy) piperidin-1-yl) ethan-1-one (99); 5- (5- ((1- (dimethylglycyl) piperidin-4-yl) oxy) -3-isopropyl-1H-indol-2-yl) -1, 3-dimethylpyridin-2 (1H) -one (100); 2- (dimethylamino) -1- (4- ((3-isopropyl-2- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -1H-indol-5-yl) oxy) piperidin-1-yl) ethan-1-one (101); 2- (dimethylamino) -1- (4- (((3-isopropyl-2- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -1H-indol-5-yl) oxy) methyl) piperidin-1-yl) ethan-1-one (102); 5- (5- ((1- (dimethylglycyl) piperidin-4-yl) methoxy) -3-isopropyl-1H-indol-2-yl) -1,3, 4-trimethylpyridin-2 (1H) -one (103); 5- (5- ((1- (dimethylglycyl) piperidin-4-yl) oxy) -3-isopropyl-1H-indol-2-yl) -1,3, 4-trimethylpyridin-2 (1H) -one (104); 1- (4- ((2- (7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) oxy) piperidin-1-yl) -2- (dimethylamino) ethan-1-one (105); 1- (4- (((2- (7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) oxy) methyl) piperidin-1-yl) -2- (dimethylamino) ethan-1-one (106); 2- (dimethylamino) -1- (3- (((3-isopropyl-2- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -1H-indol-5-yl) oxy) methyl) azetidin-1-yl) ethan-1-one (107); 1- (3- (((2- (7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) oxy) methyl) azetidin-1-yl) -2- (dimethylamino) ethan-1-one (108); 1- (4- ((2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-1H-indol-5-yl) oxy) piperidin-1-yl) -2- (methylamino) ethanone (109); 2- (4- (((2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-1H-indol-5-yl) oxy) methyl) piperidin-1-yl) -N-methylacetamide (110); 2- (4- (((2- (1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -3-isopropyl-1H-indol-5-yl) oxy) methyl) piperidin-1-yl) -N-methylacetamide (111); 2- (4- ((2- (1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -3-isopropyl-1H-indol-5-yl) oxy) piperidin-1-yl) -N-methylacetamide (112); 2- (4- (((3-isopropyl-2- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -1H-indol-5-yl) oxy) methyl) piperidin-1-yl) -N-methylacetamide (113); 2- (4- ((3-isopropyl-2- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -1H-indol-5-yl) oxy) piperidin-1-yl) -N-methylacetamide (114); 2- (4- ((3-isopropyl-2- (1,4, 5-trimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -1H-indol-5-yl) oxy) piperidin-1-yl) -N-methylacetamide (115); 2- (4- (((3-isopropyl-2- (1,4, 5-trimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -1H-indol-5-yl) oxy) methyl) piperidin-1-yl) -N-methylacetamide (116); (S) -2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -N- (pyrrolidin-3-ylmethyl) acetamide (117); 2- (3, 4-dimethoxyphenyl) -3-ethyl-5- ((1 '-isobutyl- [1,4' -bipiperidin ] -4-yl) oxy) -1H-indole (118); (S) -2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -N- (pyrrolidin-3-ylmethyl) acetamide (119); (S) -1- (3-aminopiperidin-1-yl) -2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) ethan-1-one (120); 2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -N-methyl-N- ((1s,4s) -quinuclidin-3-yl) acetamide (121); 1- (3- (2-aminoethyl) piperidin-1-yl) -2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) ethan-1-one (122); 1- ((6R,7S) -7-amino-2-azaspiro [5.5] undecan-2-yl) -2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) ethan-1-one (123); 2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -N- ((5S) -8-methyl-8-azabicyclo [3.2.1] octan-2-yl) acetamide (124); 2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -N- ((1s,4s) -quinuclidin-3-yl) acetamide (125); 2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -N- (piperidin-2-ylmethyl) acetamide (126); 2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -N-methyl-N- (piperidin-3-yl) acetamide (127); n- (3-aminocyclohexyl) -2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) acetamide (128); 2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -1- (piperazin-1-yl) ethan-1-one (129); n- ((1R,2R) -2-aminocyclohexyl) -2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) acetamide (130); n- (4-aminocyclohexyl) -2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) acetamide (131); 1- ((1R,4R) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) -2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) ethan-1-one (132); 2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -N- ((4-hydroxy-1-methylpiperidin-4-yl) methyl) acetamide (133); (S) -2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -N- (pyrrolidin-3-yl) acetamide (134); (R) -2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -N- (pyrrolidin-3-yl) acetamide (135); 2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -N- (piperidin-4-yl) acetamide (136); (R) -2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -N- (piperidin-3-yl) acetamide (137); 2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -1- (4- (piperidin-4-yloxy) piperidin-1-yl) ethan-1-one (138); 2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -N- (1-isopropylpiperidin-4-yl) acetamide (139); 2- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) -1- (2, 6-diazaspiro [3.5] nonan-6-yl) ethan-1-one (140); 2- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) -1- (2, 7-diazaspiro [3.5] nonan-2-yl) ethan-1-one (141); 2- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) -N- (octahydrocyclopenta [ c ] pyrrol-4-yl) acetamide (142); 1- ([2,4' -bipiperidin ] -1-yl) -2- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) ethan-1-one (143); 2- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) -1- (2, 8-diazaspiro [4.5] decan-2-yl) ethan-1-one (144); 1- (hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) -2- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) ethan-1-one (145); 2- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) -N- (2- (piperidin-3-yl) ethyl) acetamide (146); 1- (4- (aminomethyl) piperidin-1-yl) -2- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) ethan-1-one (147); 2- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) -N-methyl-N- (piperidin-4-yl) acetamide (148); 2- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) -1- (5-methylhexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) ethan-1-one (149); 2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -N- (2-hydroxy-2-methylpropyl) acetamide (150); n- (2-hydroxy-2-methylpropyl) -2- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) acetamide (151); (R) -N- (2-fluoro-3-hydroxy-3-methylbutyl) -2- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) acetamide (152); 2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -N- (3-hydroxy-3-methylbutyl) acetamide (153); (R) -2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -N- (2-fluoro-3-hydroxy-3-methylbutyl) acetamide (154); n- (3-hydroxy-3-methylbutyl) -2- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) acetamide (155); 5- (3-isopropyl-5- (piperidin-4-yloxy) -1H-indol-2-yl) -1, 3-dimethylpyridin-2 (1H) -one (156); (R) -3-isopropyl-2- (2-methylpyridin-4-yl) -5- (pyrrolidin-3-yloxy) -1H-indole (157); 2- (3, 4-dimethoxyphenyl) -3-isopropyl-5- (2- (piperidin-4-yl) ethoxy) -1H-indole (158); 2- (3, 4-dimethoxyphenyl) -3-isopropyl-5- (piperidin-4-ylmethoxy) -1H-indole (159); 5- ((1-benzylpiperidin-4-yl) methoxy) -2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indole (160); 3-ethyl-2- (2-methylpyridin-4-yl) -5- (piperidin-4-ylmethoxy) -1H-indole (161); 2- (3, 4-dimethoxyphenyl) -3-ethyl-5- (piperidin-4-ylmethoxy) -1H-indole (162); 3-ethyl-2- (2-methylpyridin-4-yl) -5- (piperidin-4-yloxy) -1H-indole (163); 3-isopropyl-2- (2-methylpyridin-4-yl) -5- (piperidin-4-yloxy) -1H-indole (164); 5- (benzyloxy) -3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indole (165); 3-isopropyl-2- (2-methylpyridin-4-yl) -5- (2- (pyrrolidin-1-yl) ethoxy) -1H-indole (166); 2- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) -N, N-dimethylethyl-1-amine (167); 4- (4- (((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) methyl) phenyl) morpholine (168); 3-isopropyl-2- (2-methylpyridin-4-yl) -5- (pyridin-3-ylmethoxy) -1H-indole (169); (S) -2- (3, 4-dimethoxyphenyl) -3-isopropyl-5- (pyrrolidin-3-yloxy) -1H-indole (170); 2- (3, 4-dimethoxyphenyl) -3-isopropyl-5- (piperidin-4-yloxy) -1H-indole (171); 2- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) -N-methylethyl-1-amine (172); 4- (2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) ethyl) morpholine (173); 3-isopropyl-2- (2-methylpyridin-4-yl) -5- (pyridin-4-ylmethoxy) -1H-indole (174); 4- (2- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) ethyl) morpholine (175); 5- ((1H-imidazol-4-yl) methoxy) -3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indole (176); 3-isopropyl-2- (2-methylpyridin-4-yl) -5- (piperidin-3-yloxy) -1H-indole (177); 5- ((1H-imidazol-4-yl) methoxy) -3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indole (178); 3-isopropyl-5- ((1-methylpiperidin-4-yl) oxy) -2- (2-methylpyridin-4-yl) -1H-indole (179); 3-isopropyl-2- (2-methylpyridin-4-yl) -5- (piperidin-3-ylmethoxy) -1H-indole (180); 3-isopropyl-5- ((1-methylpiperidin-3-yl) methoxy) -2- (2-methylpyridin-4-yl) -1H-indole (181); (S) -3-ethyl-2- (2-methylpyridin-4-yl) -5- (pyrrolidin-3-yloxy) -1H-indole (182); 3-ethyl-5- ((1-methylpiperidin-4-yl) methoxy) -2- (2-methylpyridin-4-yl) -1H-indole (183); 3-isopropyl-2- (2-methylpyridin-4-yl) -5- ((4- (piperidin-4-yloxy) cyclohexyl) oxy) -1H-indole (184-; 3-isopropyl-5- ((1-isopropylpiperidin-4-yl) oxy) -2- (2-methylpyridin-4-yl) -1H-indole (186); 3-isopropyl-2- (2-methylpyridin-4-yl) -5- ((1- (3,3, 3-trifluoropropyl) piperidin-4-yl) oxy) -1H-indole (187); 3-isopropyl-5- ((1-methylpiperidin-4-yl) methoxy) -2- (2-methylpyridin-4-yl) -1H-indole (188); 3-ethyl-5- ((1-methylpiperidin-4-yl) oxy) -2- (2-methylpyridin-4-yl) -1H-indole (189); 3-ethyl-5- ((1-isopropylpyrrolidin-3-yl) oxy) -2- (2-methylpyridin-4-yl) -1H-indole (190); 3-isopropyl-5- ((1-isopropylpiperidin-4-yl) methoxy) -2- (2-methylpyridin-4-yl) -1H-indole (191); 3-ethyl-2- (2-methylpyridin-4-yl) -5- (2- (pyrrolidin-1-yl) ethoxy) -1H-indole (192); (R) -3-isopropyl-2- (2-methylpyridin-4-yl) -5- ((1-methylpyrrolidin-3-yl) oxy) -1H-indole (193); 3-isopropyl-5- ((1- (2-methoxyethyl) pyrrolidin-3-yl) methoxy) -2- (2-methylpyridin-4-yl) -1H-indole (194); 3-isopropyl-5- ((1 '-isopropyl- [1,4' -bipiperidin ] -4-yl) oxy) -2- (2-methylpyridin-4-yl) -1H-indole (195); 2- (dimethylamino) -1- (4- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) piperidin-1-yl) ethan-1-one (196); and 2- (4- ((2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-1H-indol-5-yl) oxy) piperidin-1-yl) acetic acid (197).
9. A pharmaceutical composition comprising a compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
10. A compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, for use in therapy in the treatment of an autoimmune disease or a chronic inflammatory disease.
11. Compound 10 or a pharmaceutically acceptable salt thereof according to claim, wherein the autoimmune or chronic inflammatory disease is selected from Systemic Lupus Erythematosus (SLE), rheumatoid arthritis, Multiple Sclerosis (MS) and schungren's syndrome.
Disclosure of Invention
The present invention provides compounds of formula (I), or stereoisomers, N-oxides, tautomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, that are useful as inhibitors of signaling through Toll-like receptors 7,8 or 9 and useful in the treatment of proliferative diseases, allergic diseases, autoimmune diseases and inflammatory diseases.
The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.
The present invention also provides a method for inhibiting Toll-like receptors 7,8 or 9 comprising administering to a host in need of such treatment a therapeutically effective amount of at least one compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof.
The present invention also provides methods for treating proliferative, metabolic, allergic, autoimmune, and inflammatory diseases comprising administering to a host in need of such treatment a therapeutically effective amount of at least one compound of the present invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.
The present invention also provides methods of treating diseases or disorders associated with Toll-like receptor 7,8 or 9 activity comprising administering to a mammal in need thereof at least one compound of formula (I) or salts, solvates and prodrugs thereof.
The invention also provides processes and intermediates useful for preparing compounds of formula (I), including salts, solvates, and prodrugs thereof.
The invention also provides at least one compound of formula (I) or salts, solvates and prodrugs thereof, for use in therapy.
The invention also provides the use of at least one compound of formula (I) or salts, solvates and prodrugs thereof, in the manufacture of a medicament for the treatment or prevention of conditions associated with Toll-like receptors 7,8 or 9, such as allergic, autoimmune, inflammatory and proliferative diseases.
The compounds of formula (I) and compositions comprising compounds of formula (I) are useful in the treatment, prevention or cure of various Toll-like receptor 7,8 or 9 related conditions. Pharmaceutical compositions comprising these compounds are useful for treating, preventing, or slowing the progression of diseases or disorders in various therapeutic areas, such as allergic diseases, autoimmune diseases, inflammatory diseases, and proliferative diseases.
These and other features of the present invention will be set forth in the expanded form as the disclosure continues.
Detailed Description
A first aspect of the invention provides at least one compound of formula (I):
an N-oxide or salt thereof, wherein:
g is:
(i)
(ii)
(iii)
(iv) a 9-membered heterocycle selected from:
or
(v) A 10-membered heterocycle selected from:
a is-L-R6；
L is a bond, - (CR)xRx)1-2-、-(CRxRx)1-2CRx(OH)-、-(CRxRx)1-2O-、-CRxRxC(O)-、-CRxRxC(O)NRx(CRxRx)0-4-、-CRxRxNRxC(O)(CRxRx)0-4-or-CRxRxNRxC(O)(CRxRx)0-4-；
R1Is H, Cl, -CN, C1-4Alkyl radical, C1-3Fluoroalkyl radical, C1-3Hydroxyalkyl radical, C1-3Hydroxy-fluoroalkyl, -CRv＝CH2、C3-6Cycloalkyl, -CH2(C3-6Cycloalkyl), -C (O) O (C)1-3Alkyl) or tetrahydropyranyl;
each R2Independently halogen, -CN, -OH, -NO2、C1-4Alkyl radical, C1-2Fluoroalkyl radical, C1-2Cyanoalkyl, C1-3Hydroxyalkyl radical, C1-3Aminoalkyl, -O (CH)2)1-2OH、-(CH2)0-4O(C1-4Alkyl group), C1-3Fluoroalkoxy, - (CH)2)1-4O(C1-3Alkyl), -O (CH)2)1-2OC(O)(C1-3Alkyl), -O (CH)2)1-2NRxRx、-C(O)O(C1-3Alkyl), - (CH)2)0-2C(O)NRyRy、-C(O)NRx(C1-5Hydroxyalkyl), -C (O) NRx(C2-6Alkoxyalkyl), -C (O) NRx(C3-6Cycloalkyl), -NR-yRy、-NRy(C1-3Fluoroalkyl group), -NRy(C1-4Hydroxyalkyl), -NR)xCH2(phenyl), -NRxS(O)2(C3-6Cycloalkyl), -NR-xC(O)(C1-3Alkyl), -NR-xCH2(C3-6Cycloalkyl), - (CH)2)0-2S(O)2(C1-3Alkyl), - (CH)2)0-2(C3-6Cycloalkyl), - (CH)2)0-2(phenyl), morpholinyl, dioxothiomorpholinyl, dimethylpyrazolyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl or-c (o) (thiazolyl);
R2ais C1-6Alkyl radical, C1-3Fluoroalkyl radical, C1-6Hydroxyalkyl radical, C1-3Aminoalkyl, - (CH)2)0-4O(C1-3Alkyl group), C3-6Cycloalkyl, - (CH)2)1-3C(O)NRxRx、-CH2(C3-6Cycloalkyl), -CH2(phenyl), tetrahydrofuranyl, tetrahydropyranyl or phenyl;
each R2bIndependently H, halogen, -CN, -NRxRx、C1-6Alkyl radical, C1-3Fluoroalkyl radical, C1-3Hydroxyalkyl radical, C1-3Fluoroalkoxy, - (CH)2)0-2O(C1-3Alkyl), - (CH)2)0-3C(O)NRxRx、-(CH2)1-3(C3-6Cycloalkyl), -C (O) O (C)1-3Alkyl), -C (O) NRx(C1-3Alkyl), -CRx＝CRxRxor-CRx＝CH(C3-6Cycloalkyl groups);
R2cis R2aOr R2b；
R2dIs R2aOr R2b(ii) a With the proviso that R2cAnd R2dOne is R2a，R2cAnd R2dAnother of (A) is R2b；
Each R5Independently F, Cl, -CN, C1-3Alkyl radical, C1-2Fluoroalkyl or-OCH3；
R6Comprises the following steps:
(i)-NRxRx、-CRxRxC(O)NRx(CRxRx)1-3OH、-CRxRxC(O)NRx(CRxRx)1-2NRxRxor-CRxRxC(O)NRx(CRxRx)1-2CHFCRxRxOH; or
(ii) Azabicyclo [3.2.1]Octyl, azaspiro [5.5]]Undecyl, azetidinyl, C3-6Cycloalkyl, diazabicyclo [2.2.1]Heptyl, diazaspiro [3.5]Nonyl, imidazolyl, morpholinyl, tetrahydrofuryl, tetrahydropyranyl, octahydrocyclopenta [ c ]]Pyrrolyl, phenyl, piperazinyl, piperidinyl, pyrrolidinyl, pyridinyl or quinuclidinyl, each substituted with 0 to 3R6a；
Each R6aIndependently F, Cl, -OH, -CN, C1-6Alkyl radical, C1-4Fluoroalkyl radical, C1-6Hydroxyalkyl, - (CH)2)1-2O(C1-3Alkyl), -NR-xRx、-(CH2)1-2NRxRx、-(CRxRx)1-2S(O)2(C1-3Alkyl), - (CR)xRx)1-2C(O)ORy、-(CRxRx)1-2C(O)NRxRx、-C(O)(CRxRx)1-2NRxRx、-(CRxRx)1-2(phenyl), oxetanyl, morpholinyl, tetrahydrofuryl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, isopropylpiperidinyl, isobutylpiperidinyl, piperazinyl, or-O (piperidinyl);
Rvis H, C1-2Alkyl or C1-2A fluoroalkyl group;
each RxIndependently is H or-CH3；
Each RyIndependently is H or C1-6An alkyl group;
n is 0, 1 or 2; and
p is 0, 1,2, 3 or 4.
A second aspect of the invention provides at least one compound of formula (I), an N-oxide or a salt thereof, wherein:
g is defined in the first aspect;
a is-L-R6；
L is a bond, - (CR)xRx)1-2-、-(CRxRx)1-2CRx(OH)-、-(CRxRx)1-2O-、-CRxRxC(O)-、-CRxRxC(O)NRx(CRxRx)0-4-、-CRxRxNRxC(O)(CRxRx)0-4-or-CRxRxNRxC(O)(CRxRx)0-4-；
R1Is H, Cl, -CN, C1-4Alkyl radical, C1-3Fluoroalkyl radical, C1-3Hydroxyalkyl radical, C1-3Hydroxy-fluoroalkyl, -CRv＝CH2、C3-6Cycloalkyl, -CH2(C3-6Cycloalkyl), -C (O) O (C)1-3Alkyl) or tetrahydropyranyl;
each R2Independently halogen, -CN, -OH, -NO2、C1-4Alkyl radical, C1-2Fluoroalkyl radical, C1-2Cyanoalkyl, C1-3Hydroxyalkyl radical, C1-3Aminoalkyl, -O (CH)2)1-2OH、-(CH2)0-4O(C1-4Alkyl group), C1-3Fluoroalkoxy, - (CH)2)1-4O(C1-3Alkyl), -O (CH)2)1-2OC(O)(C1-3Alkyl), -O (CH)2)1-2NRxRx、-C(O)O(C1-3Alkyl), - (CH)2)0-2C(O)NRyRy、-C(O)NRx(C1-5Hydroxyalkyl), -C (O) NRx(C2-6Alkoxyalkyl), -C (O) NRx(C3-6Cycloalkyl), -NR-yRy、-NRy(C1-3Fluoroalkyl group), -NRy(C1-4Hydroxyalkyl), -NR)xCH2(phenyl), -NRxS(O)2(C3-6Cycloalkyl), -NR-xC(O)(C1-3Alkyl), -NR-xCH2(C3-6Cycloalkyl), - (CH)2)0-2S(O)2(C1-3Alkyl), - (CH)2)0-2(C3-6Cycloalkyl), - (CH)2)0-2(phenyl), morpholinyl, dioxothiomorpholinyl, dimethylpyrazolyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl or-c (o) (thiazolyl);
R2ais C1-6Alkyl radical, C1-3Fluoroalkyl radical, C1-6Hydroxyalkyl radical, C1-3Aminoalkyl, - (CH)2)0-4O(C1-3Alkyl group), C3-6Cycloalkyl, - (CH)2)1-3C(O)NRxRx、-CH2(C3-6Cycloalkyl), -CH2(phenyl), tetrahydrofuranyl, tetrahydropyranyl or phenyl;
each R2bIndependently H, halogen, -CN, -NRxRx、C1-6Alkyl radical, C1-3Fluoroalkyl radical, C1-3Hydroxyalkyl radical, C1-3Fluoroalkoxy, - (CH)2)0-2O(C1-3Alkyl), - (CH)2)0-3C(O)NRxRx、-(CH2)1-3(C3-6Cycloalkyl), -C (O) O (C)1-3Alkyl), -C (O) NRx(C1-3Alkyl), -CRx＝CRxRxor-CRx＝CH(C3-6Cycloalkyl groups);
R2cis R2aOr R2b；
R2dIs R2aOr R2b(ii) a With the proviso that R2cAnd R2dOne is R2a，R2cAnd R2dAnother of (A) is R2b；
Each R5Independently F, Cl, -CN, C1-3Alkyl radical, C1-2Fluoroalkyl or-OCH3；
R6Comprises the following steps:
(i)-CRxRxC(O)NRx(CRxRx)1-3OH、-CRxRxC(O)NRx(CRxRx)1-2NRxRxor-CRxRxC(O)NRx(CRxRx)1-2CHFCRxRxOH; or
(ii) Azabicyclo [3.2.1]Octyl, azaspiro [5.5]]Undecyl, azetidinyl, C3-6Cycloalkyl, diazabicyclo [2.2.1]Heptyl, diazaspiro [3.5]Nonyl, morpholinyl, tetrahydrofuryl, tetrahydropyranyl, octahydrocyclopenta [ c]Pyrrolyl, piperazinyl, piperidinyl, pyrrolidinyl or quinuclidinyl, each substituted with 0 to 3R6a；
Each R6aIndependently F, Cl, -OH, -CN, C1-6Alkyl radical, C1-4Fluoroalkyl radical, C1-6Hydroxyalkyl, - (CH)2)1-2O(C1-3Alkyl), -NR-xRx、-(CH2)1-2NRxRx、-(CRxRx)1-2S(O)2(C1-3Alkyl), - (CR)xRx)1-2C(O)NRxRx、-C(O)(CRxRx)1-2NRxRxOxetanyl, tetrahydrofuryl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, isobutylpiperidinyl, piperazinyl, or-O (piperidinyl);
Rvis H, C1-2Alkyl or C1-2A fluoroalkyl group;
each RxIndependently is H or-CH3；
Each RyIndependently is H or C1-6An alkyl group;
n is 0, 1 or 2; and
p is 0, 1,2, 3 or 4.
One embodiment provides a compound of formula (I) or a salt thereof, wherein G is:and A, R1、R5And n is defined in the first aspect or the second aspect.
One embodiment provides a compound of formula (I), an N-oxide or salt thereof, wherein G is: and A, R1、R2、R5N and p are defined in the first aspect or the second aspect.
One embodiment provides a compound of formula (I) or a salt thereof, wherein G is And A, R1、R2a、R2b、R2c、R2d、R5、RxN and p are defined in the first aspect or the second aspect. Included in this embodiment are compounds wherein R2aIs C1-4Alkyl radical, C1-2Fluoroalkyl radical, C1-4Hydroxyalkyl, - (CH)2)1-3OCH3、C3-6Cycloalkyl, -CH2C(O)NRxRx、-CH2(C3-6Cycloalkyl), -CH2(phenyl), tetrahydrofuranyl or phenyl; and each R2bIndependently H, F, Cl, -CN, -NRxRx、C1-6Alkyl radical, C1-2Fluoroalkyl radical, C1-3Hydroxyalkyl, - (CH)2)0-2O(C1-2Alkyl), - (CH)2)0-2C(O)NRxRx、-(CH2)1-3(cyclopropyl), -C (O) O (C)1-2Alkyl), -C (O) NRx(C1-3Alkyl), -CRx＝CH2or-CH ═ CH (C)3-6Cycloalkyl groups). Also included in this embodiment are compounds wherein R2ais-CH3(ii) a And each R2bIndependently H, Cl or-CH3。
One embodiment provides a compound of formula (I) or a salt thereof, wherein G is a 9-membered heterocyclic ring selected from:
and A, R1、R2、R5N and p are defined in the first aspect or the second aspect.
One embodiment provides a compound of formula (I) or a salt thereof, wherein G is a 10-membered heterocyclic ring selected from:
and A, R1、R2、R5N and p are defined in the first aspect or the second aspect.
An embodiment provides a compound of formula (I), an N-oxide or a salt thereof, wherein G is (I) And A, R1、R2、R2a、R2b、R5N and p are defined in the first aspect or the second aspectAnd (5) defining. Included in this embodiment are compounds wherein R1is-CH2CH3or-CH (CH)3)2(ii) a Each R2Independently is-CH3or-OCH3；R2ais-CH3(ii) a Each R2bIndependently H, Cl or-CH3(ii) a L is a bond, -CH2-、-CH2CH2-、-CH2C(O)-、-CH2C(O)NH-、-CH2C(O)N(CH3)-、-CH2C(O)NHCH2-or-CH2C(O)NHCH2CH2-；R6Comprises the following steps: (i) -CH2C(O)NHCH2C(CH3)2OH、-CH2C(O)NHCH2CH2C(CH3)2OH、-CH2C(O)NHCH2CH2NH2or-CH2C(O)NHCH2CHFC(CH3)2OH; or (ii) azabicyclo [3.2.1]Octyl, azaspiro [5.5]]Undecyl, azetidinyl, cyclohexyl, diazabicyclo [2.2.1]Heptyl, diazaspiro [3.5]Nonyl, morpholinyl, octahydrocyclopenta [ c ]]Pyrrolyl, piperazinyl, piperidinyl, pyrrolidinyl or quinuclidinyl, each substituted with 0 to 2R6a(ii) a Each R6aIndependently F, -OH, -CH3、-CH2CH2CH3、-C(CH3)2、-CH2CH(CH3)2、-CH2CH2CF3、-CH2CH2CH2CF3、-CH2CH2OH、-CH2CH2CH2OH、-CH2CH(CH3)OH、-CH2C(CH3)2OH、-CH2CH2OCH3、-NH2、-N(CH3)2、-CH2NH2、-CH2CH2NH2、-CH2CH2S(O)2CH3、-CH2C(O)OH、-CH2C(O)N(CH3)2、-C(O)CH2N(CH3)2、-CH2(phenyl), morpholinyl, oxetanyl, tetrahydropyranyl, piperidinylIsopropylpiperidinyl, isobutylpiperidinyl or-O (piperidinyl); n is 0; and p is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R1Is H, Cl, -CN, C1-4Alkyl radical, C1-3Fluoroalkyl radical, C1-3Hydroxyalkyl radical, C1-3Hydroxy-fluoroalkyl, C3-6Cycloalkyl, -CH2(C3-6Cycloalkyl) or-C (O) O (C)1-3Alkyl groups); and G, A, R5And n is defined in the first aspect or the second aspect. Included in this embodiment are compounds wherein R1Is H, Cl, -CN, C1-4Alkyl radical, C1-2Fluoroalkyl radical, C1-2Hydroxyalkyl or-C (O) O (C)1-2Alkyl groups). Also included in this embodiment are compounds wherein R1is-CH2CH3or-CH (CH)3)2。
One embodiment provides a compound of formula (I) or a salt thereof, wherein each R2Independently F, Cl, Br, -CN, -OH, -NO2、C1-4Alkyl radical, C1-2Fluoroalkyl radical, C1-2Cyanoalkyl, C1-3Hydroxyalkyl radical, C1-3Aminoalkyl radicals, -OCH2OH、-(CH2)0-2O(C1-4Alkyl group), C1-2Fluoroalkoxy, - (CH)2)1-2O(C1-3Alkyl), -O (CH)2)1-2OC(O)(C1-2Alkyl), -O (CH)2)1-2NRxRx、-C(O)O(C1-2Alkyl), -C (O) NRyRy、-C(O)NRx(C1-5Hydroxyalkyl), -C (O) NRx(C2-6Alkoxyalkyl), -C (O) NRx(C3-6Cycloalkyl), -NR-yRy、-NRy(C1-3Fluoroalkyl group), -NRy(C1-4Hydroxyalkyl), -NR)xC(O)(C1-3Alkyl), - (CH)2)0-2S(O)2(C1-3Alkyl group), C3-6Cycloalkyl, phenyl, morpholinyl, dioxothiomorpholinyl, dimethylpyrazolyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl or triazolyl; and A, G, R1、R5、Rx、RyN and p are defined in the first aspect or the second aspect. Included in this embodiment are compounds wherein each R is2Independently F, Cl, -CN, -OH, C1-4Alkyl radical, C1-2Fluoroalkyl radical, C1-2Cyanoalkyl, C1-3Hydroxyalkyl radical, C1-3Aminoalkyl, - (CH)2)0-2O(C1-4Alkyl), -NR-yRy、-(CH2)0-2C(O)NRyRy、-C(O)NRx(C1-4Hydroxyalkyl), -C (O) NRx(C2-4Alkoxyalkyl), -C (O) NRx(C3-6Cycloalkyl), - (CH)2)0-2S(O)2(C1-3Alkyl), - (CH)2)0-1(C3-6Cycloalkyl), morpholinyl, - (CH)2)0-1(phenyl) or dimethylpyrazolyl. Also included in this embodiment are compounds wherein each R is2Independently is-CH3or-OCH3。
An embodiment provides a compound of formula (I) or a salt thereof, wherein L is a bond, - (CR)xRx)1-2-、-CRxRxC(O)-、-CRxRxC(O)NRx(CRxRx)0-2-、-CRxRxNRxC(O)(CRxRx)0-2-or-CRxRxNRxC(O)(CRxRx)0-2-; and A, G, R1、R5、R6、RxAnd n is defined in the first aspect or the second aspect. Included in this embodiment are compounds wherein L is a bond, - (CR)xRx)1-2-、-CH2C(O)-、-CH2C(O)NRx(CRxRx)0-2-、-CH2NRxC (O) -or-CH2NRxC(O)CH2-. Also included in this embodiment are compounds wherein L is a bond, -CH2-、-CH2CH2-、-CH2C(O)-、-CH2C(O)NH-、-CH2C(O)N(CH3)-、-CH2C(O)NHCH2-or-CH2C(O)NHCH2CH2-。
One embodiment provides a compound of formula (I) or a salt thereof, wherein L is a bond; and A, G, R1、R5、R6And n is defined in the first aspect or the second aspect. Included in this embodiment are compounds wherein R6Is azetidinyl, cyclohexyl, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl or quinuclidinyl, each substituted with 0 to 2R6a(ii) a And each R6aIndependently F, -OH, -CH3、-CH2CH2CH3、-C(CH3)2、-CH2CH(CH3)2、-CH2CH2CF3、-CH2CH2CH2CF3、-CH2CH2OH、-CH2CH2CH2OH、-CH2CH(CH3)OH、-CH2C(CH3)2OH、-CH2CH2OCH3、-NH2、-N(CH3)2、-CH2NH2、-CH2CH2NH2、-CH2CH2S(O)2CH3、-CH2C(O)N(CH3)2、-C(O)CH2N(CH3)2Oxetanyl, tetrahydropyranyl, piperidinyl, isobutylpiperidinyl or-O (piperidinyl).
One embodiment provides a compound of formula (I) or a salt thereof, wherein L is a bond; r6Is azetidinyl, cyclohexyl, imidazolyl, morpholinyl, phenyl, piperazinyl, piperidinyl, pyrrolidinyl, pyridinyl or quinuclidinyl, each substituted with 0 to 2R6a(ii) a And each R6aIndependently F, -OH, -CH3、-CH2CH2CH3、-C(CH3)2、-CH2CH(CH3)2、-CH2CH2CF3、-CH2CH2CH2CF3、-CH2CH2OH、-CH2CH2CH2OH、-CH2CH(CH3)OH、-CH2C(CH3)2OH、-CH2CH2OCH3、-NH2、-N(CH3)2、-CH2NH2、-CH2CH2NH2、-CH2CH2S(O)2CH3、-CH2C(O)OH、-CH2C(O)N(CH3)2、-C(O)CH2N(CH3)2、-CH2(phenyl), morpholinyl, oxetanyl, tetrahydropyranyl, piperidinyl, isopropylpiperidinyl, isobutylpiperidinyl or-O (piperidinyl); and G, R1、R5And n is defined in the first aspect or the second aspect.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R6is-NRxRx、-CRxRxC(O)NRx(CRxRx)1- 3OH、-CRxRxC(O)NRx(CRxRx)1-2NRxRxor-CRxRxC(O)NRx(CRxRx)1-2CHFCRxRxOH; and A, G, R1、R5、RxAnd n is defined in the first aspect or the second aspect. Included in this embodiment are compounds wherein R6is-NRxRx、-CH2C(O)NHCH2CRxRxOH、-CH2C(O)NHCH2CH2CRxRxOH、-CH2C(O)NHCH2CH2NRxRxor-CH2C(O)NHCH2CHFCRxRxAnd (5) OH. Also included in this embodiment are compounds wherein R6is-NH (CH)3)、-N(CH3)2、-CH2C(O)NHCH2C(CH3)2OH、-CH2C(O)NHCH2CH2C(CH3)2OH、-CH2C(O)NHCH2CH2NH2or-CH2C(O)NHCH2CHFC(CH3)2OH。
One embodiment provides a compound of formula (I) or a salt thereof, wherein R6Is azabicyclo [3.2.1]Octyl, azaspiro [5.5]]Undecyl, azetidinyl, C3-6Cycloalkyl, diazabicyclo [2.2.1]Heptyl, diazaspiro [3.5]Nonyl, imidazolyl, morpholinyl, tetrahydropyranyl, octahydrocyclopenta [ c]Pyrrolyl, phenyl, piperazinyl, piperidinyl, pyrrolidinyl, pyridinyl or quinuclidinyl, each substituted with 0 to 3R6a(ii) a And A, G, L, R1、R5、R6aAnd n is defined in the first aspect or the second aspect. Included in this embodiment are compounds wherein R6Is azabicyclo [3.2.1]Octyl, azaspiro [5.5]]Undecyl, azetidinyl, cyclohexyl, diazabicyclo [2.2.1]Heptyl, diazaspiro [3.5]Nonyl, morpholinyl, octahydrocyclopenta [ c ]]Pyrrolyl, piperazinyl, piperidinyl, pyrrolidinyl or quinuclidinyl, each substituted with 0 to 2R6a(ii) a And each R6aIndependently F, -OH, C1-4Alkyl radical, C1-4Fluoroalkyl radical, C1-4Hydroxyalkyl, - (CH)2)1-2OCH3、-NRxRx、-(CH2)1-2NRxRx、-(CH2)1-2S(O)2(C1-2Alkyl), - (CH)2)1-2C(O)NRxRx、-C(O)CH2NRxRxOxetanyl, tetrahydrofuryl, tetrahydropyranyl, piperidinyl, isobutylpiperidinyl, piperazinyl or-O (piperidinyl); and RxDefined in the first aspect. Additionally, included in this embodiment are compounds wherein each R is6aIndependently F, -OH, -CH3、-CH2CH2CH3、-C(CH3)2、-CH2CH(CH3)2、-CH2CH2CF3、-CH2CH2CH2CF3、-CH2CH2OH、-CH2CH2CH2OH、-CH2CH(CH3)OH、-CH2C(CH3)2OH、-CH2CH2OCH3、-CH2C(O)OH、-NH2、-N(CH3)2、-CH2NH2、-CH2CH2NH2、-CH2CH2S(O)2CH3、-CH2C(O)N(CH3)2、-C(O)CH2N(CH3)2Oxetanyl, tetrahydropyranyl, piperidinyl, isopropyl, isobutylpiperidinyl or-O (piperidinyl).
One embodiment provides a compound of formula (I) or a salt thereof, wherein each R5Independently F, Cl, -CN, C1-2Alkyl radical, C1-2Fluoroalkyl or-OCH3(ii) a And A, G, R1And n is defined in the first aspect or the second aspect. Included in this embodiment are compounds wherein each R is5Independently F, Cl, -CN, C1-2Alkyl or-OCH3(ii) a And n is 0 or 1. Also included in this embodiment are compounds wherein n is 0.
One embodiment provides a compound of formula (I), an N-oxide or a salt thereof, wherein the compound is selected from 2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-5- (piperidin-4-yloxy) -1H-indole (1); (S) -5- (3-isopropyl-5- (piperidin-3-yloxy) -1H-indol-2-yl) -1, 3-dimethylpyridin-2 (1H) -one (8); (S) -6- (3-isopropyl-5- (piperidin-3-yloxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (9); 6- (3-isopropyl-5- (piperidin-4-yloxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (10); 5- (3-isopropyl-5- (piperidin-4-yloxy) -1H-indol-2-yl) -1, 3-dimethylpyridin-2 (1H) -one (11); 3-chloro-5- (3-isopropyl-5- (piperidin-4-yloxy) -1H-indol-2-yl) -1, 4-dimethylpyridin-2 (1H) -one (13); 5- (3-isopropyl-5- (piperidin-4-yloxy) -1H-indol-2-yl) -1,3, 4-trimethylpyridin-2 (1H) -one (14); 6- (3-isopropyl-5- (piperidin-4-yloxy) -1H-indol-2-yl) -7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridine (17); 6- (3-isopropyl-5- (piperidin-4-yloxy) -1H-indol-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridine (20); 1- (4- ((2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-1H-indol-5-yl) oxy) piperidin-1-yl) -2-methylpropan-2-ol (21); 1- (4- ((3-isopropyl-2- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -1H-indol-5-yl) oxy) piperidin-1-yl) -2-methylpropan-2-ol (22); 2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-5- ((1-methylpiperidin-4-yl) oxy) -1H-indole (29); 2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-5- ((1-isopropylpiperidin-4-yl) oxy) -1H-indole (31); 6- (3-isopropyl-5- ((1-methylpiperidin-4-yl) oxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (32); (S) -5- (3-isopropyl-5- ((1-methylpiperidin-3-yl) oxy) -1H-indol-2-yl) -1, 3-dimethylpyridin-2 (1H) -one (37); (S) -6- (3-isopropyl-5- ((1-methylpiperidin-3-yl) oxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (38); 5- (3-isopropyl-5- ((1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) oxy) -1H-indol-2-yl) -1, 3-dimethylpyridin-2 (1H) -one (39); (S) -5- (3-isopropyl-5- ((1- (tetrahydro-2H-pyran-4-yl) piperidin-3-yl) oxy) -1H-indol-2-yl) -1, 3-dimethylpyridin-2 (1H) -one (40); 5- (3-isopropyl-5- ((1-isopropylpiperidin-4-yl) oxy) -1H-indol-2-yl) -1,3, 4-trimethylpyridin-2 (1H) -one (45); 3-chloro-5- (3-isopropyl-5- ((1-methylpiperidin-4-yl) oxy) -1H-indol-2-yl) -1, 4-dimethylpyridin-2 (1H) -one (46); 6- (3-isopropyl-5- ((1-isopropylpiperidin-4-yl) oxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (47); 5- (3-isopropyl-5- ((1-isopropylpiperidin-4-yl) oxy) -1H-indol-2-yl) -1,3, 4-trimethylpyridin-2 (1H) -one (48); 5- (3-isopropyl-5- ((1- (oxetan-3-yl) piperidin-4-yl) oxy) -1H-indol-2-yl) -1,3, 4-trimethylpyridin-2 (1H) -one (50); 6- (3-isopropyl-5- ((1-methylpiperidin-4-yl) oxy) -1H-indol-2-yl) -7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridine (53); 6- (3-isopropyl-5- ((1- (oxetan-3-yl) piperidin-4-yl) oxy) -1H-indol-2-yl) -7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridine (56); 6- (3-isopropyl-5- ((1-isopropylpiperidin-4-yl) oxy) -1H-indol-2-yl) -7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridine (57); 6- (3-isopropyl-5- ((1-propylpiperidin-4-yl) oxy) -1H-indol-2-yl) -7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridine (63); 4- ((3-isopropyl-2- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -1H-indol-5-yl) oxy) -N, N-dimethylcyclohex-1-amine (64); 6- (3-isopropyl-5- ((1-methylpiperidin-4-yl) oxy) -1H-indol-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridine (65); 6- (3-isopropyl-5- ((1-isopropylpiperidin-4-yl) oxy) -1H-indol-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridine (66); 6- (3-isopropyl-5- ((1-propylpiperidin-4-yl) oxy) -1H-indol-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridine (67); 6- (3-isopropyl-5- ((1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) oxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (68); 1- (4- ((2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-1H-indol-5-yl) oxy) piperidin-1-yl) propan-2-ol (69); 2- (4- ((2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-1H-indol-5-yl) oxy) piperidin-1-yl) ethan-1-ol (70); 3- (4- ((2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-1H-indol-5-yl) oxy) piperidin-1-yl) propan-1-ol (72); 2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-5- ((1- (2-methoxyethyl) piperidin-4-yl) oxy) -1H-indole (75); 5- (5- ((1-isobutylpiperidin-4-yl) oxy) -3-isopropyl-1H-indol-2-yl) -1, 3-dimethylpyridin-2 (1H) -one (76); 6- (5- ((1-isobutylpiperidin-4-yl) oxy) -3-isopropyl-1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (77); 5- (3-isopropyl-5- ((1- (4,4, 4-trifluorobutyl) piperidin-4-yl) oxy) -1H-indol-2-yl) -1, 3-dimethylpyridin-2 (1H) -one (78); 2- (4- ((2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-1H-indol-5-yl) oxy) piperidin-1-yl) -N, N-dimethylacetamide (79); (S) -2- (3- ((2- (1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -3-isopropyl-1H-indol-5-yl) oxy) piperidin-1-yl) -N, N-dimethylacetamide (82); (S) -2- (3- ((3-isopropyl-2- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -1H-indol-5-yl) oxy) piperidin-1-yl) -N, N-dimethylacetamide (83); 2- (3- ((2- (1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -3-isopropyl-1H-indol-5-yl) oxy) piperidin-1-yl) -N, N-dimethylacetamide (84); 2- (4- ((3-isopropyl-2- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -1H-indol-5-yl) oxy) piperidin-1-yl) -N, N-dimethylacetamide (85); 2- (4- ((3-isopropyl-2- (1,4, 5-trimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -1H-indol-5-yl) oxy) piperidin-1-yl) -N, N-dimethylacetamide (87); 2- (4- ((2- (7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) oxy) piperidin-1-yl) -N, N-dimethylacetamide (90); 2- (dimethylamino) -1- (4- ((2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-1H-indol-5-yl) oxy) piperidin-1-yl) ethanone (95); (S) -5- (5- ((1- (dimethylglycyl) piperidin-3-yl) oxy) -3-isopropyl-1H-indol-2-yl) -1, 3-dimethylpyridin-2 (1H) -one (98); (S) -2- (dimethylamino) -1- (3- ((3-isopropyl-2- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -1H-indol-5-yl) oxy) piperidin-1-yl) ethan-1-one (99); 5- (5- ((1- (dimethylglycyl) piperidin-4-yl) oxy) -3-isopropyl-1H-indol-2-yl) -1, 3-dimethylpyridin-2 (1H) -one (100); 2- (dimethylamino) -1- (4- ((3-isopropyl-2- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -1H-indol-5-yl) oxy) piperidin-1-yl) ethan-1-one (101); 5- (5- ((1- (dimethylglycyl) piperidin-4-yl) oxy) -3-isopropyl-1H-indol-2-yl) -1,3, 4-trimethylpyridin-2 (1H) -one (104); 1- (4- ((2- (7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) oxy) piperidin-1-yl) -2- (dimethylamino) ethan-1-one (105); 1- (4- ((2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-1H-indol-5-yl) oxy) piperidin-1-yl) -2- (methylamino) ethanone (109); 2- (4- ((2- (1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -3-isopropyl-1H-indol-5-yl) oxy) piperidin-1-yl) -N-methylacetamide (112); 2- (4- ((3-isopropyl-2- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -1H-indol-5-yl) oxy) piperidin-1-yl) -N-methylacetamide (114); 2- (4- ((3-isopropyl-2- (1,4, 5-trimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -1H-indol-5-yl) oxy) piperidin-1-yl) -N-methylacetamide (115); 2- (3, 4-dimethoxyphenyl) -3-ethyl-5- ((1 '-isobutyl- [1,4' -bipiperidin ] -4-yl) oxy) -1H-indole (118); (R) -3-isopropyl-2- (2-methylpyridin-4-yl) -5- (pyrrolidin-3-yloxy) -1H-indole (157); 3-ethyl-2- (2-methylpyridin-4-yl) -5- (piperidin-4-yloxy) -1H-indole (163); 3-isopropyl-2- (2-methylpyridin-4-yl) -5- (piperidin-4-yloxy) -1H-indole (164); (S) -2- (3, 4-dimethoxyphenyl) -3-isopropyl-5- (pyrrolidin-3-yloxy) -1H-indole (170); 2- (3, 4-dimethoxyphenyl) -3-isopropyl-5- (piperidin-4-yloxy) -1H-indole (171); 3-isopropyl-2- (2-methylpyridin-4-yl) -5- (piperidin-3-yloxy) -1H-indole (177); 3-isopropyl-5- ((1-methylpiperidin-4-yl) oxy) -2- (2-methylpyridin-4-yl) -1H-indole (179); (S) -3-ethyl-2- (2-methylpyridin-4-yl) -5- (pyrrolidin-3-yloxy) -1H-indole (182); 3-isopropyl-2- (2-methylpyridin-4-yl) -5- ((4- (piperidin-4-yloxy) cyclohexyl) oxy) -1H-indole (184-; 3-isopropyl-5- ((1-isopropylpiperidin-4-yl) oxy) -2- (2-methylpyridin-4-yl) -1H-indole (186); 3-isopropyl-2- (2-methylpyridin-4-yl) -5- ((1- (3,3, 3-trifluoropropyl) piperidin-4-yl) oxy) -1H-indole (187); 3-ethyl-5- ((1-isopropylpyrrolidin-3-yl) oxy) -2- (2-methylpyridin-4-yl) -1H-indole (190); (R) -3-isopropyl-2- (2-methylpyridin-4-yl) -5- ((1-methylpyrrolidin-3-yl) oxy) -1H-indole (193); 3-isopropyl-5- ((1 '-isopropyl- [1,4' -bipiperidin ] -4-yl) oxy) -2- (2-methylpyridin-4-yl) -1H-indole (195); 2- (dimethylamino) -1- (4- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) piperidin-1-yl) ethan-1-one (196); and 2- (4- ((2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-1H-indol-5-yl) oxy) piperidin-1-yl) acetic acid (197).
One embodiment provides a compound of formula (I), an N-oxide or a salt thereof, wherein the compound is selected from 6- (3-isopropyl-5- (2- (pyrrolidin-1-yl) ethoxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (2); 6- (5- (2- (4, 4-difluoropiperidin-1-yl) ethoxy) -3-isopropyl-1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (3); 6- (5- (2- (3-fluoropiperidin-1-yl) ethoxy) -3-isopropyl-1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (4); 4- (2- ((3-isopropyl-2- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -1H-indol-5-yl) oxy) ethyl) morpholine (5); 2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-5- (piperidin-4-ylmethoxy) -1H-indole (6); 5- (3-isopropyl-5- (piperidin-4-ylmethoxy) -1H-indol-2-yl) -1, 3-dimethylpyridin-2 (1H) -one (7); 6- (3-isopropyl-5- (piperidin-4-ylmethoxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (12); 5- (3-isopropyl-5- (piperidin-4-ylmethoxy) -1H-indol-2-yl) -1,3, 4-trimethylpyridin-2 (1H) -one (15); 6- (3-isopropyl-5- (piperidin-4-ylmethoxy) -1H-indol-2-yl) -7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridine (16); 6- (5- (azetidin-3-ylmethoxy) -3-isopropyl-1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (18); 6- (5- (azetidin-3-ylmethoxy) -3-isopropyl-1H-indol-2-yl) -7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridine (19); 1- (3- (((2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-1H-indol-5-yl) oxy) methyl) piperidin-1-yl) -2-methylpropan-2-ol (23); 1- (4- (((2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-1H-indol-5-yl) oxy) methyl) piperidin-1-yl) -2-methylpropan-2-ol (24); 5- (5- ((1- (2-hydroxy-2-methylpropyl) piperidin-4-yl) methoxy) -3-isopropyl-1H-indol-2-yl) -1, 3-dimethylpyridin-2 (1H) -one (25); 1- (3- (((3-isopropyl-2- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -1H-indol-5-yl) oxy) methyl) azetidin-1-yl) -2-methylpropan-2-ol (26); 1- (4- (((3-isopropyl-2- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -1H-indol-5-yl) oxy) methyl) piperidin-1-yl) -2-methylpropan-2-ol (27); 1- (3- (((2- (7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) oxy) methyl) azetidin-1-yl) -2-methylpropan-2-ol (28); 2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-5- ((1-methylpiperidin-3-yl) methoxy) -1H-indole (30); 2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-5- ((1-methylpiperidin-4-yl) methoxy) -1H-indole (33); 5- (3-isopropyl-5- ((1-methylpiperidin-4-yl) methoxy) -1H-indol-2-yl) -1, 3-dimethylpyridin-2 (1H) -one (34); 2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-5- ((1-isopropylpiperidin-4-yl) methoxy) -1H-indole (35); 5- (3-isopropyl-5- ((1-isopropylpiperidin-4-yl) methoxy) -1H-indol-2-yl) -1, 3-dimethylpyridin-2 (1H) -one (36); 6- (3-isopropyl-5- ((1-methylpiperidin-4-yl) methoxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (41); 6- (3-isopropyl-5- ((1-isopropylpiperidin-4-yl) methoxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (42); 6- (3-isopropyl-5- ((1- (oxetan-3-yl) piperidin-4-yl) methoxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (43); 6- (3-isopropyl-5- ((1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) methoxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (44); 5- (3-isopropyl-5- ((1-isopropylpiperidin-4-yl) methoxy) -1H-indol-2-yl) -1,3, 4-trimethylpyridin-2 (1H) -one (49); 5- (3-isopropyl-5- ((1- (oxetan-3-yl) piperidin-4-yl) methoxy) -1H-indol-2-yl) -1,3, 4-trimethylpyridin-2 (1H) -one (51); 6- (3-isopropyl-5- ((1- (oxetan-3-yl) piperidin-4-yl) methoxy) -1H-indol-2-yl) -7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridine (52); 6- (3-isopropyl-5- ((1-methylpiperidin-4-yl) methoxy) -1H-indol-2-yl) -7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridine (54); 6- (3-isopropyl-5- ((1-isopropylpiperidin-4-yl) methoxy) -1H-indol-2-yl) -7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridine (55); 6- (3-isopropyl-5- ((1-isopropylazetidin-3-yl) methoxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (58); 6- (3-isopropyl-5- ((1-methylazetidin-3-yl) methoxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (59); 6- (3-isopropyl-5- ((1- (oxetan-3-yl) azetidin-3-yl) methoxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (60); 6- (3-isopropyl-5- ((1-methylazetidin-3-yl) methoxy) -1H-indol-2-yl) -7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridine (61); 6- (3-isopropyl-5- ((1-propylpiperidin-4-yl) methoxy) -1H-indol-2-yl) -7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridine (62); 2- (4- (((2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-1H-indol-5-yl) oxy) methyl) piperidin-1-yl) ethan-1-ol (71); 2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-5- ((1- (2-methoxyethyl) piperidin-4-yl) methoxy) -1H-indole (73); 5- (3-isopropyl-5- ((1- (2-methoxyethyl) piperidin-4-yl) methoxy) -1H-indol-2-yl) -1, 3-dimethylpyridin-2 (1H) -one (74); 2- (4- (((2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-1H-indol-5-yl) oxy) methyl) piperidin-1-yl) -N, N-dimethylacetamide (80); 2- (4- (((2- (1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -3-isopropyl-1H-indol-5-yl) oxy) methyl) piperidin-1-yl) -N, N-dimethylacetamide (81); 2- (4- (((3-isopropyl-2- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -1H-indol-5-yl) oxy) methyl) piperidin-1-yl) -N, N-dimethylacetamide (86); 2- (4- (((3-isopropyl-2- (1,4, 5-trimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -1H-indol-5-yl) oxy) methyl) piperidin-1-yl) -N, N-dimethylacetamide (88); 2- (4- (((2- (7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) oxy) methyl) piperidin-1-yl) -N, N-dimethylacetamide (89); 6- (3-isopropyl-5- ((1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) methoxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (91); 6- (3-isopropyl-5- ((1- (2- (methylsulfonyl) ethyl) azetidin-3-yl) methoxy) -1H-indol-2-yl) -8-methyl- [1,2,4] triazolo [1,5-a ] pyridine (92); 2- (4- ((3-isopropyl-2- (8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -1H-indol-5-yl) oxy) piperidin-1-yl) -N, N-dimethylacetamide (93); 2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-5- (piperidin-3-ylmethoxy) -1H-indole, 2TFA (94); 2- (dimethylamino) -1- (4- (((2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-1H-indol-5-yl) oxy) methyl) piperidin-1-yl) ethan-1-one (96); 5- (5- ((1- (dimethylglycyl) piperidin-4-yl) methoxy) -3-isopropyl-1H-indol-2-yl) -1, 3-dimethylpyridin-2 (1H) -one (97); 2- (dimethylamino) -1- (4- (((3-isopropyl-2- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -1H-indol-5-yl) oxy) methyl) piperidin-1-yl) ethan-1-one (102); 5- (5- ((1- (dimethylglycyl) piperidin-4-yl) methoxy) -3-isopropyl-1H-indol-2-yl) -1,3, 4-trimethylpyridin-2 (1H) -one (103); 1- (4- (((2- (7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) oxy) methyl) piperidin-1-yl) -2- (dimethylamino) ethan-1-one (106); 2- (dimethylamino) -1- (3- (((3-isopropyl-2- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -1H-indol-5-yl) oxy) methyl) azetidin-1-yl) ethan-1-one (107); 1- (3- (((2- (7, 8-dimethyl- [1,2,4] triazolo [4,3-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) oxy) methyl) azetidin-1-yl) -2- (dimethylamino) ethan-1-one (108); 2- (4- (((2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-1H-indol-5-yl) oxy) methyl) piperidin-1-yl) -N-methylacetamide (110); 2- (4- (((2- (1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -3-isopropyl-1H-indol-5-yl) oxy) methyl) piperidin-1-yl) -N-methylacetamide (111); 2- (4- (((3-isopropyl-2- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -1H-indol-5-yl) oxy) methyl) piperidin-1-yl) -N-methylacetamide (113); 2- (4- (((3-isopropyl-2- (1,4, 5-trimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -1H-indol-5-yl) oxy) methyl) piperidin-1-yl) -N-methylacetamide (116); (S) -2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -N- (pyrrolidin-3-ylmethyl) acetamide (117); (S) -2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -N- (pyrrolidin-3-ylmethyl) acetamide (119); (S) -1- (3-aminopiperidin-1-yl) -2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) ethan-1-one (120); 2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -N-methyl-N- ((1s,4s) -quinuclidin-3-yl) acetamide (121); 1- (3- (2-aminoethyl) piperidin-1-yl) -2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) ethan-1-one (122); 1- ((6R,7S) -7-amino-2-azaspiro [5.5] undecan-2-yl) -2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) ethan-1-one (123); 2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -N- ((5S) -8-methyl-8-azabicyclo [3.2.1] octan-2-yl) acetamide (124); 2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -N- ((1s,4s) -quinuclidin-3-yl) acetamide (125); 2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -N- (piperidin-2-ylmethyl) acetamide (126); 2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -N-methyl-N- (piperidin-3-yl) acetamide (127); n- (3-aminocyclohexyl) -2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) acetamide (128); 2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -1- (piperazin-1-yl) ethan-1-one (129); n- ((1R,2R) -2-aminocyclohexyl) -2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) acetamide (130); n- (4-aminocyclohexyl) -2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) acetamide (131); 1- ((1R,4R) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) -2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) ethan-1-one (132); 2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -N- ((4-hydroxy-1-methylpiperidin-4-yl) methyl) acetamide (133); (S) -2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -N- (pyrrolidin-3-yl) acetamide (134); (R) -2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -N- (pyrrolidin-3-yl) acetamide (135); 2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -N- (piperidin-4-yl) acetamide (136); (R) -2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -N- (piperidin-3-yl) acetamide (137); 2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -1- (4- (piperidin-4-yloxy) piperidin-1-yl) ethan-1-one (138); 2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -N- (1-isopropylpiperidin-4-yl) acetamide (139); 2- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) -1- (2, 6-diazaspiro [3.5] nonan-6-yl) ethan-1-one (140); 2- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) -1- (2, 7-diazaspiro [3.5] nonan-2-yl) ethan-1-one (141); 2- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) -N- (octahydrocyclopenta [ c ] pyrrol-4-yl) acetamide (142); 1- ([2,4' -bipiperidin ] -1-yl) -2- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) ethan-1-one (143); 2- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) -1- (2, 8-diazaspiro [4.5] decan-2-yl) ethan-1-one (144); 1- (hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) -2- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) ethan-1-one (145); 2- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) -N- (2- (piperidin-3-yl) ethyl) acetamide (146); 1- (4- (aminomethyl) piperidin-1-yl) -2- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) ethan-1-one (147); 2- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) -N-methyl-N- (piperidin-4-yl) acetamide (148); 2- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) -1- (5-methylhexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) ethan-1-one (149); 2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -N- (2-hydroxy-2-methylpropyl) acetamide (150); n- (2-hydroxy-2-methylpropyl) -2- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) acetamide (151); (R) -N- (2-fluoro-3-hydroxy-3-methylbutyl) -2- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) acetamide (152); 2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -N- (3-hydroxy-3-methylbutyl) acetamide (153); (R) -2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) -N- (2-fluoro-3-hydroxy-3-methylbutyl) acetamide (154); n- (3-hydroxy-3-methylbutyl) -2- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) acetamide (155); 5- (3-isopropyl-5- (piperidin-4-yloxy) -1H-indol-2-yl) -1, 3-dimethylpyridin-2 (1H) -one (156); 2- (3, 4-dimethoxyphenyl) -3-isopropyl-5- (2- (piperidin-4-yl) ethoxy) -1H-indole (158); 2- (3, 4-dimethoxyphenyl) -3-isopropyl-5- (piperidin-4-ylmethoxy) -1H-indole (159); 5- ((1-benzylpiperidin-4-yl) methoxy) -2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indole (160); 3-ethyl-2- (2-methylpyridin-4-yl) -5- (piperidin-4-ylmethoxy) -1H-indole (161); 2- (3, 4-dimethoxyphenyl) -3-ethyl-5- (piperidin-4-ylmethoxy) -1H-indole (162); 5- (benzyloxy) -3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indole (165); 3-isopropyl-2- (2-methylpyridin-4-yl) -5- (2- (pyrrolidin-1-yl) ethoxy) -1H-indole (166); 2- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) -N, N-dimethylethyl-1-amine (167); 4- (4- (((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) methyl) phenyl) morpholine (168); 3-isopropyl-2- (2-methylpyridin-4-yl) -5- (pyridin-3-ylmethoxy) -1H-indole (169); 2- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) -N-methylethyl-1-amine (172); 4- (2- ((2- (3, 4-dimethoxyphenyl) -3-isopropyl-1H-indol-5-yl) oxy) ethyl) morpholine (173); 3-isopropyl-2- (2-methylpyridin-4-yl) -5- (pyridin-4-ylmethoxy) -1H-indole (174); 4- (2- ((3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indol-5-yl) oxy) ethyl) morpholine (175); 5- ((1H-imidazol-4-yl) methoxy) -3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indole (176); 5- ((1H-imidazol-4-yl) methoxy) -3-isopropyl-2- (2-methylpyridin-4-yl) -1H-indole (178); 3-isopropyl-2- (2-methylpyridin-4-yl) -5- (piperidin-3-ylmethoxy) -1H-indole (180); 3-isopropyl-5- ((1-methylpiperidin-3-yl) methoxy) -2- (2-methylpyridin-4-yl) -1H-indole (181); 3-ethyl-5- ((1-methylpiperidin-4-yl) methoxy) -2- (2-methylpyridin-4-yl) -1H-indole (183); 3-isopropyl-5- ((1-methylpiperidin-4-yl) methoxy) -2- (2-methylpyridin-4-yl) -1H-indole (188); 3-ethyl-5- ((1-methylpiperidin-4-yl) oxy) -2- (2-methylpyridin-4-yl) -1H-indole (189); 3-isopropyl-5- ((1-isopropylpiperidin-4-yl) methoxy) -2- (2-methylpyridin-4-yl) -1H-indole (191); 3-ethyl-2- (2-methylpyridin-4-yl) -5- (2- (pyrrolidin-1-yl) ethoxy) -1H-indole (192); and 3-isopropyl-5- ((1- (2-methoxyethyl) pyrrolidin-3-yl) methoxy) -2- (2-methylpyridin-4-yl) -1H-indole (194).
The present invention may be embodied in other specific forms without departing from its spirit or essential attributes. The present invention includes all combinations of aspects and/or embodiments of the inventions mentioned in the present application. It is to be understood that any and all embodiments of the present invention may be employed to describe additional embodiments in conjunction with any other embodiment or embodiments. It is also to be understood that each individual element of these embodiments is intended to describe additional embodiments in combination with any and all other elements from any embodiment.
Definition of
The features and advantages of the present invention will be more readily understood by those of ordinary skill in the art upon reading the following detailed description. It is to be understood that certain features of the invention, which are, for clarity, described above and below in the context of separate embodiments, may also be combined to form a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be combined to form sub-combinations thereof. The embodiments identified herein as exemplary or preferred are intended to be illustrative and not limiting.
References made in the singular may also include the plural unless the application explicitly states otherwise. For example, "a" and "an" may refer to one or more/multiple.
As used herein, the phrase "compound" refers to at least one compound. For example, a compound of formula (I) includes one compound of formula (I) and two or more compounds of formula (I).
Unless otherwise indicated, it is assumed that any heteroatom having a valence that is not satisfied has a hydrogen atom sufficient to satisfy the valence.
The definitions set forth herein take precedence over definitions set forth in any patent, patent application, and/or patent application publication incorporated by reference.
The following sets forth definitions of various terms used to describe the present invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances) individually or as part of a larger group.
Throughout the specification, groups and substituents thereof may be selected by one skilled in the art to provide stable moieties and compounds.
According to the convention used in the art, the structural formulae of the present application are used
To depict bonds as points of attachment of moieties or substituents to the core or backbone structure.
The terms "halo" and "halogen" as used herein refer to F, Cl, Br and I.
The term "cyano" refers to the group-CN.
The term "amino" refers to the group-NH2。
The term "oxo" refers to the group ═ O.
The term "alkyl" as used herein refers to both branched and straight chain saturated aliphatic hydrocarbon groups containing, for example, from 1 to 12 carbon atoms, from 1 to 6 carbon atoms, and from 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, sec-butyl and tert-butyl) and pentyl (e.g., n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl and 4-methylpentyl. When symbol "When a number appears in a subscript following C ", the subscript more specifically defines the number of carbon atoms that a particular group may contain. For example, "C1-6Alkyl "denotes straight and branched chain alkyl groups having 1 to 6 carbon atoms.
The term "fluoroalkyl" as used herein is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms. For example, "C1-4Fluoroalkyl "is intended to include C substituted with one or more fluorine atoms1、C2、C3And C4An alkyl group. Representative examples of fluoroalkyl groups include, but are not limited to, -CF3and-CH2CF3。
The term "cyanoalkyl" includes both branched and straight chain saturated alkyl groups substituted with one or more cyano groups. For example, "cyanoalkyl" includes-CH2CN、-CH2CH2CN and C1-4Cyanoalkyl group.
The term "aminoalkyl" includes both branched and straight chain saturated alkyl groups substituted with one or more amine groups. For example, "aminoalkyl" includes-CH2NH2、-CH2CH2NH2And C1-4An aminoalkyl group.
The term "hydroxyalkyl" includes both branched and straight chain saturated alkyl groups substituted with one or more hydroxyl groups. For example, "hydroxyalkyl" includes-CH2OH、-CH2CH2OH, and C1-4A hydroxyalkyl group.
The term "hydroxy-fluoroalkyl" includes both branched and straight chain saturated alkyl groups substituted with one or more hydroxyl groups and one or more fluorine atoms. For example, "hydroxy-fluoroalkyl" includes-CHFCH2OH、-CH2CHFC(CH3)2OH and C1-4A hydroxy-fluoroalkyl group.
The term "cycloalkyl" as used herein refers to a group derived from a non-aromatic monocyclic or polycyclic hydrocarbon molecule by the removal of one hydrogen atom from a saturated ring carbon atom. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. When a number appears in the subscript following the symbol "C",the subscript more specifically defines the number of carbon atoms that a particular cycloalkyl group may contain. For example, "C3-C6Cycloalkyl "denotes cycloalkyl having 3 to 6 carbon atoms.
The term "alkoxy" as used herein, means an alkyl group attached to the parent molecular moiety through an oxygen atom, e.g., methoxy (-OCH)3). For example, "C1-3Alkoxy "means an alkoxy group having 1 to 3 carbon atoms.
The term "alkoxyalkyl" as used herein, means an alkoxy group attached to the alkyl group through an oxygen atom, which is attached to the parent molecular moiety, e.g., methoxymethyl (-CH)2OCH3). For example, "C2-4Alkoxyalkyl "refers to an alkoxyalkyl group having 2 to 4 carbon atoms, e.g., -CH2OCH3、-CH2CH2OCH3、-CH2OCH2CH3and-CH2CH2OCH2CH3。
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The compounds of formula (I) may be provided as amorphous solids or crystalline solids. Lyophilization may be used to provide the compound of formula (I) as an amorphous solid.
It is also understood that solvates (e.g., hydrates) of the compounds of formula (I) are also within the scope of the present invention. The term "solvate" means a physical association of a compound of formula (I) with one or more solvent molecules, whether organic or inorganic. Such physical associations include hydrogen bonding. In some cases, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "solvates" includes both solution phases and isolatable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Methods of solvation are known in the art.
Various forms of prodrugs are well known in the art and are described in:
a) the Practice of Medicinal Chemistry, Camile G.Wermuth et al, Chapter 31, (Academic Press, 1996);
b) design of Prodrugs, edited by H.Bundgaard, (Elsevier, 1985);
c) a Textbook of Drug Design and Development, edited by P.Krogsgaard-Larson and H.Bundgaard, Chapter 5, pp.113-191 (Harwood Academic Publishers, 1991); and
d) hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and JoachimM. Mayer, (Wiley-VCH, 2003).
Furthermore, the compound of formula (I) may be isolated and purified (after its preparation) to obtain a component containing the compound of formula (I) in an amount equal to or greater than 99% by weight ("substantially pure"), which component is then used or formulated as described herein. Such "substantially pure" compounds of formula (I) are also contemplated as part of the present invention in the present application.
"stable compound" and "stable structure" are intended to indicate a compound that is sufficiently robust to withstand isolation from a reaction mixture in a useful degree of purity and formulation into an effective therapeutic agent. The present invention is directed to the implementation of stable compounds.
A "therapeutically effective amount" is intended to include an amount of a compound of the invention alone, or in combination with a plurality of claimed compounds, or in combination with other active ingredients effective to act as an inhibitor of TLR7/8/9, or to treat or prevent autoimmune and/or inflammatory disease states such as SLE, IBD, Multiple Sclerosis (MS) and schunger's syndrome, and rheumatoid arthritis.
As used herein, "treatment" encompasses treatment of a disease state in a mammal (particularly a human) and includes: (a) preventing the disease state from occurring in a mammal, particularly when such mammal is predisposed to the disease state, but has not yet been diagnosed as having the disease state; (b) inhibiting the disease state, i.e., arresting its development; and/or (c) alleviating, i.e., causing regression of, the disease state.
The compounds of the present invention are intended to include all isotopes of atoms occurring in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example, and not limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include13C and14C. isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein using an appropriate isotopically-labeled reagent in place of an otherwise employed unlabeled reagent. For example, methyl (-CH)3) Also included are deuterated methyl groups, such as-CD3。
Utility of
The human immune system has evolved to defend the body against microorganisms, viruses and parasites that may cause infection, disease or death. The complex regulatory mechanisms ensure that various cellular components of the immune system target foreign substances or organisms without causing permanent or significant damage to the individual. While the initiating event is not well understood at this time, in autoimmune disease states, the immune system directs its inflammatory response to the target organs in the afflicted individual. Different autoimmune diseases are typically characterized by a major or initial target organ or affected tissue; such as the joints in the case of rheumatoid arthritis, the thyroid in the case of hashimoto's thyroiditis, the central nervous system in the case of multiple sclerosis, the pancreas in the case of type I diabetes and the intestine in the case of inflammatory bowel disease.
The compounds of the invention inhibit signaling through Toll-like receptors 7 or 8 or 9(TLR7, TLR8, TLR9) or combinations thereof. Thus, compounds of formula (I) have utility in the treatment of conditions associated with inhibition of signaling through one or more of TLR7, TLR8 or TLR 9. Such conditions include TLR7, TLR8, or TLR9 receptor-related diseases in which cytokine levels are modulated by intracellular signaling.
As used herein, the term "treatment" encompasses the treatment of a disease state in a mammal (particularly a human) and includes: (a) preventing or delaying the onset of a disease state in a mammal, particularly when such mammal is predisposed to the disease state but has not yet been diagnosed as having the disease state; (b) inhibiting the disease state, i.e., arresting its development; and/or (c) achieve complete or partial relief of a symptom or disease state, and/or reduce, ameliorate, reduce or cure a disease or disorder and/or symptoms thereof.
In view of their activity as selective inhibitors of TLR7, TLR8 or TLR9, compounds of formula (I) are useful for treating TLR7, TLR8 or TLR9 family receptor-related diseases, but are not limited to inflammatory diseases such as crohn's disease, ulcerative colitis, asthma, graft versus host disease, allograft rejection, chronic obstructive pulmonary disease; autoimmune diseases such as graves' disease, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, psoriasis; autoinflammatory diseases including Cryopyrin-associated periodic syndrome (CAPS), TNF receptor-associated periodic syndrome (TRAPS), Familial Mediterranean Fever (FMF), adult Steyr's disease, systemic onset juvenile idiopathic arthritis, gout, gouty arthritis; metabolic disorders including type 2 diabetes, atherosclerosis, myocardial infarction; destructive bone disorders (destructive bone disorders), such as bone resorption diseases, osteoarthritis, osteoporosis, multiple myeloma-related bone disorders; proliferative diseases such as acute myeloid leukemia, chronic myeloid leukemia; angiogenic diseases such as angiogenic diseases including solid tumors, ocular neovessels, and infantile hemangiomas; infectious diseases such as sepsis, septic shock, and shigellosis; neurodegenerative diseases such as alzheimer's disease, parkinson's disease, cerebral ischemia caused by traumatic injury, or neurodegenerative diseases; neoplastic diseases and viral diseases such as metastatic melanoma, kaposi's sarcoma, multiple myeloma, HIV infection, CMV retinitis, and AIDS.
More specifically, specific conditions or diseases that may be treated with the compounds of the invention include, but are not limited to, pancreatitis (acute or chronic), asthma, allergy, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, graves ' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, crohn's disease, psoriasis, graft-versus-host disease, endotoxin induced inflammatory responses, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, gout, Traumatic arthritis, rubella arthritis, acute synovitis, pancreatic beta cell disease; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis and other arthritic conditions, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption disease, allograft rejection, fever and myalgia from infection, cachexia secondary to infection, keloid formation, scar tissue formation, ulcerative colitis, pyretic disease (pyresis), influenza, osteoporosis, osteoarthritis, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, kaposi's sarcoma, multiple myeloma, sepsis, septic shock and shigellasis; alzheimer's disease, Parkinson's disease, cerebral ischemia or neurodegenerative diseases caused by traumatic injury; angiogenic diseases including solid tumors, ocular neovascularisation and infantile hemangiomas; viral diseases including acute hepatitis infections (including hepatitis a, hepatitis b and hepatitis c), HIV infection and CMV retinitis, AIDS, ARC or malignancy and herpes; stroke, myocardial ischemia, ischemia in stroke heart attack, organ hypoxia, vascular proliferation, cardiac and renal reperfusion injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and/or toxic shock syndrome, conditions associated with prostaglandin endoperoxidase synthase-2, and pemphigus vulgaris. Included in this embodiment are methods of treatment wherein the condition is selected from the group consisting of lupus, including lupus nephritis and Systemic Lupus Erythematosus (SLE), crohn's disease, ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis, and pemphigus vulgaris. Also included are methods of treatment wherein the condition is selected from ischemia reperfusion injury, including cerebral ischemia reperfusion injury caused by stroke and myocardial ischemia reperfusion injury caused by myocardial infarction. Another method of treatment is one in which the condition is multiple myeloma.
In one embodiment, the compounds of formula (I) may be used for the treatment of cancer, including Waldenstrom's Macroglobulinemia (WM), diffuse large B-cell lymphoma (DLBCL), Chronic Lymphocytic Leukemia (CLL), cutaneous diffuse large B-cell lymphoma, and primary CNS lymphoma.
In addition, the TLR7, TLR8, or TLR9 inhibitors of the invention inhibit the expression of inducible pro-inflammatory proteins such as prostaglandin endoperoxide synthase-2 (PGHS-2), also known as cyclooxygenase-2 (COX-2), IL-1, IL-6, IL-18, chemokines. Thus, additional TLR 7/8/9-related conditions include edema, analgesia, fever, and pain (such as neuromuscular pain, headache, pain due to cancer, dental pain, and arthritic pain). The compounds of the invention are also useful in the treatment of veterinary viral infections, such as lentiviral infections, including but not limited to equine infectious anemia virus; or a retroviral infection, including feline immunodeficiency virus, bovine immunodeficiency virus, and canine immunodeficiency virus.
Accordingly, the present invention provides a method for treating such conditions comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of formula (I) or a salt thereof. A "therapeutically effective amount" is intended to include an amount of a compound of the present invention that is effective to inhibit autoimmune disease or chronic inflammatory disease when administered alone or in combination.
Methods of treating TLR7, TLR8, or TLR 9-associated conditions may comprise administering a compound of formula (I), alone or in combination with each other and/or other suitable therapeutic agents for treating such conditions. Thus, "therapeutically effective amount" is also intended to include an amount of a combination of claimed compounds effective to inhibit TLR7, TLR8, or TLR9 and/or to treat a disease associated with TLR7, TLR8, or TLR 9.
Examples of such other therapeutic agents include corticosteroids, rolipram, calphostins C, cytokine inhibitory anti-inflammatory drugs (CSAID), interleukin-10, glucocorticoids, salicylates, nitric oxide and other immunosuppressive agents; nuclear translocation inhibitors such as Deoxyspergualin (DSG); non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, celecoxib, and rofecoxib; steroids such as prednisone or dexamethasone; antiviral agents such as abacavir; antiproliferative agents, such as methotrexate, leflunomide, FK506 (tacrolimus,) Antimalarial drugs such as hydroxychloroquine, cytotoxic drugs such as azathioprine and cyclophosphamide, TNF- α inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptors and rapamycin (sirolimus or sirolimus)) Or a derivative thereof.
When used in combination with the compounds of the present invention, the above other therapeutic agents may be used, for example, in the amounts indicated in the Physicians' desk reference (pdr) or as otherwise determined by one of ordinary skill in the art. Such other therapeutic agent or agents may be administered prior to, concurrently with, or subsequent to the compound of the invention in the methods of the invention. The invention also provides pharmaceutical compositions capable of treating TLR7/8/9 receptor-related conditions, including IL-1 family receptor-mediated diseases as described above.
The compositions of the invention may contain other therapeutic agents as described above, and may be formulated, for example, by using conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of administration desired (e.g., excipients, binders, preservatives, stabilizers, flavoring agents, etc.) according to those techniques well known in the art of pharmaceutical formulation.
Accordingly, the invention also includes compositions comprising one or more compounds of formula (I) and a pharmaceutically acceptable carrier.
By "pharmaceutically acceptable carrier" is meant a vehicle generally accepted in the art for delivering biologically active agents to animals, particularly mammals. Pharmaceutically acceptable carriers are formulated according to a number of factors within the purview of one of ordinary skill in the art. These include, but are not limited to, the type and nature of the active agent being formulated; a subject to be administered a composition containing an agent; the intended route of administration of the composition; and the therapeutic indications for which it is intended. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can also include many different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons well known to those of ordinary skill in the art (e.g., stabilization of the active agent, binder, etc.). A description of suitable pharmaceutically acceptable carriers and the factors involved in their selection are found in a variety of readily available sources (e.g., Remington's pharmaceutical sciences, 17 th edition (1985)), which are incorporated herein by reference in their entirety.
The compound according to formula (I) may be administered by any means suitable for the condition to be treated, which may depend on the requirements of site-specific therapy or the amount of compound of formula (I) to be delivered.
Also included in the present invention are pharmaceutical compositions comprising a compound of formula (I) and one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as "carrier" materials), and if desired other active ingredients. The compounds of formula (I) may be administered by any suitable route, preferably in the form of pharmaceutical compositions adapted to such route, and in dosages effective for the intended treatment. The compounds and compositions of the present invention may be administered, for example, orally, mucosally, or parenterally (including intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly, and intrasternally) in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles. For example, the pharmaceutical carrier may comprise a mixture of mannitol or lactose and microcrystalline cellulose. The mixture may contain additional components such as lubricants (e.g., magnesium stearate) and disintegrants (such as crospovidone). The carrier mixture may be filled into gelatin capsules or compressed into tablets. For example, the pharmaceutical composition may be administered as an oral dosage form or infusion.
For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, liquid capsule, suspension, or liquid. The pharmaceutical compositions are preferably prepared in the form of dosage units containing specific amounts of the active ingredient. For example, the pharmaceutical composition may be provided as a tablet or capsule containing the active ingredient in an amount ranging from about 0.1 to 1000mg, preferably from about 0.25 to 250mg, and more preferably from about 0.5 to 100 mg. For humans or other mammals, suitable daily dosages may vary widely depending on the condition of the patient and other factors, but can be determined using routine methods.
Any pharmaceutical composition contemplated herein can be delivered orally, for example, by any acceptable and suitable oral formulation. Exemplary oral formulations include, but are not limited to, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs, for example. Pharmaceutical compositions intended for oral administration may be prepared according to any method known in the art for preparing pharmaceutical compositions intended for oral administration. In order to provide pharmaceutically palatable preparations, the pharmaceutical compositions according to the present invention may contain at least one agent chosen from sweetening agents, flavouring agents, colouring agents, demulcents, antioxidants and preserving agents.
Tablets may be prepared, for example, by mixing at least one compound of formula (I) with at least one non-toxic pharmaceutically acceptable excipient suitable for the manufacture of tablets. Exemplary excipients include, but are not limited to, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrating agents, such as microcrystalline cellulose, croscarmellose sodium, corn starch and alginic acid; binding agents, such as starch, gelatin, polyvinylpyrrolidone and acacia; and lubricating agents, such as magnesium stearate, stearic acid, and talc. In addition, tablets may be uncoated or coated by known techniques to mask the unpleasant taste of the drug, which is unpleasant to taste, or to delay disintegration and absorption of the active ingredient in the gastrointestinal tract, thereby maintaining the effect of the active ingredient for a longer period. Exemplary water-soluble taste-masking materials include, but are not limited to, hydroxypropylmethyl cellulose and hydroxypropyl cellulose. Exemplary time delay materials include, but are not limited to, ethyl cellulose and cellulose acetate butyrate.
Hard gelatin capsules may be prepared, for example, by mixing at least one compound of formula (I) with at least one inert solid diluent (e.g., calcium carbonate; calcium phosphate; and kaolin).
Soft gelatin capsules may be prepared, for example, by mixing at least one compound of formula (I) with at least one water-soluble carrier (e.g., polyethylene glycol) and at least one oil medium (e.g., peanut oil, liquid paraffin, and olive oil).
Aqueous suspensions may be prepared, for example, by mixing at least one compound of formula (I) with at least one excipient suitable for the manufacture of aqueous suspensions. Exemplary excipients suitable for the production of aqueous suspensions include, but are not limited to, suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents, such as naturally occurring phosphatides, for example lecithin; condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate; condensation products of ethylene oxide with long chain aliphatic alcohols, such as heptadecaethylene-oxycetanol; condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, for example polyoxyethylene sorbitol monooleate; and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspension may further contain at least one preservative, such as ethyl parahydroxybenzoate and n-propyl parahydroxybenzoate; at least one colorant; at least one flavoring agent; and/or at least one sweetener including, but not limited to, sucrose, saccharin, and aspartame, for example.
Oily suspensions may be prepared, for example, by suspending at least one compound of formula (I) in a vegetable oil (e.g. arachis oil, olive oil, sesame oil, and coconut oil) or in a mineral oil (e.g. liquid paraffin). The oily suspensions may also contain at least one thickening agent, for example beeswax, hard paraffin and cetyl alcohol. To provide a palatable oily suspension, at least one sweetening agent and/or at least one flavouring agent, which have been described above, may be added to the oily suspension. The oily suspensions may also contain at least one preservative including, but not limited to, for example, antioxidants such as butylated hydroxyanisole and alpha-tocopherol.
Dispersible powders and granules can be prepared, for example, by mixing at least one compound of formula (I) with at least one dispersing and/or wetting agent; at least one suspending agent; and/or at least one preservative. Suitable dispersing, wetting and suspending agents are those already described above. Exemplary preservatives include, but are not limited to, for example, antioxidants, such as ascorbic acid. In addition, dispersible powders and granules may also contain at least one excipient including, but not limited to, for example, sweetening, flavoring and coloring agents.
Emulsions of at least one compound of formula (I) thereof may for example be prepared as oil-in-water emulsions. The oily phase of the emulsion comprising the compound of formula (I) may be constituted in a known manner by known ingredients. The oily phase may be provided by, but is not limited to, vegetable oils (e.g., olive oil and peanut oil), mineral oils (e.g., liquid paraffin), and mixtures thereof, for example. Although this phase may comprise only emulsifiers, it may comprise mixtures of at least one emulsifier with a fat or an oil or with both a fat and an oil. Suitable emulsifiers include, but are not limited to, for example, naturally occurring phospholipids, such as soy lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate; and condensation products of partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier, which acts as a stabilizer. It is also preferred to include both oil and fat. Emulsifiers, with or without stabilizers, constitute the so-called emulsifying waxes, and waxes, together with oils and fats, constitute the so-called emulsifying ointment bases, which form the oily dispersed phase of cream formulations. The emulsions may also contain sweetening agents, flavouring agents, preservatives and/or antioxidants. Emulsifiers and emulsion stabilizers suitable for use in the formulations of the present invention include tween 60, span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate alone or with a wax, or other materials well known in the art.
For example, the compounds of formula (I) may also be delivered intravenously, subcutaneously and/or intramuscularly via any pharmaceutically acceptable and suitable injectable form. Exemplary injectable forms include, but are not limited to, for example, sterile aqueous solutions containing an acceptable vehicle and solvent, such as water, ringer's solution and isotonic sodium chloride solution; a sterile oil-in-water microemulsion; and aqueous or oily suspensions.
Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules using one or more of the carriers or diluents mentioned for use in formulations for oral administration or by using other suitable dispersing or wetting agents and suspending agents. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum and/or various buffers. Other adjuvants and modes of administration are well known in the pharmaceutical art. The active ingredient may also be administered by injection as a composition with a suitable carrier, including saline, dextrose or water, or with cyclodextrin (i.e., Captisol), co-solvent solubilization (i.e., propylene glycol) or micelle solubilization (i.e., tween 80).
The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Acceptable vehicles and solvents that may be used are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Sterile injectable oil-in-water microemulsions may be prepared, for example, by: 1) dissolving at least one compound of formula (I) in an oil phase (e.g., a mixture of soybean oil and lecithin); 2) combining an oil phase comprising formula (I) with a mixture of water and glycerol; and 3) processing the combination to form a microemulsion.
Sterile aqueous or oily suspensions may be prepared according to methods known in the art. For example, sterile aqueous solutions or suspensions may be prepared with a non-toxic parenterally-acceptable diluent or solvent, for example 1, 3-butanediol; and sterile oily suspensions may be prepared with sterile, non-toxic, acceptable solvents or suspending media, such as sterile fixed oils, for example synthetic mono-or diglycerides, and fatty acids, for example oleic acid.
Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, Self Emulsifying Drug Delivery Systems (SEDDS) such as d- α -tocopherol polyethylene glycol 1000 succinate, surfactants for pharmaceutical dosage forms such as tweens, polyethoxylated castor oil such as CREMOPHOR surfactant (BASF), or other similar polymeric delivery matrices, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin. Cyclodextrins, such as alpha-, beta-, and gamma-cyclodextrins, or chemically modified derivatives such as hydroxyalkyl cyclodextrins, including 2-and 3-hydroxypropyl-cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of the compounds of the formulae described herein.
The pharmaceutically active compounds of the present invention may be processed according to conventional pharmaceutical procedures to produce pharmaceutical agents for administration to patients, including humans and other mammals. The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, buffers and the like. Tablets and pills may additionally be prepared with an enteric coating. Such compositions may also contain adjuvants such as wetting agents, sweetening, flavoring and perfuming agents.
The amount of compound administered and the dosage regimen used to treat a condition with a compound and/or composition of the invention depends on a variety of factors including the age, weight, sex, medical condition of the subject, the type of disease, the severity of the disease, the route and frequency of administration, and the particular compound used. Thus, the dosage regimen may vary widely, but can be determined routinely using standard methods. A daily dosage of about 0.001 to 100mg/kg body weight, preferably about 0.0025 to about 50mg/kg body weight, and most preferably about 0.005 to 10mg/kg body weight may be appropriate. The daily dose can be administered in one to four doses per day. Other dosing regimens include cycles of one dose per week and one dose every two days.
For therapeutic purposes, the active compounds of the invention are usually combined with one or more adjuvants appropriate for the indicated route of administration. If administered orally, the compounds can be mixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled release formulation, which may be provided in a dispersion of the active compound in hydroxypropylmethylcellulose.
The pharmaceutical compositions of the present invention comprise at least one compound of formula (I) and optionally an additional agent selected from any pharmaceutically acceptable carrier, adjuvant and vehicle. The alternative compositions of the invention comprise a compound of formula (I) as described herein, or a prodrug thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.
The invention also includes articles of manufacture. As used herein, articles of manufacture are intended to include, but are not limited to, kits and packages. The article of the present invention comprises: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition comprises: a first therapeutic agent comprising: a compound of the invention or a pharmaceutically acceptable salt form thereof; and (c) package insert indicating that the pharmaceutical composition is useful for the treatment of inflammatory and/or autoimmune diseases (as defined hereinbefore). In another embodiment, the package insert indicates that the pharmaceutical composition can be used in combination with a second therapeutic agent (as previously defined) to treat an inflammatory disease and/or an autoimmune disease. The article may further comprise: (d) a second container, wherein components (a) and (b) are located within the second container and component (c) is located within or outside the second container. Being located within the first and second containers means that the respective container contains the item within its boundaries.
The first container is a receiving container for containing a pharmaceutical composition. The container may be used for manufacturing, storage, transport and/or individual/bulk sale. The first container is intended to encompass a bottle, jar, vial, flask, syringe, tube (e.g., for a cream formulation), or any other container for manufacturing, containing, storing, or distributing a pharmaceutical product.
The second container is a container for holding the first container and optionally packaging instructions. Examples of such secondary containers include, but are not limited to, boxes (e.g., paperboard or plastic), crates, cartons, bags (e.g., paper or plastic bags), pouches, and bags. The package insert may be physically attached to the outside of the first container by tape, glue, staples or other attachment means, or it may be placed inside the second container without any physical means of attachment to the first container. Alternatively, the package insert is located outside the second container. When located outside the second container, it is preferred that the package insert is physically attached by tape, glue, staples or other attachment means. Alternatively, it may be adjacent to or in contact with the outside of the second container, rather than being physically attached.
The package insert is a label, indicia, etc. that lists information relating to the pharmaceutical composition located in the first container. The listed information will typically be determined by a regulatory agency (e.g., the U.S. food and drug administration) that governs the region in which the article is sold. In one embodiment, the package insert specifically recites the indications for which the pharmaceutical composition is approved. The package insert may be made of any material from which a person can read the information contained therein or thereon. For example, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive-backed paper or plastic, etc.) on which the desired information has been formed (e.g., printed or applied).
Preparation method
The compounds of the present invention can be prepared in a variety of ways well known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, along with synthetic methods known in the art of synthetic organic chemistry or variations thereof as understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited in this application are incorporated by reference in their entirety.
The compounds of the present invention can be prepared using the reactions and techniques described in this section. These reactions are carried out in solvents appropriate to the reagents and materials used and suitable for the transformations carried out. Furthermore, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and work-up procedures, are selected as conditions standard for the reaction, as will be readily recognized by those skilled in the art. It will be appreciated by those skilled in the art of organic synthesis that the functional groups present on the various parts of the molecule must be compatible with the reagents and reactions proposed. Such limitations on substituents compatible with these reaction conditions will be apparent to those skilled in the art, and alternative methods may be used. This will sometimes require a judgment to modify the order of the synthetic steps or to select a particular process scheme over another in order to obtain the desired compound of the invention. It will also be appreciated that another major consideration in the planning of any synthetic route in this field is the judicious choice of protecting groups for protecting the reactive functional groups present in the compounds described in the present invention. Authoritative explanations describing many alternatives to trained practitioners are Greene and Wuts (Protective Groups In Organic Synthesis, third edition, Wileyand Sons, 1999).
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