Substituted amide compounds useful as farnesoid X receptor modulators
阅读说明：本技术 可用作类法尼醇x受体调节剂的取代酰胺化合物 (Substituted amide compounds useful as farnesoid X receptor modulators ) 是由 D·A·威克 S·J·奈良 S·切鲁库 K·萨库南 F·A·杰普里 S·坦加尔 R·纳拉 于 2020-02-14 设计创作，主要内容包括：公开了式(I)的化合物：或其立体异构体、互变异构体或药学上可接受的盐或溶剂化物,其中Q是：(i)卤代、氰基、羟基、-NR～(x)R～(x)、-C(O)OH、-C(O)NH-(2)、被零至6个R～(1a)取代的C-(1-6)烷基或-P(O)R～(1c)R～(1c)；或(ii)-L-R～(1)；并且A、X～(1)、X～(2)、X～(3)、X～(4)、Z～(1)、Z～(2)、R～(1)、R～(1a)、R～(1c)、R～(2)、R～(3a)、R～(3b)、R～(x)、L、a、b和d在本文中有定义。还公开了使用这些化合物调节类法尼醇X受体(FXR)的活性的方法；包含这些化合物的药物组合物；以及通过使用所述化合物和药物组合物治疗与FXR调节异常相关的疾病、障碍或病症如病理性纤维化、移植排斥、癌症、骨质疏松症和炎性障碍的方法。(Disclosed are compounds of formula (I): or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein Q is: (i) halo, cyano, hydroxy, -NR x R x 、‑C(O)OH、‑C(O)NH 2 From zero to 6R 1a Substituted C 1‑6 Alkyl or-P (O) R 1c R 1c (ii) a Or (ii) -L-R 1 (ii) a And A, X 1 、X 2 、X 3 、X 4 、Z 1 、Z 2 、R 1 、R 1a 、R 1c 、R 2 、R 3a 、R 3b 、R x L, a, b and d are defined herein. Also disclosed are methods of using these compounds to modulate the activity of Farnesoid X Receptor (FXR); pharmaceutical compositions comprising these compounds; and methods of treating diseases, disorders, or conditions associated with dysregulation of FXR such as pathological fibrosis, transplant rejection, cancer, osteoporosis, and inflammatory disorders by using the compounds and pharmaceutical compositions.)
1. A compound of formula (I):
or a stereoisomer, tautomer, or salt or solvate thereof, wherein:
X1is CR5aOr N;
X2is CR5bOr N;
X3is CR5cOr N;
X4is CR5dOr N; provided that X1、X2、X3And X4Zero, 1 or 2 of are N;
Z1and Z2Independently is CH2Or O; provided that Z is1And Z2Is CH2；
a is zero or 1;
b is zero, 1 or 2;
d is zero, 1 or 2; provided that when a, b and d are each zero, Z1And Z2Each is CH2；
Q is:
(i) halo, cyano, hydroxy, -NRxRx、-C(O)OH、-C(O)NH2From zero to 6R1aSubstituted C1-6Alkyl or-P (O) R1cR1c(ii) a Or
(ii)-L-R1；
L is-O-, -OCR1dR1dC(O)-、-C(O)--C(O)O-、-C(O)NR1e-、-C(O)NR1eC(O)-、-NR1e-、-NR1eC(O)-、-NR1eC(O)O-、-NR1eC(O)NR1e-、-NR1eS(O)2-、-S(O)2-or-S (O)2NR1e-；
R1Is substituted by zero to 6R1aSubstituted C1-6Alkyl or a cyclic group selected from 3 to 8 membered carbocyclyl, 6 to 10 membered aryl, 4 to 10 membered heterocyclyl and 5 to 10 membered heteroaryl, wherein the cyclic group is interrupted by zero to 3R1bSubstitution; provided that when R is1When it is said cyclic group, Z1And Z2Each is CH2；
Each R1aIndependently of one another, halo, hydroxy, -NRwRwOxo, cyano, C1-3Alkoxy radical, C1-3Haloalkoxy, -C (O) ORx、-C(O)NRwRwor-NRxC(O)Ry；
Each R1bIndependently is halo, oxo, cyano, hydroxy, -NH2、C1-6Alkyl radical, C1-6Alkoxy, -NH (C)1-6Alkyl), -N (C)1-6Alkyl radical)2、-NRxC(O)(C1-6Alkyl) or C3-6Cycloalkyl, wherein each of said alkyl, alkoxy and cycloalkyl is substituted with zero to 6R 1aSubstitution;
each R1cIndependently is C1-6An alkyl group;
each R1dIndependently of one another is hydrogen, halo, C1-3Alkyl or C3-6A cycloalkyl group;
each R1eIndependently of each other is hydrogen, C1-3Alkyl or C3-6A cycloalkyl group;
R2the method comprises the following steps:
(i)C1-6alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy or-NRvRvWherein each of said alkyl, alkenyl, alkynyl and alkoxy is substituted with zero to 6R2aSubstitution;
(ii)C3-8carbocyclyl, C6-8Spirobicyclic, 4-to 7-membered heterocyclyl, phenyl, or 5-to 6-membered heteroaryl, wherein each of said carbocyclic, spirobicyclic, heterocyclyl, phenyl, and heteroaryl is substituted with zero to 3R2bSubstitution; or
(iii)-CH2(C3-6Cycloalkyl), -CH2(4-to 6-membered heterocyclyl), -NRx(CH2)0-2(C3-6Cycloalkyl), -NR-x(CH2)0-2(C5-8Bicycloalkyl), -NRx(CH2)0-2(C5-8Spirobicycloalkyl), -NRx(CH2)0-2(4-to 6-membered heterocyclyl), -NRx(CH2)0-2(5-to 6-membered heteroaryl), -NRx(CH2)0-2(phenyl), -O (CH)2)0-2(C3-6Cycloalkyl), -O (CH)2)0-2(C5-8Bicycloalkyl), -O (CH)2)0-2(C5-8Spirobicycloalkyl), -O (CH)2)0-2(4-to 6-membered heterocyclic group), -O (CH)2)0-2(5-to 6-membered heteroaryl) or-O (CH)2)0-2(phenyl) wherein each of said cycloalkyl, heterocyclyl, bicycloalkyl, spirobicycloalkyl, aryl and heteroaryl is substituted with zero to 3R2bSubstitution;
each R2aIndependently is halo, alkyl, cyano, hydroxy, oxo, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Halogenated Alkoxy, -NRxRx、-C(O)(C1-6Alkyl), -C (O) (C)3-6Cycloalkyl), -NR-xC(O)Ry、-C(O)(C1-6Alkyl), -C (O) ORx、-C(O)NRwRw、-S(O)2Ry、-S(O)2(C1-3Fluoroalkyl group), -NRxS(O)2(C1-3Alkyl), -NR-xS(O)2(C3-6Cycloalkyl), -S (O)2NRzRzor-P (O) RyRy；
Each R2bIndependently is halo, cyano, hydroxy, oxo, C1-6Alkyl radical, C1-6Alkoxy, -NRxRx、-NRxC(O)O(C1-3Alkyl), -C (O) (C)1-3Alkyl) or-S (O)2(C1-3Alkyl) wherein each of said alkyl and alkoxy is substituted with zero to 6R2aSubstitution;
R3aand R3bIndependently of each other is hydrogen, C1-3Alkyl radical, C1-3Haloalkyl or C3-6Cycloalkyl, or R3aAnd R3bTogether with the carbon atom to which they are attached form C3-6A cycloalkyl group;
a is:
(i) a cyano group;
(ii) phenyl or 5 to 10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, wherein each of said phenyl and heteroaryl is substituted with zero to 3R4aSubstitution; or
(iii)
Each R4aIndependently is halo, cyano, hydroxy, -NH2、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy, - (CH)2)0-3NH(C1-6Alkyl), - (CH)2)0-2N(C1-6Alkyl radical)2、-(CH2)0-3(C3-6Carbocyclyl) or- (CH2)0-3(4-to 6-membered heterocyclyl), wherein each of the alkyl, alkoxy, alkenyl, and alkynyl is substituted with zero to 6R4dAnd each of said carbocyclyl and heterocyclyl is substituted with zero to 3R4eSubstitution;
R4bis C1-6Alkyl, - (CH)2)0-3(C3-6Cycloalkyl) or- (CH)2)0-3(4-to 6-membered heterocyclyl), wherein each of said alkyl groups is substituted with zero to 6R 4dAnd each of said cycloalkyl and heterocyclyl is substituted with zero to 3R4eSubstitution;
each R4cIndependently of each other is hydrogen, C1-6Alkyl radical, C3-6Cycloalkyl, 4-to 6-membered heterocyclyl, phenyl, or 5-to 6-membered heteroaryl;
each R4dIndependently of one another, halo, hydroxy, -NRxRxOxo, cyano, C1-3Alkoxy or C1-3A haloalkoxy group;
each R4eIndependently is halo, oxo, cyano, hydroxy, -NH2、C1-6Alkyl radical, C1-6Alkoxy, -NH (C)1-6Alkyl) or-N (C)1-6Alkyl radical)2Wherein each of said alkyl and alkoxy groups is substituted with zero to 6R4dSubstitution;
R5a、R5b、R5cand R5dEach of which is independently hydrogen, halo, hydroxy, cyano, substituted with zero to 6R5eSubstituted C1-6Alkyl, by zero to 6R5eSubstituted C1-6Alkoxy, -C (O) ORx、-C(O)NRwRw、-S(O)2Ry、-S(O)2NRzRzOr by zero to 3R5fSubstituted phenyl;
R5eeach of which is independently halo, hydroxy, -NRxRxOxo, cyano, C1-3Alkoxy or C1-3A haloalkoxy group;
each R5fIndependently is halo, oxo, cyano, hydroxy, -NH2、C1-6Alkyl radical, C1-6Alkoxy, -NH (C)1-6Alkyl) or-N (C)1-6Alkyl radical)2Wherein each of said alkyl and alkoxy groups is substituted with zero to 6R5eSubstitution;
each RvIndependently of each other is hydrogen, C1-6Alkyl or alternatively, two RvTogether with the nitrogen atom to which they are attached form a 4-to 7-membered bicyclic or spirocyclic ring moiety containing zero to 2 additional heteroatoms independently selected from N, O and S, wherein each ring may be interrupted by zero to 6R 2aSubstitution;
each RwIndependently of each other is hydrogen, C1-6Alkyl or C3-6A cycloalkyl group; or alternatively, two RwTogether with the nitrogen atom to which they are attached form a 4 to 7 membered ring moiety containing zero to 2 additional heteroatoms independently selected from N, O and S;
each RxIndependently of each other is hydrogen, C1-6Alkyl or C3-6A cycloalkyl group;
Ryis C1-6Alkyl or C3-6A cycloalkyl group; and is
Each RzIndependently of each other is hydrogen, C1-6Alkyl or C3-6A cycloalkyl group; or alternatively, two RzTogether with the nitrogen atom to which they are attached form a 4 to 7 membered ring moiety containing zero to 2 additional heteroatoms independently selected from N, O and S.
2. A compound according to claim 1, or a stereoisomer, tautomer, or salt or solvate thereof, wherein:
q is:
(i) f, Cl, Br, cyano, hydroxy, -NRxRx、-C(O)OH、-C(O)NH2From zero to 6R1dSubstituted C1-4Alkyl or-P (O) R1cR1c(ii) a Or
(ii)-L-R1；
L is-O-, -OCR1aR1aC(O)-、-C(O)--C(O)O-、-C(O)NR1b-、-NR1b-、-NR1bC(O)-、-NR1bC(O)NR1b-、-NR1bS(O)2-、-S(O)2-or-S (O)2NR1b-；
R1Is substituted by zero to 6R1aSubstituted C1-6Alkyl or is selected from C3-6Cyclic groups of cycloalkyl, phenyl, 4-to 10-membered heterocyclyl and 5-to 10-membered heteroaryl, wherein the cyclic group is substituted with zero to 3R1bSubstitution;
each R1aIndependently F, Cl, hydroxy, -NRwRwOxo, cyano, C1-3Alkoxy radical, C1-3Haloalkoxy, -C (O) OH or-C (O) O (C) 1-2Alkyl groups);
each R1bIndependently F, Cl, cyano, hydroxy, oxo, -NH2、C1-4Alkyl radical, C1-4Alkoxy, -NH (C)1-4Alkyl), -N (C)1-4Alkyl radical)2、-NRxC(O)(C1-6Alkyl) or C3-4Cycloalkyl, wherein each of said alkyl, alkoxy and cycloalkyl is substituted with zero to 6R1aSubstitution;
each R1cIndependently is C1-4An alkyl group;
R2the method comprises the following steps:
(i)C1-4alkyl radical, C1-4Alkoxy or-NRvRvWherein each of said alkyl and alkoxy groups is substituted with zero to 4R2aSubstitution;
(ii)C3-8carbocyclyl, C6-8Spirobicyclic group, phenyl or 4-to 7-membered heterocyclic group, wherein each of said carbocyclic group, spirobicyclic group and heterocyclic group is substituted with zero to 3R2bSubstitution; or
(iii)-CH2(C3-5Cycloalkyl), -CH2(4-to 6-membered heterocyclyl), -NRx(CH2)0-2(C3-5Cycloalkyl), -NR-x(CH2)0-2(4-to 6-membered heterocyclyl), -NRx(CH2)0-2(phenyl) or-O (phenyl)) Wherein each of said cycloalkyl, heterocyclyl, phenyl and pyridyl is substituted with zero to 3R2bSubstitution;
each R2aIndependently F, Cl, hydroxy, -NRxRxOxo, cyano, C1-3Alkoxy radical, C1-3Haloalkoxy or-C (O) OH;
each R2bIndependently F, Cl, cyano, hydroxy, C1-4Alkyl radical, C1-3Alkoxy, -NRxRx、-NRxC(O)O(C1-3Alkyl), -C (O) (C)1-2Alkyl) or-S (O)2(C1-2Alkyl) wherein each of said alkyl and alkoxy is substituted with zero to 4R2aSubstitution;
a is:
(i) A cyano group;
(ii) phenyl or 5 to 6 membered heteroaryl containing zero to 4 heteroatoms independently selected from N, O and S, wherein each of said phenyl and heteroaryl is substituted with zero to 3R4aSubstitution; or
(iii)
Each R4aIndependently F, Cl, cyano, hydroxy, -NH2、C1-4Alkyl radical, C1-4Alkoxy, - (CH)2)0-3NH(C1-6Alkyl), - (CH)2)0-3N(C1-6Alkyl radical)2、-(CH2)0-3(C3-6Carbocyclyl) or- (CH2)0-3(4-to 6-membered heterocyclyl), wherein each of the alkyl and alkoxy is substituted with zero to 4R4dSubstitution; and each of said carbocyclyl and heterocyclyl is substituted with zero to 3R4eSubstitution;
R4bis C1-4Alkyl, - (CH)2)0-3(C3-6Cycloalkyl) or- (CH)2)0-3(4-to 6-membered heterocyclyl), wherein each of said alkyl groups is substituted with zero to 4R4dAnd each of said cycloalkyl and heterocyclyl is substituted with zero to 3R4eSubstitution;
each R4cIndependently of each other is hydrogen, C1-3Alkyl or C3-6A cycloalkyl group;
each R4dIndependently F, Cl, hydroxy, -NRxRxOxo, cyano, C1-3Alkoxy or C1-3A fluoroalkoxy group;
each R4eIndependently F, Cl, oxo, cyano, hydroxy, -NH2、C1-4Alkyl radical, C1-4Alkoxy, -NH (C)1-6Alkyl) or-N (C)1-6Alkyl radical)2Wherein each of said alkyl and alkoxy groups is substituted with zero to 4R4dSubstitution;
R5a、R5b、R5cand R5dEach of which is independently hydrogen, F, Cl, hydroxy, cyano, substituted with zero to 4R 5eSubstituted C1-3Alkyl, by zero to 4R5eSubstituted C1-3Alkoxy, -C (O) ORx、-C(O)NRwRw、-S(O)2Ry、-S(O)2NRzRzOr by zero to 3R5fSubstituted phenyl;
R5a、R5b、R5cand R5dEach of which is independently hydrogen, F, Cl, hydroxy, cyano, substituted with zero to 4R5eSubstituted C1-3Alkyl, by zero to 4R5eSubstituted C1-3Alkoxy, -C (O) ORx、-C(O)NRwRw、-S(O)2Ry、-S(O)2NRzRzOr by zero to 3R5fSubstituted phenyl;
each RwIndependently of each other is hydrogen, C1-4Alkyl or C3-6A cycloalkyl group; or alternatively, two RwTogether with the nitrogen atom to which they are attached form a 4 to 7 membered ring moiety containing zero to 2 additional heteroatoms independently selected from N, O and S;
each RxIndependently is H, C1-4Alkyl or C3-6A cycloalkyl group;
Ryis C1-4Alkyl or C3-6A cycloalkyl group; and is
Each RzIndependently of each other is hydrogen, C1-4Alkyl or C3-6A cycloalkyl group; or alternatively, two RzTogether with the nitrogen atom to which they are attached form a 4 to 7 membered ring moiety containing zero to 2 additional heteroatoms independently selected from N, O and S.
3. A compound according to claim 1, or a stereoisomer, tautomer, or salt or solvate thereof, wherein:
X1is CH;
X2is CH;
X3is CH;
X4is N or CH;
q is:
(i) f, Cl, Br, cyano, hydroxy, -CF3、-C(CH3)2OH、-CH2CH2C(O)OCH3、-C(O)OH、-C(O)NH2or-P (O) (CH)3)2(ii) a Or
(ii)-L-R1；
L is-O-, -OCR1aR1aC(O)O-、-C(O)O-、-C(O)NR1b-、-NR1b-、-NR1bC(O)O-、-NR1bS(O)2-、-S(O)2-or-S (O)2NR1b-；
R1Is substituted by zero to 4R 1aSubstituted C1-4Alkyl radical, C3-4Cycloalkyl or a cyclic group selected from phenyl, thiazolyl, pyridyl and pyrimidinyl, wherein the cyclic group is substituted with zero to 1R1bSubstitution;
each R1aIndependently is F, cyano, hydroxy, -C (O) OH or-C (O) OCH3；
Each R1bIndependently is C1-2Alkyl radical, C1-2Fluoroalkyl radical, C1-2Alkoxy, -OC (CH)3)2CN, cyclopropyl or cyanocyclopropyl;
R2is-NHCH2C(CH3)2CH2OH、-NHCH2CH2C(CH3)2OH, -NH (hydroxycyclohexyl), -NH (methyl-hydroxycyclohexyl) or a group selected from cyclopropyl, cyclobutyl, cyclohexyl, tetrahydropyranyl, bicyclo [1.1.1]Pentyl and dioxotetrahydrothiopyranyl, each cyclic group being substituted with zero to 2 substituents independently selected from F, hydroxy, oxo, -CH3、-CF3and-C (CH)3)2Substituent substitution of OH;
R3ais hydrogen or-CH3；
R3bIs hydrogen;
a is phenyl, pyrazolyl, oxadiazolyl, pyridinyl or indazolyl, each of which is substituted with zero to 3 heteroatoms independently selected from N, O and S, with zero to 2R4aSubstitution;
each R4aIndependently Cl, -CH3、-CH3、-C(CH3)3、-CF3、-CF2CH3、-C(CH3)2F、-N(CH3)2、-C(O)NH2Cyclopropyl or fluorocyclopropyl; and is
R5a、R5b、R5cAnd R5dEach is independently hydrogen, F, Cl, cyano, -CH3or-CF3。
4. A compound according to claim 1, or a stereoisomer, tautomer, or salt or solvate thereof, wherein R 2Is C3-5Carbocyclic ring, -NRx(CH2)0-2(C3-6Cycloalkyl) or a 4 to 5 membered heterocyclyl having 1 or 2 heteroatoms independently selected from N, O and S, wherein each of said cycloalkyl, carbocycle and heterocyclyl is independently substituted with zero to 3R2bAnd (4) substitution.
5. A compound according to claim 1 or a stereoisomer, tautomer or thereofA salt or solvate thereof, wherein Z1Is CH2(ii) a And Z2Is CH2。
6. A compound according to claim 1, or a stereoisomer, tautomer, or salt or solvate thereof, wherein Z1And Z2Is CH2And Z is1And Z2Is O.
7. A compound according to claim 1, or a stereoisomer, tautomer, or salt or solvate thereof, wherein a is:
(i) a 5-membered heteroaryl containing zero to 3 heteroatoms independently selected from N, O and S, wherein the heteroaryl is substituted with zero to 3R4aSubstitution; or
(ii)
8. The compound of claim 1, or a stereoisomer, tautomer, or salt or solvate thereof, wherein a is a 5-membered heteroaryl containing zero to 3 heteroatoms independently selected from N, O and S, wherein the heteroaryl is substituted with zero to 3R4aAnd (4) substitution.
9. A compound according to claim 1, or a stereoisomer, tautomer, or salt or solvate thereof, wherein: q is F, Cl, Br, cyano, -CF 3、-CH2CH2C(O)OCH3、-C(O)NH2or-P (O) (CH)3)2。
10. A compound according to claim 1, or a stereoisomer, tautomer, or salt or solvate thereof, wherein: q is-L-R1。
11. A compound according to claim 1 or a stereoisomer, tautomer, or salt or solvate thereof, wherein
Q is:
(i) f, Cl, Br, cyano, -CF3、-CH2CH2C(O)OCH3、-C(O)NH2or-P (O) (CH)3)2(ii) a Or
(ii)-C(O)OCH3、-C(O)NH(CH2CH3)、-OCH3、-OCH2CH3、-OCHF2、-OCH2C(O)OCH3、-NHC(O)OC(CH3)3、-NHS(O)2CH3、-S(O)2CH3、-S(O)2NH (cyclopropyl), -S (O)2NH(CH3)、-P(O)(CH3)2-C (O) NH (thiazolyl), -NH (trifluoromethylphenyl), -NH (ethylphenyl), -NH (ethoxyphenyl) or-NH (difluoromethylphenyl); and is
A is pyrazolyl, oxadiazolyl, phenyl, pyridyl or indazolyl, each of which is substituted with zero to 3R4aAnd (4) substitution.
12. The compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein the compound is:
n- (3-chlorophenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (1);
n- (3-chlorophenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (2);
n- (3-chlorophenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -4, 4-difluorocyclohexane-1-carboxamide (3);
N- (3-cyanophenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (4);
n- (3-cyanophenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (5);
n- (3-cyanophenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -4, 4-difluorocyclohexane-1-carboxamide (6);
n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3-fluorophenyl) bicyclo [1.1.1] pentane-1-carboxamide (7);
n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-fluorophenyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (8);
n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -4, 4-difluoro-N- (3-fluorophenyl) cyclohexane-1-carboxamide (9);
n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3, 4-difluorophenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (10);
n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3, 4-difluorophenyl) -4, 4-difluorocyclohexane-1-carboxamide (11);
N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (difluoromethoxy) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (12);
n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (difluoromethoxy) phenyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (13);
n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3- (trifluoromethyl) phenyl) bicyclo [1.1.1] pentane-1-carboxamide (14);
n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) -N- (3- (trifluoromethyl) phenyl) cyclobutane-1-carboxamide (15);
n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -4, 4-difluoro-N- (3- (trifluoromethyl) phenyl) cyclohexane-1-carboxamide (16);
n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (2-methoxypyridin-4-yl) bicyclo [1.1.1] pentane-1-carboxamide (17);
n- (3- (N-cyclopropylsulfamoyl) phenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (18);
(1S,3S) -N- (3- (N-cyclopropylsulfamoyl) phenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (19);
n- (3- (N-cyclopropylsulfamoyl) phenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -4, 4-difluorocyclohexane-1-carboxamide (20);
n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3- (N-methylsulfamoyl) phenyl) bicyclo [1.1.1] pentane-1-carboxamide (21);
(1S,3S) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-N- (3- (N-methylsulfamoyl) phenyl) -3- (trifluoromethyl) cyclobutane-1-carboxamide (22);
n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -4, 4-difluoro-N- (3- (N-methylsulfamoyl) phenyl) cyclohexane-1-carboxamide (23);
n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (dimethylphosphoryl) phenyl) -4, 4-difluorocyclohexane-1-carboxamide (24);
n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (dimethylphosphoryl) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (25);
(1S,3S) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (dimethylphosphoryl) phenyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (26);
methyl 3- (N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide) benzoate (27);
n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (ethylcarbamoyl) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (28);
n- (3-carbamoylphenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (29);
1- (3-bromophenyl) -1- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- ((1R,4R) -4-hydroxy-4-methylcyclohexyl) urea (30);
n- (3-bromophenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -2, 2-difluorocyclopropane-1-carboxamide (31);
tert-butyl (3- (N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamido) phenyl) carbamate (32);
N- (3-bromophenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (33);
n- (3-bromophenyl) -3-fluoro-N- ((4- (5- (1-fluorocyclopropyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) bicyclo [1.1.1] pentane-1-carboxamide (34);
n- (3-bromophenyl) -3-fluoro-N- ((4- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) bicyclo [1.1.1] pentane-1-carboxamide (35);
(1S,3S) -N- (3-bromophenyl) -N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (36);
n- (3-bromo-4-chlorophenyl) -N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (37);
n- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-cyanophenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (38);
(1S,3S) -N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-cyanophenyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (39);
(1S,3S) -N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-cyanophenyl) -3-hydroxy-3-methylcyclobutane-1-carboxamide (40);
N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-cyanophenyl) -3, 3-difluorocyclobutane-1-carboxamide (41);
n- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-cyanophenyl) -4, 4-difluorocyclohexane-1-carboxamide (42);
n- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (dimethylphosphoryl) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (43);
n- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (dimethylphosphoryl) phenyl) -3, 3-difluorocyclobutane-1-carboxamide (44);
(1S,3S) -N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (dimethylphosphoryl) phenyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (45);
n- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (dimethylphosphoryl) phenyl) tetrahydro-2H-pyran-4-carboxamide (46);
n- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (dimethylphosphoryl) phenyl) tetrahydro-2H-thiopyran-4-carboxamide 1, 1-dioxide (47);
N- (3-bromophenyl) -N- ((4- (5- (1, 1-difluoroethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (48);
n- (3-cyanophenyl) -N- ((4- (5- (1, 1-difluoroethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (49);
(1S,3S) -N- (3-cyanophenyl) -N- ((4- (5- (1, 1-difluoroethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3-methylcyclobutane-1-carboxamide (50);
(1S,3S) -N- (3-cyanophenyl) -N- ((4- (5- (1, 1-difluoroethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (51);
n- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-ethoxyphenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (52);
n- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-ethoxyphenyl) -3, 3-difluorocyclobutane-1-carboxamide (53);
n- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-ethoxyphenyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (54);
n- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-ethoxyphenyl) tetrahydro-2H-pyran-4-carboxamide (55);
N- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-ethoxyphenyl) tetrahydro-2H-thiopyran-4-carboxamide 1, 1-dioxide (56);
(1S,3S) -N- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-N- (3-methoxyphenyl) -3- (trifluoromethyl) cyclobutane-1-carboxamide (57);
n- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3-methoxyphenyl) bicyclo [1.1.1] pentane-1-carboxamide (58);
n- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3, 3-difluoro-N- (3-methoxyphenyl) cyclobutane-1-carboxamide (59);
n- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-methoxyphenyl) tetrahydro-2H-pyran-4-carboxamide (60);
n- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-methoxyphenyl) tetrahydro-2H-thiopyran-4-carboxamide 1, 1-dioxide (61);
n- (3-cyano-5-fluorophenyl) -N- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (62);
(1S,3S) -N- (3-cyano-5-fluorophenyl) -N- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (63);
N- (3-cyano-5-fluorophenyl) -N- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3, 3-difluorocyclobutane-1-carboxamide (64);
n- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3, 3-difluoro-N- (3- (methylsulfonamido) phenyl) cyclobutane-1-carboxamide (65);
n- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3- (methylsulfonamido) phenyl) bicyclo [1.1.1] pentane-1-carboxamide (66);
(1S,3S) -N- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-N- (3- (methylsulfonamido) phenyl) -3- (trifluoromethyl) cyclobutane-1-carboxamide (67);
n- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3- (methylsulfonyl) phenyl) bicyclo [1.1.1] pentane-1-carboxamide (68);
n- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -4, 4-difluoro-N- (3- (methylsulfonyl) phenyl) cyclohexane-1-carboxamide (69);
n- (3-cyanophenyl) -N- (1- (4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) ethyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (70);
n- (3-bromophenyl) -N- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclopropanesulfonamide (71);
N- (3-cyanophenyl) -N- ((4- (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (72);
n- (3-cyanophenyl) -N- ((4- (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -4, 4-difluorocyclohexane-1-carboxamide (73);
(1S,3S) -N- (3-cyanophenyl) -N- ((4- (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3-methylcyclobutane-1-carboxamide (74);
(1S,3S) -N- (3-cyanophenyl) -N- ((4- (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (75);
(1S,3S) -N- ((4- (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-N- (3- (methylsulfonyl) phenyl) -3- (trifluoromethyl) cyclobutane-1-carboxamide (76);
n- ((4- (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -4, 4-difluoro-N- (3- (methylsulfonyl) phenyl) cyclohexane-1-carboxamide (77);
n- ((4- (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3- (methylsulfonyl) phenyl) bicyclo [1.1.1] pentane-1-carboxamide (78);
Methyl 2- (3- (N- ((4- (3-chloro-4- (dimethylamino) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenoxy) acetate (79);
methyl 2- (3- (N- ((4- (4- (dimethylamino) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenoxy) acetate (80);
methyl 2- (3- (N- ((1- (1-methyl-1H-indazol-5-yl) -2-oxabicyclo [2.2.2] oct-4-yl) methyl) tetrahydro-2H-pyran-4-carboxamido) phenoxy) acetate (81);
3- (N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamide) -N- (thiazol-2-yl) benzamide (82);
n- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- ((4-ethoxyphenyl) amino) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (83);
n- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- ((4- (difluoromethoxy) phenyl) amino) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (84);
n- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- ((4-ethoxyphenyl) amino) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (85);
n- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- ((4-ethylphenyl) amino) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (86);
N- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3- ((4- (trifluoromethyl) phenyl) amino) phenyl) bicyclo [1.1.1] pentane-1-carboxamide (87);
methyl 3- (3- (N- ((4- (4- (dimethylamino) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) propanoate (88);
methyl 3- (3- (N- ((4- (4- (dimethylamino) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) propanoate (89);
(1S,3S) -N- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-N- (3- (methylsulfonyl) phenyl) -3- (trifluoromethyl) cyclobutane-1-carboxamide (90);
(1S,3S) -N- (3- ((4- (1-cyanocyclopropyl) phenyl) amino) phenyl) -N- ((4- (5- (1-fluorocyclopropyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (91);
(1S,3S) -N- (3- ((4- ((2-cyanoprop-2-yl) oxy) phenyl) amino) phenyl) -N- ((4- (5- (1, 1-difluoroethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (92);
(1S,3S) -N- (3- ((4- (1-cyanocyclopropyl) phenyl) amino) phenyl) -N- ((4- (5- (1, 1-difluoroethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (93);
N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (5-cyanopyridin-3-yl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (94);
1- (3-cyanophenyl) -1- ((4- (5- (2-fluoropropan-2-yl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- ((1R,4R) -4-hydroxy-4-methylcyclohexyl) urea (95);
1- (3-cyanophenyl) -1- ((4- (5- (2-fluoropropan-2-yl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- ((1R,4R) -4-hydroxycyclohexyl) urea (96);
1- (3-cyanophenyl) -1- ((4- (5- (2-fluoropropan-2-yl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- (3-hydroxy-2, 2-dimethylpropyl) urea (97);
1- (3-cyanophenyl) -1- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- ((1R,4R) -4-hydroxycyclohexyl) urea (98);
1- (3-cyanophenyl) -1- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- ((1R,4R) -4-hydroxy-4-methylcyclohexyl) urea (99);
1- (3-cyanophenyl) -1- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- (3-hydroxy-2, 2-dimethylpropyl) urea (100);
1- (3-bromo-4-fluorophenyl) -1- ((4- (5- (2-fluoropropan-2-yl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- ((1R,4R) -4-hydroxycyclohexyl) urea (101);
N- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- ((5- (difluoromethoxy) pyrimidin-2-yl) amino) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (102);
n- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- ((2-cyclopropylpyrimidin-5-yl) amino) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (103);
n- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- ((5- (difluoromethoxy) pyridin-2-yl) amino) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (104);
n- (3- ((5-cyclopropylpyrimidin-2-yl) amino) phenyl) -3-fluoro-N- ((4- (5- (trifluoromethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) bicyclo [1.1.1] pentane-1-carboxamide (105);
n- (3- ((5- (difluoromethoxy) pyrimidin-2-yl) amino) phenyl) -3-fluoro-N- ((4- (5- (trifluoromethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) bicyclo [1.1.1] pentane-1-carboxamide (106);
n- (3- ((4- (difluoromethoxy) phenyl) amino) phenyl) -3-fluoro-N- ((4- (5- (trifluoromethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) bicyclo [1.1.1] pentane-1-carboxamide (107);
n- (3- ((5- (difluoromethoxy) pyridin-2-yl) amino) phenyl) -3-fluoro-N- ((4- (5- (trifluoromethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) bicyclo [1.1.1] pentane-1-carboxamide (108);
N- (3- ((5-cyclopropylpyridin-2-yl) amino) phenyl) -3-fluoro-N- ((4- (5- (trifluoromethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) bicyclo [1.1.1] pentane-1-carboxamide (109);
n- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3-hydroxyphenyl) bicyclo [1.1.1] pentane-1-carboxamide (110);
n- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (cyanomethoxy) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (111);
n- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3- (2-hydroxy-2-methylpropoxy) phenyl) bicyclo [1.1.1] pentane-1-carboxamide (112);
2- (3- (N- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamido) phenoxy) -2-methylpropanoic acid (113);
n- (3-cyanophenyl) -3-fluoro-N- ((4- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) bicyclo [1.1.1] pentane-1-carboxamide (114);
(1S,3S) -N- (3-cyanophenyl) -3-hydroxy-3- (trifluoromethyl) -N- ((4- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclobutane-1-carboxamide (115);
N- (3-cyanophenyl) -N- ((4- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) tetrahydro-2H-pyran-4-carboxamide (116);
(1S,3S) -N- (3-cyanophenyl) -3-hydroxy-3-methyl-N- ((4- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclobutane-1-carboxamide (117);
n- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- ((5- (difluoromethoxy) pyrimidin-2-yl) oxy) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (118);
n- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- ((5- (difluoromethoxy) pyridin-2-yl) oxy) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (119);
3- (N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide) benzoic acid (120);
n- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-carbamoyl-4-fluorophenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (121);
n- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (ethylcarbamoyl) -4-fluorophenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (122);
(1S,3S) -N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-N- (3-isopropoxyphenyl) -3- (trifluoromethyl) cyclobutane-1-carboxamide (123);
(1S,3S) -N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-N- (3-isopropoxyphenyl) -3- (trifluoromethyl) cyclobutane-1-carboxamide (124);
(1S,3S) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-N- (3-isopropoxyphenyl) -3-methylcyclobutane-1-carboxamide (125);
(1S,3S) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-N- (3-isopropoxyphenyl) -3- (trifluoromethyl) cyclobutane-1-carboxamide (126);
n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3-isopropoxyphenyl) bicyclo [1.1.1] pentane-1-carboxamide (127);
n- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (4-fluoro-3- (2-hydroxypropan-2-yl) phenyl) bicyclo [1.1.1] pentane-1-carboxamide (128);
n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3-methoxyphenyl) bicyclo [1.1.1] pentane-1-carboxamide (129);
N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-ethoxyphenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (130);
(S) -1- (3-bromophenyl) -1- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- (2-fluoro-3-hydroxy-3-methylbutyl) urea (131);
n- (3-bromophenyl) -N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.1] hept-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (132);
(1S,3S) -N- (3-bromophenyl) -N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.1] hept-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (133);
n- (3-bromophenyl) -N- ((4- (5- (2-fluoropropan-2-yl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- (2-hydroxypropan-2-yl) bicyclo [1.1.1] pentane-1-carboxamide (134);
n- (3-cyano-5-fluorophenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (135);
(1S,3S) -N- (3-cyano-5-fluorophenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (136);
N- (3-cyano-5-fluorophenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3, 3-difluorocyclobutane-1-carboxamide (137);
n- (3-cyano-5-fluorophenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) tetrahydro-2H-thiopyran-4-carboxamide 1, 1-dioxide (138);
3- (4- (((1S,3S) -N- (3-bromophenyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamido) methyl) bicyclo [2.2.2] oct-1-yl) -1,2, 4-oxadiazole-5-carboxamide (139); or
3- (4- ((N- (3-bromophenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamido) methyl) bicyclo [2.2.2] oct-1-yl) -1,2, 4-oxadiazole-5-carboxamide (140).
13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
14. A compound according to any one of claims 1 to 12, or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof, for use in the treatment of pathological fibrosis, cancer, inflammatory disorders, metabolic disorders or cholestatic disorders.
15. The compound for use according to claim 14, wherein the pathological fibrosis is liver fibrosis, kidney fibrosis, biliary fibrosis or pancreatic fibrosis.
16. A compound according to any one of claims 1 to 12, or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof, for use in the treatment of non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic nephropathy, Primary Sclerosing Cholangitis (PSC) or Primary Biliary Cirrhosis (PBC).
17. A compound according to any one of claims 1 to 13, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, for use in the treatment of Idiopathic Pulmonary Fibrosis (IPF).
Technical Field
The present invention relates generally to substituted amide compounds useful as Farnesoid X Receptor (FXR) modulators, pharmaceutical compositions comprising such compounds, and to their use in therapy, particularly in the treatment or prevention of diseases, disorders, and conditions for which FXR modulators are indicated.
Background
FXR or NR1H4 (member 4 of nuclear receptor subfamily 1H group) is a nuclear receptor that activates the expression of specific target genes in a ligand-dependent manner. FXR is expressed in the liver, throughout the gastrointestinal tract, colon, ovaries, adrenal glands, kidney, and in the gallbladder and biliary tree in humans. FXR forms heterodimers with Retinoid X Receptor (RXR) and binds to specific response elements in target genes to regulate gene transcription (b.m. forman et al, Cell 1995; 81: 687; w.seol et al, mol.endocrinol.1995; 9: 72). The FXR/RXR heterodimer typically binds to the inverted repeat (i.e., the IR-1 sequence) of a consensus hexanucleotide sequence (AGGTCA) separated by a single nucleotide. Relevant physiological ligands for FXR are bile acids including chenodeoxycholic acid and its taurine conjugates (d.j. parks et al, Science 1999; 284: 1365; m.makishima et al, Science 1999; 284: 1362). FXR activation regulates the expression of multiple genes encoding enzymes and transporters involved in bile acid synthesis, flow into and out of the liver and gut, resulting in a net reduction in total endogenous bile acids in the negative feedback loop. FXR is involved in paracrine and endocrine signaling by upregulating the expression of the cytokines fibroblast growth factor 15 (rodents) or 19 (primates), which may also contribute to the regulation of bile acid concentrations (Holt et al, Genes Dev.2003; 17: 1581; Inagaki et al, Cell Metab 2005; 2: 217). Therefore, FXR is considered to be a major regulator of bile acid homeostasis.
One use of FXR agonists is for the treatment of diseases of bile acid dysregulation, including cholestatic diseases (e.g., primary biliary cirrhosis and primary sclerosing cholangitis), which may lead to fibrosis, cirrhosis, cholangiocarcinoma, hepatocellular carcinoma, liver failure, and death. While elevated concentrations of bile acids in the liver have deleterious effects, bile acids also affect the microflora and integrity of the small intestine. Obstruction of bile flow in humans or rodents causes intestinal bacterial proliferation and mucosal damage, which may lead to bacterial translocation across mucosal barriers and systemic infection (Berg, Trends microbiol.1995; 3: 149-. Mice lacking FXR have increased levels of ileal bacteria and an impaired epithelial barrier, whereas activation of intestinal FXR plays an important role in preventing bacterial overgrowth and maintaining the integrity of the intestinal epithelium (Inagaki et al, Proc Natl Acad Sci 2006; 103: 3920-. Over time, FXR deficient mice spontaneously develop hepatocellular carcinoma, and this condition can be eliminated by selectively reactivating FXR in the gut (Degirolamo et al, Hepatology 61: 161-170). In rodent models of cholestasis, activation of FXR with small molecule agonist drugs or transgene expression of FXR in the gut normalizes bile acid concentrations, reduces cell proliferation in the hepatobiliary duct and reduces inflammatory cell infiltration, necrotic area and liver fibrosis (Liu et al, j.clin.invest.2003; 112: 1678-. Some of these beneficial effects observed in preclinical models of cholestasis have been transferred to human patients, and the FXR agonist obeticholic acid (OCA or OCALIVA) TM) Has been approved for the treatment of primary biliary cirrhosis (https:// www.fda.gov/newsevents/newfrom/precursors/ucm503964. htm).
In addition to controlling bile acid homeostasis, FXR agonists regulate hepatic expression of hundreds of genes encoding proteins involved in: cholesterol and lipid metabolism and transport, glucose homeostasis, inflammation, chemotaxis and apoptosis, as well as other pathways (Zhan et al, PLoS One 2014; 9: e 105930; Ijssennagger et al, J Hepatol 2016; 64: 1158-. Consistent with these broad effects on gene expression, FXR agonists have also been studied in preclinical models of fibrosis, cancer, inflammatory diseases and metabolic disorders, including dyslipidemia, obesity, type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), and metabolic syndrome (Crawley, Expert opin.
FXR agonists are also being investigated in human clinical trials for the treatment of NAFLD (a more advanced form of fatty liver disease), nonalcoholic steatohepatitis (NASH), and related complications. NAFLD is one of the most common causes of chronic liver disease in the world today (Vernon et al, Aliment Pharmacol Ther 2011; 34: 274-285). Risk factors for NAFLD include obesity, type 2 diabetes (T2DM), insulin resistance, hypertension and dyslipidemia. In a 6-week clinical trial with T2DM patients with NAFLD, the FXR agonist OCA statistically significantly improved insulin sensitivity and lost body weight, showing beneficial effects on some of these risk factors (Mudaliar et al, Gastroenterology 2013; 145: 574-. NASH is the most severe and progressive form of NAFLD and includes hepatic steatosis, inflammation and ballooning degeneration with altered amounts of pericellular fibrosis (Sanyal et al, Hepatology 2015; 61: 1392-. OCA statistically significantly improved hepatic steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis in a 72-week clinical trial in patients with NASH, as assessed by histological analysis of liver biopsies (Neuschwander-Tetri et al, Lancet 2015; 385: 956-. Given that NASH is the second leading cause of hepatocellular carcinoma (HCC) and liver transplantation in the united states, these data also suggest that FXR agonists may show benefit in clinical outcome (Wong et al, Hepatology 2014; 59: 2188-.
Applicants have discovered compounds useful for treating a disease, disorder or condition associated with Farnesoid X Receptor (FXR) activity in a patient in need thereof. These compounds are provided as medicaments having desirable stability, bioavailability, therapeutic index and toxicity values important to their drugability.
Disclosure of Invention
The present invention provides compounds of formula (I) and subgenus and species thereof, including stereoisomers, tautomers, pharmaceutically acceptable salts and solvates thereof, which are useful as FXR modulators.
The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof.
The compounds of formula (I) and compositions comprising the compounds of formula (I) may be used in therapy, alone or in combination with one or more additional therapeutic agents.
The invention also provides processes and intermediates for preparing the compounds of formula (I) and/or salts thereof.
The compounds of the invention may be used for the treatment of a disease, disorder or condition associated with the activity of Farnesoid X Receptors (FXR) in a patient in need of such treatment by: by administering to the patient a therapeutically effective amount of the compound, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof. The disease, disorder or condition may be associated with pathological fibrosis. The compounds of the present invention may be used alone, in combination with one or more compounds of the present invention, or in combination with one or more (e.g., one to two) other therapeutic agents.
The compounds of the present invention may be used as single agents or in combination with other agents for the treatment of a disease, disorder or condition selected from: nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic nephropathy, Primary Sclerosing Cholangitis (PSC), and Primary Biliary Cirrhosis (PBC). The compounds of the invention may be used as single agents or in combination with other agents for the treatment of Idiopathic Pulmonary Fibrosis (IPF).
The compounds of the present invention may be used in the manufacture of a medicament for the treatment of a disease, disorder or condition in a patient in need of such treatment.
Other features and advantages of the invention will become apparent from the following detailed description, and from the claims.
Detailed Description
The present application provides compounds according to formula (I), including all stereoisomers, solvates, prodrugs and pharmaceutically acceptable salts and solvate forms thereof. The present application also provides pharmaceutical compositions containing at least one compound according to formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, and optionally at least one additional therapeutic agent. Further, the present application provides methods for treating a patient suffering from an FXR modulated disease or disorder, such as, for example, biliary fibrosis, liver fibrosis, kidney fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), Primary Sclerosing Cholangitis (PSC), Primary Biliary Cirrhosis (PBC), and pancreatic fibrosis, by: administering to a patient in need of such treatment a therapeutically effective amount of a compound of the present invention, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof (and optionally in combination with at least one additional therapeutic agent).
A first aspect of the invention provides at least one compound of formula (I):
or a stereoisomer, tautomer, or salt or solvate thereof, wherein:
X1is CR5aOr N;
X2is CR5bOr N;
X3is CR5cOr N;
X4is CR5dOr N; provided that X1、X2、X3And X4Zero, 1 or 2 of are N;
Z1and Z2Independently is CH2Or O; provided that Z is1And Z2Is CH2；
a is zero or 1;
b is zero, 1 or 2;
d is zero, 1 or 2; provided that when a, b and d are each zero, Z1And Z2Each is CH2；
Q is:
(i) halo, cyano, hydroxy, -NRxRx、-C(O)OH、-C(O)NH2From zero to 6R1aSubstituted C1-6Alkyl or-P (O) R1cR1c(ii) a Or
(ii)-L-R1；
L is-O-, -OCR1dR1dC(O)-、-C(O)--C(O)O-、-C(O)NR1e-、-C(O)NR1eC(O)-、-NR1e-、-NR1eC(O)-、-NR1eC(O)O-、-NR1eC(O)NR1e-、-NR1eS(O)2-、-S(O)2-or-S (O)2NR1e-；
R1Is substituted by zero to 6R1aSubstituted C1-6Alkyl or a cyclic group selected from 3 to 8 membered carbocyclyl, 6 to 10 membered aryl, 4 to 10 membered heterocyclyl and 5 to 10 membered heteroaryl, wherein the cyclic group is interrupted by zero to 3R1bSubstitution; provided that when R is1When it is said cyclic group, Z1And Z2Each is CH2；
Each R1aIndependently of one another, halo, hydroxy, -NRwRwOxo, cyano, C1-3Alkoxy radical, C1-3Haloalkoxy, -C (O) ORx、-C(O)NRwRwor-NRxC(O)Ry；
Each R1bIndependently is halo, oxo, cyano, hydroxy, -NH2、C1-6Alkyl radical, C1-6Alkoxy, -NH (C)1-6Alkyl), -N (C)1-6Alkyl radical)2、-NRxC(O)(C1-6Alkyl) or C3-6Cycloalkyl, wherein each of said alkyl, alkoxy and cycloalkyl is substituted with zero to 6R 1aSubstitution;
each R1cIndependently is C1-6An alkyl group;
each R1dIndependently of one another is hydrogen, halo, C1-3Alkyl or C3-6A cycloalkyl group;
each R1eIndependently of each other is hydrogen, C1-3Alkyl or C3-6A cycloalkyl group;
R2the method comprises the following steps:
(i)C1-6alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy or-NRvRvWherein each of said alkyl, alkenyl, alkynyl and alkoxy is substituted with zero to 6R2aSubstitution;
(ii)C3-8carbocyclyl, C6-8Spirobicyclic, 4-to 7-membered heterocyclyl, phenyl, or 5-to 6-membered heteroaryl, wherein each of said carbocyclic, spirobicyclic, heterocyclyl, phenyl, and heteroaryl is substituted with zero to 3R2bSubstitution; or
(iii)-CH2(C3-6Cycloalkyl), -CH2(4-to 6-membered heterocyclyl), -NRx(CH2)0-2(C3-6Cycloalkyl), -NR-x(CH2)0-2(C5-8Bicycloalkyl), -NRx(CH2)0-2(C5-8Spirobicycloalkyl), -NRx(CH2)0-2(4-to 6-membered heterocyclyl), -NRx(CH2)0-2(5-to 6-membered heteroaryl), -NRx(CH2)0-2(phenyl), -O (CH)2)0-2(C3-6Cycloalkyl), -O (CH)2)0-2(C5-8Bicycloalkyl), -O (CH)2)0-2(C5-8Spirobicycloalkyl), -O (CH)2)0-2(4-to 6-membered heterocyclic group), -O (CH)2)0-2(5-to 6-membered heteroaryl) or-O (CH)2)0-2(phenyl) wherein each of said cycloalkyl, heterocyclyl, bicycloalkyl, spirobicycloalkyl, aryl and heteroaryl is substituted with zero to 3R2bSubstitution;
each R2aIndependently is halo, alkyl, cyano, hydroxy, oxo, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy, -NR xRx、-C(O)(C1-6Alkyl), -C (O) (C)3-6Cycloalkyl), -NR-xC(O)Ry、-C(O)(C1-6Alkyl), -C (O) ORx、-C(O)NRwRw、-S(O)2Ry、-S(O)2(C1-3Fluoroalkyl group), -NRxS(O)2(C1-3Alkyl), -NR-xS(O)2(C3-6Cycloalkyl), -S (O)2NRzRzor-P (O) RyRy；
Each R2bIndependently is halo, cyano, hydroxy, oxo, C1-6Alkyl radical, C1-6Alkoxy, -NRxRx、-NRxC(O)O(C1-3Alkyl), -C (O) (C)1-3Alkyl) or-S (O)2(C1-3Alkyl) wherein each of said alkyl and alkoxy is substituted with zero to 6R2aSubstitution;
R3aand R3bIndependently of each other is hydrogen, C1-3Alkyl radical, C1-3Haloalkyl or C3-6Cycloalkyl, or R3aAnd R3bTogether with the carbon atom to which they are attached form C3-6A cycloalkyl group;
a is:
(i) a cyano group;
(ii) phenyl or 5 to 10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, wherein each of said phenyl and heteroaryl is substituted with zero to 3R4aSubstitution; or
Each R4aIndependently is halo, cyano, hydroxy, -NH2、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy, - (CH)2)0-3NH(C1-6Alkyl), - (CH)2)0-2N(C1-6Alkyl radical)2、-(CH2)0-3(C3-6Carbocyclyl) or- (CH2)0-3(4-to 6-membered heterocyclyl), wherein each of the alkyl, alkoxy, alkenyl, and alkynyl is substituted with zero to 6R4dAnd each of said carbocyclyl and heterocyclyl is substituted with zero to 3R4eSubstitution;
R4bis C1-6Alkyl, - (CH)2)0-3(C3-6Cycloalkyl) or- (CH)2)0-3(4-to 6-membered heterocyclyl), wherein each of said alkyl groups is substituted with zero to 6R 4dAnd each of said cycloalkyl and heterocyclyl is substituted with zero to 3R4eSubstitution;
each R4cIndependently of each other is hydrogen, C1-6Alkyl radical, C3-6Cycloalkyl, 4-to 6-membered heterocyclyl, phenyl, or 5-to 6-membered heteroaryl;
each R4dIndependently of one another, halo, hydroxy, -NRxRxOxo, cyano, C1-3Alkoxy or C1-3A haloalkoxy group;
each R4eIndependently is halo, oxo, cyano, hydroxy, -NH2、C1-6Alkyl radical, C1-6Alkoxy, -NH (C)1-6Alkyl) or-N (C)1-6Alkyl radical)2Wherein each of said alkyl and alkoxy groups is substituted with zero to 6R4dSubstitution;
R5a、R5b、R5cand R5dEach of which is independently hydrogen, halo, hydroxy, cyano, substituted with zero to 6R5eSubstituted C1-6Alkyl, by zero to 6R5eSubstituted C1-6Alkoxy, -C (O) ORx、-C(O)NRwRw、-S(O)2Ry、-S(O)2NRzRzOr by zero to 3R5fSubstituted phenyl;
R5eeach of which is independently halo, hydroxy, -NRxRxOxo, cyano, C1-3Alkoxy or C1-3A haloalkoxy group;
each R5fIndependently is halo, oxo, cyano, hydroxy, -NH2、C1-6Alkyl radical, C1-6Alkoxy, -NH (C)1-6Alkyl) or-N (C)1-6Alkyl radical)2Wherein each of said alkyl and alkoxy groups is substituted with zero to 6R5eSubstitution;
each RvIndependently of each other is hydrogen, C1-6Alkyl or alternatively, two RvTogether with the nitrogen atom to which they are attached form a 4-to 7-membered bicyclic or spirocyclic ring moiety containing zero to 2 additional heteroatoms independently selected from N, O and S, wherein each ring may be interrupted by zero to 6R 2aSubstitution;
each RwIndependently of each other is hydrogen, C1-6Alkyl or C3-6A cycloalkyl group; or alternatively, two RwTogether with the nitrogen atom to which they are attached form a 4 to 7 membered ring moiety containing zero to 2 additional heteroatoms independently selected from N, O and S;
each RxIndependently of each other is hydrogen, C1-6Alkyl or C3-6A cycloalkyl group;
Ryis C1-6Alkyl or C3-6A cycloalkyl group; and is
Each RzIndependently of each other is hydrogen, C1-6Alkyl or C3-6A cycloalkyl group; or alternatively, two RzTogether with the nitrogen atom to which they are attached form a 4 to 7 membered ring moiety containing zero to 2 additional heteroatoms independently selected from N, O and S.
In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein:
q is:
(i) f, Cl, Br, cyano, hydroxy, -NRxRx、-C(O)OH、-C(O)NH2From zero to 6R1dSubstituted C1-4Alkyl or-P (O) R1cR1c(ii) a Or
(ii)-L-R1；
L is-O-, -OCR1aR1aC(O)-、-C(O)--C(O)O-、-C(O)NR1b-、-NR1b-、-NR1bC(O)-、-NR1bC(O)NR1b-、-NR1bS(O)2-、-S(O)2-or-S (O)2NR1b-；
R1Is substituted by zero to 6R1aSubstituted C1-6Alkyl or is selected from C3-6Cyclic groups of cycloalkyl, phenyl, 4-to 10-membered heterocyclyl and 5-to 10-membered heteroaryl, wherein the cyclic group is substituted with zero to 3R1bSubstitution;
each R1aIndependently F, Cl, hydroxy, -NRwRwOxo, cyano, C1-3Alkoxy radical, C1-3Haloalkoxy, -C (O) OH or-C (O) O (C) 1-2Alkyl groups);
each R1bIndependently F, Cl, cyano, hydroxy, oxo, -NH2、C1-4Alkyl radical, C1-4Alkoxy, -NH (C)1-4Alkyl), -N (C)1-4Alkyl radical)2、-NRxC(O)(C1-6Alkyl) or C3-4Cycloalkyl, wherein each of said alkyl, alkoxy and cycloalkyl is substituted with zero to 6R1aSubstitution;
each R1cIndependently is C1-4An alkyl group;
R2the method comprises the following steps:
(i)C1-4alkyl radical, C1-4Alkoxy or-NRvRvWherein each of said alkyl and alkoxy groups is substituted with zero to 4R2aSubstitution;
(ii)C3-8carbocyclyl, C6-8Spirobicyclic group, phenyl or 4-to 7-membered heterocyclic group, wherein each of said carbocyclic group, spirobicyclic group and heterocyclic group is substituted with zero to 3R2bSubstitution; or
(iii)-CH2(C3-5Cycloalkyl), -CH2(4-to 6-membered heterocyclyl), -NRx(CH2)0-2(C3-5Cycloalkyl), -NR-x(CH2)0-2(4-to 6-membered heterocyclyl), -NRx(CH2)0-2(phenyl) or-O (phenyl), wherein each of said cycloalkyl, heterocyclyl, phenyl and pyridyl is substituted with zero to 3R2bSubstitution;
each R2aIndependently F, Cl, hydroxy, -NRxRxOxo, cyano, C1-3Alkoxy radical, C1-3Haloalkoxy or-C (O) OH;
each R2bIndependently F, Cl, cyano, hydroxy, C1-4Alkyl radical, C1-3Alkoxy, -NRxRx、-NRxC(O)O(C1-3Alkyl), -C (O) (C)1-2Alkyl) or-S (O)2(C1-2Alkyl) wherein each of said alkyl and alkoxy is substituted with zero to 4R2aSubstitution;
a is:
(i) A cyano group;
(ii) phenyl or 5 to 6 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, wherein each of said phenyl and heteroaryl is substituted with zero to 3R4aSubstitution; or
Each R4aIndependently F, Cl, cyano, hydroxy, -NH2、C1-4Alkyl radical, C1-4Alkoxy, - (CH)2)0-3NH(C1-6Alkyl), - (CH)2)0-3N(C1-6Alkyl radical)2、-(CH2)0-3(C3-6Carbocyclyl) or- (CH2)0-3(4-to 6-membered heterocyclyl), wherein each of the alkyl and alkoxy is substituted with zero to 4R4dSubstitution; and each of said carbocyclyl and heterocyclyl is substituted with zero to 3R4eSubstitution;
R4bis C1-4Alkyl, - (CH)2)0-3(C3-6Cycloalkyl) or- (CH)2)0-3(4-to 6-membered heterocyclyl), wherein each of said alkyl groups is substituted with zero to 4R4dAnd each of said cycloalkyl and heterocyclyl is substituted with zero to 3R4eSubstitution;
each R4cIndependently of each other is hydrogen, C1-3Alkyl or C3-6A cycloalkyl group;
each R4dIndependently F, Cl, hydroxy, -NRxRxOxo, cyano, C1-3Alkoxy or C1-3A fluoroalkoxy group;
each R4eIndependently F, Cl, oxo, cyano, hydroxy, -NH2、C1-4Alkyl radical, C1-4Alkoxy, -NH (C)1-6Alkyl) or-N (C)1-6Alkyl radical)2Wherein each of said alkyl and alkoxy groups is substituted with zero to 4R4dSubstitution;
R5a、R5b、R5cand R5dEach of which is independently hydrogen, F, Cl, hydroxy, cyano, substituted with zero to 4R 5eSubstituted C1-3Alkyl, by zero to 4R5eSubstituted C1-3Alkoxy, -C (O) ORx、-C(O)NRwRw、-S(O)2Ry、-S(O)2NRzRzOr by zero to 3R5fSubstituted phenyl;
R5a、R5b、R5cand R5dEach of which is independently hydrogen, F, Cl, hydroxy, cyano, substituted with zero to 4R5eSubstituted C1-3Alkyl, by zero to 4R5eSubstituted C1-3Alkoxy, -C (O) ORx、-C(O)NRwRw、-S(O)2Ry、-S(O)2NRzRzOr by zero to 3R5fSubstituted phenyl;
each RwIndependently of each other is hydrogen, C1-4Alkyl or C3-6A cycloalkyl group; or alternatively, two RwTogether with the nitrogen atom to which they are attached form a 4 to 7 membered ring moiety containing zero to 2 additional heteroatoms independently selected from N, O and S;
each RxIndependently is H, C1-4Alkyl or C3-6A cycloalkyl group;
Ryis C1-4Alkyl or C3-6A cycloalkyl group; and is
Each RzIndependently of each other is hydrogen, C1-4Alkyl or C3-6A cycloalkyl group; or alternatively, two RzTogether with the nitrogen atom to which they are attached form a 4 to 7 membered ring moiety containing zero to 2 additional heteroatoms independently selected from N, O and S.
In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein X1Is CR5a；X2Is CR5b；X3Is CR5c；X4Is CR5d. The compounds of this embodiment have the structure of formula (Ia):
included in this embodiment are compounds wherein R 5a、R5b、R5cAnd R5dEach is independently hydrogen, F, Cl, cyano, -CH3or-CF3. Also included in this embodiment are compounds wherein R5a、R5b、R5cAnd R5dOne of which is F, Cl, cyano, -CH3or-CF3(ii) a And R is5a、R5b、R5cAnd R5dThree of which are hydrogen.
In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein X1Is CR5aOr N; x2Is CR5bOr N; x3Is CR5cOr N; x4Is CR5dOr N; and X1、X2、X3And X4Is N. The compounds of this embodiment have one of the following structures: the structure of formula (Ib), the structure of formula (Ic), the structure of formula (Id) and the structure of formula (Ie):
included in this embodiment are compounds wherein R5a、R5b、R5cAnd R5dEach is independently hydrogen, F, Cl, cyano, -CH3or-CF3。
In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein X1Is CR5aOr N; x2Is CR5bOr N; x3Is CR5cOr N; x4Is CR5dOr N; and X1、X2、X3And X4Two of which are N. The compounds of this embodiment have one of the following structures: a structure of formula (If), a structure of formula (Ig), a structure of formula (Ih), a structure of formula (Ii), a structure of formula (Ij), and a structure of formula (Ik):
Included in this embodiment are compounds wherein R5a、R5b、R5cAnd R5dEach is independently hydrogen, F, Cl, cyano, -CH3or-CF3。
In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein Z is1And Z2Each is CH2. The compound of this embodiment has the structure of formula (Il):
included in this embodiment are compounds wherein each of a, b, and d is 1. Also included in this embodiment are compounds wherein each of a, b, and d is zero or 1. Also included in this embodiment are compounds wherein each of a, b, and d is 1 or 2.
In one implementationIn a scheme, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein Z is1And Z2Is CH2And Z is1And Z2Is O. The compound of this embodiment has any one of a structure of formula (Im) and a structure of formula (In):
included in this embodiment are compounds wherein each of a, b, and d is 1. Also included in this embodiment are compounds wherein each of a, b, and d is zero or 1. Also included in this embodiment are compounds wherein each of a, b, and d is 1 or 2.
In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein Q is: (i) f, Cl, Br, cyano, hydroxy, -NRxRx、-C(O)OH、-C(O)NH2By zero or 6R1dSubstituted C1-4Alkyl or-P (O) R1cR1c(ii) a Or (ii) -L-R1. Included in this embodiment are compounds wherein Q is: (i) f, Cl, Br, cyano, hydroxy, -CF3、-C(CH3)2OH、-CH2CH2C(O)OCH3、-C(O)OH、-C(O)NH2or-P (O) (CH)3)2(ii) a Or (ii) -L-R1(ii) a L is-O-, -OCR1aR1aC(O)O-、-C(O)O-、-C(O)NR1b-、-NR1b-、-NR1bC(O)O-、-NR1bS(O)2-、-S(O)2-or-S (O)2NR1b-；R1Is substituted by zero to 4R1aSubstituted C1-4Alkyl radical, C3-4Cycloalkyl, or a cyclic group selected from phenyl, thiazolyl, pyridyl and pyrimidinyl, wherein the cyclic group is substituted with zero to 1R1bAnd (4) substitution. Also included in this embodiment are compounds wherein R1is-CH3、-CH2CH3、-C(CH3)3、-CHF2Cyclopropyl, thiazolyl or by-CHF2、-CF3、-CH2CH3or-OCH2CH3A substituted phenyl group. Further included in this embodiment are compounds wherein Q is: (i) f, Cl, Br, cyano, -CF3、-CH2CH2C(O)OCH3、-C(O)NH2or-P (O) (CH)3)2(ii) a Or (ii) -C (O) OCH3、-C(O)NH(CH2CH3)、-OCH3、-OCH2CH3、-OCHF2、-OCH2C(O)OCH3、-NHC(O)OC(CH3)3、-NHS(O)2CH3、-S(O)2CH3、-S(O)2NH (cyclopropyl), -S (O)2NH(CH3)、-P(O)(CH3)2-C (O) NH (thiazolyl), -NH (trifluoromethylphenyl), -NH (ethylphenyl), -NH (ethoxyphenyl) or-NH (difluoromethylphenyl).
In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein a is cyano. Included in this embodiment are compounds wherein X 1、X2、X3And X4Each of which is CH. Also included in this embodiment are compounds wherein Z1And Z2Each of which is CH2。
In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein a is: (i) phenyl or 5 to 6 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, wherein each of said phenyl and heteroaryl is substituted with zero to 3R4aSubstitution; or (ii) Included in this embodiment are compounds which areEach R in4aIndependently F, Cl, cyano, hydroxy, -NH2、C1-4Alkyl radical, C1-4Alkoxy, - (CH)2)0-3NH(C1-6Alkyl), - (CH)2)0-3N(C1-6Alkyl radical)2、-(CH2)0-3(C3-6Carbocyclyl) or- (CH2)0-3(4-to 6-membered heterocyclyl), wherein each of the alkyl and alkoxy is substituted with zero to 4R4dSubstitution; and each of said carbocyclyl and heterocyclyl is substituted with zero to 3R4eSubstitution; r4bIs C1-4Alkyl, - (CH)2)0-3(C3-6Cycloalkyl) or- (CH)2)0-3(4-to 6-membered heterocyclyl), wherein each of said alkyl groups is substituted with zero to 4R4dAnd each of said cycloalkyl and heterocyclyl is substituted with zero to 3R4eSubstitution; each R4cIndependently of each other is hydrogen, C1-3Alkyl or C3-6A cycloalkyl group; each R4dIndependently F, Cl, hydroxy, -NR xRxOxo, cyano, C1-3Alkoxy or C1-3A fluoroalkoxy group; and each R4eIndependently F, Cl, oxo, cyano, hydroxy, -NH2、C1-4Alkyl radical, C1-4Alkoxy, -NH (C)1-6Alkyl) or-N (C)1-6Alkyl radical)2Wherein each of said alkyl and alkoxy groups is substituted with zero to 4R4dAnd (4) substitution.
In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein a is phenyl or a 5-to 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, wherein each of the phenyl and heteroaryl is substituted with zero to 3R4aAnd (4) substitution. Included in this embodiment are compounds wherein a is phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxatriazolyl, pyridyl, pyrazinyl, pyrimidinyl, or pyridazinyl, each of which is substituted with zero to 3R4aSubstitution. Also included in this embodiment are compounds wherein a is oxadiazolyl, oxazolyl, phenyl, pyrazolyl, pyridyl, pyrimidinyl, or thiazolyl, each of which is substituted with zero to 2 substituents independently selected from the group consisting of: azetidinyl, fluorobicyclo [1.1.1 ]Pentyl radical, C1-4Alkyl radical, C1-2Fluoroalkyl, -C (CH)3)2CN、-C(CH3)2OH、-OCH3、-N(CH3)2、-CH2(cyclopropyl), cyclopropyl, trifluoromethylcyclopropyl, cyanocyclopropyl, difluorocyclopropyl, methylcyclopropyl, morpholinyl, methyloxetanyl and tetrahydropyranyl.
In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein a is substituted with zero to 3R containing 1 to 4 heteroatoms independently selected from N, O and S4aA substituted 5-membered heteroaryl. Included in this embodiment are compounds wherein a is furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, or oxatriazolyl, each of which is substituted with zero to 3R4aAnd (4) substitution. Also included in this embodiment are compounds wherein a is pyrazolyl, oxadiazolyl, oxazolyl, or thiazolyl, each of which is substituted with zero to 2 substituents independently selected from the group consisting of: cl, -CH3、-C(CH3)3、-CF3、-CF2CH3、-N(CH3)2Cyclopropyl and fluorocyclopropyl.
In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein a is:
Included in this embodiment are compounds whereinA is:
also included in this embodiment are compounds wherein R4bIs C1-4Alkyl, - (CH)2)0-3(C3-6Cycloalkyl) or- (CH)2)0-3(4-to 6-membered heterocyclyl), wherein each of said alkyl groups is substituted with zero to 4R4dAnd each of said cycloalkyl and heterocyclyl is substituted with zero to 3R4eSubstitution; each R4cIndependently of each other is hydrogen, C1-3Alkyl or C3-6A cycloalkyl group; each R4dIndependently F, Cl, hydroxy, -NRxRxOxo, cyano, C1-3Alkoxy or C1-3A fluoroalkoxy group; and each R4eIndependently F, Cl, oxo, cyano, hydroxy, -NH2、C1-4Alkyl radical, C1-4Alkoxy, -NH (C)1-6Alkyl) or-N (C)1-6Alkyl radical)2Wherein each of said alkyl and alkoxy groups is substituted with zero to 4R4dAnd (4) substitution.
In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein R is2Is (i) C1-4Alkyl radical, C1-4Alkoxy or-NRvRvWherein each of said alkyl and alkoxy groups is substituted with zero to 4R2aSubstitution; (ii) c3-8Carbocyclyl, C6-8Spirobicyclic group, phenyl or 4-to 7-membered heterocyclic group, wherein each of said carbocyclic group, spirobicyclic group and heterocyclic group is substituted with zero to 3R2bSubstitution; or (iii) -CH 2(C3-5Cycloalkyl), -CH2(4-to 6-membered heterocyclyl), -NRx(CH2)0-2(C3-5Cycloalkyl), -NR-x(CH2)0-2(4-to 6-membered heterocyclyl), -NRx(CH2)0-2(phenyl), -O (phenyl) or-S (O)2(C3-6Cycloalkyl), wherein the cycloalkyl, heterocyclyl and benzeneEach of the radicals being substituted by zero to 3R2bAnd (4) substitution. Included in this embodiment are compounds wherein R2Is C1-3Alkyl radical, C1-3Alkoxy or-NRvRvWherein each of said alkyl and alkoxy groups is substituted with zero to 4R2aSubstitution; (ii) c3-8Carbocyclyl, C6-8Spirobicyclic group, phenyl or 4-to 7-membered heterocyclic group, wherein each of said carbocyclic group, spirobicyclic group and heterocyclic group is substituted with zero to 3R2bSubstitution; or (iii) -CH2(C3-5Cycloalkyl), -CH2(4-to 6-membered heterocyclyl), -NRx(CH2)0-2(C3-5Cycloalkyl), -NR-x(CH2)0-2(4-to 6-membered heterocyclyl), -NRx(CH2)0-2(phenyl), -O (phenyl) or-S (O)2(C3-6Cycloalkyl), wherein each of said cycloalkyl, heterocyclyl and phenyl is substituted with zero to 3R2bAnd (4) substitution.
In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein R is2Is (i) C1-4Alkyl radical, C1-4Alkoxy or-NRvRvWherein each of said alkyl and alkoxy groups is substituted with zero to 4R2aSubstitution; or (ii) C3-8Carbocyclyl, C6-8Spirobicyclic group, phenyl or 4-to 5-membered heterocyclic group, wherein each of said carbocyclic group, spirobicyclic group and heterocyclic group is substituted with zero to 3R 2bAnd (4) substitution.
In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein R is2Is C3-5Carbocyclic ring, C6-8Spirobicyclic group, -NRx(CH2)0-2(C3-6Cycloalkyl) or a 4 to 5 membered heterocyclyl having 1 or 2 heteroatoms independently selected from N, O and S, wherein each of said cycloalkyl, carbocycle and heterocyclyl is independently substituted with zero to 3R2bAnd (4) substitution. Further included in this embodiment are compounds wherein R is2is-NH (methyl-hydroxycyclopropyl) or is selected from cyclopropylCyclobutyl, cyclohexyl, tetrahydropyranyl, bicyclo [1.1.1]Pentyl and dioxotetrahydrothiopyranyl, each cyclic group being substituted with zero to 2 substituents independently selected from F, -OH, -CH3and-CF3Is substituted with the substituent(s).
In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein R is2The method comprises the following steps:
in one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein R is2The method comprises the following steps:
in one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein R is 2The method comprises the following steps:
in one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein:
q is:
(i) f, Cl, Br, cyano, hydroxy, -NRxRx、-C(O)OH、-C(O)NH2From zero to 6R1dSubstituted C1-4Alkyl or-P (O) R1cR1c(ii) a Or
(ii)-L-R1；
L is-O-, -OCR1aR1aC(O)-、-C(O)--C(O)O-、-C(O)NR1b-、-NR1b-、-NR1bC(O)-、-NR1bC(O)NR1b-、-NR1bS(O)2-、-S(O)2-or-S (O)2NR1b-；
R1Is substituted by zero to 6R1aSubstituted C1-6Alkyl or is selected from C3-6Cyclic groups of cycloalkyl, phenyl, 4-to 10-membered heterocyclyl and 5-to 10-membered heteroaryl, wherein the cyclic group is substituted with zero to 3R1bSubstitution;
R2is (i) C1-4Alkyl radical, C1-4Alkoxy or-NRvRvWherein each of said alkyl and alkoxy groups is substituted with zero to 4R2aSubstitution; (ii) c3-5A carbocyclyl or a 4-to 5-membered heterocyclyl having 1 or 2 heteroatoms independently selected from N, O and S, wherein each of said cycloalkyl, carbocycle and heterocyclyl is independently substituted with zero to 3R2bSubstitution; or (iii) -NRx(CH2)0-2(C3-5Cycloalkyl) or-NRx(CH2)0-2(phenyl); and is
A is a substituted or unsubstituted alkyl radical containing 1 to 3 heteroatoms independently selected from N, O and S, with zero to 3R4aA substituted 5-membered heteroaryl.
In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein:
q is:
(i) f, Cl, Br, cyano, -CF 3、-CH2CH2C(O)OCH3、-C(O)NH2or-P (O) (CH)3)2(ii) a Or
(ii)-L-R1；
L is-O-, -OCR1aR1aC(O)O-、-C(O)O-、-C(O)NR1b-、-NR1b-、-NR1bC(O)O-、-NR1bS(O)2-、-S(O)2-or-S (O)2NR1b-；
R1is-CH3、-CH2CH3、-C(CH3)3、-CHF2Cyclopropyl, thiazolyl or by-CHF2、-CF3、-CH2CH3or-OCH2CH3Substituted phenyl;
R2is-NH (methyl-hydroxycyclopropyl) or is selected from cyclopropyl, cyclobutyl and bicyclo [1.1.1]A pentyl group of cyclic groups, each cyclic group being independently selected from zero to 2 of F, -OH, -CH3and-CF3Substituted with the substituent(s);
a is a substituted or unsubstituted alkyl radical containing 1 to 3 heteroatoms independently selected from N, O and S, with zero to 3R4aA substituted 5-membered heteroaryl.
Included in this embodiment are compounds wherein a is pyrazolyl or oxadiazolyl, each of which is substituted with zero to 3R4aAnd (4) substitution. Also included in this embodiment are compounds wherein Q is: (i) -CF3、-CH2CH2C(O)OCH3、-C(O)NH2or-P (O) (CH)3)2(ii) a Or (ii) -C (O) OCH3、-C(O)NH(CH2CH3)、-OCH3、-OCH2CH3、-OCHF2、-OCH2C(O)OCH3、-NHC(O)OC(CH3)3、-NHS(O)2CH3、-S(O)2CH3、-S(O)2NH (cyclopropyl), -S (O)2NH(CH3)、-P(O)(CH3)2-C (O) NH (thiazolyl), -NH (trifluoromethylphenyl), -NH (ethylphenyl), -NH (ethoxyphenyl) or-NH (difluoromethylphenyl).
In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein a is pyrazolyl, oxadiazolyl, phenyl, pyridinyl, or indazolyl, each of which is substituted with zero to 3R4aSubstitution; and Q is: (i) -CF3、-CH2CH2C(O)OCH3、-C(O)NH2or-P (O) (CH)3)2(ii) a Or (ii) -C (O) OCH 3、-C(O)NH(CH2CH3)、-OCH3、-OCH2CH3、-OCHF2、-OCH2C(O)OCH3、-NHC(O)OC(CH3)3、-NHS(O)2CH3、-S(O)2CH3、-S(O)2NH (cyclopropyl), -S (O)2NH(CH3)、-P(O)(CH3)2-C (O) NH (thiazolyl), -NH (trifluoromethylphenyl), -NH (ethylphenyl), -NH (ethoxyphenyl) or-NH (difluoromethylphenyl). Included in this embodiment are compounds wherein a is pyrazolyl or oxadiazolyl, each of which is substituted with zero to 3R4aSubstitution;
in one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein Z is1And Z2Each of which is CH2(ii) a a is 1; b is 1; d is 1; and A is pyrazolyl, oxadiazolyl, phenyl, pyridinyl or indazolyl, each of which is substituted with zero to 3R4aAnd (4) substitution.
In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein R is3aAnd R3bIndependently of each other is hydrogen, C1-3Alkyl radical, C1-3Fluoroalkyl or C3-6A cycloalkyl group; or R3aAnd R3bTogether with the carbon atom to which they are attached form C3-6A cycloalkyl group. Included in this embodiment are compounds wherein R3aAnd R3bIndependently of each other is hydrogen, C1-2Alkyl, -CH2F、-CHF2、-CF3Or C3-4A cycloalkyl group; or R3aAnd R3bTogether with the carbon atom to which they are attached form C3-4A cycloalkyl group. Also included in this embodiment are compounds wherein R 3aAnd R3bIndependently of each other is hydrogen, -CH3Or cyclopropyl; or R3aAnd R3bTogether with the carbon atom to which they are attached form a cyclopropyl group. Further included in this embodiment are compounds wherein R is3aAnd R3bOne of them is hydrogen or-CH3And R is3aAnd R3bIs hydrogen.
In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein:
X1is CH; x2Is CH; x3Is CH; x4Is CR5dOr N;
a is 1;
b is 1;
d is 1;
q is:
(i) f, Cl, Br, cyano, hydroxy, -CF3、-C(CH3)2OH、-CH2CH2C(O)OCH3、-C(O)OH、-C(O)NH2or-P (O) (CH)3)2(ii) a Or
(ii)-L-R1；
L is-O-, -OCR1aR1aC(O)O-、-C(O)O-、-C(O)NR1b-、-NR1b-、-NR1bC(O)O-、-NR1bS(O)2-、-S(O)2-or-S (O)2NR1b-；
R1is-CH3、-CH2CH3、-C(CH3)3、-CHF2Cyclopropyl, thiazolyl or by-CHF2、-CF3、-CH2CH3or-OCH2CH3Substituted phenyl;
a is pyrazolyl, oxadiazolyl, phenyl, pyridyl or indazolyl, each of which is substituted with zero to 3R4aAnd (4) substitution.
Each R4aIndependently Cl, -CH3、-C(CH3)3、-CF3、-CF2CH3、-N(CH3)2Cyclopropyl or fluorocyclopropyl;
R5dis hydrogen, F or Cl.
Included in this embodiment are compounds wherein a is pyrazolyl or oxadiazolyl, each of which is substituted with zero to 3R4aAnd (4) substitution.
In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein a is:
Each R4aIndependently F, Cl, cyano, hydroxy, -NH2、C1-4Alkyl radical, C1-4Alkoxy, - (CH)2)0-3NH(C1-6Alkyl), - (CH)2)0-3N(C1-6Alkyl radical)2、-(CH2)0-3(C3-6Carbocyclyl) or- (CH2)0-3(4-to 6-membered heterocyclyl), wherein each of the alkyl and alkoxy is substituted with zero to 4R4dSubstitution; and each of said carbocyclyl and heterocyclyl is substituted with zero to 3R4eSubstitution; r4bIs C1-4Alkyl, - (CH)2)0-3(C3-6Cycloalkyl) or- (CH)2)0-3(4-to 6-membered heterocyclyl), wherein each of said alkyl groups is substituted with zero to 4R4dAnd each of said cycloalkyl and heterocyclyl is substituted with zero to 3R4eSubstitution; each R4cIndependently of each other is hydrogen, C1-3Alkyl or C3-6A cycloalkyl group; each R4dIndependently F, Cl, hydroxy, -NRxRxOxo, cyano, C1-3Alkoxy or C1-3A fluoroalkoxy group; and each R4eIndependently F, Cl, oxo, cyano, hydroxy, -NH2、C1-4Alkyl radical, C1-4Alkoxy, -NH (C)1-6Alkyl) or-N (C)1-6Alkyl radical)2Wherein each of said alkyl and alkoxy groups is substituted with zero to 4R4dAnd (4) substitution.
In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein each R iswIndependently of each other is hydrogen, C1-4Alkyl or C3-6A cycloalkyl group; or alternatively, two RwTogether with the nitrogen atom to which they are attached form a 4 to 7 membered ring moiety containing zero to 2 additional heteroatoms independently selected from N, O and S. Included in this embodiment are compounds wherein each R is wIndependently of each other is hydrogen, C1-4Alkyl or C3-6A cycloalkyl group. Also included in this embodiment are compounds wherein two R areWTogether with the nitrogen atom to which they are attached form a 4 to 7 membered ring moiety selected from: pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl.
In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein each R iszIndependently of each other is hydrogen, C1-4Alkyl or C3-6A cycloalkyl group; or alternatively, two RzTogether with the nitrogen atom to which they are attached form a 4 to 7 membered ring moiety containing zero to 2 additional heteroatoms independently selected from N, O and S. Included in this embodiment are compounds wherein each R iszIndependently of each other is hydrogen, C1-4Alkyl or C3-6A cycloalkyl group. Also included in this embodiment are compounds wherein two R areWTogether with the nitrogen atom to which they are attached form a 4 to 7 membered ring moiety selected from: pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl.
In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein said compound is N- (3-chlorophenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (1); n- (3-chlorophenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (2); n- (3-chlorophenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -4, 4-difluorocyclohexane-1-carboxamide (3); n- (3-cyanophenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (4); n- (3-cyanophenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (5); n- (3-cyanophenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -4, 4-difluorocyclohexane-1-carboxamide (6); n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3-fluorophenyl) bicyclo [1.1.1] pentane-1-carboxamide (7); n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-fluorophenyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (8); n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -4, 4-difluoro-N- (3-fluorophenyl) cyclohexane-1-carboxamide (9); n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3, 4-difluorophenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (10); n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3, 4-difluorophenyl) -4, 4-difluorocyclohexane-1-carboxamide (11); n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (difluoromethoxy) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (12); n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (difluoromethoxy) phenyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (13); n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3- (trifluoromethyl) phenyl) bicyclo [1.1.1] pentane-1-carboxamide (14); n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) -N- (3- (trifluoromethyl) phenyl) cyclobutane-1-carboxamide (15); n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -4, 4-difluoro-N- (3- (trifluoromethyl) phenyl) cyclohexane-1-carboxamide (16); n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (2-methoxypyridin-4-yl) bicyclo [1.1.1] pentane-1-carboxamide (17); n- (3- (N-cyclopropylsulfamoyl) phenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (18); (1S,3S) -N- (3- (N-cyclopropylsulfamoyl) phenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (19); n- (3- (N-cyclopropylsulfamoyl) phenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -4, 4-difluorocyclohexane-1-carboxamide (20); n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3- (N-methylsulfamoyl) phenyl) bicyclo [1.1.1] pentane-1-carboxamide (21); (1S,3S) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-N- (3- (N-methylsulfamoyl) phenyl) -3- (trifluoromethyl) cyclobutane-1-carboxamide (22); n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -4, 4-difluoro-N- (3- (N-methylsulfamoyl) phenyl) cyclohexane-1-carboxamide (23); n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (dimethylphosphoryl) phenyl) -4, 4-difluorocyclohexane-1-carboxamide (24); n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (dimethylphosphoryl) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (25); (1S,3S) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (dimethylphosphoryl) phenyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (26); methyl 3- (N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide) benzoate (27); n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (ethylcarbamoyl) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (28); n- (3-carbamoylphenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (29); 1- (3-bromophenyl) -1- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- ((1R,4R) -4-hydroxy-4-methylcyclohexyl) urea (30); n- (3-bromophenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -2, 2-difluorocyclopropane-1-carboxamide (31); tert-butyl (3- (N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamido) phenyl) carbamate (32); n- (3-bromophenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (33); n- (3-bromophenyl) -3-fluoro-N- ((4- (5- (1-fluorocyclopropyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) bicyclo [1.1.1] pentane-1-carboxamide (34); n- (3-bromophenyl) -3-fluoro-N- ((4- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) bicyclo [1.1.1] pentane-1-carboxamide (35); (1S,3S) -N- (3-bromophenyl) -N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (36); n- (3-bromo-4-chlorophenyl) -N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (37); n- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-cyanophenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (38); (1S,3S) -N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-cyanophenyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (39); (1S,3S) -N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-cyanophenyl) -3-hydroxy-3-methylcyclobutane-1-carboxamide (40); n- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-cyanophenyl) -3, 3-difluorocyclobutane-1-carboxamide (41); n- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-cyanophenyl) -4, 4-difluorocyclohexane-1-carboxamide (42); n- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (dimethylphosphoryl) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (43); n- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (dimethylphosphoryl) phenyl) -3, 3-difluorocyclobutane-1-carboxamide (44); (1S,3S) -N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (dimethylphosphoryl) phenyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (45); n- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (dimethylphosphoryl) phenyl) tetrahydro-2H-pyran-4-carboxamide (46); n- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (dimethylphosphoryl) phenyl) tetrahydro-2H-thiopyran-4-carboxamide 1, 1-dioxide (47); n- (3-bromophenyl) -N- ((4- (5- (1, 1-difluoroethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (48); n- (3-cyanophenyl) -N- ((4- (5- (1, 1-difluoroethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (49); (1S,3S) -N- (3-cyanophenyl) -N- ((4- (5- (1, 1-difluoroethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3-methylcyclobutane-1-carboxamide (50); (1S,3S) -N- (3-cyanophenyl) -N- ((4- (5- (1, 1-difluoroethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (51); n- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-ethoxyphenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (52); n- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-ethoxyphenyl) -3, 3-difluorocyclobutane-1-carboxamide (53); n- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-ethoxyphenyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (54); n- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-ethoxyphenyl) tetrahydro-2H-pyran-4-carboxamide (55); n- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-ethoxyphenyl) tetrahydro-2H-thiopyran-4-carboxamide 1, 1-dioxide (56); (1S,3S) -N- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-N- (3-methoxyphenyl) -3- (trifluoromethyl) cyclobutane-1-carboxamide (57); n- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3-methoxyphenyl) bicyclo [1.1.1] pentane-1-carboxamide (58); n- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3, 3-difluoro-N- (3-methoxyphenyl) cyclobutane-1-carboxamide (59); n- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-methoxyphenyl) tetrahydro-2H-pyran-4-carboxamide (60); n- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-methoxyphenyl) tetrahydro-2H-thiopyran-4-carboxamide 1, 1-dioxide (61); n- (3-cyano-5-fluorophenyl) -N- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (62); (1S,3S) -N- (3-cyano-5-fluorophenyl) -N- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (63); n- (3-cyano-5-fluorophenyl) -N- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3, 3-difluorocyclobutane-1-carboxamide (64); n- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3, 3-difluoro-N- (3- (methylsulfonamido) phenyl) cyclobutane-1-carboxamide (65); n- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3- (methylsulfonamido) phenyl) bicyclo [1.1.1] pentane-1-carboxamide (66); (1S,3S) -N- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-N- (3- (methylsulfonamido) phenyl) -3- (trifluoromethyl) cyclobutane-1-carboxamide (67); n- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3- (methylsulfonyl) phenyl) bicyclo [1.1.1] pentane-1-carboxamide (68); n- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -4, 4-difluoro-N- (3- (methylsulfonyl) phenyl) cyclohexane-1-carboxamide (69); n- (3-cyanophenyl) -N- (1- (4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) ethyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (70); n- (3-bromophenyl) -N- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclopropanesulfonamide (71); n- (3-cyanophenyl) -N- ((4- (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (72); n- (3-cyanophenyl) -N- ((4- (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -4, 4-difluorocyclohexane-1-carboxamide (73); (1S,3S) -N- (3-cyanophenyl) -N- ((4- (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3-methylcyclobutane-1-carboxamide (74); (1S,3S) -N- (3-cyanophenyl) -N- ((4- (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (75); (1S,3S) -N- ((4- (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-N- (3- (methylsulfonyl) phenyl) -3- (trifluoromethyl) cyclobutane-1-carboxamide (76); n- ((4- (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -4, 4-difluoro-N- (3- (methylsulfonyl) phenyl) cyclohexane-1-carboxamide (77); n- ((4- (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3- (methylsulfonyl) phenyl) bicyclo [1.1.1] pentane-1-carboxamide (78); methyl 2- (3- (N- ((4- (3-chloro-4- (dimethylamino) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenoxy) acetate (79); methyl 2- (3- (N- ((4- (4- (dimethylamino) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenoxy) acetate (80); methyl 2- (3- (N- ((1- (1-methyl-1H-indazol-5-yl) -2-oxabicyclo [2.2.2] oct-4-yl) methyl) tetrahydro-2H-pyran-4-carboxamido) phenoxy) acetate (81); 3- (N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamide) -N- (thiazol-2-yl) benzamide (82); n- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- ((4-ethoxyphenyl) amino) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (83); n- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- ((4- (difluoromethoxy) phenyl) amino) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (84); n- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- ((4-ethoxyphenyl) amino) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (85); n- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- ((4-ethylphenyl) amino) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (86); n- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3- ((4- (trifluoromethyl) phenyl) amino) phenyl) bicyclo [1.1.1] pentane-1-carboxamide (87); methyl 3- (3- (N- ((4- (4- (dimethylamino) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) propanoate (88); methyl 3- (3- (N- ((4- (4- (dimethylamino) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) propanoate (89); (1S,3S) -N- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-N- (3- (methylsulfonyl) phenyl) -3- (trifluoromethyl) cyclobutane-1-carboxamide (90); (1S,3S) -N- (3- ((4- (1-cyanocyclopropyl) phenyl) amino) phenyl) -N- ((4- (5- (1-fluorocyclopropyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (91); (1S,3S) -N- (3- ((4- ((2-cyanoprop-2-yl) oxy) phenyl) amino) phenyl) -N- ((4- (5- (1, 1-difluoroethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (92); (1S,3S) -N- (3- ((4- (1-cyanocyclopropyl) phenyl) amino) phenyl) -N- ((4- (5- (1, 1-difluoroethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (93); n- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (5-cyanopyridin-3-yl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (94); 1- (3-cyanophenyl) -1- ((4- (5- (2-fluoropropan-2-yl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- ((1R,4R) -4-hydroxy-4-methylcyclohexyl) urea (95); 1- (3-cyanophenyl) -1- ((4- (5- (2-fluoropropan-2-yl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- ((1R,4R) -4-hydroxycyclohexyl) urea (96); 1- (3-cyanophenyl) -1- ((4- (5- (2-fluoropropan-2-yl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- (3-hydroxy-2, 2-dimethylpropyl) urea (97); 1- (3-cyanophenyl) -1- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- ((1R,4R) -4-hydroxycyclohexyl) urea (98); 1- (3-cyanophenyl) -1- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- ((1R,4R) -4-hydroxy-4-methylcyclohexyl) urea (99); 1- (3-cyanophenyl) -1- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- (3-hydroxy-2, 2-dimethylpropyl) urea (100); 1- (3-bromo-4-fluorophenyl) -1- ((4- (5- (2-fluoropropan-2-yl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- ((1R,4R) -4-hydroxycyclohexyl) urea (101); n- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- ((5- (difluoromethoxy) pyrimidin-2-yl) amino) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (102); n- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- ((2-cyclopropylpyrimidin-5-yl) amino) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (103); n- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- ((5- (difluoromethoxy) pyridin-2-yl) amino) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (104); n- (3- ((5-cyclopropylpyrimidin-2-yl) amino) phenyl) -3-fluoro-N- ((4- (5- (trifluoromethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) bicyclo [1.1.1] pentane-1-carboxamide (105); n- (3- ((5- (difluoromethoxy) pyrimidin-2-yl) amino) phenyl) -3-fluoro-N- ((4- (5- (trifluoromethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) bicyclo [1.1.1] pentane-1-carboxamide (106); n- (3- ((4- (difluoromethoxy) phenyl) amino) phenyl) -3-fluoro-N- ((4- (5- (trifluoromethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) bicyclo [1.1.1] pentane-1-carboxamide (107); n- (3- ((5- (difluoromethoxy) pyridin-2-yl) amino) phenyl) -3-fluoro-N- ((4- (5- (trifluoromethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) bicyclo [1.1.1] pentane-1-carboxamide (108); n- (3- ((5-cyclopropylpyridin-2-yl) amino) phenyl) -3-fluoro-N- ((4- (5- (trifluoromethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) bicyclo [1.1.1] pentane-1-carboxamide (109); n- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3-hydroxyphenyl) bicyclo [1.1.1] pentane-1-carboxamide (110); n- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (cyanomethoxy) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (111); n- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3- (2-hydroxy-2-methylpropoxy) phenyl) bicyclo [1.1.1] pentane-1-carboxamide (112); 2- (3- (N- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamido) phenoxy) -2-methylpropanoic acid (113); n- (3-cyanophenyl) -3-fluoro-N- ((4- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) bicyclo [1.1.1] pentane-1-carboxamide (114); (1S,3S) -N- (3-cyanophenyl) -3-hydroxy-3- (trifluoromethyl) -N- ((4- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclobutane-1-carboxamide (115); n- (3-cyanophenyl) -N- ((4- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) tetrahydro-2H-pyran-4-carboxamide (116); (1S,3S) -N- (3-cyanophenyl) -3-hydroxy-3-methyl-N- ((4- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclobutane-1-carboxamide (117); n- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- ((5- (difluoromethoxy) pyrimidin-2-yl) oxy) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (118); n- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- ((5- (difluoromethoxy) pyridin-2-yl) oxy) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (119); 3- (N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide) benzoic acid (120); n- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-carbamoyl-4-fluorophenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (121); n- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (ethylcarbamoyl) -4-fluorophenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (122); (1S,3S) -N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-N- (3-isopropoxyphenyl) -3- (trifluoromethyl) cyclobutane-1-carboxamide (123); (1S,3S) -N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-N- (3-isopropoxyphenyl) -3- (trifluoromethyl) cyclobutane-1-carboxamide (124); (1S,3S) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-N- (3-isopropoxyphenyl) -3-methylcyclobutane-1-carboxamide (125); (1S,3S) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-N- (3-isopropoxyphenyl) -3- (trifluoromethyl) cyclobutane-1-carboxamide (126); n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3-isopropoxyphenyl) bicyclo [1.1.1] pentane-1-carboxamide (127); n- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (4-fluoro-3- (2-hydroxypropan-2-yl) phenyl) bicyclo [1.1.1] pentane-1-carboxamide (128); n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3-methoxyphenyl) bicyclo [1.1.1] pentane-1-carboxamide (129); n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-ethoxyphenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (130); (S) -1- (3-bromophenyl) -1- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- (2-fluoro-3-hydroxy-3-methylbutyl) urea (131); n- (3-bromophenyl) -N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.1] hept-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (132); (1s,3s) -N- (3-bromophenyl) -N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.1] hept-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (133); n- (3-bromophenyl) -N- ((4- (5- (2-fluoropropan-2-yl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- (2-hydroxypropan-2-yl) bicyclo [1.1.1] pentane-1-carboxamide (134); n- (3-cyano-5-fluorophenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide (135); (1S,3S) -N- (3-cyano-5-fluorophenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide (136); n- (3-cyano-5-fluorophenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3, 3-difluorocyclobutane-1-carboxamide (137); n- (3-cyano-5-fluorophenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) tetrahydro-2H-thiopyran-4-carboxamide 1, 1-dioxide (138); 3- (4- (((1S,3S) -N- (3-bromophenyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamido) methyl) bicyclo [2.2.2] oct-1-yl) -1,2, 4-oxadiazole-5-carboxamide (139); or 3- (4- ((N- (3-bromophenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamido) methyl) bicyclo [2.2.2] oct-1-yl) -1,2, 4-oxadiazole-5-carboxamide (140).
The present invention may be embodied in other specific forms without departing from its spirit or essential attributes. The present invention encompasses all combinations of aspects and/or embodiments of the invention described herein. It is to be understood that any and all embodiments of the present invention may be combined with any one or more other embodiments to describe additional embodiments. It is also to be understood that each individual element of an embodiment 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 may be more readily understood by those of ordinary skill in the art after reading the following detailed description. It is to be understood that certain features of the invention, which are, for clarity, described 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 provided in combination to form a sub-combination 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 context clearly dictates otherwise. For example, "a" and "an" may refer to one or more.
As used herein, the phrase "compound and/or salt thereof" refers to at least one compound, at least one salt of the compound, or a combination thereof. For example, compounds of formula (I) and/or salts thereof include compounds of formula (I); two compounds of formula (I); a salt of a compound of formula (I); a compound of formula (I) and one or more salts of a compound of formula (I); and two or more salts of the compound of formula (I).
Unless otherwise indicated, any atom having an unsaturated valence is assumed to have 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 herein.
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.
Used in the formulae herein according to the conventions used in the art
To depict bonds as attachment points for moieties or substituents to the core or backbone structure.
As used herein, the terms "halo" and "halogen" refer to F, Cl, Br, and I.
The term "cyano" refers to the group-CN.
The term "hydroxy" refers to the group-OH.
The term "amino" refers to the group-NH2。
The term "oxo" refers to the group ═ O.
As used herein, the term "alkyl" 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 a number appears in a subscript following the symbol "C," the subscript more specifically defines the number of carbon atoms that a particular group may contain. For example, "C1-4Alkyl "denotes straight and branched chain alkyl groups having one to four carbon atoms.
The term "haloalkyl" as used herein is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups substituted with one or more halogen atoms. For example, "C 1-4Haloalkyl "is intended to include C substituted with one or more halogen atoms1、C2、C3And C4An alkyl group. Representative examples of haloalkyl groups include, but are not limited to, -CF3、-CCl3、-CHF2and-CF2CCl3。
The term "fluoroalkyl" as used herein is intended to mean a fluoroalkyl groupBoth branched and straight chain saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms are included. 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 "hydroxyalkyl" as used herein is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups substituted with one or more hydroxyl groups. For example, "C1-4Hydroxyalkyl "is intended to include C substituted with one or more hydroxy groups1、C2、C3And C4An alkyl group. Representative examples of fluoroalkyl groups include, but are not limited to, -CH2OH、-CH2CH2OH and-C (CH)3)2OH。
The term "alkenyl" refers to a straight or branched hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon-carbon double bond. Exemplary such groups include vinyl or allyl. For example, "C2-6Alkenyl "denotes straight and branched chain alkenyl groups having two to six carbon atoms.
The term "alkynyl" refers to a straight or branched hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon to carbon triple bond. Exemplary such groups include ethynyl. For example, "C 2-6Alkynyl "denotes straight and branched chain alkynyl groups having two to six carbon atoms.
The term "alkoxy," as used herein, refers to 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 one to three carbon atoms.
The terms "haloalkoxy" and "-O (haloalkyl)" denote a haloalkyl group as defined above attached through an oxygen linkage (-O-). For example, "C1-4Haloalkoxy "is intended to include C1、C2、C3And C4A haloalkoxy group.
The terms "fluoroalkoxy" and "-O (fluoroalkyl)" mean an attachment such as through an oxygen linkage (-O-) asFluoroalkyl as hereinbefore defined. For example, "C1-4Fluoroalkoxy "is intended to include C1、C2、C3And C4A fluoroalkoxy group.
As used herein, the term "cycloalkyl" 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, "C3-6Cycloalkyl "denotes cycloalkyl having three to six carbon atoms.
The terms "carbocycle", or "carbocyclyl" are used interchangeably and refer to a cyclic group having at least one saturated or partially saturated non-aromatic ring in which all of the atoms of the ring are carbon, and include groups having one or more bridged rings in which a bridged ring occurs when one or more carbon atoms connects two non-adjacent carbon atoms. The term includes non-aromatic rings such as, for example, cycloalkyl and cycloalkenyl, bicyclo [1.1.1] pentyl, bicyclo [2.2.2] octyl, adamantyl, and tetrahydronaphthyl.
As used herein, the term "bicycloalkyl" refers to a carbocyclyl group having at least one bridge. Representative examples of bicycloalkyl groups include, but are not limited to, bicyclo [1.1.1] pentyl, bicyclo [2.2.2] octyl, and adamantyl.
As used herein, the term "aryl" refers to a group of atoms derived from a molecule containing one or more aromatic rings by the removal of one hydrogen bonded to the aromatic ring or rings. Representative examples of aryl groups include, but are not limited to, phenyl and naphthyl. The aryl ring may be unsubstituted or, where valency permits, may contain one or more substituents.
The term "heteroatom" refers to oxygen (O), sulfur (S) and nitrogen (N).
The terms "heterocycle" (heterocyclo), "heterocycle" (or "heterocyclyl" are used interchangeably and refer to a cyclic group having an at least saturated or partially saturated non-aromatic ring, wherein one or more rings have at least one heteroatom (O, S or N), preferably 1 to 3 heteroatoms independently selected from O, S and/or N. The rings of this heteroatom-containing group may contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less, and further provided that the ring contains at least one carbon atom. The nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atoms may optionally be quaternized. The heterocyclic group may be attached at any available nitrogen or carbon atom. Heterocycles may be unsubstituted or, where valency permits, may contain one or more substituents.
Exemplary monocyclic heterocyclyl groups include pyrrolidinyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxopazepinyl, azepinyl, 4-piperidinonyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1, 3-dioxolane, tetrahydro-1, 1-dioxothienyl, dihydroisoindolyl, and tetrahydroquinolinyl.
The terms "spirobicyclic group" and "spirobicyclic ring" are used interchangeably and refer to a bicyclic group in which two rings are attached at a single carbon atom that is a member of each of the two rings. The term includes both spirobicycloalkyl, where the two rings are cycloalkyl rings attached at a single carbon atom which is a member of each of the two rings; also included are spirobicyclic heteroalkyl groups in which one ring is a heterocyclyl ring and the other ring is a cycloalkyl ring attached to a single carbon atom which is a member of each of the two rings, or in which both rings are heterocyclyl rings attached to a single carbon atom which is a member of each of the two rings. Examples of spiro bicyclic groups include spiro [3.3] heptenyl, spiro [3.4] octyl, azaspiro [3.3] heptyl, oxaazaspiro [3.3] heptyl, oxa-azaspiro [3.3] heptyl and azaspiro [3.4] octyl.
The term "heteroaryl" refers to substituted and unsubstituted aromatic 5-or 6-membered monocyclic groups and 9-or 10-membered bicyclic groups having at least one heteroatom (O, S or N) in at least one ring, preferably 1, 2 or 3 heteroatoms independently selected from O, S and/or N. The heteroatom-containing heteroaryl groups can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms per ring, provided that the total number of heteroatoms in each ring is four or less, and each ring has at least one carbon atom. The fused rings completing the bicyclic group are aromatic and may contain only carbon atoms. The nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atoms may optionally be quaternized. The bicyclic heteroaryl group must include only aromatic rings. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. The heteroaryl ring system may be unsubstituted or may contain one or more substituents.
Exemplary monocyclic heteroaryls include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl.
Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, and pyrrolopyridyl.
As used herein, the term "tautomer" refers to each of two or more isomers of a compound that exist in equilibrium together and are readily interchanged by the migration of atoms or groups within the molecule. For example, it will be readily understood by those skilled in the art that 1,2, 3-triazole exists in two tautomeric forms as defined above:
thus, the disclosure is intended to cover all possible tautomers, even when the structure depicts only one of all possible tautomers. For example, a compound of formula (Ia) wherein R is 5cIs hydroxy and R5a、R5bAnd R5dMay exist in tautomeric forms when each of them is hydrogen:
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 form salts, which are also within the scope of the present invention. Unless otherwise indicated, reference to a compound of the invention is understood to include reference to one or more salts thereof. The term "salt(s)" denotes acid and/or base salts formed with inorganic and/or organic acids and bases. Furthermore, the term "salt(s)" may include zwitterions (inner salts), for example when the compound of formula (I) contains a basic moiety, such as an amine or pyridine or imidazole ring, and an acidic moiety, such as a carboxylic acid. Pharmaceutically acceptable (i.e., non-toxic physiologically acceptable) salts are preferred, such as, for example, acceptable metal and amine salts in which the cation does not significantly contribute to the toxicity or biological activity of the salt. However, other salts may for example be useful in the isolation or purification steps employed during preparation and are therefore considered within the scope of the present invention. Salts of compounds of formula (I) may be formed, for example, by: the compound of formula (I) is reacted with an amount (e.g. an equivalent amount) of an acid or base in a medium (e.g. a medium in which the salt precipitates) or in an aqueous medium, followed by lyophilization. A list of suitable salts is found in Remington's Pharmaceutical Sciences, 18 th edition, Mack Publishing Company, Easton, Pa (1990), the disclosure of which is hereby incorporated by reference.
Exemplary acid addition salts include acetate salts (such as those formed with acetic acid or trihaloacetic acid (e.g., trifluoroacetic acid)), adipate salts, alginate salts, ascorbate salts, aspartate salts, benzoate salts, benzenesulfonate salts, bisulfate salts, borate salts, butyrate salts, citrate salts, camphorate salts, camphorsulfonate salts, cyclopentanepropionate salts, digluconate salts, dodecylsulfate salts, ethanesulfonate salts, fumarate salts, glucoheptonate salts, glycerophosphate salts, hemisulfate salts, heptanoate salts, hexanoate salts, hydrochloride salts (formed with hydrochloric acid), hydrobromide salts (formed with hydrobromic acid), hydroiodide salts, maleate salts (formed with maleic acid), 2-hydroxyethanesulfonate salts, lactate salts, methanesulfonate salts (formed with methanesulfonic acid), 2-naphthalenesulfonate salts, nicotinate salts, nitrate salts, oxalate salts, pectate salts, borate salts, butyrate salts, citrate salts, and the like, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (such as those formed with sulfuric acid), sulfonate (such as those mentioned herein), tartrate, thiocyanate, tosylate (such as tosylate), undecanoate, and the like.
Exemplary basic salts include ammonium salts; alkali metal salts such as sodium, lithium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; barium, zinc and aluminum salts; salts with organic bases (e.g., organic amines) such as trialkylamines (e.g., triethylamine), procaine, dibenzylamine, N-benzyl- β -phenylethylamine, 1-diphenylmethylamine (ephenamine), N' -dibenzylethylene-diamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine, or similar pharmaceutically acceptable amines; and salts with amino acids (e.g., arginine, lysine, etc.). Basic nitrogen-containing groups can be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and the like. Preferred salts include monohydrochloride, bisulfate, mesylate, phosphate or nitrate salts.
The compounds of formula (I) may be provided as amorphous solids or crystalline solids. Lyophilization may be employed to provide the compound of formula (I) as a 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" encompasses both solution phases and isolatable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Solvation methods 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, P.Krogsgaard-Larson and H.Bundgaard, eds Chapter 5, pp 113-191 (Harwood Academic Publishers, 1991); and
d) hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and Joachim M.Mayer, (Wiley-VCH, 2003).
e) Rautio, J.et al, Nature Review Drug Discovery,17, 559-.
Furthermore, the compound of formula (I) may be isolated and purified after its preparation to obtain a composition containing the compound of formula (I) in an amount equal to or greater than 99% by weight ("substantially pure"), which is then used or formulated as described herein. Such "substantially pure" compounds of formula (I) are also contemplated herein as part of the present invention.
"stable compound" and "stable structure" are intended to indicate that the compound is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into an effective therapeutic agent. The present invention is directed to stable compounds.
"therapeutically effective amount" is intended to include the amount of a compound of the invention alone or in combination with the claimed compounds or in combination with other active ingredients effective to act as an FXR agonist or to treat or prevent disorders associated with aberrant bile acid regulation, such as pathological fibrosis, cancer, inflammatory disorders, metabolic disorders or cholestatic disorders.
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 number of atoms but different mass numbers. By way of general example, and not limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include 13C 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 the unlabeled reagent employed. Such compounds have a variety of potential uses, for example as standards and reagents in determining the ability of a potential pharmaceutical compound to bind to a target protein or receptor or for imaging compounds of the invention that bind to biological receptors in vivo or in vitro.
In another embodiment, the present invention provides a composition comprising at least one compound of the present invention or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.
In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound of the present invention or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.
In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound of the present invention or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.
In another embodiment, the invention provides a process for preparing a compound of the invention.
In another embodiment, the invention provides intermediates useful in the preparation of the compounds of the invention.
In another embodiment, the present invention provides a pharmaceutical composition as defined above further comprising one or more additional therapeutic agents.
Practicality of use
In one embodiment, the present invention provides a method for treating a disease, disorder or condition associated with bile acid dysregulation in a patient in need of such treatment, and which comprises administering to the patient a therapeutically effective amount of a compound of the present invention, or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof.
In another embodiment, the present invention provides a method for treating a disease, disorder or condition associated with activity of Farnesoid X Receptor (FXR) in a patient in need of such treatment, which comprises administering to the patient a therapeutically effective amount of a compound of the invention, or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof.
In another embodiment, the invention provides a method for treating such a disease, disorder or condition, comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one compound of the invention (alone or optionally in combination with another compound of the invention and/or at least one other type of therapeutic agent).
In another embodiment, the present invention provides a method for eliciting a Farnesoid X Receptor (FXR) agonistic effect in a patient comprising administering to the patient a therapeutically effective amount of a compound of the present invention, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.
In some embodiments, the disease, disorder or condition associated with FXR dysfunction includes pathological fibrosis, cancer, inflammatory disorders, metabolic disorders or cholestatic disorders.
In some embodiments, the disease, disorder, or condition is associated with fibrosis, including liver, biliary, renal, cardiac, skin, eye, and pancreatic fibrosis.
In other embodiments, the disease, disorder or condition is associated with a cell proliferative disorder (e.g., cancer). In some embodiments, the cancer comprises a solid tumor growth or neoplasia. In other embodiments, the cancer comprises tumor metastasis. In some embodiments, the cancer is liver cancer, gallbladder cancer, small intestine cancer, large intestine cancer, kidney cancer, prostate cancer, bladder cancer, blood cancer, bone cancer, brain cancer, breast cancer, central nervous system cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, genital cancer, genitourinary tract cancer, head cancer, throat cancer, lung cancer, muscle tissue cancer, neck cancer, oral or nasal mucosa cancer, ovarian cancer, pancreatic cancer, skin cancer, spleen cancer, stomach cancer, testicular cancer, or thyroid cancer. In other embodiments, the cancer is a carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma.
Examples of diseases, disorders or conditions associated with the activity of FXR that may be prevented, modulated or treated according to the present invention include, but are not limited to, transplant injection, fibrotic disorders (e.g., liver fibrosis, kidney fibrosis), inflammatory disorders (e.g., acute hepatitis, chronic hepatitis, nonalcoholic steatohepatitis (NASH), Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD)), and cell proliferative disorders (e.g., cancer, myeloma, fibroma, hepatocellular carcinoma, colorectal cancer, prostate cancer, leukemia, kaposi's sarcoma, solid tumors).
Fibrotic disorders, inflammatory disorders, and cell proliferative disorders suitable for prevention or treatment by a compound of the invention include, but are not limited to, non-alcoholic fatty liver disease (NAFLD), alcoholic or non-alcoholic steatohepatitis (NASH), acute hepatitis, chronic hepatitis, cirrhosis, primary biliary cirrhosis, primary sclerosing cholangitis, drug-induced hepatitis, biliary cirrhosis, portal hypertension, regenerative failure, hepatic hypofunction, hepatic blood flow disorders, kidney disease, Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), pancreatic secretion abnormalities, benign prostatic hyperplasia, neurogenic bladder disease, diabetic nephropathy (diabetic nephropathies), focal segmental glomerulosclerosis, IgA nephropathy, drug-or transplant-induced nephropathy, autoimmune nephropathy, lupus nephritis, liver fibrosis, kidney fibrosis, Chronic Kidney Disease (CKD), Diabetic nephropathy (DKD), skin fibrosis, keloids, systemic sclerosis, scleroderma, virus-induced fibrosis, Idiopathic Pulmonary Fibrosis (IPF), interstitial lung disease, non-specific interstitial pneumonia (NSIP), interstitial pneumonia vulgaris (UIP), radiation-induced fibrosis, familial pulmonary fibrosis, airway fibrosis, Chronic Obstructive Pulmonary Disease (COPD), spinal cord tumors, herniated discs, spinal stenosis, heart failure, cardiac fibrosis, vascular fibrosis, perivascular fibrosis, foot and mouth disease, cancer, myeloma, fibroma, hepatocellular carcinoma, colorectal cancer, prostate cancer, leukemia, chronic lymphocytic leukemia, kaposi's sarcoma, solid tumors, cerebral infarction, cerebral hemorrhage, neuropathic pain, peripheral neuropathy, age-related macular degeneration (AMD), glaucoma, ocular fibrosis, Corneal scarring, diabetic retinopathy, Proliferative Vitreoretinopathy (PVR), cicatricial pemphigoid, glaucoma filtration surgery scarring, crohn's disease, or systemic lupus erythematosus; keloid formation caused by abnormal wound healing; fibrosis, myelofibrosis and fibroids that occur after organ transplantation. In one embodiment, the present invention provides a method for treating a fibrotic disorder, an inflammatory disorder or a cell proliferative disorder, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one compound of the present invention (alone or optionally in combination with another compound of the present invention and/or at least one other type of therapeutic agent).
In another embodiment, the invention provides a compound of the invention for use in therapy.
In another embodiment, the invention provides a compound of the invention for use in therapy to treat a fibrotic disorder, an inflammatory disorder or a cell proliferative disorder thereof.
In another embodiment, the invention also provides the use of a compound of the invention for the manufacture of a medicament for the treatment of a fibrotic disorder, an inflammatory disorder or a cell proliferative disorder thereof.
In another embodiment, the present invention provides a method for treating a fibrotic disorder, an inflammatory disorder or a cell proliferative disorder, the method comprising administering to a patient in need thereof a therapeutically effective amount of a first therapeutic agent and a second therapeutic agent, wherein the first therapeutic agent is a compound of the present invention.
In another embodiment, the invention provides a combined preparation of a compound of the invention and one or more additional therapeutic agents for simultaneous, separate or sequential use in therapy.
In another embodiment, the invention provides a combined preparation of a compound of the invention and one or more additional therapeutic agents for simultaneous, separate or sequential use in the treatment of a fibrotic disorder, an inflammatory disorder or a cell proliferative disorder.
The compounds of the present invention may be employed in combination with one or more additional therapeutic agents, such as one or more anti-fibrotic and/or anti-inflammatory therapeutic agents.
In one embodiment, the one or more additional therapeutic agents for use in the combination pharmaceutical composition or the combination method or the combination use are selected from one or more, preferably one to three, of the following therapeutic agents: TGF β receptor inhibitors (e.g., galinstein), TGF β synthesis inhibitors (e.g., pirfenidone), Vascular Endothelial Growth Factor (VEGF), platelet-derived growth factor (PDGF), and Fibroblast Growth Factor (FGF) receptor kinase inhibitors (e.g., nintedanib), humanized anti- α, and methods of making and using the sameVMonoclonal antibodies to beta 6 integrin (e.g., 3G9), human recombinant transudin-2, recombinant human serum amyloid P, antibodies against TGF-1, TGF-beta-2 and TGF beta-3, endothelin receptor antagonists (e.g., macitentan), interferon gamma, c-Jun amino terminal kinase (JNK) inhibitors (e.g., 4- [ [9- [ (3S) -tetrahydro-3-furanyl)]-8- [ (2,4, 6-trifluorophenyl) amino group]-9H-purin-2-yl]Amino group]Trans-cyclohexanol, 3-pentylphenylacetic acid (PBI-4050), manganese (III) -containing tetrasubstituted porphyrin derivative, monoclonal antibody targeting eotaxin-2, interleukin-13 (IL-13) antibody (e.g., Lebrikizumab (Lebrikizumab), Trilobitumab (tralokinumab)), bispecific antibody targeting interleukin 4(IL-4) and interleukin 13(IL-13), NK1 tachykinin receptor agonist (e.g., Sar) 9、Met(O2)11Substance P), Cintredekin Besudotox, human recombinant DNA-derived IgG1 kappa monoclonal antibody to connective tissue growth factor and fully human IgG1 kappa antibody selective for CC chemokine ligand 2 (e.g., carlumab, CCX140), antioxidants (e.g., N-acetylcysteine), phosphodiesterase 5(PDE5) inhibitors (e.g., sildenafil), agents for treating obstructive airway diseases such as muscarinic antagonists (e.g., tiotropium bromide, ipratropium bromide), adrenergic beta 2 agonists (e.g., salbutamol, salmeterol), corticosteroids (e.g., triamcinolone, dexamethasone, fluticasone), immunosuppressive agents (e.g., tacrolimus, rapamycin, pimecrolimus), and agents useful for treating fibrotic disorders (e.g., liver fibrosis, cholefibrosis and renal fibrosis, non-alcoholic liver disease (lfd), Non-alcoholic steatohepatitis (NASH), cardiac fibrosis, Idiopathic Pulmonary Fibrosis (IPF), and systemic sclerosis). Therapeutic agents that may be used to treat such fibrotic disorders include, but are not limited to, FXR agonists (e.g., OCA, GS-9674 and LJN452), LOXL2 inhibitors (e.g., trastuzumab (simtuzumab)), LPA1 antagonists (e.g., BMS-986020 and SAR 100842), PPAR modulators (e.g., Eptifiporin (elafinibor), pioglitazone and Saroglitazar (saroglitazar), IVA337), SSAO/VAP-1 inhibitors (e.g., PXS-4728A and SZE5302), ASK-1 inhibitors (e.g., GS-4997 or Seogluta (selonerstab)), ACC inhibitors (e.g., CP-640186 and NDI-010976 or-0976), FGF21 mimetics (e.g., LY2405319 and BMS-986036), Caspase inhibitors (e.g., emlicarban (emricasan)), NOX4 inhibitors (e.g., GKT137831), MGAT2 inhibitors (e.g., BMS-963272), α V integrin inhibitors (e.g., abituzumab), and bile acid/fatty acid conjugates (e.g., alamex (aramchol)). FXR agonists of various embodiments of the invention may also be used in combination with one or more therapeutic agents such as: CCR2/5 inhibitors (e.g., ceniviroc), galectin-3 inhibitors (e.g., TD-139, GR-MD-02), leukotriene receptor antagonists (e.g., tylosin (tipelukast), montelukast), SGLT2 inhibitors (e.g., dacemazin, remogliflozin), GLP-1 receptor agonists (e.g., liraglutide and semaglutide), FAK inhibitors (e.g., GSK-2256098), CB1 inverse agonists (e.g., JD-5037), CB2 agonists (e.g., APD-371 and JBT-101), autotaxin (autotaxin) inhibitors (e.g., GLPG1690), prolyl t-RNA synthase inhibitors (e.g., halofugenone), FPR2 agonists (e.g., ZK-994), and THR agonists (e.g., MGL: 3196). In another embodiment, the one or more additional therapeutic agents for use in the combination pharmaceutical composition or the combination method or the combination use are selected from one or more, preferably one to three, immunotumoral agents such as: alemtuzumab, altlizumab, yipimima, nivolumab, ofatumumab, pembrolizumab, and rituximab.
The compounds of the invention may be administered for any of the uses described herein by any suitable means: e.g., orally, such as tablets, capsules (each of which includes sustained-release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions; lingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., as sterile injectable aqueous or nonaqueous solutions or suspensions); nasally, including application to nasal membranes, such as by inhalation spray; topically, e.g., in the form of a cream or ointment; or rectally, such as in the form of suppositories. They may be administered alone, but will generally be administered with a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice.
The term "pharmaceutical composition" means a composition comprising a compound of the invention in combination with at least one additional pharmaceutically acceptable carrier. By "pharmaceutically acceptable carrier" is meant a vehicle commonly accepted in the art for delivering biologically active agents to animals (particularly mammals), including, depending on the mode of administration and the nature of the dosage form, adjuvants, excipients, or vehicles such as diluents, preservatives, fillers, flow control agents, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, and dispersants. The pharmaceutically acceptable carrier is formulated according to a number of factors well within the purview of one of ordinary skill in the art. These factors 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 targeted therapeutic indications. 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 may 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). The description of suitable pharmaceutically acceptable carriers and the selection thereof involves factors found in various readily available sources, such as, for example, Remington's Pharmaceutical Sciences, 18 th edition (1990).
The term "treating" or "treatment" as used herein refers to a method for obtaining beneficial or desired results, including clinical results, by use of a compound or composition of the present invention. For purposes of the present invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing the severity and/or frequency of one or more symptoms caused by a disease, disorder or condition; reducing the extent of or causing regression of a disease, disorder, or condition; stabilizing the disease, disorder, or condition (e.g., preventing or delaying the worsening of the disease, disorder, or condition); delaying or slowing the progression of the disease, disorder or condition; ameliorating a disease, disorder or condition state; reducing the dose of one or more other drugs required to treat the disease, disorder or condition; and/or improve quality of life.
The pharmaceutically acceptable carrier is formulated according to a number of factors well within the purview of one of ordinary skill in the art. These factors 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 targeted therapeutic indications. 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 may 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). A description of suitable pharmaceutically acceptable carriers and their selection involves factors found in various readily available sources, such as, for example, Allen, L.V.Jr. et al Remington: The Science and Practice of Pharmacy (Vol.2), 22 nd edition (2012), Pharmaceutical Press.
Of course, the dosage regimen of the compounds of the invention will vary depending upon known factors such as: the pharmacodynamic characteristics of a particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient and the desired effect.
By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effect, will range between about 0.01 to about 5000 mg/day, preferably between about 0.01 to about 1000 mg/day, most preferably between about 0.01 to about 250 mg/day. Intravenously, during a constant rate infusion, the most preferred dose will range from about 0.01 to about 10 mg/kg/minute. The compounds of the invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times daily.
The compounds are generally administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration (e.g., oral tablets, capsules, elixirs and syrups), and consistent with conventional pharmaceutical practice.
Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 mg to about 2000 mg of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient will generally be present in an amount of about 0.1% to 95% by weight, based on the total weight of the composition.
A typical capsule for oral administration contains at least one compound of the invention (250mg), lactose (75mg) and magnesium stearate (15 mg). The mixture was passed through a 60 mesh screen and filled into size 1 gelatin capsules.
Typical injectable formulations are produced by aseptically placing at least one compound of the invention (250mg) into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2mL of physiological saline to produce an injectable formulation.
The present invention includes within its scope pharmaceutical compositions comprising as an active ingredient a therapeutically effective amount of at least one compound of the present invention, alone or in combination with a pharmaceutical carrier. Optionally, the compounds of the present invention may be used alone, in combination with other compounds of the present invention, or in combination with one or more (preferably one to three) other therapeutic agents (e.g., ASK-1 inhibitors, CCR2/5 antagonists, homechemoattractant inhibitors, LPA1 receptor antagonists or other pharmaceutically active materials).
When employed in combination with the compounds of the present invention, the above-described other therapeutic agents may be employed, for example, in the amounts indicated in the Physicians' Desk Reference, as in the patents listed above, or as otherwise determined by one of ordinary skill in the art.
Especially when provided as single dosage units, the possibility exists of chemical interactions between the active ingredients of the combination. For this reason, when the compound of the present invention and the second therapeutic agent are combined in a single dosage unit, they are formulated such that, despite the active ingredients being combined in a single dosage unit, physical contact between the active ingredients is minimized (that is, reduced). For example, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, not only contact between the combined active ingredients can be minimized, but also the release of one of the components in the gastrointestinal tract can be controlled such that one of the components is not released in the stomach but in the intestinal tract. One of the active ingredients may also be coated with a material that achieves sustained release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-release component may additionally be enteric coated, so that the release of this component takes place only in the intestinal tract. Yet another approach would involve formulating a combination product in which one component is coated with a sustained-release and/or enteric-release polymer and the other component is also coated with a polymer, such as low viscosity grade hydroxypropyl methylcellulose (HPMC), or other suitable materials as are known in the art, to further separate the active ingredients. The polymer coating is used to form an additional barrier against interaction with another component.
These and other ways of minimizing contact between the components of the combination product of the invention, whether administered in a single dosage form or in separate forms but administered in the same manner at the same time, will be readily apparent to those skilled in the art after having the benefit of this disclosure.
The compounds of the present invention may be administered alone or in combination with one or more (preferably one to three) additional therapeutic agents. By "combined administration" or "combination therapy" is meant that a compound of the invention and one or more (preferably one to three) additional therapeutic agents are administered simultaneously to the mammal being treated. When administered in combination, each component may be administered at the same time or sequentially in any order at different time points. Thus, each component may be administered separately, but close enough in time to provide the desired therapeutic effect.
Combination therapy is intended to encompass the administration of these therapeutic agents in a sequential manner (i.e., wherein each therapeutic agent is administered at a different time) as well as the administration of these therapeutic agents or at least two of these therapeutic agents in a substantially simultaneous manner. Substantially simultaneous administration can be achieved, for example, by administering to the subject a single dosage form having a fixed ratio of each therapeutic agent or in multiple single dosage forms of each therapeutic agent. Sequential or substantially simultaneous administration of each therapeutic agent may be achieved by any suitable route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents may be administered by the same route or by different routes. For example, a first therapeutic agent of a selected combination may be administered by intravenous injection, while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or may be administered by intravenous injection. Combination therapy may also include the administration of a therapeutic agent as described above further in combination with other bioactive ingredients and non-drug therapy (e.g., surgery or radiation therapy). Where combination therapy also includes non-drug treatment, the non-drug treatment may be carried out at any suitable time, so long as the beneficial effect is achieved from the combined action of the therapeutic agent and the non-drug treatment. For example, where appropriate, the beneficial effect is still achieved when the non-drug treatment is temporarily removed from administration of the therapeutic agent (perhaps days or even weeks).
The compounds of the invention may also be used as standard or reference compounds in tests or assays involving FXR agonists, for example as quality standards or controls. Such compounds may be provided in commercial kits, for example for use in pharmaceutical studies involving FXR agonist activity. For example, a compound of the invention can be used as a reference in an assay to compare its known activity to a compound with unknown activity. This will ensure that the experimenter is performing the assay correctly and provide a basis for comparison, particularly if the test compound is a derivative of the reference compound. When developing new assays or protocols, compounds according to the invention can be used to test their effectiveness.
The invention also encompasses 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 a 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) a package insert indicating that the pharmaceutical composition can be used to treat dyslipidemia and its sequelae. In another embodiment, the package insert indicates that the pharmaceutical composition can be used in combination with a second therapeutic agent (as previously defined) for treating fibrosis and its sequelae. 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 containers hold the item within their boundaries.
The first container is a receiving container for holding 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, holding, storing, or dispensing a pharmaceutical product.
The second container is a container for holding the first container and optionally a package insert. Examples of 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 sacks. The package insert may be physically attached to the outside of the first container via tape, glue, staples, or another method of attachment, or it may rest inside the second container without any physical means of attachment to the first container. Alternatively, the package insert is located on the outside of the second container. When located on the outside of the second container, it is preferred that the package insert is physically attached via tape, glue, staples or another attachment method. 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 (label), tag, mark (marker) that lists information about the pharmaceutical composition located in the first container. The listed information will typically be determined by the regulatory agency (e.g., the U.S. food and drug administration) that manages the region where the article is sold. Preferably, the package insert specifically lists the indications for which the pharmaceutical composition has been approved. The package insert may be made of any material from which a person can read information contained therein or thereon. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive-backed paper or plastic) on which the desired information has been formed (e.g., printed or applied).
Preparation method
The compounds of the present invention can be synthesized by a variety of methods available to those skilled in the art of organic chemistry. The general synthetic schemes for preparing the compounds of the present invention are described below. These schemes are illustrative and are not intended to limit the possible techniques available to those skilled in the art for preparing the compounds disclosed herein. Different methods of preparing the compounds of the invention will be clear to the skilled person. Examples of compounds of the invention prepared by the methods described in the general schemes are given in the examples section set forth below. Homochiral embodiments can be prepared by techniques known to those skilled in the art. For example, homochiral compounds can be prepared by separation of racemic products or diastereomers via chiral phase preparative HPLC. Alternatively, the example compounds may be prepared by known methods to give enantiomerically or diastereomerically enriched products.
The reactions and techniques described in this section are carried out in solvents appropriate to the reagents and materials used, and are suitable for the transformations carried out. Furthermore, in the description of the synthetic methods given below, it is understood that all proposed reaction conditions (including the choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and work-up procedure) are selected as conditions standard for the reaction, as will be readily recognized by the skilled person. It will be appreciated by those skilled in the art of organic synthesis that the functional groups present on each part of the molecule must be compatible with the reagents and reactions proposed. Such limitations on substituents that are compatible with reaction conditions should be readily apparent to those skilled in the art, where alternatives are required when incompatible substituents are present. This will sometimes require a judgment to modify the order of the synthetic steps or to select a particular method scheme over another in order to obtain the compounds 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 of the invention. An authoritative explanation for describing many alternatives for trained practitioners is Wuts and Greene, Greene's Protective Groups in Organic Synthesis, fourth edition, Wiley and Sons (2007).
Examples
The following examples illustrate specific and preferred embodiments of the present invention and do not limit the scope of the invention. Unless otherwise indicated, chemical abbreviations and symbols as well as scientific abbreviations and symbols have their usual and customary meaning. Additional abbreviations employed in the examples and elsewhere in this application are defined below. Common intermediates are generally useful for preparing more than one example and are identified sequentially (e.g., intermediate 1, intermediate 2) and are abbreviated as int.1 or I1, int.2, or I2. The compounds of the examples are identified by the examples and procedures for their preparation (e.g., "1-a" represents example 1, step a), or by the examples only in the case where the compound is the title compound of the example (e.g., "1" represents the title compound of example 1). In some cases, alternative preparations of intermediates or examples are described. In general, those skilled in the art of synthesis can design alternative preparations that may be desirable based on one or more considerations such as: shorter reaction times, less expensive starting materials, easy handling or isolation, improved yields, suitability for catalysis, avoidance of toxic reagents, availability of specialized equipment and a reduced number of linear steps. The purpose of describing the alternative preparation is to further enable the preparation of the embodiments of the invention. In some cases, in the embodiments outlined And some of the functional groups in the claims may be replaced by well known bioisosteric substitutes known in the art, such as replacing the carboxylic acid group with a tetrazole or phosphate moiety. Collected in deuterated dimethyl sulfoxide1H NMR data was suppressed using water at data processing. The reported spectra were not corrected for water inhibition. Protons adjacent to a water suppression frequency of 3.35ppm exhibited reduced signal intensity.
Abbreviations
The following abbreviations are used in the schemes, examples and elsewhere herein:
EtOAc ═ ethyl acetate
PE-Petroleum Ether
DMF ═ dimethylformamide
THF ═ tetrahydrofuran
K2CO3Arbutine potassium carbonate
Na2CO3Sodium carbonate (sodium bicarbonate)
MgSO4Magnesium sulfate ═ magnesium sulfate
DCM＝CH2Cl2Methylene chloride ═
MeOH ═ methanol
HCl ═ hydrochloric acid
AcOH ═ acetic acid
Cs2CO3Cesium carbonate (MCH)
DMSO ═ dimethyl sulfoxide
TEA ═ triethylamine
BOP (BOP) tris (dimethylamino) phosphonium hexafluorophosphate
DMAP ═ 4-dimethylaminopyridine
2-DMAP ═ 2-dimethylaminopyridine
Pyridinium PCC (chloride chromate)
Pyridinium dichromate PDC ═ pyridinium dichromate
DIBAL-H ═ diisobutylaluminum hydride
rotovap ═ rotary evaporation
min is minutes
h or hr-hour
d is day
rt-room temperature
mL to mL
g is g ═ g
mg ═ mg
mmol ═ mmol
LRMS (low resolution mass spectrometry)
NMR (nuclear magnetic resonance)
HPLC ═ high performance liquid chromatography
Synthesis of
The compounds of the present invention may be prepared in a variety of ways well known to those skilled in the art of organic synthesis. The compounds of the invention can be synthesized using the methods described below, together with synthetic methods known in the art of 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 herein are hereby incorporated by reference in their entirety.
The reactions and techniques described in this section can be used to prepare novel compounds of formula I. The reaction is carried out in a solvent appropriate to the reagents and materials used and suitable for the conversion carried out. Furthermore, in the description of the synthetic methods described below, it is understood that all proposed reaction conditions (including solvents, reaction atmospheres, reaction temperatures, duration of the experiment, and work-up procedures) are selected as conditions standard for the reaction, as one skilled in the art would readily recognize. Those skilled in the art of organic synthesis understand that the functional groups present on each part of the reporter molecule must be compatible with the reagents and reactions proposed. Not all compounds of formula I falling within a given class may be compatible with some of the reaction conditions required in some of the described methods. Such limitations on substituents compatible with reaction conditions should be readily apparent to those skilled in the art, and alternative methods must be used.
Scheme 1
Scheme 1 describes the synthesis of compounds of formula I. Intermediate 3 can be synthesized by coupling intermediate 1 and intermediate 2 under reductive amination conditions, which are known methods as would be recognized by one skilled in the art. Imine synthesis can be carried out in the presence of an acid (e.g., acetic acid) in a suitable polar protic solvent (e.g., MeOH, EtOH, etc.) at room or reflux temperature, followed by reduction of the imine with a reducing agent (e.g., sodium cyanoborohydride, sodium triacetoxyborohydride, etc.) to afford intermediate 3. A variety of different transformations of intermediate 3 may be performed to give variants of formula I using a number of known methods recognized by those skilled in the art, including but not limited to the following:
amide: intermediate 4 may be obtained from commercial sources or may be synthesized by known methods readily recognizable to those skilled in the art. Intermediate 4 may be activated for acylation at a temperature ranging between-30 ℃ to reflux temperature in a polar aprotic solvent (e.g., DCM, THF, etc.) using any number of reagents that would be recognized by one skilled in the art (e.g., phosphoryl chloride, thionyl chloride, oxalyl chloride, methyl or ethyl chloroformate, etc.). The activated acid intermediate may then be reacted with intermediate 3 in the presence of a base (e.g., pyridine, DMAP, 2- (dimethylamino) pyridine, N-methylmorpholine, and the like, or a combination of at least two of these) to produce a compound of formula I.
Urea: can be prepared at room temperature in a polar aprotic solvent (e.g., DCM, DCE, etc.) in a base (e.g., Et)3N, DIPEA, pyridine, etc.) with an isocyanate to give a urea of formula I. Alternatively, the solvent can be prepared by dissolving in a solvent (e.g., DCM, DCE, etc.) in a base (e.g., Et) at 0 deg.C to room temperature3N, DIPEA, etc.) was treated with triphosgene to activate intermediate 3. The reaction mixture can then be dissolved in a solvent (e.g., DCM, DCE, THF, etc.) in a base (e.g., Et) at room temperature3N, DIPEA, etc.) is treated with a substituted alkyl or aryl or heteroaryl amine to give a urea of formula I.
Carbamate ester: can be carried out in a polar aprotic solvent (e.g., DCM, DCE, DC,THF, etc.), in a base (e.g., Et)3N, DIPEA, pyridine, t-BuOK, etc.) with chloroformate (or alcohol, activated to carbonate) to give carbamate represented by formula I.
Intermediate 1 (scheme 1) may be obtained from commercial sources or may be synthesized by known methods readily recognizable to those skilled in the art. Intermediate 1 can be obtained in various ways as depicted in schemes 2-10 using many known methods recognized by those skilled in the art, including but not limited to the following methods.
Scheme 2
Intermediate 1 can be obtained in various ways as depicted in scheme 2. Intermediates 5, 6 and 7 can be obtained from commercial sources or can be synthesized by known methods readily recognized by those skilled in the art. The Metal-Catalyzed Cross-Coupling Reactions of intermediates 5, 6 and 7 can be carried out using a number of known methods recognized by those skilled in the art, including but not limited to Metal-Catalyzed Cross-Coupling Reactions, arnin de Meijere,diederich, volume 2, second revision and supplement, 2004, ISBN:3-527-30518-1, Wiley-VCH and the references cited therein. Various metal-catalyzed reactions (including but not limited to reactions such as Ullmann, Buchwald, Suzuki, Stille, Sonogashira couplings, etc.) can be performed on intermediates 5, 6 and 7. Can be carried out in the presence of a metal catalyst (e.g., CuBr, Pd (OAc) as required)2、Pd2(dba)3、Pd(PPh3)4、Pd(PPh3)2Cl2、Pd(dppf)Cl2Etc.) and a suitable ligand (including but not limited to ligands such as proline, 1, 10-phenanthroline, tricyclohexylphosphine, dppf, etc.). Can be coupled to various coupling partners (e.g. alkyl or cycloalkyl or heterocycle)Alkyl or cycloalkyl or heterocyclyl or heteroarylalcohol, phenol, etc.) to the Ullmann and Buchwald coupling reactions of intermediate 5. The Suzuki, Heck, Chan-Lam coupling reactions of intermediates 6 and 7 can be performed with various coupling partners (e.g., alkenes, alkenyl halides, or triflates, etc.). Intermediate 5 can be cross-coupled with a coupling partner (e.g., alkyl, allyl, alkenyl boronic acids, boronic esters, trifluoroborates; alkyl, allyl, alkynyl, organotin reagents, etc.) by Suzuki, Stille, etc. Can be in the presence of a base (if desired) (including but not limited to Na) 2CO3、K2CO3、NaHCO3、K3PO4、NaOtBu, etc.) and a solvent (e.g., dioxane, THF, DME, toluene, methanol, DMF, water, etc., or a mixture of two or three of these solvents) under heating conditions to obtain intermediate 1. Alternatively, intermediate 5 can be converted to an organotin reagent using hexamethylditin at reflux temperature in the presence of a palladium catalyst and in a solvent (e.g., toluene, THF, etc.) which, after coupling with a suitable coupling partner (e.g., alkyl, acyl, alkenyl, allyl halide, triflate, etc.) in a Stille coupling fashion (sher, b. et al PCT international application, 2016/039734,2016), yields the compound represented by formula I. Can be carried out in a solvent (e.g., dioxane, DMSO, etc.) over a palladium catalyst (e.g., Pd (dppf) Cl) at reflux temperature2) And a base (e.g., potassium acetate) using bis (pinacolato) diboron, bis (neopentylglycol) diboron, and the like, to convert intermediate 5 to an organoboron reagent that upon coupling with a suitable coupling partner (e.g., an alkene, alkenyl halide, or triflate, and the like) in a Suzuki coupling manner yields the compound represented by formula I. Intermediate 7a can be coupled with dimethylphosphine oxide with heating in the presence of a palladium catalyst (such as palladium bis (dibenzylideneacetone)) and a ligand (such as XantPhos) and an inorganic base (such as cesium carbonate) in a solvent (such as dioxane, DMSO, etc.) to give the corresponding phosphine oxide.
Intermediate 7 or 7a is followed by a coupling reaction as described above to give a nitro intermediate, which can be reduced to give intermediate 1 using conditions recognized by those skilled in the art, including but not limited to reduction at ambient pressure and temperature in the presence of a catalyst such as Pd and hydrogen.
Scheme 3
Intermediates 1a-d can be obtained in various ways as depicted in scheme 3. Intermediate 8 may be obtained from commercial sources or may be synthesized by known methods readily recognized by those skilled in the art. A variety of different transformations of intermediate 8 may be performed to give intermediates 9-12 using a number of known methods recognized by those skilled in the art, including but not limited to the following:
amide: intermediate 8 can be reacted with an activated acid intermediate in the presence of a base (e.g., pyridine, DMAP, 2- (dimethylamino) pyridine, N-methylmorpholine, etc.) in a polar aprotic solvent (e.g., DCM, THF, etc.) to produce intermediate 9.
Carbamate ester: can be prepared in polar aprotic solvents (e.g., DCM, DCE, THF, etc.) in bases (e.g., Et) at 0 deg.C to room temperature3N, DIPEA, pyridine, t-BuOK, etc.) to intermediate 8 with a chloroformate (or alcohol, activated to a carbonate) to afford intermediate 10.
Urea: can be prepared at room temperature in a polar aprotic solvent (e.g., DCM, DCE, etc.) in a base (e.g., Et)3N, DIPEA, pyridine, etc.) with an isocyanate to give intermediate 11. Alternatively, the solvent can be prepared by dissolving in a solvent (e.g., DCM, DCE, etc.) in a base (e.g., Et) at 0 deg.C to room temperature3N, DIPEA, etc.) was treated with triphosgene to activate intermediate 8. The reaction mixture can then be dissolved in a solvent (e.g., DCM, DCE, etc.) in a base (e.g., Et) at room temperature3N, DIPEA, etc.) is treated with a substituted alkyl or aryl or heteroaryl amine to afford intermediate 11.
Sulfonamide: intermediate 8 can be treated with sulfonyl chloride in the presence of a base (e.g., pyridine, DMAP, 2- (dimethylamino) pyridine, N-methylmorpholine, etc.) in a polar aprotic solvent (e.g., DCM, THF, etc.) at a temperature ranging between 0 ℃ and 90 ℃ to form intermediate 12.
Intermediates 9-12 can be reduced to yield intermediates 1a-d, respectively (as shown in scheme 3) using conditions recognized by those skilled in the art, including but not limited to reduction at ambient pressure and temperature in the presence of a catalyst (e.g., Pd) and hydrogen.
Scheme 4
Intermediate 1e can be obtained as depicted in scheme 3. Intermediate 13 may be obtained from commercial sources or may be synthesized by known methods readily recognized by those skilled in the art. Intermediate 13 can be alkylated to give intermediate 14 using a number of known methods recognized by those skilled in the art, including but not limited to, in a polar aprotic solvent (e.g., acetone, etc.), in a base (e.g., K), etc2CO3、Na2CO3Etc.) with an alkyl or aryl or heteroaryl 2-bromoacetate under heating. Intermediate 14 can be reduced to produce intermediate 1e using conditions recognized by those skilled in the art, including, but not limited to, reduction at ambient pressure and temperature in the presence of a catalyst (e.g., Pd) and hydrogen.
Scheme 5
Scheme 5 describes the synthesis of intermediate 1 f. Intermediate 15 may be obtained from commercial sources or may be synthesized by known methods readily recognized by those skilled in the art. Intermediate 16 may be prepared from intermediate 15 by using any number of reagents that would be recognized by one skilled in the art (but not limited to those described herein), such as phosphoryl chloride, thionyl chloride, oxalyl chloride, methyl or ethyl chloroformate, and the like, in a polar aprotic solvent (e.g., DCM, THF, and the like) at a temperature ranging between-30 ℃ and reflux temperature. The activated acid intermediate 16 can then be reacted with intermediate 18 in the presence of a base (e.g., pyridine, DMAP, 2- (dimethylamino) pyridine, N-methylmorpholine, etc.) to produce intermediate 17. Intermediate 17 can be reduced to produce intermediate 1f using conditions recognized by those skilled in the art, including but not limited to reduction at ambient pressure and temperature in the presence of a catalyst (e.g., Pd) and hydrogen.
Scheme 6
Scheme 6 describes the synthesis of intermediate 1 g. Intermediate 19 may be obtained from commercial sources or may be synthesized by known methods readily recognized by those skilled in the art. Intermediate 19 can then be reacted with intermediate 18 in the presence of a base (e.g., pyridine, DMAP, 2- (dimethylamino) pyridine, N-methylmorpholine, etc.) to produce intermediate 20. Intermediate 20 may be reduced to produce intermediate 1g using conditions recognized by those skilled in the art, including but not limited to reduction at ambient pressure and temperature in the presence of a catalyst (e.g., Pd) and hydrogen.
Scheme 7
Scheme 7 describes the synthesis of intermediate 1 h. Intermediate 21 may be obtained from commercial sources or may be synthesized by known methods readily recognized by those skilled in the art. Intermediate 21 may be reduced to produce intermediate 1h using conditions recognized by those skilled in the art, including but not limited to reduction at ambient pressure and temperature in the presence of a catalyst (e.g., Pd) and hydrogen. Intermediate 1h may also be obtained from commercial sources or may be synthesized by known methods readily recognized by those skilled in the art, including but not limited to the methods described herein.
Scheme 8
Scheme 8 describes the synthesis of intermediate 1 i. Intermediate 16 (synthesized as described in scheme 5) can be reacted with a sulfonamide in the presence of a base (e.g., pyridine, DMAP, 2- (dimethylamino) pyridine, N-methylmorpholine, etc.) in a polar aprotic solvent (e.g., DCM, THF, etc.) at a temperature ranging between 0 ℃ and 90 ℃ to produce intermediate 22. Intermediate 22 may be reduced to produce intermediate 1i using conditions recognized by those skilled in the art, including but not limited to reduction at ambient pressure and temperature in the presence of a catalyst (e.g., Pd) and hydrogen.
Scheme 9
Scheme 9 describes the synthesis of intermediate 1 j. Intermediate 16 (synthesized as described in scheme 5) can be reacted with an alcohol or phenol in a polar aprotic solvent (e.g., DCM, THF, etc.) in the presence of a base (e.g., pyridine, DMAP, 2- (dimethylamino) pyridine, N-methylmorpholine, etc.) at a temperature ranging between 0 ℃ and 90 ℃ to produce intermediate 23. Intermediate 23 can be reduced to produce intermediate 1j using conditions recognized by those skilled in the art, including but not limited to reduction at ambient pressure and temperature in the presence of a catalyst (e.g., Pd) and hydrogen.
Scheme 10
Scheme 10 depicts the synthesis of intermediate 1 k. Intermediate 24 may be obtained from commercial sources or may be readily prepared by one skilled in the artKnown methods are known for synthesis. Can be in a polar protic solvent (e.g., water, methanol, ethanol, etc.) in a base (e.g., K)2CO3、Na2CO3Etc.) with an alkyl 2- (dimethoxyphosphoryl) acetate to give intermediate 24 a. Intermediate 24a can be reduced to give intermediate 1k using conditions recognized by those skilled in the art, including but not limited to the conditions described, such as heating in a polar protic solvent (e.g., water) in the presence of tin (II) chloride dihydrate. Intermediate 1k may be converted to the compound of formula I by using the procedures described in scheme 1.
Intermediate 2 (scheme 1) can be obtained in various ways as depicted in scheme 11 using many known methods recognized by those skilled in the art, including but not limited to the following methods.
Scheme 11
Scheme 11 describes the synthesis of intermediate 2. Commercially available 4- (methoxycarbonyl) bicyclo [2.2.2] octane-1-carboxylic acid 25 can be subjected to heterocyclic synthesis to obtain a compound of intermediate 26.
The heterocyclic ring forms (A). The formate moiety of compound 25 can be converted to the various heterocycles (a) using a number of known methods recognized by those skilled in the art, including but not limited to the following methods:
a ═ 1,2, 4-oxadiazole. Intermediate 25 can be coupled with various amidoximes (derived from the corresponding nitriles by reaction with hydroxylamine; see Hirawat, s. et al WO 2006/110483) using amide bond coupling reagents (e.g. CDI, BOP, EDC, etc.) in polar aprotic solvents (e.g. THF, 1, 4-dioxane, DMF, etc.) at room temperature. The acyclic intermediate can then be cyclized at elevated temperature (60 ℃ to 100 ℃). Alternatively, in situ cyclization can be achieved by performing the coupling of acid 25 to the amide oxime at elevated temperature (60 ℃ to 100 ℃).
A ═ 1,2, 5-oxadiazole. Intermediate 25 can be converted to a 1,2, 5-oxadiazole, e.gJ. Et al, med, chem.2012,55, 1817-.
A ═ 1,3, 4-oxadiazole or a ═ 1,3, 4-thiadiazole. Intermediate 25 can be coupled with acetic acid hydrazide using amide bond coupling reagents (e.g., CDI, BOP, EDC, etc.) in polar aprotic solvents (e.g., THF, 1, 4-dioxane, DMF, MeCN, etc.) (described in WO 2014/071247, Bradner, j.e. et al). The acyclic hydrazide intermediate can then be cyclized to the 1,3, 4-oxadiazole or 1,3, 4-thiadiazole using 4-toluenesulfonic acid (Stabile, P. et al Tetrahedron Lett.2010,51, 4801-.
A ═ 3-substituted 5-alkyl-1-methyl-1H-pyrazole. The methyl ketone can be treated with the basic and acidic chlorides of intermediate 25 to provide a diketone which, after reaction with a substituted or unsubstituted hydrazonium salt in a polar protic solvent such as ethanol at reflux temperature, provides ester 26 wherein a is an alkyl substituted or unsubstituted pyrazole. (as described in Cadilla, R. et al WO 03/074495A 1).
A is isoxazole. The diketones prepared from intermediate 25 as described above can be reacted with hydroxylamine hydrochloride in a polar protic solvent (e.g., ethanol) at reflux temperature to give ester 26, where A is an alkyl substituted isoxazole (as described in Cadilla, R. et al, WO 03/074495A 1).
A ═ 5- (3-alkyl-1-methyl-1H-pyrazole). The diketones prepared from intermediate 25 as described above can be reacted with alkylhydrazines in polar protic solvents (e.g., ethanol) at reflux temperature to provide ester 26, where A is an alkyl substituted pyrazole.
A is substituted heteroaryl. Intermediate 25 can be subjected to a Minisci reaction with a substituted heteroaryl compound (e.g., pyridine, pyrimidine, pyridazine, pyrazine, quinoline, pyrazole, etc.) in the presence of silver nitrate and potassium persulfate or ammonium persulfate in a mixture of DCM (or any other condition useful for generating carbon-centered radicals) and water as a solvent at ambient temperature to give ester 26 (e.g., as described in Ling-Bo, Qu et al, org. Biomol. Chem.,2015,13, 2750-.
A ═ 2-benzothiazole. The method A comprises the following steps: intermediate 25 can be coupled to a substituted 2-aminobenzenethiol using an amide bond coupling reagent (e.g., BOP, T3P, EDC, etc.) in a polar aprotic solvent (e.g., DCE, THF, etc.) (see generally Chedekel, M.R. et al Synth. Commun.1980,10, 167-173; synthesis of various 2-aminobenzenethiols). The coupling reaction may be carried out at elevated temperatures (60 ℃ to 80 ℃) to achieve in situ formation of the cyclized 2-benzothiazole.
The method B comprises the following steps: alternatively, amide bond coupling reagents (e.g., T3P, BOP, etc.) or by using any number of reagents (e.g., oxalyl chloride, POCl, etc.) may be used3Etc.) to activate intermediate 25 for acylation to couple intermediate 25 with a substituted 2-chloroaniline (commercially available). The in-situ cyclization to 2-benzothiazole can be achieved by treating the resulting formamide with Lawesson's reagent at elevated temperature (120 ℃).
A ═ 2-benzoxazole. Intermediate 25 can be coupled with a substituted 2-aminophenol (commercially available) using an amide bond coupling reagent (e.g., BOP, EDC, etc.) in a polar aprotic solvent (e.g., DMF, THF, etc.). Cyclization can be achieved in refluxing toluene in the presence of p-toluenesulfonic acid.
A ═ 2-benzimidazole. Intermediate 25 can be coupled with ethyl 3, 4-diaminobenzoate using an amide bond coupling reagent (e.g., TBTU, T3P, PyBOP, etc.) in a polar aprotic solvent (e.g., DMF, NMP, etc.) and then cyclized to 2-benzimidazole under acidic conditions (neat AcOH) at elevated temperature (115 ℃).
A is 2-quinazoline. Intermediate 25 can be coupled with 4-amino-3- (aminomethyl) benzoic acid dihydrochloride using an amide bond coupling reagent (e.g., HBTU, EDC, PyBOP, etc.) in a polar aprotic solvent (e.g., MeCN, THF, etc.) (Pascal, r. et al eur.j. org.chem.2000,22, 3755-. The cyclization can be effected under acidic conditions (pure AcOH) at elevated temperature (115 ℃). The resulting dihydroquinazoline intermediate may be oxidized to 2-quinazoline using an oxidizing agent (e.g., DDQ).
A is 1-triazole. Intermediate 25 can be converted to the corresponding amine via a Curtius rearrangement (as described in Shioiri, T. et al J. Am. chem. Soc.1972,94, 6203-6205). Amines treated with reagents such as p-toluenesulfonylazide may be converted to the corresponding azides which, upon reaction with the appropriate alkyne (as described in Boren, b.c. et al, j.am. chem. soc.,2008,130, 8923-one 8930), yield a triazole.
A is substituted 1,2, 4-triazole. Intermediate 25 can be converted to the corresponding hydrazide and can be reacted with a substituted formamide in the presence of triflic anhydride and 2-fluoropyridine with heating as described by Charette, a.b. et al org.lett.,2015,17, 1184-propan 1187.
"A" may be other heterocycles such as substituted and unsubstituted oxazoles, thiazoles, imidazoles, isoxazoles, triazoles, pyrazoles, and may be synthesized as described in the references Wlochal, J. et al org. Lett.2014,16,4094-. Alternatively, the acid functional groups of intermediate 25 may be converted to heterocycles as described in schemes 2-9 using the methods described therein and literature references.
Can be obtained by reducing the solvent (such as LAH, DIBAL-H, NaBH) in chlorinated or ethereal solvents (such as DCM, diethyl ether, 1, 4-dioxane, THF, etc.)4Etc.) reduction of intermediate 26 to give intermediate 27. Intermediate 27 can be oxidized using oxidation conditions (e.g., Dess-Martin periodinane, Swern oxidation conditions, PDC, etc.) by methods recognized by those skilled in the art to afford intermediate 2.
Scheme 12
Scheme 12 describes the replacement of the synthesis of compounds of formula I with a modified sequence of steps. Can be used in a hydride-based reducing agent (e.g., LAH, DIBAL-H, NaBH) 4Etc.) in the presence of a catalyst comprising a mixture of a commercially available 4- (methoxy) compoundAlkylcarbonyl) bicyclo [2.2.2]Octane-1-carboxylic acid 25 was reduced to give intermediate 28. Oxidation of intermediate 28 to intermediate 29 can be accomplished by methods recognized by those skilled in the art using oxidation conditions (e.g., dessimutan oxidant, Swern oxidation conditions, PDC or PCC, etc.). Intermediate 1 and intermediate 29 can be reacted in the presence of an acid (e.g., acetic acid) in a suitable polar protic solvent (e.g., MeOH, EtOH, etc.) at room or reflux temperature, followed by reduction with a reducing agent (e.g., sodium cyanoborohydride, sodium triacetoxyborohydride, etc.) to provide intermediate 30. Intermediate 4 may be activated for acylation at a temperature ranging between-30 ℃ to reflux temperature in a polar aprotic solvent (e.g., DCM, THF, etc.) using any number of reagents that would be recognized by one skilled in the art (e.g., thionyl chloride, phosphoryl chloride, oxalyl chloride, methyl or ethyl chloroformate, etc.). The activated acid intermediate may be reacted with intermediate 30 in the presence of a base to form the corresponding amide. Subsequent basic hydrolysis of the methyl ester with an alkaline hydroxide provides intermediate 31. Intermediate 31 may be converted to the various heterocycles (a) to give compounds of formula I using a number of known methods recognized by those skilled in the art, including but not limited to the methods described in scheme 11.
Alternatively, intermediate 29 and intermediate 5a or 5b can be subjected to reductive amination using a number of known methods as would be recognized by one skilled in the art. Imine synthesis is carried out in the presence of an acid (e.g., acetic acid) in a suitable polar protic solvent (e.g., MeOH, EtOH, etc.) at room or reflux temperature, followed by reduction of the imine with a reducing agent (e.g., sodium cyanoborohydride, sodium triacetoxyborohydride, etc.) to afford intermediate 30 a. Intermediate 4 may be activated for acylation at a temperature ranging between-30 ℃ to reflux temperature in a polar aprotic solvent (e.g., DCM, THF, etc.) using any number of reagents that would be recognized by one skilled in the art (e.g., thionyl chloride, phosphoryl chloride, oxalyl chloride, methyl or ethyl chloroformate, etc.). The activated acid intermediate may be reacted with intermediate 30a in the presence of a base to form the corresponding amide. Subsequent basic hydrolysis of the methyl ester with an alkaline hydroxide may provide intermediate 31 a. Can use the capabilityMany known methods recognized by those skilled in the art, including but not limited to the method described in scheme 11, convert intermediate 31a to various heterocycles (a) to give intermediate 31 b. The intermediate 31b may be subjected to a Metal-Catalyzed Cross-Coupling reaction using a number of known methods recognized by those skilled in the art, including, but not limited to, Metal-Catalyzed Cross-Coupling Reactions, Armin de Meijere, Diederich, volume 2, second revision and supplement, 2004, ISBN:3-527-30518-1, Wiley-VCH and the references cited therein. Various metal-catalyzed reactions (including but not limited to reactions such as Ullmann, Buchwald, Suzuki, Stille, Sonogashira couplings, etc.) can be performed on intermediate 31 b. Can be carried out in the presence of a metal catalyst (e.g., CuBr, Pd (OAc) as and when desired2、Pd2(dba)3、Pd(PPh3)4、Pd(PPh3)2Cl2、Pd(dppf)Cl2Etc.) and a suitable ligand (including but not limited to ligands such as proline, 1, 10-phenanthroline, tricyclohexylphosphine, dppf, etc.). The Ullmann and Buchwald coupling reactions of intermediate 31b may be carried out with various coupling partners such as alkyl or cycloalkyl or heterocyclyl or heteroarylamines, alkyl or cycloalkyl or heterocyclyl or heteroarylalcohols, phenols, and the like. Intermediate 31b can be cross-coupled with coupling partners (e.g., alkyl, allyl, alkenyl boronic acids, boronic esters, trifluoroborates; alkyl, allyl, alkynyl, organotin reagents, etc.) by Suzuki, Heck, Stille, etc. Can be in the presence of a base (if desired) (including but not limited to Na)2CO3、K2CO3、NaHCO3、K3PO4、NaOtBu, etc.) and a solvent (e.g., dioxane, THF, DME, toluene, methanol, DMF, water, etc., or a mixture of two or three of these solvents) under heating conditions to obtain the compound of formula I. Alternatively, it may be at reflux temperature, in the presence of a palladium catalyst and in a solvent (e.g., toluene, THF, etc.) Intermediate 31b is converted to an organotin reagent using hexamethylditin which, upon coupling with a suitable coupling partner (e.g., alkyl, acyl, alkenyl, allyl halide, triflate, etc.) in a Stille coupling manner (sher, b. et al PCT international application, 2016/039734,2016), yields a compound represented by formula I. Can be carried out in a solvent (e.g., dioxane, DMSO, etc.) over a palladium catalyst (e.g., Pd (dppf) Cl) at reflux temperature2) And a base (e.g., potassium acetate) using bis (pinacolato) diboron, bis (neopentylglycol) diboron, and the like, to convert intermediate 31b to an organoboron reagent that, upon coupling with a suitable coupling partner (e.g., an alkene, alkenyl halide, or triflate, and the like) in a Suzuki coupling manner, provides the compound represented by formula I. Intermediate 31b can be coupled with dimethylphosphine oxide with heating in the presence of a palladium catalyst (such as palladium bis (dibenzylideneacetone)) and a ligand (such as XantPhos) and an inorganic base (such as cesium carbonate) in a solvent (e.g., dioxane, DMSO, etc.) to give the corresponding phosphine oxide.
Scheme 13
Scheme 13 describes the synthesis of compounds of formula I with a modified sequence of steps.
Intermediate 30 (depicted in scheme 12) can be subjected to methyl ester hydrolysis with a basic hydroxide base to provide intermediate 32. Intermediate 32 can be converted to the various heterocycles (a) to give compounds of formula 33 using a number of known methods recognized by those skilled in the art, including but not limited to the methods described in scheme 11. Intermediate 4 may be activated for acylation at a temperature ranging between-30 ℃ to reflux temperature in a polar aprotic solvent (e.g., DCM, THF, etc.) using any number of reagents that would be recognized by one skilled in the art (e.g., thionyl chloride, phosphoryl chloride, oxalyl chloride, methyl or ethyl chloroformate, etc.). The activated acid intermediate may be reacted with intermediate 33 in the presence of a base to produce the compound of formula I.
Alternatively, intermediate 30a (described in scheme 12) may be subjected to methyl ester hydrolysis with a basic hydroxide base to provide intermediate 32 a. Intermediate 32a may be converted to various heterocycles (a) using a number of known methods recognized by those skilled in the art, including but not limited to the methods described in scheme 11, to give compounds of formula 33 a. Intermediate 4 may be activated for acylation at a temperature ranging between-30 ℃ to reflux temperature in a polar aprotic solvent (e.g., DCM, THF, etc.) using any number of reagents that would be recognized by one skilled in the art (e.g., thionyl chloride, phosphoryl chloride, oxalyl chloride, methyl or ethyl chloroformate, etc.). The activated acid intermediate may be reacted with intermediate 33a in the presence of a base to produce intermediate 33 b. The intermediate 33b may be subjected to a Metal-Catalyzed Cross-Coupling reaction using a number of known methods recognized by those skilled in the art, including, but not limited to, Metal-Catalyzed Cross-Coupling Reactions, Armin de Meijere, Diederich, volume 2, second revision and supplement, 2004, ISBN:3-527-30518-1, Wiley-VCH and the references cited therein. Various metal-catalyzed reactions (including but not limited to reactions such as Ullmann, Buchwald, Suzuki, Stille, Sonogashira couplings, etc.) can be performed on intermediate 33 b. Can be carried out in the presence of a metal catalyst (e.g., CuBr, Pd (OAc) as and when desired2、Pd2(dba)3、Pd(PPh3)4、Pd(PPh3)2Cl2、Pd(dppf)Cl2Etc.) and a suitable ligand (including but not limited to ligands such as proline, 1, 10-phenanthroline, tricyclohexylphosphine, dppf, etc.). The Ullmann and Buchwald coupling reactions of intermediate 33b may be carried out with various coupling partners, such as alkyl or cycloalkyl or heterocyclyl or heteroarylamines, alkyl or cycloalkyl or heterocyclyl or heteroarylalcohols, phenols, and the like. Intermediate 33b may be reacted with a coupling partner (e.g., alkyl, allyl, alkenyl boronic acids, boronic esters, trifluoroborates; alkyl, alkenePropyl, alkynyl, organotin reagents, etc.) for Suzuki, Heck, Stille, etc. cross-coupling. Can be in the presence of a base (if desired) (including but not limited to Na)2CO3、K2CO3、NaHCO3、K3PO4、NaOtBu, etc.) and a solvent (e.g., dioxane, THF, DME, toluene, methanol, DMF, water, etc., or a mixture of two or three of these solvents) under heating conditions to obtain the compound of formula I. Alternatively, intermediate 33b can be converted to an organotin reagent using hexamethylditin at reflux temperature in the presence of a palladium catalyst and in a solvent (e.g., toluene, THF, etc.) which, after coupling with a suitable coupling partner (e.g., alkyl, acyl, alkenyl, allyl halide, triflate, etc.) in a Stille coupling fashion (sher, b. et al PCT international application, 2016/039734,2016), yields the compound represented by formula I. Can be carried out in a solvent (e.g., dioxane, DMSO, etc.) over a palladium catalyst (e.g., Pd (dppf) Cl) at reflux temperature 2) And a base (e.g., potassium acetate) using bis (pinacolato) diboron, bis (neopentylglycol) diboron, and the like, to convert intermediate 33b to an organoboron reagent that, upon coupling with a suitable coupling partner (e.g., an alkene, alkenyl halide, or triflate, and the like) in a Suzuki coupling manner, provides the compound represented by formula I. Intermediate 33b may be coupled with dimethylphosphine oxide in the presence of a palladium catalyst (e.g., palladium bis (dibenzylideneacetone)) and a ligand (e.g., XantPhos) and an inorganic base (e.g., cesium carbonate) in a solvent (e.g., dioxane, DMSO, etc.) with heating to provide the corresponding phosphine oxide.
Scheme 14
Scheme 14 describes the synthesis of intermediate 40, wherein a is a 3- (5-substituted-1, 2, 4-oxadiazolyl) ring. Can be prepared by dissolving in a solvent (such as DCM, DMF, etc.) and an organic base (such as Et) at ambient temperature3N, DIPEA, etc.) in the presence of ammonium chloride, with an activating agent (e.g., ammonium chloride)BOP, HATU, etc.) to the commercially available 4- (methoxycarbonyl) bicyclo [2.2.2]Octane-1-carboxylic acid 25 was subjected to amide synthesis to give intermediate 34. Can be prepared by treatment with trifluoroacetic anhydride in pyridine at 0 deg.C or with POCl3And base (e.g., imidazole) treatment to convert intermediate 34 to intermediate 35. Intermediate 36 may be synthesized by reaction of intermediate 35 with hydroxylamine; see Hirawat, s. et al WO 2006/110483. Various substituted intermediates 37 can be coupled to intermediate 36 using amide bond coupling reagents (e.g., CDI, BOP, EDC, etc.) in polar aprotic solvents (e.g., THF, 1, 4-dioxane, DMF, etc.) at room temperature. The acyclic intermediate can then be cyclized at elevated temperature (60 ℃ to 100 ℃). Alternatively, in situ cyclization can be achieved by performing the coupling of acid 37 and amidoxime 36 at elevated temperature (60 ℃ to 100 ℃) to give an intermediate of formula 38. Can be in chlorinated or ethereal solvents (e.g., DCM, diethyl ether, 1, 4-dioxane, THF, etc.) in hydride-based reducing agents (e.g., LAH, DIBAL-H, NaBH) 4Etc.) to effect reduction of intermediate 38 to afford intermediate 39. Oxidation of intermediate 39 to intermediate 40 can be accomplished by methods recognized by those skilled in the art using oxidation conditions (e.g., dessimutan oxidizer, Swern oxidation conditions, PDC or PCC, etc.). Intermediate 40 can be converted to the compound of formula I by the steps described in scheme 1.
Scheme 15
Scheme 15 describes the synthesis of compounds of formula I (a-d). The esterification can be performed on an intermediate represented by formula 31 (the synthesis is described in scheme 12). Intermediate 31 may be activated for acylation at a temperature ranging between-30 ℃ to reflux temperature using any number of reagents that would be recognized by one skilled in the art (e.g., thionyl chloride, phosphoryl chloride, oxalyl chloride, methyl or ethyl chloroformate, etc.) in a polar aprotic solvent (e.g., DCM, THF, etc.). The activated acid intermediate may be reacted with an alcohol in the presence of a base to produce a compound of formula Ia. Can be used forBy heating at ambient temperature or in a solvent (e.g. DCM, DMF, etc.) in a base (e.g. Et)3N, DIPEA, etc.) and activating the acid with an activator (e.g., BOP, CDI, HATU, etc.) in the presence of ammonium chloride or a substituted amine (e.g., alkyl, cycloalkyl, aryl, heteroaryl, etc.) to amide intermediate 31 to provide an amide of formula Ib. Can be prepared by dissolving in a solvent (e.g., DCM, DMF, etc.) in a base (e.g., Et) at ambient temperature 3N, DIPEA, etc.) and ammonium chloride with an activating agent (e.g., BOP, CDI, HATU, etc.) to perform the primary amide synthesis on intermediate 31. It is possible to use either i) trifluoroacetic anhydride in pyridine at 0 ℃ or ii) POCl3And imidazole treatment of the primary amide thus obtained to give the nitrile of formula Ic. Intermediate 31 may be activated using any number of reagents (e.g., thionyl chloride, phosphorus oxychloride, oxalyl chloride, methyl or ethyl chloroformate, etc.) as would be recognized by one skilled in the art in a polar aprotic solvent (e.g., DCM, THF, etc.) at a temperature ranging between-30 ℃ and reflux temperature. The activated acid intermediate may be reacted with a sulfonamide in the presence of a base (e.g., pyridine, DMAP, 2- (dimethylamino) pyridine, N-methylmorpholine, etc.) in a polar aprotic solvent (e.g., DCM, THF, etc.) at a temperature ranging between 0 ℃ and 90 ℃ to produce the acylsulfonamide of formula Id.
Scheme 16
Scheme 16 describes the synthesis of intermediate 2 a. Intermediate 52 can be synthesized according to the method described by Singh, s.b. et al (ACS med.chem.lett.2014,5, 609-614). Intermediate 53 may be deprotonated with n-BuLi in an ethereal solvent (e.g., THF, 1, 4-dioxane, etc.) at a temperature varying between-78 ℃ and 0 ℃ and then reacted with intermediate 52 to yield intermediate 54. Intermediate 54 can be cyclized at elevated temperature (70 ℃) in the presence of an alkaline hydroxide base to form intermediate 55. Any number of reagents (e.g., NCS, Hg (ClO) can be used 4)2DDQ, etc.) to achieve thioacetal depulpingTo provide aldehydes, by using an oxidizing agent (NaClO)2PCC or PDC, KMnO4Etc.) to the acid, and then subsequently esterified by reaction with methyl iodide to provide intermediate 56. Subsequent basic hydrolysis of intermediate 56 with basic hydroxide can provide intermediate 57. Intermediate 57 may be converted to the various heterocyclic rings (a) to give compounds of intermediate 58 using a number of known methods recognized by those skilled in the art, including but not limited to the methods described in scheme 11. Intermediate 58 can be treated with an acetate salt (e.g., CsOAc, KOAc, etc.) in a polar aprotic solvent (e.g., DMF, NMP, etc.) at an elevated temperature (120 ℃) to provide the corresponding acetate ester which upon subsequent hydrolysis under acidic conditions (HCl) affords intermediate 59. Intermediate 59 may be oxidized by methods recognized by those skilled in the art using oxidation conditions (e.g., dessimutan oxidizer, Swern oxidation conditions, PDC or PCC, etc.) to provide a compound of formula 2 a. Intermediate 2a may be converted to the compound of formula I by using the procedures described in scheme 1.
Scheme 17
Alternative synthesis of intermediate 2b is depicted in scheme 17. Intermediate 52 can be synthesized according to the method described by Singh, s.b. et al (ACS med.chem.lett.2014,5, 609-614). Halogenated heterocycle 60 (commercially available or obtained by methods known to those skilled in the art) may be treated with a base such as (n-BuLi, s-BuLi, MeLi, etc.) in an ethereal solvent (e.g., THF, 1, 4-dioxane, etc.) at a temperature varying between-78 ℃ and 0 ℃, and then reacted with ketone 52 to give intermediate 61. Intermediate 61 may be cyclized in the presence of an alkaline hydroxide base at elevated temperature (70 ℃) to provide intermediate 62. Intermediate 62 can be treated with an acetate salt (e.g., CsOAc, KOAc, etc.) in a polar aprotic solvent (e.g., DMF, NMP, etc.) at an elevated temperature (120 ℃) to provide the corresponding acetate ester which upon subsequent hydrolysis under acidic conditions (HCl) affords intermediate 63. Intermediate 63 may be oxidized by methods recognized by those skilled in the art using oxidation conditions (e.g., dessimutan oxidizer, Swern oxidation conditions, PDC or PCC, etc.) to afford intermediate 2 b. Intermediate 2b may be converted to the compound of formula I by using the procedures described in scheme 1.
Scheme 18A
Scheme 18A describes an alternative synthesis of compounds of formula I. Can be used in a hydride-based reducing agent (e.g., LAH, DIBAL-H, NaBH)4Etc.) to intermediate 57 (the synthesis is described in scheme 16) to give intermediate 64. The oxidation of intermediate 64 to aldehyde 65 can be carried out by methods recognized by those skilled in the art using oxidation conditions (e.g., dessimutan oxidant, Swern oxidation conditions, PDC or PCC, etc.). Intermediate 1 and intermediate 65 can be reductively aminated at room temperature or reflux temperature in a suitable polar protic solvent (e.g., MeOH, EtOH, etc.) in the presence of an acid (e.g., acetic acid) using a number of known methods as would be recognized by one skilled in the art, followed by reduction of the imine with a reducing agent (e.g., sodium cyanoborohydride, sodium triacetoxyborohydride, etc.) to afford intermediate 66. Intermediate 66 can be treated with an acetate salt (e.g., CsOAc, KOAc, etc.) in a polar aprotic solvent (e.g., DMF, NMP, etc.) at an elevated temperature (120 ℃) to provide the corresponding acetate ester which upon subsequent hydrolysis under acidic conditions (HCl) affords intermediate 67. Can be prepared by using an oxidizing agent (NaClO)2PCC or PDC, KMnO 4Etc.) oxidation of intermediate 67 to the acid followed by synthesis of the various heterocycles (a) to give intermediates 68 using a number of known methods recognized by those skilled in the art, including but not limited to the method described in scheme 11. Any number of reagents (e.g., thionyl chloride, phosphorus oxychloride, oxalyl chloride, methyl or ethyl chloride) as would be recognized by one skilled in the art can be used in a polar aprotic solvent (e.g., DCM, THF, etc.) at temperatures ranging between-30 ℃ and reflux temperatureFormate ester, etc.) activates intermediate 4 for acylation. The activated acid intermediate may be reacted with intermediate 68 in the presence of a base to produce the compound of formula I.
Scheme 18B
Scheme 18B describes an alternative synthesis of compounds of formula I. Intermediate 86 and intermediate 65 (as depicted in scheme 18A) can be reductively aminated at room temperature or reflux temperature in a suitable polar protic solvent (e.g., MeOH, EtOH, etc.) in the presence of an acid (e.g., acetic acid) using a number of known methods that will be recognized by those skilled in the art, followed by reduction of the imine with a reducing agent (e.g., sodium cyanoborohydride, sodium triacetoxyborohydride, etc.) to afford intermediate 66 a. Intermediate 66a can be treated with an acetate salt (e.g., CsOAc, KOAc, etc.) in a polar aprotic solvent (e.g., DMF, NMP, etc.) at an elevated temperature (120 ℃) to provide the corresponding acetate ester which upon subsequent hydrolysis under acidic conditions (HCl) affords intermediate 67 a. Can be prepared by using an oxidizing agent (NaClO) 2PCC or PDC, KMnO4Etc.) oxidation of intermediate 67a to the acid followed by synthesis of the various heterocycles (a) to give intermediates 68a using a number of known methods recognized by those skilled in the art, including but not limited to the method described in scheme 11. Intermediate 68a may be converted to the compound of formula I via sequential amide synthesis and coupling by the following steps described in scheme 13.
Scheme 19
Scheme 19 describes an alternative synthesis of compounds of formula I. Can be carried out in ethereal solvents (such as Et) at temperatures varying between-78 ℃ and 0 ℃2O, THF, etc.) was treated with an organomagnesium reagent to afford intermediate 70. Can be used in the presence of an oxidant (such as dessimutan oxidant, PDC or PC)C, etc.), intermediate 70 is oxidized to intermediate 71 by methods recognized by those skilled in the art. Intermediate 71 and intermediate 1 in a polar protic solvent such as (MeOH, EtOH, etc.) can be treated with triethylsilane and indium chloride at ambient temperature to give an intermediate of formula 72. Intermediate 4 may be activated for acylation at a temperature ranging between-30 ℃ to reflux temperature in a polar aprotic solvent (e.g., DCM, THF, etc.) using any number of reagents that would be recognized by one skilled in the art (e.g., thionyl chloride, phosphoryl chloride, oxalyl chloride, methyl or ethyl chloroformate, etc.). The activated acid intermediate may be reacted with intermediate 72 in the presence of a base to produce the compound of formula I.
Scheme 20
Scheme 20 describes the synthesis of compounds of formula I (e-g) (where "a" is an amide, sulfonamide, urea, or carbamate). Intermediate 25 can be converted to intermediate 73 via a Curtius rearrangement (as described in Shioiri, T. et al J.Am.chem.Soc.1972,94, 6203-6205). Can be used in a hydride-based reducing agent (e.g., LAH, DIBAL-H, NaBH)4Etc.) to obtain intermediate 74. The intermediate 74 can be oxidized to the aldehyde 75 by methods recognized by those skilled in the art using oxidation conditions (e.g., dessimutan oxidizer, Swern oxidation conditions, PDC or PCC, etc.). Intermediate 1 and intermediate 75 can be reductively aminated at room temperature or reflux temperature in a suitable polar protic solvent (e.g., MeOH, EtOH, etc.) in the presence of an acid (e.g., acetic acid) using a number of known methods that will be recognized by those skilled in the art, followed by reduction of the imine with a reducing agent (e.g., sodium cyanoborohydride, sodium triacetoxyborohydride, etc.) to afford intermediate 76. Any number of reagents (e.g., thionyl chloride, phosphoryl chloride, oxalyl chloride, methyl or ethyl chloroformate) as would be recognized by one skilled in the art may be used in a polar aprotic solvent (e.g., DCM, THF, etc.) at temperatures ranging between-30 deg.C and reflux temperature Etc.) activate intermediate 4 for acylation. The activated acid intermediate may be reacted with intermediate 76 in the presence of a base to form the corresponding amide. Boc deprotection of the amide intermediate using trifluoroacetic acid in a polar aprotic solvent (e.g., DCM, THF, etc.) can be performed at room temperature to afford intermediate 77. A variety of different transformations of intermediate 77 may be performed to arrive at the variant of formula I using a number of known methods recognized by those skilled in the art, including but not limited to the following:
amide: intermediate 77 can be reacted with an activated acid intermediate in the presence of a base (e.g., pyridine, DMAP, 2- (dimethylamino) pyridine, N-methylmorpholine, etc.) in a polar aprotic solvent (e.g., DCM, THF, etc.) to produce the amide of formula Ie.
Sulfonamide: intermediate 77 can be treated with sulfonyl chloride in the presence of a base (e.g., pyridine, DMAP, 2- (dimethylamino) pyridine, N-methylmorpholine, etc.) in a polar aprotic solvent (e.g., DCM, THF, etc.) at a temperature ranging between 0 ℃ and 90 ℃ to produce the sulfonamide of formula If.
Urea: can be prepared at room temperature in a polar aprotic solvent (e.g., DCM, DCE, etc.) in a base (e.g., Et) 3N, DIPEA, pyridine, etc.) with an isocyanate to give a urea of formula Ig. Alternatively, the solvent can be prepared by dissolving in a solvent (e.g., DCM, DCE, etc.) in a base (e.g., Et) at 0 deg.C to room temperature3N, DIPEA, etc.) was treated with triphosgene to activate intermediate 77. The reaction mixture can then be dissolved in a solvent (e.g., DCM, DCE, etc.) in a base (e.g., Et) at room temperature3N, DIPEA, etc.) is treated with a substituted alkyl or aryl or heteroaryl amine to afford a urea represented by formula Ig.
Carbamate ester: can be prepared in polar aprotic solvents (e.g., DCM, DCE, THF, etc.) in bases (e.g., Et) at 0 deg.C to room temperature3N, DIPEA, pyridine, t-BuOK, etc.) to intermediate 77 with a chloroformate (or alcohol, activated to a carbonate) to give a carbamate represented by formula Ih.
Scheme 21
Scheme 21 describes the synthesis of intermediate 82, wherein a is a 3- (5-substituted-1, 2, 4-oxadiazolyl) ring. Intermediate 30a may be base hydrolyzed with a basic hydroxide (synthesized as described in scheme 12) to give intermediate 78. Can be prepared by dissolving in a polar aprotic solvent (DCM, DMF, etc.) in a base (e.g. Et) at ambient temperature 3N, DIPEA, etc.) in the presence of ammonium chloride and activating the acid with an activating agent (BOP, CDI, HATU, etc.) to give intermediate 79. Intermediate 79 may be converted to intermediate 80 using various methods recognized by those skilled in the art, including, but not limited to, using reagents (POCl)3、SOCl2TFAA, etc.) and bases (imidazole, Et)3N, DIPEA, etc.). Intermediate 81 may be synthesized by reaction of intermediate 80 with hydroxylamine; see Hirawat, s. et al WO 2006/110483. Intermediate 37 may be obtained from commercial sources or may be synthesized by known methods readily recognized by those skilled in the art. Intermediate 37 can be coupled to intermediate 81 using an amide bond coupling reagent (e.g., CDI, BOP, EDC, etc.) in a polar aprotic solvent (e.g., THF, 1, 4-dioxane, DMF, etc.) at room temperature. The acyclic intermediate can then be cyclized at elevated temperature (60 ℃ to 100 ℃). Alternatively, in situ cyclization can be achieved by coupling intermediate 37 with intermediate 81 at elevated temperatures (60 ℃ to 100 ℃) to give oxadiazole 82. Intermediate 82 can be converted to compounds of formula I via sequential amide synthesis and coupling as described in scheme 13.
Scheme 22
Scheme 22 describes the synthesis of compounds of formula I (wherein "a" is phenyl). Can be prepared in dibromomethane as solvent under heating condition in the presence of mercuric oxideThe obtained 4- (methoxycarbonyl) bicyclo [2.2.2]Octane-1-carboxylic acid 25 is brominated with bromine to give intermediate 90 (as described by Owen et al PCT international application No. 2014113485,2014). May be carried out in AlCl under the conditions described in PCT International application No. 2015005901,2015 to Piyasena et al3Intermediate 90 is converted to intermediate 91 in benzene in the presence of oxygen. Can be prepared at room temperature in CHCl3Intermediate 91 is brominated in the presence of silver trifluoroacetate and bromine to give intermediate 92 (described by Piyasena et al PCT International application, 2015005901,2015). Can be used in a hydride-based reducing agent (e.g., LAH, DIBAL-H, NaBH)4Etc.) to give intermediate 93. The oxidation of intermediate 93 to aldehyde 94 can be carried out by methods recognized by those skilled in the art using oxidation conditions (e.g., dessimutan oxidizer, Swern oxidation conditions, PDC or PCC, etc.). Intermediate 1 and intermediate 94 can be reductively aminated at room temperature or reflux temperature in a suitable polar protic solvent (e.g., MeOH, EtOH, etc.) in the presence of an acid (e.g., acetic acid) using a number of known methods that will be recognized by those skilled in the art, followed by reduction of the imine with a reducing agent (e.g., sodium cyanoborohydride, sodium triacetoxyborohydride, etc.) to afford intermediate 95. Intermediate 4 may be activated for acylation at a temperature ranging between-30 ℃ to reflux temperature in a polar aprotic solvent (e.g., DCM, THF, etc.) using any number of reagents that would be recognized by one skilled in the art (e.g., thionyl chloride, phosphoryl chloride, oxalyl chloride, methyl or ethyl chloroformate, etc.). The activated acid intermediate can be reacted with intermediate 95 in the presence of a base to produce intermediate 96. If necessary, in the presence of a metal catalyst (e.g., CuBr, Pd (OAc) 2、Pd2(dba)3、Pd(PPh3)4、Pd(PPh3)2Cl2、Pd(dppf)Cl2) And a suitable ligand (including but not limited to ligands such as tricyclohexylphosphine, dppf, and the like), various metal-catalyzed reactions (including but not limited to reactions such as Ullmann, Suzuki, Buchwald, Stille coupling, and the like) are performed on intermediate 96. Can be intermediate with various coupling partners (such as alkyl or aryl or heteroaryl amines, thiols and alcohols, etc.)96 Ullmann and Buchwald coupling reactions. The Suzuki, Stille coupling reaction of intermediate 96 can be performed with various coupling partners (e.g., alkenyl, aryl or heteroaryl boronic acids, boronic esters, organotin reagents, etc.). Can be in the presence of a base (whenever desired) (including but not limited to Na)2CO3、K2CO3、NaHCO3、K3PO4、NaOtBu, etc.) and a solvent (e.g., dioxane, THF, DME, toluene, methanol, DMF, water, etc., or a mixture of two or three of these solvents) under heating conditions to obtain the compound of formula I.
Scheme 23
Scheme 23 depicts the synthesis of intermediate 99. Commercially available 4- (methoxycarbonyl) bicyclo [2.2.2 ] can be treated as described in scheme 22]Octane-1-carboxylic acid 25 is brominated, followed by Friedel-Crafts arylation in the presence of an appropriately substituted aromatic hydrocarbon to afford intermediate 97. Alternatively, intermediate 97 may be synthesized via decarboxylation Negishi or Suzuki-type cross-coupling reactions. Intermediate 25 may be activated to N-hydroxyphthalimide ester or N-hydroxybenzotriazole ester, etc., as redox active esters, and may be in the presence of a metal catalyst (e.g., Fe (acac)) 3、FeCl3、NiCl2Glyme, etc.) with an organozinc or an organoboronic acid or Grignard reagent of various substituted aryl groups, as described by Torriyama, f, et al, j.am.chem.soc.2016,138,11132-11135 and references cited therein, to afford intermediate 97. Can be used in a hydride-based reducing agent (e.g., LAH, DIBAL-H, NaBH)4Etc.) to yield intermediate 98. The intermediate 98 may be oxidized to the aldehyde 99 by methods recognized by those skilled in the art using oxidation conditions (e.g., dessimutan oxidizer, Swern oxidation conditions, PDC or PCC, etc.). Intermediate 99 can be converted to compounds of formula I (where "a" is phenyl) by using the procedures described in scheme 1.
Scheme 24
Scheme 24 describes an alternative synthesis of compounds of formula I (where "a" is an amide, sulfonamide, urea, or carbamate). Can be prepared by using an oxidizing agent (NaClO)2PCC or PDC, KMnO4Etc.) oxidation of intermediate 67 (synthesized as described in scheme 18A) to afford intermediate 100. Intermediate 100 can be converted to intermediate 101 via a Curtius rearrangement (as described in Shioiri, T. et al J.Am.chem.Soc.1972,94, 6203-6205). Intermediate 101 can be subjected to sequential amide synthesis and boc deprotection as described in scheme 20 to afford amine intermediate 102. A variety of different transformations of intermediate 102 may be performed to obtain variants of formula I (where "a" is an amide, sulfonamide, urea, or carbamate) using a number of known methods recognized by those skilled in the art, including, but not limited to, the methods described in scheme 20.
Scheme 25
Scheme 25 describes the synthesis of compounds of formula I (I, j, k, m) (where "a" is an amide, sulfonamide, urea, or carbamate). Can be prepared by using an oxidizing agent (NaClO)2PCC or PDC, KMnO4Etc.) oxidation of intermediate 67a (synthesized as described in scheme 18B) to afford intermediate 100 a. Intermediate 100a can be converted to intermediate 101a via a Curtius rearrangement (as described in Shioiri, T. et al J.Am.Chem.Soc.1972,94, 6203-Bus6205). Intermediate 101a can be subjected to sequential amide synthesis and boc deprotection as described in scheme 20 to afford amine intermediate 102 a.
A variety of different transformations of intermediate 102a may be performed to arrive at a variant of formula I using a number of known methods recognized by those skilled in the art, including but not limited to the following:
amide: intermediate 102a can be reacted with an activated acid intermediate in the presence of a base (e.g., pyridine, DMAP, 2- (dimethylamino) pyridine, N-methylmorpholine, etc.) in a polar aprotic solvent (e.g., DCM, THF, etc.) to produce intermediate 103.
Sulfonamide: intermediate 102a can be treated with sulfonyl chloride in the presence of a base (e.g., pyridine, DMAP, 2- (dimethylamino) pyridine, N-methylmorpholine, etc.) in a polar aprotic solvent (e.g., DCM, THF, etc.) at a temperature ranging between 0 ℃ and 90 ℃ to form intermediate 104.
Urea: can be prepared at room temperature in a polar aprotic solvent (e.g., DCM, DCE, etc.) in a base (e.g., Et)3N, DIPEA, pyridine, etc.) with an isocyanate to give intermediate 105. Alternatively, the solvent can be prepared by dissolving in a solvent (e.g., DCM, DCE, etc.) in a base (e.g., Et) at 0 deg.C to room temperature3N, DIPEA, etc.) is treated with triphosgene to activate intermediate 102 a. The reaction mixture can then be dissolved in a solvent (e.g., DCM, DCE, etc.) in a base (e.g., Et) at room temperature3N, DIPEA, etc.) is treated with a substituted alkyl or aryl or heteroaryl amine to afford intermediate 105.
Carbamate ester: can be prepared in polar aprotic solvents (e.g., DCM, DCE, THF, etc.) in bases (e.g., Et) at 0 deg.C to room temperature3N, DIPEA, pyridine, t-BuOK, etc.) to intermediate 102a with a chloroformate (or alcohol, activated to a carbonate) to afford intermediate 106.
The Metal-Catalyzed Cross-Coupling reaction of intermediate 103-106 can be carried out using a number of known methods recognized by those skilled in the art, including, but not limited to, Metal-Catalyzed Cross-Coupling Reactions, Armin de Meijere, Diederich, volume 2, second revision and supplement, 2004, ISBN:3-527-30518-1, Wiley-VCH and the references cited therein. Various metal-catalyzed reactions (including but not limited to, such as Ullmann's, and the like) can be performed on intermediate 103-106,Reactions of Buchwald, Suzuki, Stille coupling, etc.). Can be carried out in the presence of a metal catalyst (e.g., CuBr, Pd (OAc) as and when desired2、Pd2(dba)3、Pd(PPh3)4、Pd(PPh3)2Cl2、Pd(dppf)Cl2Etc.) and a suitable ligand (including but not limited to ligands such as proline, 1, 10-phenanthroline, tricyclohexylphosphine, dppf, etc.). The Ullmann and Buchwald coupling reactions of intermediates 103-106 can be carried out with various coupling partners (e.g., heterocyclyl or heteroarylamines, etc.). Intermediate 103-106 can be cross-coupled with coupling partners such as cycloalkyl or alkenyl or aryl or heteroaryl boronic acids, boronic esters, organotin reagents, and the like, by Suzuki, Stille, and the like. Can be in the presence of a base (if desired) (including but not limited to Na)2CO3、K2CO3、NaHCO3、K3PO4、NaOtBu, etc.) and a solvent (e.g., dioxane, THF, DME, toluene, methanol, DMF, water, etc., or a mixture of two or three of these solvents) under heating conditions to obtain the compound of formula I. Alternatively, intermediate 103-106 can be converted to an organotin reagent using hexamethylditin at reflux temperature in the presence of a palladium catalyst and in a solvent (e.g., toluene, THF, etc.) which yields the compound represented by formula I after coupling with a suitable coupling partner (e.g., cycloalkenyl, aryl or heteroaryl halide, triflate, etc.) in a Stille coupling manner (sher, b. et al PCT international application, 2016/039734,2016). Can be carried out in a solvent (e.g., dioxane, DMSO, etc.) over a palladium catalyst (e.g., Pd (dppf) Cl) at reflux temperature 2) And the use of bis (pinacolato) diboron, bis (neopentylglycol) diboron, and the like in the presence of a base such as potassium acetate, converts intermediate 103-106 to an organoboron reagent which, upon coupling with a suitable coupling partner such as a cycloalkenyl, aryl or heteroaryl halide, or triflate, and the like, in a Suzuki coupling manner, provides the compound represented by formula I (I, j, k, m).
The sequence of steps involving the installation of groups "Q" and "a" may be performed interchangeably in the schemes where appropriate. Oxadiazole regioisomers can be generated by using the sequences attached to the oxabicyclic ring systems described in schemes 11 and 14.
Example 1
N- (3-chlorophenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
Step A. preparation of intermediate 1 A.4-carbamoylbicyclo [2.2.2] octane-1-carboxylic acid methyl ester
To 4- (methoxycarbonyl) bicyclo [2.2.2] under nitrogen atmosphere]To a stirred solution of octane-1-carboxylic acid (0.5g, 2.35mmol) in DMF (10mL) were added ammonium chloride (1.26g, 23.56mmol), TEA (1.3mL, 9.42mmol) and BOP (1.0g, 2.35 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water (20mL) and extracted with EtOAc (30 mL). The combined organic extracts were washed with brine solution (20mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a white solid (0.4g, 1.89mmol, 80% yield). 1H NMR(400MHz,DMSO-d6)δ6.95(br.s.,1H),6.74(br.s.,1H),3.57(s,3H),1.74-1.61(m,12H)。MS(ESI)212(M+H)。
Step B. preparation of intermediate 1 B.4-cyanobicyclo [2.2.2] octane-1-carboxylic acid methyl ester
A stirred solution of intermediate 1A (0.35g, 1.65mmol) in pyridine (7mL) was cooled to 0 ℃. Trifluoroacetic anhydride (1.74g, 8.28mmol) was added dropwise and the reaction mixture was stirred at 0 ℃ for 30 min. The reaction mixture was washed with 10% NaHCO3The aqueous solution was quenched, diluted with water (20mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine solution (20mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (24g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 30% B; flow rate ═ 24 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound as an off-white solid (0.25g, 1.22mmol, 74% yield).1H NMR(400MHz,DMSO-d6)δ3.58(s,3H),1.93-1.83(m,6H),1.78-1.68(m,6H)。
Step C. preparation of intermediate 1 C.4-cyanobicyclo [2.2.2] octane-1-carboxylic acid methyl ester
To a stirred solution of intermediate 1B (0.25g, 1.29mmol) in ethanol (5mL) was added hydroxylamine (50% aqueous solution, 0.32mL, 5.17 mmol). The reaction mixture was refluxed at 80 ℃ for 2 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was diluted with water (10 mL). The precipitated solid was filtered and dried in vacuo to give the title compound as a white solid (0.28g, 1.18mmol, 91% yield). 1H NMR (400MHz, chloroform-d) Δ 8.88(s,1H),5.15(s,2H),3.57(s,3H),1.73-1.62(m, 12H). MS (ESI)227(M + H).
Step D. preparation of intermediate 1D.4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] octane-1-carboxylic acid methyl ester
To a stirred solution of intermediate 1C (5g, 22.10mmol) in DMF (100mL) was added 2, 2-difluoropropionic acid (3.16g, 28.7mmol), TEA (12.32mL, 88mmol) and BOP (10.75g, 24.31mmol) at room temperature. The reaction mixture was stirred at 110 ℃ overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (100mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine solution (20mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (40g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 30% B; flow rate ═ 24 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound as a colourless gummy solid (4.2g, 11.75mmol, 53% yield). MS (ESI)301(M + H).
Step E. preparation of intermediate 1e. (4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methanol
DIBAL-H (35mL, 35.0mmol) was added dropwise to a stirred solution of intermediate 1D (4.2g, 13.99mmol) in THF (20mL) at-78 deg.C. The reaction mixture was stirred at-78 ℃ for 1 h. The reaction mixture was allowed to warm to 0 ℃ and quenched with 1.5N aqueous HCl (100 mL). The aqueous solution was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine solution (20mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (40g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 40% B; flow rate ═ 40 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound as a colorless liquid (3g, 10.58mmol, 76% yield). MS (ESI)273(M + H).
Step F. preparation of intermediate 1F.4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] octane-1-carbaldehyde
To a stirred solution of intermediate 1E (3g, 11.02mmol) in DCM (70mL) was added dessimutane oxidant (5.6g, 13.22mmol) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 30 min. The reaction mixture was allowed to warm to room temperature, diluted with DCM (50mL), and taken up in 10% aqueous sodium bicarbonate (3 × 20mL) ) And (6) washing. The organic layer was washed with brine solution (20mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (24g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 30% B; flow rate ═ 24 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound as a colorless white gummy solid (2g, 7.40mmol, 67% yield).1H NMR(400MHz,DMSO-d6)δ9.46(br.s.,1H),2.16(t,J＝19.6Hz,3H),1.94-1.76(m,12H)。
Step G. preparation of intermediate 1 G.3-chloro-N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) aniline
To a stirred solution of intermediate 1F (50mg, 0.18mmol) in MeOH (1mL) was added 3-chloroaniline (23mg, 0.18mmol), AcOH (0.02mL, 0.37mmol), followed by additionMolecular sieves (5 mg). The reaction mixture was heated to 60 ℃ and stirred overnight. The reaction mixture was allowed to return to room temperature and then cooled to 0 ℃. Sodium cyanoborohydride (23.25mg, 0.37mmol) was added to the reaction mixture. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was diluted with ethyl acetate (25mL), washed with water (10mL), brine solution (10mL) and concentrated under reduced pressure. The crude material was purified by flash column chromatography (4g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 50% B; flow rate ═ 24 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound as a brown solid (60mg, 0.14mmol, 78% yield). MS (ESI)382(M + H).
EXAMPLE 1 preparation of N- (3-chlorophenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
Intermediate 1G (20mg, 0.05mmol) in DCM (1 m) at room temperatureL) to the stirred solution was added 3-fluorobicyclo [1.1.1]Pentane-1-carboxylic acid (10.22mg, 0.08mmol) was added followed by pyridine (0.03mL, 0.36 mmol). The reaction mixture was cooled to 0 ℃ and POCl was added3(0.02mL, 0.16 mmol). After stirring at 0 ℃ for 1h, the reaction mixture was diluted with DCM (25 mL). The organic layer was washed with 10% aqueous sodium bicarbonate (2 × 15mL), then brine solution (15mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via preparative LC/MS using the following conditions: column: waters XBridge C18, 150mm x 19mm, 5 μm particles; mobile phase A: 5:95 acetonitrile, water containing 10mM ammonium acetate; mobile phase B: 95:5 acetonitrile, water containing 10mM ammonium acetate; gradient: hold at 30% B for 2 minutes, 30% -75% B over 25 minutes, then hold at 100% B for 5 minutes; flow rate: 15 mL/min; column temperature: at 25 ℃. The collection of fractions is triggered by a signal. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (4.8mg, 9.72 μmol, 19% yield). 1H NMR(400MHz,DMSO-d6)δ7.59(s,1H),7.54-7.45(m,2H),7.41(dt,J＝5.7,2.7Hz,1H),3.59(br.s.,1H),3.51(br.s.,1H),2.14(t,J＝19.7Hz,3H),1.88(br.s.,6H),1.84-1.62(m,6H),1.53-1.32(m,6H)。FXR EC50(nM)＝11。MS(ESI)494(M+H)。
The following examples were prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 1G and the corresponding acid where appropriate:
example 4
N- (3-cyanophenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
Step A. preparation of intermediate 4A.3- (((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) amino) benzonitrile
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G by substituting intermediate 1F and 3-aminobenzonitrile where appropriate: (60mg, 0.15mmol, 86% yield).1H NMR(400MHz,DMSO-d6)δ7.24-7.18(m,1H),6.97-6.92(m,2H),6.85(dt,J＝7.5,1.3Hz,1H),6.01(t,J＝6.0Hz,1H),2.86(d,J＝6.0Hz,2H),2.15(t,J＝19.6Hz,3H),1.91-1.82(m,6H),1.61-1.53(m,6H)。MS(ESI)373(M+H)。
Step B. example 4 preparation of N- (3-cyanophenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 4A where appropriate: (7mg, 0.06mmol, 28% yield).1H NMR(400MHz,DMSO-d6)δ8.05(s,1H),7.88(d,J＝7.8Hz,1H),7.84-7.77(m,1H),7.71-7.59(m,1H),3.58(br.s.,2H),2.14(t,J＝19.6Hz,3H),1.87(br.s.,6H),1.84-1.66(m,6H),1.53-1.30(m,6H)。FXR EC50(nM)＝12。MS(ESI)485(M+H)。
The following examples were prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 4A and the corresponding acid where appropriate:
Example 7
N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3-fluorophenyl) bicyclo [1.1.1] pentane-1-carboxamide
Step a. intermediate 7a. preparation of n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoroaniline
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G by substituting intermediate 1F and 3-fluoroaniline where appropriate: (60mg, 0.16mmol, 89% yield).1H NMR(400MHz,DMSO-d6)δ7.05-6.98(m,1H),6.43(d,J＝8.5Hz,1H),6.39-6.33(m,1H),6.25-6.18(m,1H),5.78(s,1H),2.81(d,J＝6.0Hz,2H),2.21-2.09(m,3H),1.90-1.83(m,6H),1.60-1.53(m,6H)。MS(ESI)366(M+H)。
Step B. example 7 preparation of N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3-fluorophenyl) bicyclo [1.1.1] pentane-1-carboxamide
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 7A where appropriate: (7mg, 0.06mmol, 27% yield).1H NMR(400MHz,DMSO-d6)δ7.50(td,J＝8.1,6.7Hz,1H),7.39(dt,J＝10.1,2.1Hz,1H),7.34-7.19(m,2H),3.61(br.s.,1H),3.50(br.s.,1H),2.14(t,J＝19.7Hz,3H),1.89(br.s.,6H),1.84-1.56(m,6H),1.54-1.35(m,6H)。FXR EC50(nM)＝30。MS(ESI)478(M+H)。
The following examples were prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 7A and the corresponding acid where appropriate:
example 10
N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3, 4-difluorophenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
Step a. intermediate 10a. preparation of n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3, 4-difluoroaniline
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G by substituting intermediate 1F and 3, 4-difluoroaniline where appropriate: (48mg, 0.12mmol, 68% yield).1H NMR(300MHz,DMSO-d6)δ7.13-7.00(m,1H),6.62-6.50(m,1H),6.38(d,J＝9.1Hz,1H),5.66(t,J＝5.6Hz,1H),2.78(d,J＝5.9Hz,2H),2.25-2.07(m,3H),1.95-1.80(m,6H),1.66-1.46(m,6H)。MS(ESI)384(M+H)。
Step B. example 10 preparation of N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3, 4-difluorophenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 10A where appropriate: (4.0mg, 15% yield).1H NMR(400MHz,DMSO-d6)δ7.78-7.63(m,1H),7.59-7.45(m,1H),7.39-7.22(m,1H),3.59(br.s.,1H),3.45(br.s.,1H),2.14(t,J＝19.6Hz,3H),1.91(br.s.,6H),1.86-1.58(m,6H),1.57-1.32(m,6H)。FXR EC50(nM)＝124。MS(ESI)496(M+H)。
Example 11
N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3, 4-difluorophenyl) -4, 4-difluorocyclohexane-1-carboxamide
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 10A where appropriate: (2mg, 7% yield).1H NMR(400MHz,DMSO-d6)δ7.77-7.66(m,1H),7.57-7.46(m,1H),7.39-7.29(m,1H),3.59-3.49(m,2H),2.42-2.34(m,1H),2.14(t,J＝19.7Hz,3H),2.00-1.87(m,2H),1.82-1.73(m,6H),1.73-1.64(m,2H),1.63-1.48(m,4H),1.45-1.37(m,6H)。FXR EC50(nM)＝881。MS(ESI)530(M+H)。
Example 12
N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (difluoromethoxy) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
Step a. intermediate 12a. preparation of n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- (difluoromethoxy) aniline
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G by substituting intermediate 1F and 3- (difluoromethoxy) aniline where appropriate: (50mg, 0.12mmol, 65% yield). MS (ESI)414(M + H).
Example 12 preparation of N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (difluoromethoxy) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 12A where appropriate: (9.0mg, 0.02mmol, 35% yield).1H NMR(400MHz,DMSO-d6)δ7.57-7.50(m,1H),7.33-7.14(m,4H),3.55(d,J＝16.1Hz,2H),2.14(t,J＝19.7Hz,3H),1.87(br.s.,6H),1.82-1.63(m,6H),1.54-1.33(m,6H)。FXR EC50(nM)＝73。MS(ESI)526(M+H)。
Example 13
N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (difluoromethoxy) phenyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 12A where appropriate: (8mg, 0.01mmol, 28% yield).1H NMR(400MHz,DMSO-d6)δ7.51-7.13(m,5H),6.53(s,1H),3.62(s,2H),2.76(t,J＝8.9Hz,1H),2.35-2.26(m,2H),2.21-1.99(m,5H),1.87-1.69(m,6H),1.54-1.31(m,6H)。FXR EC50(nM)＝302。MS(ESI)580(M+H)。
Example 14
N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3- (trifluoromethyl) phenyl) bicyclo [1.1.1] pentane-1-carboxamide
Step a. intermediate 14a. preparation of n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- (trifluoromethyl) aniline
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G by substituting intermediate 1F and 3- (trifluoromethyl) aniline where appropriate: (65mg, 0.13mmol, 69% yield). MS (ESI)416(M + H).
Step B. example 14 preparation of N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3- (trifluoromethyl) phenyl) bicyclo [1.1.1] pentane-1-carboxamide
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 14A where appropriate: (4mg, 7.58. mu. mol, 16% yield).1H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.81-7.74(m,2H),7.71(d,J＝7.8Hz,1H),3.67-3.48(m,2H),2.14(t,J＝19.7Hz,3H),1.90-1.72(m,12H),1.50-1.36(m,6H)。FXR EC50(nM)＝29。MS(ESI)528(M+H)。
The following examples were prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 14A and the corresponding acid where appropriate:
example 17
N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (2-methoxypyridin-4-yl) bicyclo [1.1.1] pentane-1-carboxamide
Step a. intermediate 17a. preparation of n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -2-methoxypyridin-4-amine
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G by substituting intermediate 1F and 2-methoxypyridin-4-amine where appropriate: (20mg, 0.05mmol, 28% yield). MS (ESI)380.2(M + H).
Step B. example 17 preparation of N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (2-methoxypyridin-4-yl) bicyclo [1.1.1] pentane-1-carboxamide
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 17A where appropriate: (2mg, 3.80. mu. mol, 7% yield).1H NMR(400MHz,DMSO-d6)δ8.24(d,J＝5.6Hz,1H),7.09(dd,J＝1.8,5.5Hz,1H),6.96(d,J＝1.7Hz,1H),3.90(s,3H),3.56(s,2H),2.14(t,J＝19.6Hz,3H),1.97(d,J＝2.4Hz,6H),1.84-1.71(m,6H),1.48-1.34(m,6H)。FXR EC50(nM)＝149。MS(ESI)491(M+H)。
Example 18
N- (3- (N-Cyclopropylsulfamoyl) phenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
Step A. preparation of intermediate 18A. N-cyclopropyl-3-nitrobenzenesulfonamide
To 3-Nitrobenzenesulfonyl chloride (250mg, 1.128mmol) and TEA (0.472mL, 3.38 mm) at 0 deg.Col) to a stirred solution in tetrahydrofuran (5mL) was added cyclopropylamine (0.08mL, 1.13 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was poured into water (10mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine solution (20mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (24g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 30% B; flow rate ═ 24 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound as a white solid (200mg, 0.82mmol, 73% yield). 1H NMR(400MHz,DMSO-d6)δ8.56-8.49(m,2H),8.30-8.20(m,2H),7.94(t,J＝7.8Hz,1H),2.18(tt,J＝6.8,3.5Hz,1H),0.55-0.48(m,2H),0.43-0.36(m,2H)。
Step B. preparation of intermediate 18 B.3-amino-N-cyclopropylbenzenesulfonamide
A stirred solution of intermediate 18A (200mg, 0.82mmol) in methanol (5mL) was degassed and backfilled with argon and 10% Pd-C (44mg, 0.04mmol) was added to the reaction mixture. After stirring under hydrogen (1atm, balloon) overnight, the reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (150mg, 0.67mmol, 81% yield).1H NMR(400MHz,DMSO-d6)δ7.72(s,1H),7.24-7.16(m,1H),7.01(t,J＝2.0Hz,1H),6.93-6.87(m,1H),6.76(ddd,J＝8.0,2.0,1.0Hz,1H),5.57(s,2H),2.08(tt,J＝6.8,3.5Hz,1H),0.52-0.36(m,4H)。
Step C. preparation of intermediate 18 C.N-cyclopropyl-3- (((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) amino) benzenesulfonamide
According to the method described for the synthesis of intermediate 1G,the title compound was prepared by substituting intermediate 1F and intermediate 18B where appropriate: (90mg, 0.18mmol, 71% yield).1H NMR(400MHz,DMSO-d6)δ7.73(d,J＝2.5Hz,1H),7.27-7.20(m,1H),7.04(s,1H),6.90(d,J＝8.0Hz,1H),6.85(dd,J＝8.3,1.8Hz,1H),6.03(t,J＝5.8Hz,1H),2.86(d,J＝5.5Hz,2H),2.22-2.09(m,3H),2.09-2.03(m,1H),1.92-1.80(m,6H),1.65-1.54(m,4H),1.49-1.42(m,2H),0.51-0.37(m,4H)。MS(ESI)467(M+H)。
Step D. example 18 preparation of N- (3- (N-cyclopropylsulfamoyl) phenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 18C where appropriate: (8mg, 0.014mmol, 34% yield). 1H NMR(400MHz,DMSO-d6)δ8.12(d,J＝3.2Hz,1H),7.86-7.79(m,1H),7.78-7.66(m,3H),3.82-3.64(m,1H),3.47(br s,1H),2.14(t,J＝19.7Hz,4H),1.99-1.82(m,6H),1.78(br t,J＝7.8Hz,6H),1.51-1.33(m,6H),0.58-0.26(m,4H)。FXR EC50(nM)＝1563。MS(ESI)579(M+H)。
The following examples were prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 18C and the corresponding acid where appropriate:
example 21
N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3- (N-methylsulfamoyl) phenyl) bicyclo [1.1.1] pentane-1-carboxamide
Step A. preparation of intermediate 21A. N-methyl-3-nitrobenzenesulfonamide
The title compound was prepared according to the procedure described for the synthesis of intermediate 18A by substituting 3-nitrobenzenesulfonyl chloride and methylamine hydrochloride where appropriate: (220mg, 0.97mmol, 86% yield).1H NMR(400MHz,DMSO-d6)δ8.53-8.48(m,2H),8.23-8.19(m,1H),7.96-7.90(m,1H),7.84(br.s.,1H),2.47(s,3H)。
Step B. preparation of intermediate 21 B.3-amino-N-methylbenzenesulfonamide
The title compound was prepared according to the procedure described for the synthesis of intermediate 18B, by substituting intermediate 21A where appropriate: (180mg, 0.822mmol, 81% yield).1H NMR(400MHz,DMSO-d6)δ7.28-7.17(m,2H),6.96(t,J＝2.0Hz,1H),6.88-6.83(m,1H),6.76(dt,J＝8.0,1.3Hz,1H),5.57(s,2H),2.39(s,3H)。
Step C. preparation of intermediate 21C.3- (((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) amino) -N-methylbenzenesulfonamide
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G, by substituting intermediate 1F and intermediate 21B where appropriate: (60mg, 0.116mmol, 45% yield). 1H NMR(400MHz,DMSO-d6)δ7.27-7.20(m,2H),7.00(t,J＝2.0Hz,1H),6.88-6.82(m,2H),6.02(t,J＝6.0Hz,1H),2.85(d,J＝6.0Hz,2H),2.40(d,J＝5.0Hz,3H),2.21-2.09(m,3H),1.93-1.83(m,6H),1.65-1.54(m,6H)。MS(ESI)441(M+H)。
Example 21 preparation of N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3- (N-methylsulfamoyl) phenyl) bicyclo [1.1.1] pentane-1-carboxamide
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 21C where appropriate: (11mg, 0.020mmol, 59% yield).1H NMR(400MHz,DMSO-d6)δ7.83-7.78(m,1H),7.76-7.62(m,4H),3.77-3.59(m,1H),3.56-3.42(m,1H),2.43(d,J＝5.1Hz,3H),2.14(t,J＝19.7Hz,3H),1.97-1.82(m,6H),1.81-1.69(m,6H),1.50-1.33(m,6H)。FXR EC50(nM)＝4000。MS(ESI)553(M+H)。
The following examples were prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 21C and the corresponding acid where appropriate:
example 24
N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (dimethylphosphoryl) phenyl) -4, 4-difluorocyclohexane-1-carboxamide
Step A. preparation of intermediate 24A. dimethyl (3-nitrophenyl) phosphine oxide
To a stirred suspension of 1-iodo-3-nitrobenzene (200mg, 0.80mmol) in anhydrous 1, 4-dioxane (2mL) was added dimethyl phosphine oxide (62mg, 0.80mmol), XantPhos (465mg, 0.80mmol) and cesium carbonate (260mg, 0.80mmol) at room temperature. The reaction mixture was degassed and backfilled with argon three times. Bis (dibenzylideneacetone) palladium (462mg, 0.803mmol) was added to the reaction mixture and the reaction vial was sealed. The reaction mixture was heated to 90 ℃ and stirred for 4 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude material was purified by flash column chromatography (24g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 20% B; flow rate ═ 24 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound as a white solid (150mg, 0.72mmol, 89% yield). MS (ESI)200(M + H).
Step B preparation of intermediate 24B. (3-aminophenyl) dimethylphosphine oxide
A solution of intermediate 24A (200mg, 1mmol) in methanol (5mL) was degassed and backfilled with nitrogen and 10% Pd-C (53mg, 0.05mmol) was added to the reaction. After stirring under hydrogen (1atm, balloon) overnight, the reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (150mg, 0.84mmol, 84% yield).1H NMR(400MHz,DMSO-d6)δ7.13(td,J＝7.7,3.8Hz,1H),6.97-6.91(m,1H),6.85-6.78(m,1H),6.69(dt,J＝8.0,1.0Hz,1H),5.30(s,2H),1.54(s,3H),1.57(s,3H)。
Step C. preparation of intermediate 24℃ (3- (((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) amino) phenyl) dimethylphosphine oxide
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G, by substituting intermediate 1F and intermediate 24B where appropriate: (85mg, 0.19mmol, 74% yield).1H NMR(400MHz,DMSO-d6)δ7.17(td,J＝7.8,3.5Hz,1H),6.97-7.00(m,1H),6.86-6.73(m,2H),5.74(t,J＝5.8Hz,1H),2.85(d,J＝5.5Hz,2H),2.16(t,J＝19.6Hz,3H),1.92-1.82(m,6H),1.64-1.54(m,12H)。MS(ESI)424(M+H)。
Step D. example 24 preparation of N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (dimethylphosphoryl) phenyl) -4, 4-difluorocyclohexane-1-carboxamide
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 24C where appropriate: (10mg, 0.02mmol, 36% yield). 1H NMR(400MHz,DMSO-d6)δ7.84-7.71(m,2H),7.67-7.55(m,2H),3.61(br d,J＝1.0Hz,2H),2.32-2.22(m,1H),2.21-2.07(m,3H),2.02-1.88(m,2H),1.82-1.64(m,15H),1.64-1.55(m,3H),1.45-1.36(m,6H)。FXR EC50(nM)＝4000。MS(ESI)570(M+H)。
The following examples were prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 24C and the corresponding acid where appropriate:
example 27
Methyl 3- (N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamido) benzoate
Step a. preparation of intermediate 27a.3- (((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) amino) benzoic acid methyl ester
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G by substituting intermediate 1F and methyl 3-aminobenzoate where appropriate: (75mg, 0.17mmol, 68% yield). MS (ESI)406.3(M + H).
Example 27.3 preparation of methyl N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamido) benzoate
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 27A where appropriate: (75mg, 0.14mmol, 77% yield).1H NMR(400MHz,DMSO-d6)δ7.97(d,J＝8.1Hz,1H),7.91-7.86(m,1H),7.77-7.70(m,1H),7.66-7.57(m,1H),3.90(s,3H),3.66-3.50(m,2H),2.14(t,J＝19.7Hz,3H),1.84(br s,6H),1.80-1.66(m,6H),1.50-1.35(m,6H)。FXR EC50(nM)＝72。MS(ESI)518.3(M+H)。
Example 28
N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (ethylcarbamoyl) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
Step a. preparation of intermediate 28a.3- (((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) amino) benzoic acid methyl ester
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G by substituting intermediate 1F and methyl 3-aminobenzoate where appropriate: (75mg, 0.18mmol, 68% yield). MS (ESI)406(M + H).
Step B. preparation of intermediate 28B.3 methyl N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamido) benzoate
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 28A where appropriate: (75mg, 0.143mmol, 77% yield).1H NMR(400MHz,DMSO-d6)δ7.97(d,J＝8.1Hz,1H),7.91-7.86(m,1H),7.77-7.70(m,1H),7.66-7.57(m,1H),3.90(s,3H),3.66-3.50(m,2H),2.14(t,J＝19.7Hz,3H),1.84(br s,6H),1.80-1.66(m,6H),1.50-1.35(m,6H)。MS(ESI)518(M+H)。
Step C. preparation of intermediate 28C.3- (N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamido) benzoic acid
To a solution of intermediate 28B (65mg, 0.126mmol) in methanol (1mL) was added a solution of sodium hydroxide (20mg, 0.502mmol) in water (1 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (5mL), acidified with 1.5n aqueous hcl and extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as an off-white solid (50mg, 0.01mmol, 79% yield). 1H NMR(400MHz,DMSO-d6) δ 7.94(d, J ═ 7.3Hz,1H),7.83(s,1H),7.70-7.62(m,1H),7.61-7.54(m,1H),3.58(s,2H),2.13(t, J ═ 19.6Hz,3H),1.83(br s,6H),1.81-1.73(m,6H),1.49-1.37(m,6H) (exchangeable protons are hidden under the solvent peak. ). MS (ESI)504(M + H).
EXAMPLE 28 preparation of N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (ethylcarbamoyl) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
To a stirred solution of intermediate 28C (20mg, 0.040mmol) in DMF (1mL) was added ethylamine (0.06mL, 0.12mmol), TEA (0.02mL, 0.16mmol) at room temperature, followed by BOP (17.57mg, 0.04 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water (10mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (10mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via preparative LC/MS using the following conditions: column: waters XBridge C18, 150mmx19mm, 5 μm particles; mobile phase A: 5:95 acetonitrile, water containing 10mM ammonium acetate; mobile phase B: 95:5 acetonitrile, water containing 10mM ammonium acetate; gradient: hold at 20% B for 0 min, 20% -59% B for 20 min, then 100% B for 5 min; flow rate: 15 mL/min; column temperature: at 25 ℃. The collection of fractions is triggered by a signal. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (11mg, 0.02mmol, 49% yield). 1H NMR(400MHz,DMSO-d6)δ8.58(t,J＝5.3Hz,1H),7.90-7.85(m,1H),7.84-7.80(m,1H),7.61-7.49(m,2H),3.68-3.50(m,2H),3.32-3.26(m,2H),2.14(t,J＝19.7Hz,3H),1.84(br s,6H),1.81-1.75(m,6H),1.49-1.40(m,6H),1.15(t,J＝7.2Hz,3H)。FXR EC50(nM)＝210。MS(ESI)531(M+H)。
Example 29
N- (3-carbamoylphenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
The title compound was prepared according to the method described for the synthesis of example 28 (step D) by substituting intermediate 28C and ammonium chloride where appropriate: (15mg, 0.03mmol, 75% yield).1HNMR(400MHz,DMSO-d6)δ8.12(s,1H),7.93-7.87(m,1H),7.86(s,1H),7.62-7.49(m,3H),3.67-3.50(m,2H),2.14(t,J＝19.7Hz,3H),1.88-1.70(m,12H),1.53-1.35(m,6H)。FXR EC50(nM)＝902。MS(ESI)503(M+H)。
Example 30
1- (3-bromophenyl) -1- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- ((1R,4R) -4-hydroxy-4-methylcyclohexyl) urea
Step a. intermediate 30 a.preparation of 3-bromo-N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) aniline
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G by substituting intermediate 1F and 3-bromoaniline where appropriate: (300mg, 0.70mmol, 86% yield).1H NMR(400MHz,DMSO-d6)δ7.01-6.93(m,1H),6.78(t,J＝2.0Hz,1H),6.65-6.57(m,2H),5.81-5.73(m,1H),2.81(d,J＝6.0Hz,2H),2.16(t,J＝19.6Hz,3H),1.93-1.81(m,6H),1.62-1.52(m,6H)。MS(ESI)427.9(M+H)。
Example 30.1 preparation of- (3-bromophenyl) -1- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- ((1R,4R) -4-hydroxy-4-methylcyclohexyl) urea
A stirred solution of intermediate 30A (15mg, 0.035mmol) and TEA (0.02mL, 0.17mmol) in DCM (3mL) was cooled to 0 ℃. Triphosgene (10mg, 0.03mmol) was added to the reaction mixture as a solution in DCM (1 mL). The reaction mixture was allowed to warm to room temperature and stirred for 12 h. To the above reaction mixture was added trans-4-amino-1-methylcyclohexanol (5.46mg, 0.04mmol), and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure. The crude compound was purified via preparative LC/MS using the following conditions: column: waters XBridge C18, 150mm x 19mm, 5 μm particles; mobile phase A: 5:95 acetonitrile, water containing 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile Water containing 0.1% trifluoroacetic acid; gradient: held at 18% B for 2 minutes, 18% -62% B over 25 minutes, then held at 100% B for 5 minutes; flow rate: 15 mL/min; column temperature: at 25 ℃. The collection of fractions is triggered by a signal. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound as an off-white solid (6mg, 10.84 μmol, 31% yield).1H NMR(400MHz,DMSO-d6)δ7.54(d,J＝1.7Hz,1H),7.44-7.38(m,1H),7.37-7.27(m,2H),5.44(d,J＝7.8Hz,1H),4.20(s,1H),3.53(s,2H),3.49-3.42(m,1H),2.14(t,J＝19.7Hz,3H),1.82-1.68(m,6H),1.65-1.53(m,2H),1.45-1.23(m,12H),1.06(s,3H)。FXR EC50(nM)＝150；MS(ESI)581(M+H)。
Example 31
N- (3-bromophenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -2, 2-difluorocyclopropane-1-carboxamide (racemate)
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 30A where appropriate: (8mg, 0.015mmol, 21% yield).1H NMR(400MHz,DMSO-d6)δ7.75-7.65(m,1H),7.59(br d,J＝7.1Hz,1H),7.51-7.34(m,2H),3.87(br d,J＝13.9Hz,1H),3.47(br d,J＝14.4Hz,1H),2.37-2.28(m,1H),2.14(t,J＝19.7Hz,3H),2.00-1.89(m,1H),1.78(br t,J＝7.9Hz,7H),1.49-1.30(m,6H)。FXR EC50(nM)＝261。MS(ESI)530(M+H)。
Example 32
(3- (N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamido) phenyl) carbamic acid tert-butyl ester
Step A. preparation of intermediate 32A. (3-nitrophenyl) carbamic acid tert-butyl ester
To a stirred solution of 3-nitroaniline (5g, 36.2mmol) in THF (50mL) was added boc-anhydride (8.40mL, 36.2mmol) at room temperature. The reaction mixture was cooled to 0 ℃ and DMAP (4.86g, 39.8mmol) was added portionwise. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate (100mL) and the organic solution was washed with water (50mL), then brine solution (2 × 50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (80g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 70% B; flow rate ═ 40 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound as a brown solid (8g, 33.6mmol, 93% yield). MS (ESI)237 (M-H).
Step B preparation of intermediate 32B. (3-aminophenyl) carbamic acid tert-butyl ester
To a stirred solution of intermediate 32A (1g, 4.20mmol) in ethanol (20mL) and water (5mL) was added ammonium chloride (3.37g, 63mmol) at room temperature followed by zinc (4.12g, 63 mmol). After stirring at room temperature overnight, the reaction mixture was filtered through a pad of celite, and the filtrate was diluted with ethyl acetate (50 mL). The organic solution was then washed with brine solution (2 × 25mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (40g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 60% B; flow rate ═ 40 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound as a brown solid (800mg, 3.73mmol, 89% yield). MS (ESI)209(M + H).
Step C. preparation of intermediate 32℃ (tert-butyl 3- (((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) amino) phenyl) carbamate
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G, by substituting intermediate 1F and intermediate 32B where appropriate: (40mg, 0.08mmol, 45% yield). MS (ESI)463(M + H).
EXAMPLE 32 preparation of tert-butyl (3- (N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamido) phenyl) carbamate
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 32C where appropriate: (15mg, 0.027mmol, 62% yield).1H NMR(400MHz,DMSO-d6)δ9.52(s,1H),7.47(br d,J＝8.6Hz,1H),7.43(t,J＝1.8Hz,1H),7.33(t,J＝7.9Hz,1H),6.98(dd,J＝1.2,7.8Hz,1H),3.59-3.42(m,2H),2.14(t,J＝19.7Hz,3H),1.87(br d,J＝9.8Hz,6H),1.82-1.71(m,6H),1.49(s,9H),1.47-1.36(m,6H)。FXR EC50(nM)＝62。MS(ESI)575(M+H)。
Example 33
N- (3-bromophenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
Step A. preparation of intermediate 33A.4- (hydroxymethyl) bicyclo [2.2.2] octane-1-carboxylic acid methyl ester
To 4- (methoxycarbonyl) bicyclo [2.2.2] at 0 deg.C]Octane-1-carboxylic acid (10g,47.1mmol) in THF (100mL) was added BH dropwise3DMS (14.3mL, 141 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was cooled to 0 ℃ and carefully quenched with methanol. The resulting solution was concentrated under reduced pressure, and the residue was diluted with water (50 mL). The aqueous solution was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine solution (20mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by flash column chromatography (80g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 70% B; flow rate ═ 40 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound (7g, 35.3mmol, 75% yield). 1H NMR(400MHz,DMSO-d6)δ4.12(dd,J＝28.40,Hz,1H),3.65(s,3H),3.29(s,2H),1.82-1.77(m,6H),1.47-1.42(m,6H)。
Step B. preparation of intermediate 33 A.4-formylbicyclo [2.2.2] octane-1-carboxylic acid methyl ester.
The title compound was prepared according to the procedure described for the synthesis of intermediate 1F by substituting intermediate 33A where appropriate. (900mg, 4.59mmol, 91% yield) as a gummy liquid.1HNMR(400MHz,DMSO-d6)δ9.43(s,1H),3.59(s,3H),1.78-1.57(m,12H)。MS(ESI)197(M+H)。
Step C. preparation of intermediate 33C.4- (((3-bromophenyl) amino) methyl) bicyclo [2.2.2] octane-1-carboxylic acid methyl ester
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G, by substituting 3-bromoaniline and intermediate 33B where appropriate. (6.4g, 18.17mmol, 79% yield) as a brown gummy liquid. MS (ESI)353(M + H).
Step D. preparation of intermediate 33D.4- ((N- (3-bromophenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamido) methyl) bicyclo [2.2.2] octane-1-carboxylic acid methyl ester
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 33C and the corresponding acid where appropriate. (2.5g, 5.38mmol, 54% yield) as a brown gummy liquid. MS (ESI)464(M + H).
Step E. preparation of intermediate 33E.4- ((N- (3-bromophenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamido) methyl) bicyclo [2.2.2] octane-1-carboxylic acid
The title compound was prepared according to the procedure described for the synthesis of intermediate 28C, by substituting intermediate 33D where appropriate. (2.1g, 4.66mmol, 98% yield) as a brown gummy liquid. MS (ESI)452(M + H).
Step F. preparation of intermediate 33F.4- ((N- (3-bromophenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamido) methyl) bicyclo [2.2.2] octane-1-carboxamide
The title compound was prepared according to the procedure described for the synthesis of intermediate 1A, by substituting intermediate 33E where appropriate. (1.6g, 3.56mmol, 97% yield). MS (ESI)450(M + H).
Step G. preparation of intermediate 33G.N- (3-bromophenyl) -N- ((4-cyanobicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
The title compound was prepared according to the procedure described for the synthesis of intermediate 1B, by substituting intermediate 33F where appropriate. (850mg, 1.97mmol, 55% yield) as a light brown gummy liquid. MS (ESI)431(M + H).
Step H. preparation of intermediate 33H. (E) -N- (3-bromophenyl) -3-fluoro-N- ((4- (N' -hydroxycarbamimidoyl)) bicyclo [2.2.2] oct-1-yl) methyl) bicyclo [1.1.1] pentane-1-carboxamide
The title compound was prepared according to the procedure described for the synthesis of intermediate 1C, by substituting intermediate 33G where appropriate. (820mg, 1.766mmol, 92% yield) as a white solid. MS (ESI)464(M + H).
Step I. example 33 preparation of N- (3-bromophenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
The title compound was prepared according to the procedure described for the synthesis of intermediate 1D by substituting intermediate 33H where appropriate. (9.6mg, 0.017mmol, 55% yield).1H NMR(400MHz,DMSO-d6)δ7.74-7.68(m,1H),7.61(dt,J＝7.3,1.7Hz,1H),7.49-7.36(m,2H),3.58(br.s.,1H),3.51(br.s.,1H),2.23-2.05(m,3H),1.88(br.s.,6H),1.82-1.69(m,6H),1.53-1.33(m,6H)。FXR EC50(nM)＝13。MS(ESI)538(M+H)。
Example 34
N- (3-bromophenyl) -3-fluoro-N- ((4- (5- (1-fluorocyclopropyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) bicyclo [1.1.1] pentane-1-carboxamide
The title compound was prepared according to the procedure described for the synthesis of intermediate 1D, by substituting intermediate 33H where appropriate: (450mg, 0.845mmol, 65% yield)Rate).1H NMR(400MHz,DMSO-d6)δ7.75-7.67(m,1H),7.61(dt,J＝7.3,1.7Hz,1H),7.50-7.36(m,2H),3.58(br.s.,1H),3.50(br.s.,1H),1.87(br.s.,6H),1.81-1.61(m,8H),1.52-1.31(m,8H)。FXR EC50(nM)＝20。MS(ESI)533(M+H)。
Example 35
N- (3-bromophenyl) -3-fluoro-N- ((4- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) bicyclo [1.1.1] pentane-1-carboxamide
The title compound was prepared according to the procedure described for the synthesis of intermediate 1D, by substituting intermediate 33H where appropriate: (1.2g, 2.18mmol, 78% yield).1H NMR(400MHz,DMSO-d6)δ7.71(t,J＝1.8Hz,1H),7.61(dt,J＝7.6,1.7Hz,1H),7.50-7.37(m,2H),3.59(br.s.,1H),3.52(br.s.,1H),1.88(br.s.,6H),1.84-1.67(m,6H),1.54-1.35(m,6H)。FXR EC50(nM)＝42。MS(ESI)543(M+H)。
Example 36
(1S,3S) -N- (3-bromophenyl) -N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide
Step A. preparation of intermediate 36A.4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] octane-1-carboxylic acid methyl ester
According to the method described for the synthesis of intermediate 1D, by substituting 4- (methoxycarbonyl) bicyclo [2.2.2] where appropriate]Octane-1-carboxylic acid and N' -hydroxypivalimide (pivalimidamide) to prepare the title compound. (2.2g, 7.52mmol, 97% yield) as a white solid. MS (ESI)293(M + H).1H NMR(400MHz,DMSO-d6)δ3.61(s,3H),1.96-1.87(m,6H),1.87-1.79(m,6H),1.29(s,9H)。
Step B. preparation of intermediate 36B. (4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methanol
The title compound was prepared according to the procedure described for the synthesis of intermediate 1E, by substituting intermediate 36A where appropriate. (1.5g, 5.62mmol, 75% yield) as a white solid. MS (ESI)265(M + H).1H NMR(400MHz,DMSO-d6)δ4.43(t,J＝5.5Hz,1H),3.09(d,J＝5.5Hz,2H),1.94-1.79(m,6H),1.52-1.39(m,6H),1.29(s,9H)。
Step C. preparation of intermediate 36C.4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] octane-1-carbaldehyde
The title compound was prepared according to the procedure described for the synthesis of intermediate 1F by substituting intermediate 36B where appropriate. (1.1g, 3.44mmol, 60% yield) as a white solid. MS (ESI)263(M + H).1H NMR(400MHz,DMSO-d6)δ9.47(s,1H),1.97-1.88(m,6H),1.76-1.65(m,6H),1.29(s,9H)。
Step D. intermediate 36 D.preparation of 3-bromo-N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) aniline
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G by substituting intermediate 36C and 3-bromoaniline where appropriate: (350mg, 0.83mmol, 72% yield). MS (ESI)419(M + H).
EXAMPLE 36 preparation of (1S,3S) -N- (3-bromophenyl) -N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 36D where appropriate: (46.3mg, 0.08mmol, 55% yield).1H NMR(400MHz,DMSO-d6)δ7.70(s,1H),7.55(d,J＝7.6Hz,1H),7.49-7.26(m,2H),6.54(s,1H),3.60(br.s.,2H),2.79-2.68(m,1H),2.40-2.24(m,2H),2.13-1.93(m,2H),1.90-1.61(m,6H),1.56-1.31(m,6H),1.31-1.14(m,9H)。FXR EC50(nM)＝135。MS(ESI)584(M+H)。
Example 37
N- (3-bromo-4-chlorophenyl) -N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
Step A. intermediate 37 A.preparation of 3-bromo-N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -4-chloroaniline
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G by substituting intermediate 36C and 3-bromo-4-chloroaniline where appropriate: (620mg, 1.37mmol, 81% yield).1H NMR(400MHz,DMSO-d6)δ7.21(d,J＝8.5Hz,1H),6.94(d,J＝2.5Hz,1H),6.67-6.62(m,1H),5.95(t,J＝5.8Hz,1H),2.81(d,J＝6.0Hz,2H),1.95-1.84(m,6H),1.60-1.49(m,6H),1.28(s,9H)。MS(ESI)452.2(M+H)。
Step B. example 37 preparation of N- (3-bromo-4-chlorophenyl) -N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 37A where appropriate: (500mg, 0.88mmol, 65% yield).1H NMR(400MHz,DMSO-d6)δ7.95(d,J＝2.4Hz,1H),7.71(d,J＝8.3Hz,1H),7.50(dd,J＝2.4,8.6Hz,1H),3.56(br s,2H),1.91(br s,6H),1.84-1.77(m,6H),1.46-1.36(m,6H),1.27(s,9H)。FXR EC50(nM)＝1078。MS(ESI)564(M+H)。
Example 38
N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-cyanophenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
Step A. preparation of intermediate 38A.3- (((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) amino) benzonitrile
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G by substituting intermediate 36C and 3-aminobenzonitrile where appropriate: (110mg, 0.3mmol, 78% yield).1H NMR(300MHz,DMSO-d6)δ7.25-7.16(m,1H),6.98-6.90(m,2H),6.88-6.81(m,1H),6.03(t,J＝6.1Hz,1H),2.86(d,J＝5.9Hz,2H),1.95-1.81(m,6H),1.61-1.49(m,6H),1.28(s,9H)。MS(ESI)365.2(M+H)。
Example 38 preparation of N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-cyanophenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 38A where appropriate: (9mg, 0.018mmol, 33% yield).1H NMR(400MHz,DMSO-d6)δ8.04(d,J＝1.5Hz,1H),7.88(d,J＝7.6Hz,1H),7.82-7.77(m,1H),7.70-7.62(m,1H),3.65-3.49(m,2H),1.87(s,6H),1.82-1.74(m,6H),1.47-1.34(m,6H),1.27(s,9H)。FXR EC50(nM)＝142。MS(ESI)477(M+H)。
The following examples were prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 38A and the corresponding acid where appropriate:
Example 43
N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (dimethylphosphoryl) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
Step a. intermediate 43A preparation of (3- (((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) amino) phenyl) dimethylphosphine oxide
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G, by substituting intermediate 36C and intermediate 24B where appropriate: (100mg, 0.23mmol, 77% yield). MS (ESI)416(M + H).
Step B. example 43 preparation of N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (dimethylphosphoryl) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
The procedure (steps) was followed for the synthesis of example 1Step H), the title compound was prepared by substituting intermediate 43A where appropriate: (16mg, 0.03mmol, 63% yield).1H NMR(400MHz,DMSO-d6)δ7.84-7.71(m,2H),7.66-7.55(m,2H),3.65-3.48(m,2H),1.91-1.75(m,12H),1.70(br d,J＝13.4Hz,6H),1.50-1.35(m,6H),1.31-1.20(m,9H)。FXR EC50(nM)＝4000。MS(ESI)528(M+H)。
The following examples were prepared according to the procedure described for the synthesis of example 1 (step H) by substituting intermediate 43A and the corresponding acid where appropriate:
example 48
N- (3-bromophenyl) -N- ((4- (5- (1, 1-difluoroethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
Step A. preparation of intermediate 48A.3- (1, 1-difluoroethyl) pyridine
To a stirred solution of 1- (pyridin-3-yl) ethan-1-one (2g, 16.51mmol) in DCM (20mL) was added DAST (17.45mL, 132mmol) at room temperature. The reaction mixture was heated to 50 ℃ and stirred overnight. The reaction mixture was cooled to room temperature and poured dropwise into a cooled aqueous 2N NaOH solution (50 mL). The resulting solution was extracted with DCM (2 × 100 mL). The combined organic layers were washed with brine solution (100mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (40g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 30% B; flow rate ═ 40 mL/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound as a pale yellow liquid (1.95g, 13.35mmol, 81% yield). Note that: the rotary evaporation was carried out at 30 ℃ under reduced pressure.1H NMR(400MHz,DMSO-d6)δ8.80(d,J＝1.0Hz,1H),8.72(d,J＝4.5Hz,1H),8.00(d,J＝8.0Hz,1H),7.58-7.51(m,1H),2.10-1.97(m,3H)。MS(ESI)145.2(M+H)。
Step B. preparation of intermediate 48B.4- (5- (1, 1-difluoroethyl) pyridin-2-yl) bicyclo [2.2.2] octane-1-carboxylic acid methyl ester
To a stirred solution of 4- (methoxycarbonyl) bicyclo [2.2.2] octane-1-carboxylic acid (2.3g, 10.84mmol) and intermediate 48A (1.86g, 13mmol) in DCM (70mL) and water (70mL) was added ammonium persulfate (2.47g, 10.84mmol) at room temperature followed by silver nitrate (0.37g, 2.16 mmol). The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with DCM (25mL) and filtered through celite. The filtrate was washed with water (30mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (40g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 60% B; flow rate ═ 40 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound as a white solid (1.6g, 5.12mmol, 47% yield). MS (ESI)310(M + H).
Step C. preparation of intermediate 48℃ (4- (5- (1, 1-difluoroethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methanol
The title compound (1.4g, 4.98mmol, 96% yield) was prepared as a brown gum according to the method described for the synthesis of intermediate 1E by substituting intermediate 48B where appropriate.1H NMR(400MHz,DMSO-d6)δ8.70(dd,J＝2.5,1.0Hz,1H),7.89(dd,J＝8.0,2.5Hz,1H),7.45(d,J＝7.5Hz,1H),4.36(t,J＝5.5Hz,1H),3.10(d,J＝5.5Hz,2H),2.08-1.93(m,3H),1.89-1.79(m,6H),1.52-1.42(m,6H)。
Step D. preparation of intermediate 48D.4- (5- (1, 1-difluoroethyl) pyridin-2-yl) bicyclo [2.2.2] octane-1-carbaldehyde
The title compound (0.9g, 3.22mmol, 64% yield) was prepared as a white solid according to the method described for the synthesis of intermediate 1F by substituting intermediate 48C where appropriate.1H NMR(400MHz,DMSO-d6)δ9.49(s,1H),8.72(dd,J＝2.5,1.0Hz,1H),7.95-7.88(m,1H),7.51-7.44(m,1H),2.01(t,J＝19.1Hz,3H),1.94-1.85(m,6H),1.76-1.67(m,6H)。
Step E. preparation of intermediate 48 E.3-bromo-N- ((4- (5- (1, 1-difluoroethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) aniline
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G by substituting intermediate 48D and 3-bromoaniline where appropriate: (300mg, 0.60mmol, 68% yield). MS (ESI)435(M + H).
Step F. example 48 preparation of N- (3-bromophenyl) -N- ((4- (5- (1, 1-difluoroethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 48E where appropriate: (300mg, 0.548mmol, 95% yield). 1H NMR(400MHz,DMSO-d6)δ8.72-8.61(m,1H),7.87(dd,J＝2.4,8.6Hz,1H),7.70(t,J＝1.7Hz,1H),7.61(td,J＝1.8,7.2Hz,1H),7.49-7.35(m,3H),3.68-3.56(m,1H),3.55-3.43(m,1H),1.99(t,J＝19.1Hz,3H),1.88(br s,6H),1.81-1.68(m,6H),1.52-1.35(m,6H)。FXR EC50(nM)＝288。MS(ESI)549(M+H)。
Example 49
N- (3-cyanophenyl) -N- ((4- (5- (1, 1-difluoroethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
Step A. preparation of intermediate 49A.3- (((4- (5- (1, 1-difluoroethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) amino) benzonitrile
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G by substituting intermediate 48D and 3-aminobenzonitrile where appropriate: (150mg, 0.32mmol, 90% yield).1HNMR(300MHz,DMSO-d6)δ8.70(d,J＝1.7Hz,1H),7.89(dd,J＝8.3,2.3Hz,1H),7.46(d,J＝8.6Hz,1H),7.26-7.16(m,1H),6.98-6.91(m,2H),6.88-6.82(m,1H),6.01(t,J＝5.4Hz,1H),2.86(d,J＝5.9Hz,2H),2.08-1.92(m,3H),1.91-1.81(m,6H),1.62-1.52(m,6H)。MS(ESI)382(M+H)。
Step B. example 49 preparation of N- (3-cyanophenyl) -N- ((4- (5- (1, 1-difluoroethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 49A where appropriate: (12.8mg, 0.026mmol, 40% yield).1H NMR(400MHz,DMSO-d6)δ8.68(d,J＝1.5Hz,1H),8.05(s,1H),7.91-7.84(m,2H),7.83-7.78(m,1H),7.70-7.62(m,1H),7.40(d,J＝8.6Hz,1H),3.68-3.44(m,2H),1.99(t,J＝19.1Hz,3H),1.92-1.68(m,12H),1.51-1.29(m,6H)。FXR EC50(nM)＝327。MS(ESI)494(M+H)。
The following examples were prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 49A and the corresponding acid where appropriate:
example 52
N- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-ethoxyphenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
Step A. preparation of intermediate 52A.4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] octane-1-carboxylic acid methyl ester
The title compound was prepared according to the procedure described for the synthesis of intermediate 1D by substituting 4- (methoxycarbonyl) bicyclo [2.2.2] octane-1-carboxylic acid and (Z) -N' -hydroxycyclopropanecarboximidamide (commercially available) where appropriate. (490mg, 1.66mmol, 71% yield). MS (ESI)277(M + H).
Step B. preparation of intermediate 52B. (4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methanol
The title compound was prepared according to the procedure described for the synthesis of intermediate 1E, by substituting intermediate 52A where appropriate. (500mg, 1.08mmol, 61% yield). MS (ESI)249(M + H).
Step C. preparation of intermediate 52C.4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] octane-1-carbaldehyde
The title compound was prepared according to the procedure described for the synthesis of intermediate 1F by substituting intermediate 52B where appropriate. (350mg, 1.421mmol, 71% yield). MS (ESI)247(M + H).
Step D. preparation of intermediate 52D.N- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-ethoxyaniline
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G by substituting intermediate 52C and 3-ethoxyaniline where appropriate: (120mg, 0.31mmol, 76% yield).1H NMR(400MHz,DMSO-d6)δ6.90(t,J＝8.0Hz,1H),6.18(dd,J＝8.0,1.5Hz,1H),6.14(t,J＝2.0Hz,1H),6.04(dd,J＝7.5,2.5Hz,1H),5.39(t,J＝6.0Hz,1H),3.91(q,J＝7.0Hz,2H),2.78(d,J＝6.0Hz,2H),2.06(tt,J＝8.3,4.8Hz,1H),1.91-1.79(m,6H),1.59-1.48(m,6H),1.28(t,J＝7.0Hz,3H),1.06-0.98(m,2H),0.89-0.81(m,2H)。MS(ESI)368.3(M+H)。
Example 52 preparation of N- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-ethoxyphenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 52D where appropriate: (8mg, 0.017mmol, 30% yield).1H NMR(400MHz,DMSO-d6)δ7.38-7.29(m,1H),7.00-6.88(m,3H),4.13-3.99(m,2H),3.63-3.55(m,1H),3.49-3.41(m,1H),2.09-2.01(m,1H),1.94-1.81(m,6H),1.81-1.71(m,6H),1.49-1.38(m,6H),1.34(t,J＝7.0Hz,3H),1.05-0.97(m,2H),0.86-0.79(m,2H)。FXR EC50(nM)＝102。MS(ESI)480(M+H)。
The following examples were prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 52D and the corresponding acid where appropriate:
example 57
(1S,3S) -N- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-N- (3-methoxyphenyl) -3- (trifluoromethyl) cyclobutane-1-carboxamide
Step A. intermediate 57A. preparation of N- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-methoxyaniline
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G by substituting intermediate 52C and 3-methoxyaniline where appropriate: (85mg, 0.23mmol, 56% yield). 1HNMR(400MHz,DMSO-d6)δ6.92(t,J＝8.0Hz,1H),6.20(dd,J＝8.3,1.3Hz,1H),6.16(t,J＝2.0Hz,1H),6.06(dd,J＝8.0,2.5Hz,1H),5.44(t,J＝6.0Hz,1H),3.66(s,3H),2.78(d,J＝6.0Hz,2H),2.11-2.02(m,1H),1.90-1.81(m,6H),1.59-1.50(m,6H),1.06-1.00(m,2H),0.89-0.83(m,2H)。MS(ESI)354.3(M+H)。
Example 57 preparation of (1S,3S) -N- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-N- (3-methoxyphenyl) -3- (trifluoromethyl) cyclobutane-1-carboxamide
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 57A where appropriate: (1mg, 1.92. mu. mol, 5% yield).1H NMR(400MHz,DMSO-d6)δ7.37-7.29(m,1H),6.98-6.86(m,3H),6.51(s,1H),3.77(s,3H),3.63-3.53(m,2H),2.98-2.88(m,1H),2.79-2.71(m,1H),2.13-2.00(m,4H),(br dd,J＝7.1,8.3Hz,6H),1.44-1.34(m,6H),1.04-0.98(m,2H),0.88-0.77(m,2H)。FXR EC50(nM)＝304。MS(ESI)520(M+H)。
The following examples were prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 57A and the corresponding acid where appropriate:
example 62
N- (3-cyano-5-fluorophenyl) -N- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
Step A. preparation of intermediate 62A.3- (((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) amino) -5-fluorobenzonitrile
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G by substituting intermediate 52C and 3-amino-5-fluorobenzonitrile where appropriate: (90mg, 0.246mmol, 48% yield).1H NMR(400MHz,DMSO-d6)δ6.85(s,1H),6.80-6.71(m,1H),6.66-6.60(m,1H),6.40-6.35(m,1H),2.87(d,J＝6.0Hz,2H),2.11-2.03(m,1H),1.90-1.82(m,6H),1.57-1.50(m,6H),1.06-1.00(m,2H),0.88-0.82(m,2H)。MS(ESI)367.2(M+H)。
Step B. example 62 preparation of N- (3-cyano-5-fluorophenyl) -N- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 62A where appropriate: (7.1 mg).1H NMR(400MHz,DMSO-d6)δ7.97(d,J＝1.2Hz,1H),7.95-7.84(m,2H),3.66-3.45(m,2H),2.05(tt,J＝4.7,8.3Hz,1H),1.98-1.84(m,6H),1.82-1.69(m,6H),1.48-1.30(m,6H),1.06-0.96(m,2H),0.87-0.76(m,2H)。FXR EC50(nM)＝185。MS(ESI)479(M+H)。
The following examples were prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 62A and the corresponding acid where appropriate:
example 65
N- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3, 3-difluoro-N- (3- (methylsulfonamido) phenyl) cyclobutane-1-carboxamide
Step A. intermediate 65A. preparation of tert-butyl (3- (((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) amino) phenyl) carbamate
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G, by substituting intermediate 32B and intermediate 52C where appropriate: (360mg, 0.82mmol, 68% yield).1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),6.91-6.78(m,2H),6.54(d,J＝7.5Hz,1H),6.22(dd,J＝8.3,1.8Hz,1H),5.38(t,J＝5.8Hz,1H),2.75(d,J＝6.0Hz,2H),2.10-2.01(m,1H),1.91-1.80(m,6H),1.59-1.49(m,6H),1.46(s,9H),1.06-0.97(m,2H),0.89-0.80(m,2H)。MS(ESI)439(M+H)。
Step B. intermediate 65B. preparation of N1- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) benzene-1, 3-diamine
To a stirred solution of intermediate 65A (60mg, 0.13mmol) in DCM (2mL) was added 4M HCl in dioxane (0.10mL, 0.41mmol) at 0 ℃. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was basified with 10% aqueous sodium bicarbonate (2 mL). The resulting aqueous solution was extracted with ethyl acetate (2 × 5 mL). The combined organic layers were washed with brine solution (10mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (40mg, 0.118mmol, 86% yield). 1H NMR(400MHz,DMSO-d6)δ6.71-6.64(m,1H),5.87-5.82(m,2H),5.80-5.74(m,1H),5.01(t,J＝6.0Hz,1H),4.68(br.s.,2H),2.73(d,J＝6.0Hz,2H),2.11-2.02(m,1H),1.90-1.80(m,6H),1.58-1.48(m,6H),1.07-0.99(m,2H),0.89-0.82(m,2H)。MS(ESI)339(M+H)。
Step C. preparation of intermediate 65C.N- (3- (((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) amino) phenyl) methanesulfonamide
To a stirred solution of intermediate 65B (60mg, 0.17mmol) in DCM (2mL) at 0 ℃ was added TEA (0.08mL, 0.53mmol) followed by methanesulfonyl chloride (30mg, 0.26 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was diluted with DCM (5mL), washed with water (5mL), brine solution (5mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a brown solid (100mg, crude). MS (ESI)417(M + H).
EXAMPLE 65. preparation of N- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3, 3-difluoro-N- (3- (methylsulfonylamino) phenyl) cyclobutane-1-carboxamide
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 65C where appropriate: (17mg, 0.03mmol, 68% yield).1H NMR(400MHz,DMSO-d6)δ9.90(s,1H),7.46-7.37(m,1H),7.22-7.08(m,3H),3.58(s,2H),3.03(s,3H),2.91-2.83(m,1H),2.79-2.63(m,2H),2.45-2.35(m,2H),2.09-2.00(m,1H),1.84-1.68(m,6H),1.48-1.27(m,6H),1.07-0.97(m,2H),0.86-0.80(m,2H)。FXR EC50(nM)＝1279。MS(ESI)535(M+H)。
The following examples were prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 65C and the corresponding acid where appropriate:
example 68
N- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3- (methylsulfonyl) phenyl) bicyclo [1.1.1] pentane-1-carboxamide
Step A. intermediate 68A. preparation of N- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- (methylsulfonyl) aniline
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G by substituting intermediate 52C and 3- (methylsulfonyl) aniline where appropriate: (110mg, 0.25mmol, 63% yield).1H NMR(400MHz,DMSO-d6)δ7.31-7.25(m,1H),7.09(t,J＝2.0Hz,1H),6.97(d,J＝6.0Hz,1H),6.91(dd,J＝7.5,2.5Hz,1H),6.11(t,J＝5.8Hz,1H),3.12(s,3H),2.87(d,J＝5.5Hz,2H),2.11-2.03(m,1H),1.90-1.84(m,6H),1.61-1.53(m,6H),1.06-1.00(m,2H),0.88-0.83(m,2H)。MS(ESI)402(M+H)。
Step B. preparation of example 68.N- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3- (methylsulfonyl) phenyl) bicyclo [1.1.1] pentane-1-carboxamide
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 68A where appropriate: (7mg, 0.014mmol, 23% yield).1H NMR(400MHz,DMSO-d6)δ7.97(d,J＝1.7Hz,1H),7.94(d,J＝8.1Hz,1H),7.84-7.78(m,1H),7.77-7.70(m,1H),3.58(s,2H),3.31(s,3H),2.09-2.00(m,1H),1.85(br s,6H),1.80-1.70(m,6H),1.47-1.33(m,6H),1.06-0.98(m,2H),0.86-0.79(m,2H)。FXR EC50(nM)＝1488。MS(ESI)534(M+H)。
The following examples were prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 68A and the corresponding acid where appropriate:
example 70
N- (3-cyanophenyl) -N- (1- (4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) ethyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
Step A. preparation of intermediate 70A.1- (4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) ethan-1-ol
To a solution of intermediate 52C (1.5g, 6.09mmol) in anhydrous tetrahydrofuran (15mL) at-78 ℃ under an argon atmosphere was added a 3M solution of methyl magnesium bromide in diethyl ether (3mL, 9.13 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was cooled to 0 ℃ with saturated NH4The Cl solution was quenched and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine solution (20mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by flash column chromatography (40g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 50% B; flow rate ═ 40 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound as an oil (1.25g, 4.53mmol, 74% yield).1H NMR(400MHz,DMSO-d6)δ4.29(d,J＝6.80Hz,1H),3.25-3.21(m,1H),2.10-2.00(m,1H),1.98-1.78(m,6H),1.53-1.37(m,6H),1.04-0.99(m,2H),0.94(d,J＝8.40Hz,3H),0.87-0.85(m,2H)。
Step B. preparation of intermediate 70B.1- (4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) ethan-1-one
According to the method described for the synthesis of intermediate 1F, byThe title compound was prepared substituting intermediate 70A where appropriate. (1g, 3.65mmol, 80% yield).1H NMR(400MHz,DMSO-d6)δ2.09-2.05(m,4H),1.99-1.85(m,6H),1.76-1.71(m,6H),1.06-1.00(m,2H),0.87-0.84(m,2H)。
Step C. preparation of intermediate 70C.3- ((1- (4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) -1l 3-ethyl) amino) benzonitrile
To a stirred solution of intermediate 70B (198mg, 0.762mmol) in methanol (2mL) was added 3-aminobenzonitrile (90mg, 0.76mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. Triethylsilane (177mg, 1.524mmol) and indium (III) chloride (16.85mg, 0.076mmol) were added to the reaction. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. And the residue was dissolved in EtOAc (20 mL). The organic solution was washed with water (10mL), then brine solution (10mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (12g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 50% B; flow rate ═ 24 mL/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound as a brown solid (110mg, 0.30mmol, 40% yield).1H NMR(300MHz,DMSO-d6)δ7.27-7.17(m,1H),6.96-6.82(m,3H),3.25(d,J＝6.6Hz,1H),2.09-20.05(d,J＝9.6Hz,1H),1.92-1.71(m,6H),1.50(d,J＝7.3Hz,3H),1.42(br.s.,3H),1.04(dd,J＝8.4,2.5Hz,2H),0.96(d,J＝6.6Hz,3H),0.85(dd,J＝4.8,2.5Hz,2H)。MS(ESI)363(M+H)。
EXAMPLE 70 preparation of N- (3-cyanophenyl) -N- (1- (4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) ethyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 70C where appropriate: (0.5mg, 1.0. mu. mol, 1% yield). 1H NMR(400MHz,DMSO-d6)δ7.97-7.85(m,2H),7.67(t,J＝5.5Hz,1H),3.18(br d,J＝5.5Hz,1H),4.80-4.70(m,1H),2.10-2.03(m,1H),1.88-1.66(m,12H),1.58-1.40(m,6H),1.06-0.91(m,5H),0.88-0.80(m,2H)。FXR EC50(nM)＝2000。MS(ESI)475(M+H)。
Example 72
N- (3-cyanophenyl) -N- ((4- (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
Step A. preparation of intermediate 72A.4- (chlorocarbonyl) bicyclo [2.2.2] octane-1-carboxylic acid methyl ester
Reacting 4- (methoxycarbonyl) bicyclo [2.2.2]Octane-1-carboxylic acid (2g) in SOCl2The solution in (15mL) was heated at reflux for 2 h. The progress of the reaction mixture was monitored by TLC (a small amount of the reaction mixture was quenched with MeOH and checked by TLC). After TLC showed the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude material was co-distilled twice with DCM and dried in vacuo to give the title compound as an off-white solid (1.8g, 7.80mmol), which was used in the next step without further purification.
Step B. preparation of intermediate 72B.4- (3-cyclopropyl-3-oxopropanoyl) bicyclo [2.2.2] octane-1-carboxylic acid methyl ester
To a stirred solution of 1M LiHMDS in THF (9.10mL, 9.10mmol) at-78 deg.C was added 1-cyclopropylethan-1-one (0.38g, 4.55 mmol). The reaction mixture was stirred at-78 ℃ for 45 min. A solution of intermediate 72A (1g, 4.33mmol) in tetrahydrofuran (10mL) was added to the reaction mixture at-78 ℃ and stirred for 1 h. The reaction mixture was allowed to warm to 0 ℃, quenched with saturated aqueous ammonium chloride (10mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine solution (20mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (24g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 30% B; flow rate ═ 24 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound as an oily liquid (800mg, 2.73mmol, 63% yield). MS (ESI)279(M + H).
Step C. preparation of intermediates 72C1 and 72C2.4- (5-cyclopropyl-1-methyl-1H-pyrazol-3-yl) bicyclo [2.2.2] octane-1-carboxylic acid methyl ester and 4- (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) bicyclo [2.2.2] octane-1-carboxylic acid methyl ester
To a stirred solution of intermediate 72B (800mg, 2.87mmol) in methanol (10mL) was added methylhydrazine sulfate (1g, 7.19mmol) at room temperature. The reaction mixture was heated to 80 ℃ and stirred overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (30mL) and extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with brine solution (20mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (24g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 30% B; flow rate ═ 24 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound as a mixture of regioisomers. Regioisomers were separated by preparative HPLC to give the first eluting isomer (RT ═ 4.31min, peak 1), intermediate 72C1(270mg, 0.89mmol, 30% yield),1H NMR(400MHz,DMSO-d6) δ 5.65(s,1H),3.71(s,3H),3.57(s,3H),1.69-1.81(m,13H),0.88-0.91(m,2H),0.52-0.57(m, 2H); and the second eluting isomer (RT ═ 4.90min, peak 2), intermediate 72C2(320mg, 1.054mmol, 37% yield), 1H NMR(400MHz,DMSO-d6)δ5.67(s,1H),3.76(s,3H),3.59(s,3H),1.75-1.83(m,12H),1.69-1.74(m,1H),0.73-0.78(m,2H),0.56-0.57(m,2H)。MS(ESI)289(M+H)。
Step D. preparation of intermediate 72D (4- (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) bicyclo [2.2.2] oct-1-yl) methanol
The title compound was prepared according to the procedure described for the synthesis of intermediate 1E, substituting intermediate 72C2 where appropriate. (120mg, 0.44mmol, 42% yield) as a pale yellow oil.1H NMR(400MHz,DMSO-d6)δ5.65(s,1H),3.75(s,3H),3.05(s,2H),1.68-1.79(m,7H),1.35-1.44(m,6H),0.72-0.78(m,2H),0.50-0.56(m,2H)。
Step E preparation of intermediate 72E.4- (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) bicyclo [2.2.2] octane-1-carbaldehyde
The title compound was prepared according to the procedure described for the synthesis of intermediate 1F by substituting intermediate 72D where appropriate. (90mg, 0.35mmol, 76% yield) as an off-white solid.1HNMR(400MHz,DMSO-d6)δ9.45(s,1H),5.69(s,1H),3.77(s,3H),1.68-1.79(m,7H),1.55-1.61(m,6H),0.73-0.79(m,2H),0.53-0.58(m,2H)。
Step F. preparation of intermediate 72F.3- (((4- (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) amino) benzonitrile
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G by substituting intermediate 72E and 3-aminobenzonitrile where appropriate: (70mg, 0.184mmol, 79% yield). HNMR (400MHz, DMSO-d)6)δ7.24-7.17(m,1H),6.97-6.89(m,2H),6.87-6.81(m,1H),6.01(t,J＝5.8Hz,1H),3.76(s,3H),2.83(d,J＝6.0Hz,2H),1.86-1.76(m,6H),1.72(tt,J＝8.5,5.0Hz,1H),1.59-1.49(m,6H),0.80-0.72(m,2H),0.58-0.52(m,2H)。MS(ESI)361(M+H)。
Step G. example 72 preparation of N- (3-cyanophenyl) -N- ((4- (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 72F where appropriate: (12mg, 0.025mmol, 61% yield). 1H NMR(400MHz,DMSO-d6)δ8.04(s,1H),7.87(d,J＝7.8Hz,1H),7.79(td,J＝1.0,8.0Hz,1H),7.70-7.61(m,1H),5.64(s,1H),3.73(s,5H),1.96-1.77(m,6H),1.76-1.63(m,7H),1.47-1.31(m,6H),0.80-0.72(m,2H),0.59-0.50(m,2H)。FXR EC50(nM)＝993。MS(ESI)473(M+H)。
The following examples were prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 72F and the corresponding acid where appropriate:
example 76
(1S,3S) -N- ((4- (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-N- (3- (methylsulfonyl) phenyl) -3- (trifluoromethyl) cyclobutane-1-carboxamide
Step A. intermediate 76A. preparation of N- ((4- (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- (methylsulfonyl) aniline
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G by substituting intermediate 72E and 3- (methylsulfonyl) aniline where appropriate: (20mg, crude). MS (ESI)414(M + H).
Step b. example 76 preparation of (1s,3s) -N- ((4- (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-N- (3- (methylsulfonyl) phenyl) -3- (trifluoromethyl) cyclobutane-1-carboxamide
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 76A where appropriate: (17mg, 0.03mmol, 59% yield).1H NMR(400MHz,DMSO-d6)δ7.95(s,1H),7.88(d,J＝7.8Hz,1H),7.83-7.77(m,1H),7.75-7.68(m,1H),6.57(s,1H),5.62(s,1H),3.72(s,3H),3.68-3.59(m,2H),3.27(s,3H),2.78-2.68(m,1H),2.38-2.26(m,2H),2.10-1.98(m,2H),1.79-1.60(m,7H),1.45-1.29(m,6H),0.78-0.70(m,2H),0.57-0.48(m,2H)。FXR EC50(nM)＝4000。MS(ESI)580(M+H)。
Example 77
N- ((4- (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -4, 4-difluoro-N- (3- (methylsulfonyl) phenyl) cyclohexane-1-carboxamide
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 76A where appropriate: (4mg, 7.15. mu. mol, 15% yield).1H NMR(400MHz,DMSO-d6)δ8.02-7.94(m,1H),7.92-7.86(m,1H),7.85-7.79(m,1H),7.77-7.68(m,1H),5.62(s,1H),3.72(s,3H),3.61(br s,2H),3.30(s,3H),2.58-2.53(m,5H),2.31-2.23(m,1H),2.03-1.89(m,2H),1.78-1.44(m,8H),1.36(br dd,J＝7.2,8.4Hz,6H),0.79-0.68(m,2H),0.58-0.48(m,2H)。FXR EC50(nM)＝4000。MS(ESI)560(M+H)。
Example 78
N- ((4- (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3- (methylsulfonyl) phenyl) bicyclo [1.1.1] pentane-1-carboxamide
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 76A where appropriate: (11mg, 0.019mmol, 40% yield).1H NMR(400MHz,DMSO-d6)δ8.02-7.88(m,2H),7.83-7.78(m,1H),7.75(d,J＝7.6Hz,1H),5.62(s,1H),3.72(s,3H),3.63-3.48(m,2H),3.31(s,3H),1.94-1.79(m,6H),1.77-1.63(m,7H),1.47-1.34(m,6H),0.77-0.69(m,2H),0.57-0.49(m,2H)。FXR EC50(nM)＝4000。MS(ESI)526(M+H)。
Example 79
2- (3- (N- ((4- (3-chloro-4- (dimethylamino) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenoxy) acetic acid methyl ester
Step A. preparation of intermediate 79 A.4-bromobicyclo [2.2.2] octane-1-carboxylic acid methyl ester
To 4- (methoxycarbonyl) bicyclo [2.2.2] at room temperature]Octane-1-carboxylic acid (1g, 4.71mmol) in CH2Br2To a stirred solution (10mL) was added mercuric oxide (1.73g, 8.01 mmol). The reaction mixture was heated to 80 ℃ and Br was added2(0.36mL, 7.07mmol) was added dropwise to the reaction mixture and stirring was continued for 3 h. The reaction mixture was cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give the title compound (b) 1g, 4.05mmol, 86% yield). This compound was used in the next step without further purification.1H NMR(300MHz,DMSO-d6)δ3.56(s,3H),2.25-2.15(m,6H),1.94-1.85(m,6H)。
Step B. preparation of intermediate 79 B.4-phenylbicyclo [2.2.2] octane-1-carboxylic acid methyl ester
Benzene (12mL, 142mmol) was cooled to-10 ℃ and aluminum chloride (2.70g, 20.23mmol) was added under a nitrogen atmosphere. The solution was stirred at-10 ℃ for 5min, and a solution of intermediate 79A (1g, 4.0mmol) in benzene (12mL) was added. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. The reaction mixture was poured into crushed ice and diluted with water (50 mL). The organic layer was separated, washed with water (2 × 10mL), over MgSO4Dried and concentrated under reduced pressure to give the title compound (0.82g, 2.10mmol, 52% yield). This compound was used in the next step without further purification.1H NMR (300MHz, chloroform-d) δ 7.34-7.30(m,4H),7.21(dt, J ═ 5.8,2.6Hz,1H),3.73(s,3H),1.99-1.84(m, 12H). MS (ESI)445(M + H).
Step C. preparation of intermediate 79C.4- (4-bromophenyl) bicyclo [2.2.2] octane-1-carboxylic acid methyl ester
A solution of intermediate 79B (0.8g, 3.27mmol) and silver trifluoroacetate (0.86g, 3.93mmol) was stirred at room temperature under a nitrogen atmosphere for 5 min. Adding Br2(0.17mL, 3.27mmol) in CHCl 3The solution in (40mL) was added to the reaction mixture and stirred for 2 h. The reaction mixture was filtered through a pad of celite, and the filtrate was evaporated under reduced pressure. The residue was triturated with n-hexane and dried under vacuum to give the title compound (0.74g, 1.58mmol, 48% yield).1H NMR (300MHz, chloroform-d) δ 7.43(d, J ═ 8.7Hz,2H),7.20(d, J ═ 8.7Hz,2H),3.69(s,3H),1.99-1.78(m, 12H). MS (ESI)323(M+H)。
Step D. preparation of intermediate 79D. (4- (4-bromophenyl) bicyclo [2.2.2] oct-1-yl) methanol
A solution of intermediate 79C (0.65g, 2.011mmol) in DCM (5mL) was cooled to-78 deg.C and DIBAL-H (4.0mL, 4.02mmol) was added to the reaction mixture. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was poured into crushed ice and diluted with water (10 mL). The aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (24g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 40% B; flow rate ═ 30 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound (0.59g, 1.9mmol, 99% yield). 1H NMR(300MHz,DMSO-d6)δ7.44(d,J＝8.7Hz,2H),7.28(d,J＝8.7Hz,2H),4.35(t,J＝5.3Hz,1H),3.08(d,J＝5.3Hz,2H),1.78-1.66(m,6H),1.51-1.39(m,6H)。
Step E. preparation of intermediate 79E. (4- (4- (dimethylamino) phenyl) bicyclo [2.2.2] oct-1-yl) methanol
To a stirred solution of intermediate 79D (200mg, 0.677mmol) in toluene (5mL) was added dimethylamine (10mL, 10.16mmol), 2-di-tert-butylphosphino-2 ',4',6' -triisopropylbiphenyl (28mg, 0.068mmol), and sodium tert-butoxide (195mg, 2.032mmol) at room temperature. The reaction mixture was degassed and backfilled with argon three times, and Pd was added2(dba)3(31.0mg, 0.034mmol) was added to the reaction mixture and the vial was sealed (pressure release vial). The reaction mixture was heated to 80 ℃ and stirred for 4 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (10mL) and extracted with ethyl acetate (2 × 10 mL). Will mergeThe organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (4g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 20% B; flow rate ═ 30 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound as a white solid (130mg, 0.501mmol, 74% yield).1H NMR(400MHz,DMSO-d6)δ7.11(dd,J＝2.00,6.80Hz,2H),6.64(dd,J＝2.00,6.80Hz,2H),4.31(t,J＝5.60Hz,1H),3.07(d,J＝5.60Hz,2H),2.77(s,6H),1.66-1.72(m,6H),1.40-1.43(m,6H)。
Step F. preparation of intermediate 79F.4- (3-chloro-4- (dimethylamino) phenyl) bicyclo [2.2.2] octane-1-carbaldehyde
To a stirred solution of oxalyl chloride (0.053mL, 0.601mmol) in anhydrous DCM (1.5mL) was added a solution of DMSO (0.10mL, 1.50mmol) in anhydrous DCM (1.5mL) under a nitrogen atmosphere at-78 ℃. The reaction mixture was stirred at-78 ℃ for 15 min. A solution of intermediate 79E (0.13g, 0.50mmol) in DCM (2.5mL) was added to the reaction mixture over a period of 10 min. The reaction mixture was stirred at-78 ℃ for 3 h. TEA (0.42mL, 3.01mmol) was added to the reaction and stirring was continued for an additional 5 min. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was diluted with DCM (10mL), washed with water (2 × 20mL), brine solution (2 × 10mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a colorless gummy liquid (0.11g, 0.28mmol, 57% yield). MS (ESI)292(M + H).
Step G. preparation of intermediate 79G.2- (3-nitrophenoxy) methyl acetate
To a stirred solution of 3-nitrophenol (2g, 14.38mmol) in acetone (40mL) was added K at room temperature2CO3(3.97g，28.8mmol)，Methyl 2-bromoacetate (3.30g, 21.57mmol) was then added. The reaction mixture was heated to 60 ℃ and stirred for 7 h. The reaction mixture was diluted with ethyl acetate (50mL) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure and the crude material was purified by flash chromatography (40g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 20% B; flow rate ═ 30 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound as a white solid (3g, 14.21mmol, 99% yield). MS (ESI)229(M +18, NH) 3An adduct).
Step H. preparation of intermediate 79H.2- (3-aminophenoxy) methyl acetate
A stirred solution of intermediate 79G (1G, 4.74mmol) in methanol (15mL) was degassed and backfilled with argon and 10% Pd/C (150mg, 0.141mmol) was added. The resulting solution was stirred under hydrogen atmosphere (balloon pressure, 1atm) overnight. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to give the title compound as a colorless gummy liquid (0.8g, 4.42mmol, 93% yield). MS (ESI)189(M + H).
Step I. preparation of intermediate 79I.2- (3- (((4- (3-chloro-4- (dimethylamino) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) amino) phenoxy) acetic acid methyl ester
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G by substituting intermediate 79D and intermediate 79H. (120mg, 0.20mmol, 59% yield) as a yellow liquid. MS (ESI)457(M + H).
EXAMPLE 79 preparation of methyl 2- (3- (N- ((4- (3-chloro-4- (dimethylamino) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acetate
To intermediate 79I (0.12g, 0.263mmol) at 0 deg.CTo a stirred solution of DCM (5mL) was added TEA (0.146mL, 1.050mmol) followed by cyclohexanecarbonyl chloride (0.05mL, 0.39 mmol). After stirring at room temperature for 2h, the reaction mixture was diluted with DCM (20 mL). The organic solution was washed with water (10mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via preparative LC/MS using the following conditions: column: waters XBridge C18, 19x150mm, 5 μm particles; mobile phase A: 10mM ammonium acetate; mobile phase B: acetonitrile; gradient: 10% -45% B over 25 minutes, then held at 100% B for 5 minutes; flow rate: 15 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to obtain the title compound (23mg, 0.04mmol, 15% yield). 1H NMR(400MHz,DMSO-d6)δ7.34(t,J＝8.0Hz,1H),7.21(d,J＝2.0Hz,1H),7.19-7.11(m,1H),7.04(d,J＝8.5Hz,1H),7.00-6.83(m,3H),4.86(s,2H),3.69(s,3H),3.54(s,2H),2.71-2.61(m,6H),1.73-1.54(m,10H),1.49(br.s.,1H),1.43-1.18(m,8H),1.09(d,J＝12.5Hz,1H),0.90(d,J＝13.1Hz,2H)。FXR EC50(nM)＝1,044。MS(ESI)567(M+H)。
Example 80
2- (3- (N- ((4- (4- (dimethylamino) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenoxy) acetic acid methyl ester
A stirred solution of example 79(30mg, 0.053mmol) in methanol (10mL) was degassed and backfilled with nitrogen and 10% Pd/C (10mg, 0.094mmol) was added. The resulting solution was stirred under hydrogen atmosphere (balloon pressure, 1atm) overnight. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The crude material was purified via preparative LC/MS using the following conditions: (column: Waters Xbridge C18, 19X150mM, 5 μm particles; mobile phase A: 10mM ammonium acetate; mobile phase B: acetonitrile; gradient: 40% -80% B over 20 minutes and then held at 100% B for 5 minutes; flow rate: 20 mL/min). The fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound as an off-white solid (6mg, 0.011mmol,21% yield).1H NMR(400MHz,DMSO-d6)δ7.34(t,J＝7.9Hz,1H),7.06(d,J＝9.0Hz,2H),7.00-6.80(m,3H),6.62(d,J＝8.8Hz,2H),3.69(s,3H),3.53(s,2H),2.87-2.77(m,6H),2.23(br.s.,1H),1.71-1.54(m,10H),1.49(br.s.,1H),1.43-1.19(m,8H),1.15-1.02(m,1H),0.90(d,J＝11.7Hz,2H)。FXR EC50(nM)1,597；MS(ESI)533(M+H)。
Example 81
2- (3- (N- ((1- (1-methyl-1H-indazol-5-yl) -2-oxabicyclo [2.2.2] oct-4-yl) methyl) tetrahydro-2H-pyran-4-carboxamido) phenoxy) acetic acid methyl ester
Step a. preparation of intermediates 81a1 and 81a2 (5-bromo-1-methyl-1H-indazole and 5-bromo-2-methyl-2H-indazole)
To a stirred solution of 5-bromo-1H-indazole (2g, 10.15mmol) in DMSO (20mL) was added methyl iodide (0.82mL, 13.20mmol) at room temperature, followed by potassium carbonate (7.0g, 50.8 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (50mL) and the aqueous solution was extracted with EtOAc (3 × 50). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (40g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 40% B; flow rate ═ 30 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to afford intermediate 81a1(1.2g, 5.40mmol, 53% yield) as a white solid and intermediate 81a2(0.6g, 2.70mmol, 27% yield) as an off-white solid. The desired compound was confirmed by NOE studies. MS (ESI)213(M + H).
Step B. preparation of intermediate 81 B.5-iodo-1-methyl-1H-indazole
To a solution of intermediate 81a1(1g, 4.74mmol) in 1, 4-dioxane (5mL) was added sodium iodide (1.42g, 9.48mmol), copper (I) iodide (0.05g, 0.237mmol) and (1r,2r) -N, N' -dimethyl-1, 2-cyclohexanediamine (0.07g, 0.474mmol) at room temperature under an argon atmosphere. The reaction mixture was heated to 110 ℃ and stirred overnight. The reaction mixture was cooled to room temperature and diluted with water (30 mL). The aqueous solution was extracted with DCM (3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (24g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 30% B; flow rate ═ 30 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound as an off-white crystalline solid (1g, 3.60mmol, 76% yield). MS (ESI)259(M + H).
Step C. preparation of intermediate 81C (4-hydroxy-4- (1-methyl-1H-indazol-5-yl) cyclohexane-1, 1-diyl) bis (methylene) bis (4-methylbenzenesulfonate)
A stirred solution of intermediate 81B (0.3g, 1.163mmol) in tetrahydrofuran (5mL) was cooled to-78 ℃ and n-BuLi (0.93mL, 2.33mmol) in hexane was added dropwise to the reaction mixture. The reaction mixture was stirred at-78 ℃ for 1 h. A solution of (4-oxocyclohexane-1, 1-diyl) bis (methylene) bis (4-methylbenzenesulfonate) (cf. ACS Med. chem. Lett.,5(5), 609-614; 2014) (0.70g, 1.511mmol) in 2mL of anhydrous THF was added to the reaction. The reaction mixture was allowed to warm to room temperature over 1 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (10mL) and the aqueous solution was extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (24g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 100% B; flow rate ═ 30 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound as an off-white solid (0.25g, 0.4mmol, 34% yield). MS (ESI)599(M + H).
Step D. preparation of intermediate 81D (1- (1-methyl-1H-indazol-5-yl) -2-oxabicyclo [2.2.2] oct-4-yl) methyl 4-methylbenzenesulfonate
To a stirred solution of intermediate 81C (0.25g, 0.418mmol) in dry 1, 2-dimethoxyethane (10mL) was added sodium hydride (0.050g, 1.253mmol) at 0 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at 0 ℃ for 30min and then heated at reflux for 12 h. The reaction mixture was cooled to 0 ℃, quenched with saturated aqueous ammonium chloride (5mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (24g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 50% B; flow rate ═ 30 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound as a white solid (0.18g, 0.401mmol, 96% yield). MS (ESI)427(M + H).
Step E. preparation of intermediate 81e. (1- (1-methyl-1H-indazol-5-yl) -2-oxabicyclo [2.2.2] oct-4-yl) methyl acetate
To a solution of intermediate 81D (2.5g, 5.86mmol) in DMF (30mL) was added sodium acetate (2.88g, 35.2mmol) in pressure tube. The reaction mixture was heated to 120 ℃ and stirred overnight. The reaction mixture was cooled to room temperature and diluted with water (50 mL). The aqueous solution was extracted with EtOAc (2 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by flash chromatography (40g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 50% B; flow rate ═ 30 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound as an off-white solid (0.6g, 1.813mmol, 31% yield). MS (ESI)315(M + H).
Step F. preparation of intermediate 81F (1- (1-methyl-1H-indazol-5-yl) -2-oxabicyclo [2.2.2] oct-4-yl) methanol
To a stirred solution of intermediate 81E (0.6g, 1.909mmol) in methanol (10mL) at 0 ℃ was added a solution of potassium carbonate (1.32g, 9.54mmol) in water (15 mL). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The solvent was removed under reduced pressure, and the residue was diluted with water (15 mL). The aqueous solution was extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a white solid (0.45g, 1.57mmol, 82% yield). MS (ESI)273(M + H).
Step G. preparation of intermediate 81G.1- (1-methyl-1H-indazol-5-yl) -2-oxabicyclo [2.2.2] octane-4-carbaldehyde
To a stirred solution of intermediate 81F (0.4g, 1.47mmol) in dichloromethane (2mL) was added dessimutane oxidant (0.748g, 1.76mmol) at 0 ℃. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was diluted with DCM (30mL) and the organic solution was washed with water (10mL) and 10% aqueous sodium bicarbonate solution (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (24g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 30% B; flow rate ═ 30 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound as a semi-solid (0.4g, 1.40mmol, 96% yield). 1H NMR(400MHz,DMSO-d6)δ9.53(s,1H),7.98(s,1H),7.87(d,J＝7.5Hz,1H),7.74-7.71(m,1H),7.57-7.53(m,1H),4.03(s,2H),4.01(s,3H),2.23-2.12(m,2H),2.01-1.85(m,6H)。
Step H. preparation of intermediate 81h.2- (3- (((1- (1-methyl-1H-indazol-5-yl) -2-oxabicyclo [2.2.2] oct-4-yl) methyl) amino) phenoxy) acetic acid methyl ester
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G, by substituting intermediate 81G and intermediate 79H where appropriate. (0.19g, 0.41mmol, 56% yield) as a pale yellow solid. MS (ESI)436(M + H).
EXAMPLE 81 preparation of methyl 2- (3- (N- ((1- (1-methyl-1H-indazol-5-yl) -2-oxabicyclo [2.2.2] oct-4-yl) methyl) tetrahydro-2H-pyran-4-carboxamido) phenoxy) acetate
The title compound was prepared according to the procedure described for the synthesis of example 79 (step J) by substituting intermediate 81H and the corresponding acid where appropriate. (8mg, 0.013mmol, 22% yield).1H NMR(400MHz,DMSO-d6)δ7.94(s,1H),7.65(s,1H),7.50(d,J＝8.8Hz,1H),7.44-7.30(m,2H),7.10-6.98(m,2H),6.95(d,J＝7.1Hz,1H),4.88(s,2H),3.99(s,3H),3.76(d,J＝8.1Hz,2H),3.70-3.64(m,6H),3.59(s,2H),3.02(t,J＝11.7Hz,2H),2.11-1.95(m,2H),1.90-1.74(m,2H),1.70-1.49(m,6H),1.44(d,J＝13.2Hz,2H)。FXR EC50(nM)4355；MS(ESI)548(M+H)。
Example 82
3- (N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamide) -N- (thiazol-2-yl) benzamide
Step A. preparation of intermediate 82 A.3-nitro-N- (thiazol-2-yl) benzamide
To a stirred solution of thiazol-2-amine (0.27g, 2.69mmol) in dichloromethane (10mL) at 0 deg.C was added TEA (1.12mL, 8.08mmol) followed by 3-nitrobenzoyl chloride (0.5g, 2.69 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with EtOAc (30 mL). The organic solution was washed with water (20mL), brine solution (10mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as an off-white solid (0.35g, 1.334mmol, 49% yield). MS (ESI)250(M + H).
Step B. preparation of intermediate 82 B.3-amino-N- (thiazol-2-yl) benzamide
To a stirred solution of intermediate 82A (0.35g, 1.40mmol) in ethanol (10mL) was added tin (II) chloride (1.06g, 5.62mmol) at room temperature. The reaction mixture was heated to 90 ℃ and stirred for 12 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude material was dissolved in EtOAc (20mL) and the resulting solution was taken up with 10% NaHCO3Aqueous (10mL) and saline (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (12g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 60% B; flow rate ═ 30 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound as an off-white solid (0.15g, 0.616mmol, 43% yield). MS (ESI)220(M + H).
Step C. preparation of intermediate 82C.4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] octane-1-carboxylic acid methyl ester
To 4- (methoxycarbonyl) bicyclo [2.2.2] at room temperature](E) -N' -Hydroxyacetimide was added to a stirred solution of octane-1-carboxylic acid (2g, 9.42mmol) in DMF (20mL)Amide (1.4g, 18.85mmol), BOP (4.17g, 9.42mmol) and TEA (4mL, 28.3 mmol). The reaction mixture was stirred at room temperature for 2h and heated at 110 ℃ overnight. The reaction mixture was cooled to room temperature, diluted with water (50mL) and extracted with EtOAc (2 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (40g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 40% B; flow rate ═ 30 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound as a white solid (0.6g, 2.27mmol, 24% yield). 1H NMR(400MHz,DMSO-d6)δ3.60(s,3H),2.29(s,3H),1.95-1.86(m,6H),1.86-1.78(m,6H)。
Step D. preparation of intermediate 82D.4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] octane-1-carboxylic acid methyl ester
To a stirred solution of intermediate 82C (0.6g, 2.397mmol) in tetrahydrofuran (20mL) at-78 deg.C under a nitrogen atmosphere was added DIBAL-H (6mL, 5.99 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was cooled to 0 ℃, quenched with 1.5N aqueous HCl (30mL) and extracted with EtOAc (2 × 25 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (24g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 30% B; flow rate ═ 30 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound as an off-white solid (0.58g, 2.35mmol, 98% yield).1H NMR(400MHz,DMSO-d6)δ4.41(br.s.,1H),3.08(s,2H),2.29(s,3H),1.90-1.80(m,6H),1.50-1.40(m,6H)。
Step E. preparation of intermediate 82E.4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] octane-1-carbaldehyde
To a stirred solution of intermediate 82D (0.58g, 2.61mmol) in dichloromethane (10mL) at 0 ℃ under a nitrogen atmosphere was added dessimutane oxidant (2.2g, 5.22 mmol). The reaction mixture was stirred at 0 ℃ for 1 h. The reaction mixture was allowed to warm to room temperature, diluted with DCM (20mL) and filtered through celite. The filtrate was washed with 10% aqueous sodium bicarbonate (2 × 20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (24g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 30% B; flow rate ═ 30 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound as a white solid (0.46g, 1.98mmol, 76% yield). 1H NMR(400MHz,DMSO-d6)δ9.46(s,1H),2.30(s,3H),1.96-1.84(m,6H),1.73-1.66(m,6H)。
Step C. preparation of intermediate 82C.3- (((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) amino) -N- (thiazol-2-yl) benzamide
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G, by substituting intermediate 82B and intermediate 82E where appropriate. (40mg, 0.09mmol, 39% yield) as a pale yellow solid. MS (ESI)424(M + H).
EXAMPLE D.preparation of 3- (N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamide) -N- (thiazol-2-yl) benzamide
The title compound was prepared according to the procedure described for the synthesis of example 79 (step J) by substituting intermediate 82C and cyclohexanecarbonyl chloride. (32mg, 0.06mmol, 72% yield).1H NMR(400MHz,DMSO-d6)δ12.68(s,1H),8.15(s,1H),8.06(d,J＝7.6Hz,1H),7.73-7.66(m,1H),7.66-7.51(m,2H),7.31(d,J＝3.7Hz,1H),3.67(br.s.,2H),2.27(s,3H),2.21(br.s.,1H),1.88-1.73(m,6H),1.61(br.s.,4H),1.49(br.s.,1H),1.46-1.27(m,8H),1.10(d,J＝13.2Hz,1H),0.90(br.s.,2H)。FXR EC50(nM)＝3011；MS(ESI)534(M+H)。
Example 83
N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- ((4-ethoxyphenyl) amino) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
Step a. intermediate 83A: preparation of N- (3-bromophenyl) -N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
The title compound was synthesized according to the procedure described for the synthesis of intermediate 1D by substituting intermediate 33E and (Z) -N' -hydroxypivalimide amide where appropriate. (200mg, 0.377mmol, 68% yield) as a brown gummy solid. MS (ESI)530(M + H).
Step b. example 83: preparation of N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- ((4-ethoxyphenyl) amino) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
To a stirred solution of intermediate 83A (30mg, 0.057mmol) in 1, 4-dioxane (2mL) was added 4-ethoxyaniline (8mg, 0.057mmol), cesium carbonate (46mg, 0.141mmol) and Xantphos (4mg, 5.66 μmol) at room temperature. The reaction mixture was degassed and backfilled with argon three times, and bis (dibenzylideneacetone) palladium (2mg, 2.83 μmol) was added. The reaction vial was sealed. The reaction mixture was heated to 110 ℃ and stirred overnight. The reaction mixture was concentrated under reduced pressure to give a residue. The crude material was purified via preparative LC/MS using the following conditions: column: waters XBridge C18, 150mm x 19mm, 5 μm particles; mobile phase A: 5:95 acetonitrile, water containing 10mM ammonium acetate; mobile phase B: 95:5 acetonitrile containing 10mM EtherWater with ammonium salt; gradient: hold at 40% B for 0 min, 40% -84% B over 20 min, then hold at 100% B for 5 min; flow rate: 15 mL/min; column temperature: at 25 ℃. The collection of fractions was triggered by an MS signal. The product-containing fractions were combined and dried via centrifugal evaporation to obtain the title compound (12mg, 0.019mmol, 34% yield). 1H NMR(400MHz,DMSO-d6)δ8.01(s,1H),7.22(t,J＝7.9Hz,1H),7.05(d,J＝8.8Hz,2H),6.96-6.80(m,3H),6.79-6.70(m,1H),6.67(d,J＝7.6Hz,1H),3.99(q,J＝6.9Hz,2H),3.49(d,J＝4.9Hz,2H),1.90(s,6H),1.87-1.67(m,6H),1.55-1.37(m,6H),1.35-1.17(m,12H)；FXR EC50(nM)＝1131；MS(ESI)587(M+H)。
Example 84
N- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- ((4- (difluoromethoxy) phenyl) amino) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
Step a. intermediate 84A: preparation of N- (3-bromophenyl) -N- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
The title compound was synthesized according to the procedure described for the synthesis of intermediate 1D by substituting intermediate 33H and the corresponding acid where appropriate. (190mg, 0.358mmol, 83% yield) as a pale yellow solid. MS (ESI)530(M + H).
Step B. intermediate 84B: preparation of N- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- ((4- (difluoromethoxy) phenyl) amino) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
Following the procedure described for the synthesis of example 83 (step B), by substituting intermediates 84A and 84B where appropriate4- (difluoromethoxy) aniline to synthesize the title compound. (0.4mg, 0.61. mu. mol, 2% yield).1H NMR(400MHz,DMSO-d6)δ8.37(s,1H),7.34-6.86(m,8H),6.80(d,J＝7.8Hz,1H),3.63-3.40(m,2H),1.91(br.s.,6H),1.82-1.70(m,6H),1.55-1.39(m,6H),1.34(s,9H)；FXR EC50(nM)＝84；MS(ESI)609(M+H)。
The following examples were synthesized according to the procedure described for the synthesis of example 83, by substituting intermediate 84A and the corresponding aryl/heteroaryl amine where appropriate.
Example 89
3- (3- (N- ((4- (4- (dimethylamino) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) propionic acid methyl ester
Step A. preparation of intermediate 89A.4- (4-bromophenyl) bicyclo [2.2.2] octane-1-carbaldehyde
To a stirred solution of oxalyl chloride (0.12mL, 1.219mmol) in anhydrous DCM (3mL) was added dropwise a solution of DMSO (0.21mL, 3.05mmol) in anhydrous DCM (2.5mL) under a nitrogen atmosphere at-78 ℃. The reaction mixture was stirred at-78 ℃ for 15 min. Dissolution of intermediate 79D (0.3g, 1.016mmol) in DCM (5mL)The solution was added to the reaction mixture over a period of 10 min. The reaction mixture was stirred at-78 ℃ for a further 3 h. Adding Et3N (0.85mL, 6.10mmol) was added to the reaction and stirring was continued at-78 deg.C for an additional 5 min. The reaction mixture was allowed to warm to 0 ℃ and stirred for 1 h. The reaction mixture was diluted with DCM (10mL) and poured onto crashed ice. The organic layer was separated and the aqueous layer was extracted with DCM (2 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (220mg, 0.75mmol, 74% yield).1H NMR (300MHz, chloroform-d) δ 9.53(s,1H),7.44(d, J ═ 8.7Hz,2H),7.20(d, J ═ 8.7Hz,2H),1.95-1.73(m, 12H).
Step B. preparation of intermediate 89B. (E) -methyl 3- (3-nitrophenyl) acrylate
To a stirred solution of methyl 2- (dimethoxyphosphoryl) acetate (1.3mL, 7.94mmol) in water (6mL) at room temperature was added K2CO3(1.82g, 13.23mmol) followed by the addition of 3-nitrobenzaldehyde (1g, 6.62 mmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with water (10mL) and extracted with EtOAc (2 × 25 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (1g, 4.83mmol, 73% yield).1H NMR(300MHz,DMSO-d6)δ8.56(t,J＝1.7Hz,1H),8.27-8.18(m,2H),7.81(d,J＝16.2Hz,1H),7.71(t,J＝8.1Hz,1H),6.87(d,J＝16.2Hz,1H),3.75(s,3H)。
Step C. preparation of intermediate 89℃ methyl (E) -3- (3-aminophenyl) acrylate
To a stirred solution of intermediate 89B (1.300g, 6.27mmol) in water (15mL) was added tin (II) chloride dihydrate (8.50g, 37.6mmol) at room temperature. The reaction mixture was heated at 80 ℃ for 3 h. Allowing the oppositeThe mixture was allowed to warm to room temperature. The reaction volume was reduced to half under reduced pressure and the remaining solution was poured onto crushed ice. The aqueous solution was saturated with Na2CO3The aqueous solution was neutralized (pH-7) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a pale yellow solid (1g, 3.84mmol, 61% yield). 1H NMR(400MHz,DMSO-d6)δ7.49(d,J＝15.6Hz,1H),7.12-7.01(m,1H),6.87-6.77(m,2H),6.67-6.59(m,1H),6.41(d,J＝16.1Hz,1H),5.18(s,2H),3.71(s,3H)。MS(ESI)178(M+H)。
Step D. preparation of intermediate 89D. (E) -methyl 3- (3- (((4- (4-bromophenyl) bicyclo [2.2.2] oct-1-yl) methyl) amino) phenyl) acrylate
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G, by substituting intermediate 89C and intermediate 89A where appropriate. (100mg, 0.178mmol, 35% yield).1HNMR(400MHz,DMSO-d6)δ7.53(d,J＝16.1Hz,1H),7.46(d,J＝8.00Hz,2H),7.30(d,J＝8.00Hz,2H),7.09(t,J＝7.8Hz,1H),6.89(s,1H),6.85-6.79(m,1H),6.72(d,J＝8.3Hz,1H),6.50(d,J＝15.9Hz,1H),5.60-5.54(m,1H),3.72(s,3H),3.18(d,J＝5.4Hz,2H),1.80-1.72(m,6H),1.63-1.53(m,6H)。MS(ESI)455(M+H)。
Step E. preparation of intermediate 89E. (E) -methyl 3- (3- (N- ((4- (4-bromophenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate
The title compound was prepared according to the procedure described for the synthesis of example 79 (step J) by substituting intermediate 89D and the corresponding acid where appropriate. (120mg, 0.172mmol, 78% yield). MS (ESI)564(M + H).
Step F. intermediates 89F1 and 89F2 preparation of methyl (E) -3- (3- (N- ((4- (4- (dimethylamino) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate and (E) -3- (3- (N- ((4- (4- (dimethylamino) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylic acid
To a stirred solution of intermediate 89E (100mg, 0.177mmol) in toluene (5mL) was added dimethylamine (0.09mL, 1.771mmol), 2-di-tert-butylphosphino-2 ',4',6' -triisopropylbiphenyl (8mg, 0.018mmol), and sodium tert-butoxide (50mg, 0.53mmol) at room temperature. The reaction mixture was degassed and backfilled with argon three times, and Pd was added 2(dba)3(8mg, 8.86. mu. mol) was added to the reaction mixture, and the vial was sealed (pressure release vial). The reaction mixture was heated to 80 ℃ and stirred for 12 h. The reaction mixture was diluted with water (10mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified via preparative HPLC using the following conditions: (column: waters XBridge C18, 19x150mM, 5 μm particles; mobile phase a: 10mM ammonium acetate; mobile phase B: acetonitrile; gradient: 40% -80% B over 20 minutes and then hold at 100% B for 5 minutes; flow rate: 15 mL/min). Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (intermediate 89F1) (9mg, 0.016mmol, 9% yield);1H NMR(400MHz,DMSO-d6)δ7.79(s,1H),7.75-7.66(m,2H),7.53-7.37(m,2H),7.10-7.00(m,J＝8.8Hz,2H),6.76(d,J＝16.1Hz,1H),6.65-6.58(m,J＝8.8Hz,2H),3.74(s,3H),3.58(br.s.,2H),2.81(s,6H),1.66-1.53(m,12H),1.42-1.28(m,8H),0.86(d,J＝6.1Hz,3H)。FXR EC50(nM) 78; MS (ESI)529(M + H). Intermediate 89F2(3mg, 4.98 μmol, 3% yield);1H NMR(400MHz,DMSO-d6)δ12.44(br.s.,1H),7.74(s,1H),7.68-7.62(m,2H),7.60(s,1H),7.47(t,J＝7.8Hz,1H),7.40(d,J＝7.8Hz,1H),7.06(d,J＝9.0Hz,2H),6.61(d,J＝9.0Hz,2H),3.58(br.s.,2H),2.81(s,6H),2.20(br.s.,1H),1.65-1.54(m,8H),1.49(d,J＝12.2Hz,2H),1.41-1.33(m,7H),1.32(br.s.,1H),1.24(s,1H),1.08(d,J＝7.1Hz,1H),0.94-0.79(m,2H)。FXR EC50(nM)1517,MS(ESI)515(M+H)。
step G. preparation of intermediate 89G.3- (3- (N- ((4- (4- (dimethylamino) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) propanoic acid
A solution of intermediate 89F2(50mg, 0.097mmol) in MeOH (3mL) was degassed at room temperature and backfilled with nitrogen three times. To the above reaction was added 10% Pd-C (20mg, 0.019mmol) and the reaction mixture was stirred under hydrogen (1atm, balloon) overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give a crude product (35 mg). MS (ESI)517(M + H).
EXAMPLE 89.3 preparation of methyl 3- (3- (N- ((4- (4- (dimethylamino) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) propanoate
To a stirred solution of intermediate 89G (35mg, 0.068mmol) in DCM (2mL) was added (trimethylsilyl) diazomethane (0.07mL, 0.135mmol, 2M solution in hexane) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 4 h. The reaction was quenched by the addition of acetic acid (0.5 mL). The reaction mixture was concentrated under reduced pressure. The crude material was purified via preparative LC/MS using the following conditions: (column: Waters Xbridge C18, 19X150mM, 5 μm particles; mobile phase A: 10mM ammonium acetate; mobile phase B: acetonitrile; gradient: 10% -45% B over 20 minutes and then held at 100% B for 5 minutes; flow rate: 15 mL/min). Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (3mg, 4.33 μmol, 6% yield).1H NMR(400MHz,DMSO-d6)δ7.38-7.29(m,1H),7.25-7.13(m,3H),7.11-7.03(m,2H),6.64(d,J＝8.8Hz,2H),3.55(s,3H),3.53(s,2H),2.93-2.86(m,2H),2.82(s,6H),2.71-2.62(m,3H),2.19(t,J＝11.5Hz,1H),1.71-1.53(m,10H),1.48(br.s.,1H),1.42-1.20(m,8H),1.08(d,J＝13.2Hz,1H),0.95-0.78(m,2H)；FXR EC50(nM)1118；MS(ESI)531(M+H)。
Example 90
(1S,3S) -N- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-N- (3- (methylsulfonyl) phenyl) -3- (trifluoromethyl) cyclobutane-1-carboxamide
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 68A and the corresponding acid where appropriate: (2mg, 3.45. mu. mol, 6% yield). 1HNMR(400MHz,DMSO-d6)δ7.97-7.92(m,1H),7.89-7.85(m,1H),7.82-7.77(m,1H),7.75-7.68(m,1H),6.57-6.52(m,1H),3.67-3.63(m,2H),3.26(s,1H),2.09-1.99(m,2H),1.80-1.69(m,2H),1.42-1.34(m,6H),1.24(s,9H),1.05-0.97(m,2H),0.89-0.79(m,2H)。FXR EC50(nM)＝4000。MS(ESI)568(M+H)。
Example 91
(1S,3S) -N- (3- ((4- (1-cyanocyclopropyl) phenyl) amino) phenyl) -N- ((4- (5- (1-fluorocyclopropyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide
Step A. preparation of intermediate 91A.4- (5- (1-fluorocyclopropyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] octane-1-carboxylic acid methyl ester
The title compound was prepared according to the procedure described for the synthesis of intermediate 1D by substituting intermediate 1C and the corresponding acid where appropriate. (2.4g, 8.07mmol, 91% yield). MS (ESI)295(M + H).
Step B. preparation of intermediate 91b. (4- (5- (1-fluorocyclopropyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methanol
The title compound was prepared according to the procedure described for the synthesis of intermediate 1E by substituting intermediate 91A and the corresponding acid where appropriate. (1.6g, 6.01mmol, 80% yield). MS (ESI)267(M + H).
Step C. preparation of intermediate 91C.4- (5- (1-fluorocyclopropyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] octane-1-carbaldehyde
The title compound was prepared according to the procedure described for the synthesis of intermediate 1F by substituting intermediate 91B where appropriate. (1.6g, 6.05mmol, 77% yield) MS (ESI)265(M + H).
Step D. intermediate 91D. (preparation of tert-butyl 3- (((4- (5- (1-fluorocyclopropyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) amino) phenyl) carbamate
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G by substituting intermediate 91C and tert-butyl (3-aminophenyl) carbamate where appropriate. (350mg, 0.767mmol, 68% yield). MS (ESI)457(M + H).
Step E. preparation of intermediate 91e. (3- ((1S,3S) -N- ((4- (5- (1-fluorocyclopropyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamido) phenyl) carbamic acid tert-butyl ester
The title compound was prepared according to the procedure described for the synthesis of example 1 (step H) by substituting intermediate 91D and the corresponding acid where appropriate. (240mg, 0.366mmol, 84% yield). MS (ESI)623(M + H).
Step F. intermediate 91F preparation of (1S,3S) -N- (3-aminophenyl) -N- ((4- (5- (1-fluorocyclopropyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide
To a stirred solution of intermediate 91E (125mg, 0.201mmol) in 1, 4-dioxane (2mL) was added 4M HCl in 1, 4-dioxane (2.00mL, 8.00mmol) and stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (15 mL). The resulting solution was washed with 10% aqueous sodium bicarbonate (10mL), then aqueous saline (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a brown solid (95mg, 0.178mmol, 89% yield). MS (ESI)523(M + H).
Example 91 preparation of (1S,3S) -N- (3- ((4- (1-cyanocyclopropyl) phenyl) amino) phenyl) -N- ((4- (5- (1-fluorocyclopropyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide
The title compound was prepared according to the procedure described for the synthesis of example 102 by substituting intermediate 91F and the corresponding aryl halide where appropriate: (6.2mg, 8.87. mu. mol, 16% yield).1H NMR(400MHz,DMSO-d6)δ8.40(s,1H),7.33-7.18(m,3H),7.09-6.90(m,4H),6.82(br d,J＝8.1Hz,1H),6.53(s,1H),3.68-3.46(m,2H),2.87-2.73(m,1H),2.41-2.27(m,2H),2.22-2.05(m,2H),1.86-1.59(m,10H),1.53-1.31(m,10H)。FXR EC50(nM)＝2191。MS(ESI)664(M+H)。
Example 92
(1S,3S) -N- (3- ((4- ((2-cyanoprop-2-yl) oxy) phenyl) amino) phenyl) -N- ((4- (5- (1, 1-difluoroethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide
Step a. intermediate 92A preparation of tert-butyl (3- (((4- (5- (1, 1-difluoroethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) amino) phenyl) carbamate
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G by substituting intermediate 48D and tert-butyl (3-aminophenyl) carbamate where appropriate. (400mg, 0.831mmol, 77% yield). MS (ESI)471(M + H).
Step B. preparation of intermediate 92B. (3- ((1S,3S) -N- ((4- (5- (1, 1-difluoroethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamido) phenyl) carbamic acid tert-butyl ester
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 92A and the corresponding acid where appropriate. (250mg, 0.369mmol, 87% yield). MS (ESI)637(M + H).
Step C. preparation of intermediate 92c. (1S,3S) -N- (3-aminophenyl) -N- ((4- (5- (1, 1-difluoroethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide
The title compound was prepared according to the procedure described for the synthesis of intermediate 91F by substituting intermediate 92B where appropriate. (100mg, 0.180mmol, 96% yield) as a brown solid. MS (ESI)537(M + H).
Step D. preparation of intermediate 92D.2- (4-bromophenyloxy) -2-methylpropanenitrile
To a stirred solution of 2- (4-bromophenoxy) -2-methylpropionic acid (2.0g, 7.72mmol) and ammonium chloride (2.064g, 38.6mmol) in DCM (20mL) was added BOP (5.12g, 11.58mmol) at room temperature. The reaction mixture was cooled (0 ℃ -5 ℃) and TEA (3.23mL, 23.16mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was then diluted with water (20mL) and the aqueous solution was extracted with DCM (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was dissolved in pyridine (20mL) and the solution was cooled to 0 ℃. Trifluoroacetic anhydride (2.432g, 11.58mmol) was added to the above reaction mixture and the reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was diluted with water (30mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with 1.5N aqueous HCl (2x50mL) followed by saturated aqueous brine (2x20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (24g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 80% B; flow rate ═ 30 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound as a brown oil (750mg, 3.12mmol, 41% yield). 1H NMR(400MHz,DMSO-d6)δ7.59-7.57(m,2H),7.15-7.13(m,2H),1.69(s,6H)。
Example 92 preparation of (1S,3S) -N- (3- ((4- ((2-cyanoprop-2-yl) oxy) phenyl) amino) phenyl) -N- ((4- (5- (1, 1-difluoroethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide
The title compound was prepared according to the procedure described for the synthesis of example 102, by substituting intermediate 92C and intermediate 92D where appropriate: (11.8mg, 0.015mmol, 28% yield).1HNMR(400MHz,DMSO-d6)δ8.67(s,1H),8.29(s,1H),7.86(dd,J＝2.4,8.3Hz,1H),7.40(d,J＝8.3Hz,1H),7.28(t,J＝7.9Hz,1H),7.08(s,4H),7.02-6.97(m,1H),6.92(s,1H),6.78(d,J＝8.6Hz,1H),6.54(s,1H),3.59(s,2H),2.81(t,J＝9.0Hz,1H),2.41-2.27(m,2H),2.22-2.11(m,2H),1.99(t,J＝19.1Hz,3H),1.84-1.74(m,6H),1.67(s,6H),1.51-1.40(m,6H)。FXR EC50(nM)＝2035。MS(ESI)697(M+H)。
Example 93
(1S,3S) -N- (3- ((4- (1-cyanocyclopropyl) phenyl) amino) phenyl) -N- ((4- (5- (1, 1-difluoroethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide
The title compound was prepared according to the procedure described for the synthesis of example 102 by substituting intermediate 92C and the corresponding aryl halide where appropriate: (8.1mg, 0.011mmol, 20% yield).1H NMR(400MHz,DMSO-d6)δ8.68(s,1H),8.41(s,1H),7.86(dd,J＝2.1,8.4Hz,1H),7.40(d,J＝8.3Hz,1H),7.30(t,J＝8.1Hz,1H),7.23(d,J＝8.6Hz,2H),7.06(d,J＝8.6Hz,2H),7.01(br d,J＝8.1Hz,1H),6.97(s,1H),6.82(d,J＝7.3Hz,1H),6.53(s,1H),3.60(br s,2H),2.87-2.75(m,1H),2.40-2.28(m,2H),2.21-2.10(m,2H),1.99(t,J＝19.1Hz,3H),1.85-1.71(m,6H),1.70-1.64(m,2H),1.52-1.35(m,8H)。FXR EC50(nM)＝1419。MS(ESI)679(M+H)。
Example 94
N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (5-cyanopyridin-3-yl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
Step A. preparation of intermediate 94A.5- (((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) amino) nicotinonitrile
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G, by substituting intermediate 36C and commercially available 5-aminonicotinonitrile where appropriate: (200mg, 0.547mmol, 33% yield). MS (ESI)366(M + H).
Step B. preparation of example 94.N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (5-cyanopyridin-3-yl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
The title compound was prepared according to the method described for the synthesis of example 1 (step H) by substituting intermediate 94A where appropriate: (2mg, 4.09. mu. mol, 3% yield).1H NMR(400MHz,DMSO-d6)δ9.04(d,J＝1.7Hz,1H),9.00(d,J＝2.4Hz,1H),8.58(t,J＝2.1Hz,1H),3.77-3.42(m,2H),2.01-1.66(m,12H),1.47-1.33(m,6H),1.27(s,9H)。FXR EC50(nM)＝1319。MS(ESI)478(M+H)。
Example 95
1- (3-cyanophenyl) -1- ((4- (5- (2-fluoropropan-2-yl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- ((1R,4R) -4-hydroxy-4-methylcyclohexyl) urea
Step A. preparation of intermediate 95A.4- (5- (2-fluoropropan-2-yl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] octane-1-carboxylic acid methyl ester
The title compound was prepared according to the procedure described for the synthesis of intermediate 1D by substituting intermediate 1C and commercially available 2-fluoro-2-methylpropionic acid where appropriate: (8.2g, 27.7mmol, 63% yield) as a colorless gummy solid. MS (ESI)297(M + H).
Step B. preparation of intermediate 95B. (4- (5- (2-fluoropropan-2-yl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methanol
The title compound was prepared according to the procedure described for the synthesis of intermediate 1E, substituting intermediate 95A where appropriate: (6.5g, 24.22mmol, 96% yield) as a colorless liquid. MS (ESI)269(M + H).
Step C. preparation of intermediate 95C.4- (5- (2-fluoropropan-2-yl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] octane-1-carbaldehyde
The title compound was prepared according to the procedure described for the synthesis of intermediate 1F, by substituting intermediate 95B where appropriate: (1.9g, 7.13mmol, 64% yield) as a colorless white gummy solid.1H NMR(400MHz,DMSO-d6)δ9.50-9.40(m,1H),1.97-1.50(m,18H)。
Step D. preparation of intermediate 95D.3- (((4- (5- (2-fluoropropan-2-yl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) amino) benzonitrile
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G by substituting intermediate 95C and commercially available 3-aminobenzonitrile where appropriate: (75mg, 0.204mmol, 72% yield). MS (ESI)369(M + H).
Example 95.1 preparation of- (3-cyanophenyl) -1- ((4- (5- (2-fluoropropan-2-yl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- ((1R,4R) -4-hydroxy-4-methylcyclohexyl) urea
The title compound was prepared according to the procedure described for the synthesis of example 30 (step B) by substituting intermediate 95D and commercially available trans-4-amino-1-methylcyclohexanol where appropriate: (15.8mg, 0.030mmol, 45% yield).1H NMR(400MHz,DMSO-d6)δ7.81(s,1H),7.70-7.62(m,2H),7.59-7.49(m,1H),5.65-5.56(m,1H),4.20(d,J＝2.4Hz,1H),3.57(s,2H),3.50-3.39(m,1H),1.80(s,3H),1.77-1.67(m,9H),1.64-1.53(m,2H),1.47-1.18(m,12H),1.07(s,3H)。FXR EC50(nM)＝181。MS(ESI)524(M+H)。
Example 96
1- (3-cyanophenyl) -1- ((4- (5- (2-fluoropropan-2-yl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- ((1R,4R) -4-hydroxycyclohexyl) urea
The title compound was prepared according to the procedure described for the synthesis of example 30 (step B) by substituting intermediate 95D and commercially available (1R,4R) -4-aminocyclohexan-1-ol where appropriate: (16.9mg, 0.033mmol, 15% yield).1H NMR(400MHz,DMSO-d6)δ7.81(s,1H),7.70-7.62(m,2H),7.59-7.49(m,1H),5.65-5.56(m,1H),4.20(d,J＝2.4Hz,1H),3.57(s,2H),3.50-3.39(m,1H),1.80(s,3H),1.77-1.67(m,9H),1.64-1.53(m,2H),1.47-1.18(m,12H),1.07(s,3H)。FXR EC50(nM)＝181。MS(ESI)524(M+H)。
Example 97
1- (3-cyanophenyl) -1- ((4- (5- (2-fluoropropan-2-yl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- (3-hydroxy-2, 2-dimethylpropyl) urea
The title compound was prepared according to the procedure described for the synthesis of example 30 (step B) by substituting intermediate 95D and commercially available 3-amino-2, 2-dimethylpropan-1-ol where appropriate: (18.4mg, 0.037mmol, 55% yield).1H NMR(400MHz,DMSO-d6)δ7.87(br d,J＝1.0Hz,1H),7.74-7.67(m,2H),7.63-7.56(m,1H),5.92(br s,1H),4.59-4.53(m,2H),3.57(s,3H),3.04(d,J＝6.1Hz,2H),2.89(br d,J＝5.4Hz,3H),1.80(s,3H),1.78-1.68(m,6H),1.42-1.33(m,6H),0.73(s,6H)。FXR EC50(nM)＝1003。MS(ESI)498(M+H)。
Example 98
1- (3-cyanophenyl) -1- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- ((1R,4R) -4-hydroxycyclohexyl) urea
Step A. preparation of intermediate 98A.3- (((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) amino) benzonitrile
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G by substituting intermediate 1F and commercially available 3-aminobenzonitrile where appropriate: (75mg, 0.201mmol, 73% yield). MS (ESI)373(M + H).
EXAMPLE 98.1 preparation of- (3-cyanophenyl) -1- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- ((1R,4R) -4-hydroxycyclohexyl) urea
The title compound was prepared according to the procedure described for the synthesis of example 30 (step B) by substituting intermediate 98A and commercially available (1R,4R) -4-aminocyclohexan-1-ol where appropriate: (25mg, 0.049mmol, 23% yield).1H NMR(400MHz,DMSO-d6)δ7.80(s,1H),7.64(d,J＝8.3Hz,2H),7.58-7.47(m,1H),5.68-5.61(m,1H),4.52-4.39(m,1H),3.56(s,2H),3.40-3.27(m,2H, combined with water), 2.13(t, J ═ 19.7Hz,3H),1.81-1.64(m,10H),1.38(br dd, J ═ 6.4,9.3Hz,6H),1.26-1.09(m, 4H). FXR EC50(nM)＝230。MS(ESI)514(M+H)。
Example 99
1- (3-cyanophenyl) -1- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- ((1R,4R) -4-hydroxy-4-methylcyclohexyl) urea
The title compound was prepared according to the method described for the synthesis of example 30 (step B) by substituting intermediate 98A and commercially available trans-4-amino-1-methylcyclohexanol where appropriate: (19.1mg, 0.036mmol, 53% yield).1H NMR(400MHz,DMSO-d6)δ7.82(s,1H),7.68-7.62(m,2H),7.61-7.51(m,1H),5.62(br d,J＝7.6Hz,1H),4.20(s,1H),3.57(s,2H),3.51-3.40(m,1H),2.13(t,J＝19.6Hz,3H),1.82-1.67(m,6H),1.65-1.53(m,2H),1.47-1.21(m,12H),1.07(s,3H)FXR EC50(nM)＝391。MS(ESI)528(M+H)。
Example 100
1- (3-cyanophenyl) -1- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- (3-hydroxy-2, 2-dimethylpropyl) urea
The title compound was prepared according to the procedure described for the synthesis of example 30 (step B) by substituting intermediate 98A and commercially available 3-amino-2, 2-dimethylpropan-1-ol where appropriate: (25.4mg, 0.050mmol, 74% yield).1H NMR(400MHz,DMSO-d6)δ7.87(s,1H),7.70(t,J＝6.8Hz,2H),7.64-7.54(m,1H),5.92(t,J＝5.5Hz,1H),4.56(t,J＝5.7Hz,1H),3.64-3.51(m,2H),3.04(d,J＝5.9Hz,2H),2.89(d,J＝5.9Hz,2H),2.14(t,J＝19.7Hz,3H),1.84-1.71(m,6H),1.47-1.30(m,6H),0.73(s,6H)。FXR EC50(nM)＝1479。MS(ESI)502(M+H)。
Example 101
1- (3-bromo-4-fluorophenyl) -1- ((4- (5- (2-fluoropropan-2-yl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- ((1R,4R) -4-hydroxycyclohexyl) urea
Step A. preparation of intermediate 101 A.3-bromo-4-fluoro-N- ((4- (5- (2-fluoropropan-2-yl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) aniline
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G by substituting intermediate 95C and commercially available 3-bromo-4-fluoroaniline where appropriate: (170mg, 0.386mmol, 59% yield). MS (ESI)440(M + H).
Example 101.1- (3-bromo-4-fluorophenyl) -1- ((4- (5- (2-fluoropropan-2-yl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- ((1R,4R) -4-hydroxycyclohexyl) urea
The title compound was prepared according to the procedure described for the synthesis of example 30 (step B) by substituting intermediate 101A and commercially available (1R,4R) -4-aminocyclohexan-1-ol where appropriate: (13.2mg, 0.022mmol, 23% yield). 1H NMR(400MHz,DMSO-d6)δ7.65(dd,J＝1.8,6.2Hz,1H),7.44-7.24(m,2H),5.46(d,J＝7.8Hz,1H),4.46(d,J＝4.4Hz,1H),3.49(s,2H),3.43-3.36(m,1H),3.29-3.20(m,1H),1.86-1.60(m,16H),1.47-1.31(m,6H),1.27-1.10(m,4H)。FXR EC50(nM)＝1520。MS(ESI)581(M+H)。
Example 102
N- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- ((5- (difluoromethoxy) pyrimidin-2-yl) amino) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
Step A. preparation of intermediate 102A.4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] octane-1-carboxylic acid methyl ester
The title compound was prepared according to the procedure described for the synthesis of intermediate 1D by substituting intermediate 1C and the corresponding acid where appropriate. (650mg, 2.22mmol, 95% yield) as a gummy mass. MS (ESI)293(M + H).
Step B. preparation of intermediate 102B. (4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methanol
The title compound was prepared according to the procedure described for the synthesis of intermediate 1E, by substituting intermediate 102A where appropriate. (500mg, 1.89mmol, 89% yield) as a white solid. MS (ESI)265(M + H).
Step C. preparation of intermediate 102C.4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] octane-1-carbaldehyde
The title compound was prepared according to the procedure described for the synthesis of intermediate 1F by substituting intermediate 102B where appropriate. (390mg, 1.487mmol, 82% yield) as a pale yellow solid. 1HNMR(400MHz,DMSO-d6)δ9.45(s,1H),1.88-1.84(m,6H),1.70-1.66(m,6H),1.35(s,9H)。
Step C. intermediate 102℃ preparation of tert-butyl (3- (((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) amino) phenyl) carbamate
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G, substituting intermediate 102C and tert-butyl (3-aminophenyl) carbamate where appropriate. (160mg, 0.345mmol, 53% yield) as a brown solid. MS (ESI)455(M + H).
Step D. preparation of intermediate 102D tert-butyl (3- (N- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamido) phenyl) carbamate
The title compound was prepared according to the procedure described for the synthesis of example 1, substituting intermediate 102C and the corresponding acid where appropriate. (120mg, 0.184mmol, 52% yield) as a white solid. MS (ESI)567(M + H).
Step E. preparation of intermediate 102E.N- (3-aminophenyl) -N- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
The title compound (95mg, 0.20mmol, 95% yield) was prepared as a brown gummy solid according to the procedure described for the synthesis of intermediate 91F by substituting intermediate 102D where appropriate. MS (ESI)467(M + H).
Step F. example 102 preparation of N- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- ((5- (difluoromethoxy) pyrimidin-2-yl) amino) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
To a stirred solution of intermediate 102E (30mg, 0.064mmol) in 1, 4-dioxane (1.5mL) was added 2-chloro-5- (difluoromethoxy) pyrimidine (17.41mg, 0.096mmol) and sodium tert-butoxide (18.54mg, 0.193mmol) at room temperature. The reaction mixture was purged with argon for 5 minutes and XantPhos (3.72mg, 6.43. mu. mol) was added followed by Pd2(dba)3(1.849mg, 3.21. mu. mol). The reaction mixture was heated to 110 ℃ and stirred overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude material was purified via preparative LC/MS using the following conditions: column: waters XBridge C18, 150mm x 19mm, 5 μm particles; mobile phase A: 5:95 acetonitrile, water containing 10mM ammonium acetate; mobile phase B: 95:5 acetonitrile, water containing 10mM ammonium acetate; gradient: hold at 40% B for 0 min, 40% -76% B over 15 min, then hold at 100% B for 5 min; flow rate: 15 mL/min; column temperature: at 25 ℃. The collection of fractions was triggered by an MS signal. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (4.4mg, 7.21 μmol, 11% yield). 1H NMR(400MHz,DMSO-d6)δ9.98(s,1H),8.50(s,2H),7.76(s,1H),7.70(d,J＝7.8Hz,1H),7.43-6.92(m,3H),3.69-3.57(m,1H),3.51-3.40(m,1H),1.93-1.89(m,6H),1.74(t,J＝7.6Hz,6H),1.45(d,J＝7.6Hz,6H),1.37-1.26(m,9H)。FXR EC50(nM)＝183。MS(ESI)611(M+H)。
The following examples were synthesized according to the methods described for the synthesis of example 102, by substituting intermediate 102E and the corresponding aryl halide where appropriate.
Example 105
N- (3- ((5-cyclopropylpyrimidin-2-yl) amino) phenyl) -3-fluoro-N- ((4- (5- (trifluoromethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) bicyclo [1.1.1] pentane-1-carboxamide
Step A. preparation of intermediate 105A.4- (5- (trifluoromethyl) pyridin-2-yl) bicyclo [2.2.2] octane-1-carboxylic acid methyl ester
To a stirred solution of 4- (methoxycarbonyl) bicyclo [2.2.2] octane-1-carboxylic acid (3g, 14.13mmol) and 3- (trifluoromethyl) pyridine (2.495g, 16.96mmol) in DCM (90mL) and water (90mL) was added ammonium persulfate (3.23g, 14.13mmol) at room temperature followed by silver nitrate (0.480g, 2.83 mmol). After stirring at room temperature overnight, the reaction mixture was diluted with DCM (25mL) and filtered through celite. The organic layer was separated and washed with brine solution (25mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (40g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 50% B). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound as a white solid (2.2g, 6.95mmol, 49% yield). MS (ESI)314(M + H).
Step B. preparation of intermediate 105B. (4- (5- (trifluoromethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methanol
The title compound was synthesized according to the procedure described for the synthesis of intermediate 1E, substituting intermediate 105A where appropriate: (1.6g, 5.05mmol, 79% yield) as a white solid. MS (ESI)286(M + H).
Step C. preparation of intermediate 105C.4- (5- (trifluoromethyl) pyridin-2-yl) bicyclo [2.2.2] octane-1-carbaldehyde
The title compound was synthesized according to the procedure described for the synthesis of intermediate 1F, substituting intermediate 105B where appropriate. (1.2g, 4.24mmol, 78% yield) as a white solid. MS (ESI)284(M + H).1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),8.89(dd,J＝2.5,1.0Hz,1H),8.18-8.07(m,1H),7.60(d,J＝8.5Hz,1H),1.98-1.83(m,6H),1.76-1.65(m,6H)。
Step D. intermediate 105D preparation of tert-butyl (3- (((4- (5- (trifluoromethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) amino) phenyl) carbamate
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G, substituting intermediate 105C and tert-butyl (3-aminophenyl) carbamate where appropriate. (300mg, 0.618mmol, 88% yield) as a brown solid. MS (ESI)476(M + H).
Step E. preparation of intermediate 105E tert-butyl (3- (3-fluoro-N- ((4- (5- (trifluoromethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) bicyclo [1.1.1] pentane-1-carboxamido) phenyl) carbamate
The title compound was prepared according to the procedure described for the synthesis of example 1, substituting intermediate 105D and the corresponding acid where appropriate. (300mg, 0.510mmol, 81% yield) as a white solid. MS (ESI)588(M + H).
Step F. preparation of intermediate 105F.N- (3-aminophenyl) -3-fluoro-N- ((4- (5- (trifluoromethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) bicyclo [1.1.1] pentane-1-carboxamide
The title compound was prepared according to the procedure described for the synthesis of intermediate 91F by substituting intermediate 105E and the corresponding acid where appropriate. (200mg, 0.410mmol, 80% yield) as a brown gummy solid. MS (ESI)488(M + H).
Step g. example 105: preparation of N- (3- ((5-cyclopropylpyrimidin-2-yl) amino) phenyl) -3-fluoro-N- ((4- (5- (trifluoromethyl) pyridin-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) bicyclo [1.1.1] pentane-1-carboxamide
The title compound was prepared according to the procedure described for the synthesis of example 102, substituting intermediate 105F where appropriate. (7.4mg, 0.012mmol, 20% yield).1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),8.85(s,1H),8.32(s,2H),8.07(dd,J＝8.9,2.1Hz,1H),7.82(s,1H),7.70(d,J＝8.6Hz,1H),7.53(d,J＝8.6Hz,1H),7.33(t,J＝7.9Hz,1H),6.91(d,J＝7.3Hz,1H),3.64(d,J＝11.0Hz,1H),3.47(d,J＝11.5Hz,1H),1.95(br.s.,3H),1.92-1.69(m,10H),1.48(d,J＝6.8Hz,6H),0.98-0.88(m,2H),0.78-0.67(m,2H)。FXR EC50(nM)＝292。MS(ESI)606(M+H)。
The following examples were synthesized according to the method described for the synthesis of example 102, by substituting intermediate 105F and the corresponding aryl halide where appropriate.
Example 110
N- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3-hydroxyphenyl) bicyclo [1.1.1] pentane-1-carboxamide
Step A. preparation of intermediate 110A.3- ((tert-butyldimethylsilyl) oxy) aniline
To a stirred solution of 3-aminophenol (2g, 18.33mmol) and imidazole (1.560g, 22.91mmol) in THF (50mL) was added TBDMS-Cl (3.45g, 22.91mmol) at room temperature. After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate (50 mL). The resulting solution was washed with 10% aqueous sodium bicarbonate (2 × 50mL), followed by aqueous saline (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (24g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 30% B; flow rate ═ 30 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give 3- ((tert-butyldimethylsilyl) oxy) aniline (3.5g, 15.51mmol, 85% yield) as a brown oil. MS (ESI)224(M + H).
Step B. intermediate 110B. preparation of N- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- ((tert-butyldimethylsilyl) oxy) aniline
The title compound was prepared according to the procedure described for the synthesis of example 1G, by substituting intermediate 110A and intermediate 102C where appropriate. (170mg, 0.362mmol, 63% yield) as a gummy solid. MS (ESI)470(M + H).
Step C. preparation of intermediate 110C.N- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- ((tert-butyldimethylsilyl) oxy) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
The title compound was prepared according to the procedure described for the synthesis of example 1, substituting intermediate 110B and the corresponding acid where appropriate. (170mg, 0.280mmol, 78% yield) as a white solid. MS (ESI)582(M + H).
Example 110 preparation of N- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3-hydroxyphenyl) bicyclo [1.1.1] pentane-1-carboxamide
To a stirred solution of intermediate 110C (170mg, 0.292mmol) in THF (3mL) was added TBAF (0.584mL, 0.584mmol) at room temperature. After stirring for 1h, the reaction mixture was diluted with water (10mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified via preparative LC/MS using the following conditions: column: waters XBridge C18, 150mm x 19mm, 5 μm particles; mobile phase A: 5:95 acetonitrile, water containing 10mM ammonium acetate; mobile phase B: 95:5 acetonitrile, water containing 10mM ammonium acetate; gradient: hold at 15% B for 2 minutes, 15% -57% B over 25 minutes, then hold at 100% B for 5 minutes; flow rate: 15 mL/min; column temperature: at 25 ℃. The collection of fractions is triggered by a signal. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound as a white solid (120mg, 0.257mmol, 88% yield). 1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),7.23(t,J＝7.9Hz,1H),6.78(td,J＝2.2,8.1Hz,2H),6.73-6.67(m,1H),3.56-3.45(m,2H),1.87(d,J＝2.4Hz,6H),1.78-1.67(m,6H),1.47-1.37(m,6H)1.34(s.9H)。FXR EC50(nM)＝65。MS(ESI)468(M+H)。
Example 111
N- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (cyanomethoxy) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
To a stirred solution of example 110(20mg, 0.043mmol) in DMF (1mL) at room temperature was added 2-bromoacetonitrile (6.16mg, 0.051mmol) followed by addition of K2CO3(14.78mg, 0.107 mmol). The reaction mixture was heated to 110 ℃ and stirred for 2 h. The reaction mixture was diluted with water (5mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via preparative LC/MS using the following conditions: column: waters XBridge C18, 150mm x 19mm, 5 μm particles; mobile phase A: 5:95 acetonitrile, water containing 10mM ammonium acetate; mobile phase B: 95:5 acetonitrile, water containing 10mM ammonium acetate; gradient: held at 18% B for 2 minutes, 18% -62% B over 25 minutes, then held at 100% B for 5 minutes; flow rate: 15 mL/min; column temperature: at 25 ℃. The collection of fractions is triggered by a signal. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (21.3mg, 0.042mmol, 97% yield).1H NMR(400MHz,DMSO-d6)δ7.47-7.39(m,1H),7.18(t,J＝2.2Hz,1H),7.10(td,J＝2.0,8.2Hz,2H),5.25(s,2H),3.61-3.47(m,2H),1.96-1.81(m,6H),1.78-1.68(m,6H),1.47-1.38(m,6H),1.33(s,9H)。FXR EC50(nM)＝618。MS(ESI)507(M+H)。
Example 112
N- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3- (2-hydroxy-2-methylpropoxy) phenyl) bicyclo [1.1.1] pentane-1-carboxamide
Step a. preparation of intermediate 112a.2- (3- (N- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamido) phenoxy) acetic acid ethyl ester.
The title compound was prepared according to the procedure described for the synthesis of example 111, by substituting example 110 and ethyl bromoacetate where appropriate. (60mg, 0.108mmol, 75% yield) as a white solid. MS (ESI)554(M + H).
Step B. example 112 preparation of N- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3- (2-hydroxy-2-methylpropoxy) phenyl) bicyclo [1.1.1] pentane-1-carboxamide
The title compound was prepared according to the procedure described for the synthesis of example 128 by substituting intermediate 112A where appropriate. (6.2mg, 0.011mmol, 31% yield).1H NMR(400MHz,DMSO-d6)δ7.39-7.29(m,1H),7.02-6.85(m,3H),4.64(s,1H),3.77(d,J＝3.2Hz,2H),3.66-3.57(m,1H),3.54-3.39(m,1H),1.87(br d,J＝8.3Hz,6H),1.79-1.66(m,6H),1.47-1.37(m,6H),1.33(s,9H),1.21(s,6H)。FXR EC50(nM)＝63。MS(ESI)540(M+H)。
Example 113
2- (3- (N- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamido) phenoxy) -2-methylpropanoic acid
Step a. intermediate 113A: preparation of ethyl 2- (3- (N- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamido) phenoxy) -2-methylpropionate
The title compound was prepared according to the procedure described for the synthesis of example 111, by substituting example 110 where appropriate. (50mg, 0.086mmol, 67% yield) as a white solid. MS (ESI)582(M + H).
Step b. example 113: preparation of 2- (3- (N- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamido) phenoxy) -2-methylpropanoic acid.
The title compound was prepared according to the procedure described for the synthesis of intermediate 28C, by substituting intermediate 113A where appropriate. (19.7mg, 0.036mmol, 83% yield).1H NMR(400MHz,DMSO-d6)δ7.35(t,J＝8.1Hz,1H),7.01(d,J＝7.6Hz,1H),6.89(dd,J＝2.2,8.1Hz,1H),6.81-6.70(m,1H),3.49(br d,J＝3.2Hz,2H),1.93-1.79(m,6H),1.78-1.64(m,6H),1.59-1.47(m,6H),1.45-1.37(m,6H),1.34(s,9H)。FXR EC50(nM)＝2000。MS(ESI)554(M+H)。
Example 114
N- (3-cyanophenyl) -3-fluoro-N- ((4- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) bicyclo [1.1.1] pentane-1-carboxamide
Step a. intermediate 114A: preparation of methyl 4- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] octane-1-carboxylate
To a stirred solution of intermediate 1C (5.0g, 22.10mmol) in DMF (50mL) at 0 ℃ was added pyridine (8.90mL, 110mmol) followed by 2,2, 2-trifluoroacetic anhydride (4.65mL, 33.1 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with cold water (50mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (40g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 30% B). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give methyl 4- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] octane-1-carboxylate (4.8g, 15.78mmol, 71% yield) as a gummy solid. MS (ESI)305(M + H).
And B: intermediate 114B: preparation of (4- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methanol.
The title compound was prepared according to the procedure described for the synthesis of intermediate 1E, by substituting intermediate 114A where appropriate. (2.1g, 7.60mmol, 48% yield) as a gummy liquid. MS (ESI)277(M + H).
And C: intermediate 114C: preparation of 4- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] octane-1-carbaldehyde
The title compound was prepared according to the procedure described for the synthesis of intermediate 1F by substituting intermediate 114B where appropriate. (1.3g, 4.74mmol, 66% yield) as a white solid. MS (ESI)275(M + H).
Step D: intermediate 114D: preparation of 3- (((4- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) amino) benzonitrile
The title compound (180mg, 0.478mmol, 87% yield) was prepared as a white gummy solid according to the method described for the synthesis of intermediate 1G by substituting intermediate 114C where appropriate. MS (ESI)377(M + H).
Step e. example 114: preparation of N- (3-cyanophenyl) -3-fluoro-N- ((4- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) bicyclo [1.1.1] pentane-1-carboxamide
The title compound was prepared according to the procedure described for the synthesis of example 1, substituting intermediate 114D and the corresponding acid where appropriate. (9.3mg, 0.019mmol, 36% yield).1HNMR(400MHz,DMSO-d6)δ8.05(s,1H),7.88(d,J＝7.8Hz,1H),7.81(dd,J＝1.5,7.3Hz,1H),7.71-7.61(m,1H),3.66-3.47(m,2H),1.87(br s,6H),1.82-1.71(m,6H),1.49-1.34(m,6H)。FXR EC50(nM)＝80。MS(ESI)489(M+H)。
The following examples were synthesized according to the method described for the synthesis of example 1, by substituting intermediate 114D and the corresponding aryl halide where appropriate.
Example 118
N- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- ((5- (difluoromethoxy) pyrimidin-2-yl) oxy) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
Step a. intermediate 118a. preparation of N- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (5, 5-dimethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
To a stirred solution of intermediate 84A (180mg, 0.339mmol) in 1, 4-dioxane (5mL) was added bis (neopentyl glycol) diboron (153mg, 0.679mmol) at room temperature followed by the addition ofPotassium acetate (150mg, 1.527 mmol). The reaction mixture was purged with argon for 10 minutes and Pd (dppf) was added2Cl2(12.41mg, 0.017 mmol). The reaction mixture was heated to 110 ℃ and stirred for 4 h. The reaction mixture was cooled to room temperature and poured into water (10mL) and extracted with EtOAc (2 × 25 mL). The combined organic layers were washed with brine (10mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (24g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 30% B; flow rate ═ 30 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound as a white solid (90mg, 0.152mmol, 45% yield). Ms (esi)496(M + H) (boronic acid fragment of the parent boronate).
Step b. intermediate 118b. preparation of N- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3-hydroxyphenyl) bicyclo [1.1.1] pentane-1-carboxamide
A solution of intermediate 118A (80mg, 0.142mmol) in DCM (3mL) was cooled to 0 deg.C and m-CPBA (29.4mg, 0.170mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure. The crude was poured into water (5mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (10mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (4g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 60% B). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound as a white solid (60mg, 0.122mmol, 86% yield). MS (ESI)468(M + H).
Step C. example 118 preparation of N- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- ((5- (difluoromethoxy) pyrimidin-2-yl) oxy) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
Intermediate 118B (25mg, 0.053mmol) and 2-chloro-5- (difluoro) were added at room temperature Methoxy) pyrimidine (9.65mg, 0.053mmol) to a solution in acetonitrile (1mL) potassium carbonate (7.39mg, 0.053mmol) was added and stirred at 90 ℃ overnight. The reaction mixture was filtered through a filter disk. The filtrate was concentrated under reduced pressure. The crude material was purified via preparative LC/MS using the following conditions: column: waters XBridge C18, 150mm x 19mm, 5 μm particles; mobile phase A: 5:95 acetonitrile, water containing 10mM ammonium acetate; mobile phase B: 95:5 acetonitrile, water containing 10mM ammonium acetate; gradient: hold at 15% B for 2 minutes, 15% -57% B over 25 minutes, then hold at 100% B for 5 minutes; flow rate: 15 mL/min; column temperature: at 25 ℃. The collection of fractions is triggered by a signal. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (18.3mg, 0.030mmol, 56% yield).1H NMR(400MHz,DMSO-d6)δ8.62(s,2H),7.58-7.48(m,1H),7.37(d,J＝2.0Hz,1H),7.34-7.17(m,3H),3.60(br.s.,1H),3.47(br.s.,1H),1.94(br.s.,6H),1.81-1.65(m,6H),1.43(d,J＝4.9Hz,6H),1.34(s,9H)。FXR EC50(nM)＝361。MS(ESI)612(M+H)
Example 119
N- ((4- (5- (tert-butyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- ((5- (difluoromethoxy) pyridin-2-yl) oxy) phenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
The title compound was synthesized according to the procedure described for the synthesis of example 118, substituting intermediate 118B and 2-bromo-5- (difluoromethoxy) pyridine where appropriate. (8.3mg, 0.013mmol, 31% yield). 1H NMR(400MHz,DMSO-d6)δ8.01(d,J＝2.9Hz,1H),7.81(dd,J＝9.0,2.9Hz,1H),7.56-7.43(m,1H),7.33-7.10(m,5H),3.59(br.s.,1H),3.47(br.s.,1H),1.93(br.s.,6H),1.81-1.58(m,6H),1.43(br.s.,6H),1.34(s,9H)。FXR EC50(nM)＝536。MS(ESI)611(M+H)。
Example 120
3- (N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamido) benzoic acid
Step A. preparation of intermediate 120A.3- (((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) amino) benzoic acid methyl ester
The title compound was synthesized according to the procedure described for the synthesis of intermediate 1G, substituting intermediate 1F and methyl 3-aminobenzoate where appropriate. (75mg, 0.176mmol, 68% yield) as a pale yellow oil. MS (ESI)406(M + H).
Step B. preparation of intermediate 120B.3- (methyl N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamido) benzoate
The title compound was synthesized according to the procedure described for the synthesis of example 1, substituting intermediate 120A and the corresponding acid where appropriate. (75mg, 0.143mmol, 77% yield).1HNMR(400MHz,DMSO-d6)δ7.97(d,J＝8.1Hz,1H),7.91-7.86(m,1H),7.77-7.70(m,1H),7.66-7.57(m,1H),3.90(s,3H),3.66-3.50(m,2H),2.14(t,J＝19.7Hz,3H),1.84(br s,6H),1.80-1.66(m,6H),1.50-1.35(m,6H)。MS(ESI)518(M+H)。
EXAMPLE 120.3 preparation of N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamido) benzoic acid
The title compound was synthesized according to the procedure described for the synthesis of intermediate 28C, substituting intermediate 120B where appropriate A compound (I) is provided. (50mg, 0.099mmol, 79% yield) as an off-white solid.1H NMR(400MHz,DMSO-d6)δ7.94(d,J＝7.3Hz,1H),7.83(s,1H),7.70-7.62(m,1H),7.61-7.54(m,1H),3.58(s,2H),2.13(t,J＝19.6Hz,3H),1.83(br s,6H),1.81-1.73(m,6H),1.49-1.37(m,6H)。FXR EC50(nM)＝4000。MS(ESI)504(M+H)。
Example 121
N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-carbamoyl-4-fluorophenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
Step a. preparation of intermediate 121a.5- (((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) amino) -2-fluorobenzoic acid methyl ester
The title compound was synthesized according to the procedure described for the synthesis of intermediate 1G, substituting intermediate 36C where appropriate. (280mg, 0.674mmol, 88% yield) as an off-white solid. MS (ESI)416(M + H).
Step B. preparation of intermediate 121 B.methyl 5- (N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide) -2-fluorobenzoate
The title compound was synthesized according to the procedure described for the synthesis of example 1, substituting intermediate 121A and the corresponding acid where appropriate. (200mg, 0.360mmol, 75% yield) as an off-white solid. MS (ESI)528(M + H).
Step C. preparation of intermediate 121C 5- (N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide) -2-fluorobenzoic acid
The title compound was synthesized according to the procedure described for the synthesis of intermediate 28C, substituting intermediate 121B where appropriate. (55mg, 0.096mmol, 78% yield) as a solid. MS (ESI)514(M + H).
EXAMPLE 121 preparation of N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-carbamoyl-4-fluorophenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
The title compound was synthesized according to the procedure described for the synthesis of intermediate 1A, by substituting intermediate 121C where appropriate. (10mg, 0.020mmol, 50% yield).1H NMR(400MHz,DMSO-d6)δ7.87-7.75(m,2H),7.64-7.51(m,2H),7.37(t,J＝9.3Hz,1H),3.60-3.48(m,2H),1.88(br s,6H),1.84-1.75(m,6H),1.48-1.36(m,6H),1.27(s,9H)。FXR EC50(nM)＝412。MS(ESI)513(M+H)。
Example 122
N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (ethylcarbamoyl) -4-fluorophenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
The title compound was synthesized according to the procedure described for the synthesis of intermediate 1A, by substituting intermediate 121C and ethylamine where appropriate. (20mg, 0.037mmol, 95% yield).1H NMR(400MHz,DMSO-d6)δ8.47-8.34(m,1H),7.61-7.50(m,2H),7.42-7.32(m,1H),3.57(br s,1H),3.53-3.44(m,1H),3.31-3.23(m,2H),1.88(br s,6H),1.84-1.70(m,6H),1.50-1.35(m,6H),1.27(s,9H),1.14(t,J＝7.1Hz,3H)。FXR EC50(nM)＝123。MS(ESI)540(M+H)。
Example 123
(1S,3S) -N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-N- (3-isopropoxyphenyl) -3- (trifluoromethyl) cyclobutane-1-carboxamide
Step A. intermediate 123A preparation of N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-isopropoxyaniline
The title compound was synthesized according to the procedure described for the synthesis of intermediate 1G by substituting intermediate 36C and 3-isopropoxyaniline where appropriate. (70mg, 0.158mmol, 69% yield) as an off-white solid. MS (ESI)398(M + H).
Example 123 preparation of (1S,3S) -N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-N- (3-isopropoxyphenyl) -3- (trifluoromethyl) cyclobutane-1-carboxamide
The title compound was synthesized according to the procedure described for the synthesis of example 1, substituting intermediate 123A and the corresponding acid where appropriate. (14mg, 0.024mmol, 47% yield).1HNMR(400MHz,DMSO-d6)δ7.36-7.25(m,1H),6.98-6.92(m,1H),6.92-6.80(m,2H),6.53(s,1H),4.72-4.62(m,1H),3.59(s,2H),2.85-2.73(m,1H),2.36-2.25(m,2H),2.09-2.00(m,2H),1.85-1.74(m,6H),1.47-1.38(m,6H),1.29-1.22(m,15H)。FXR EC50(nM)＝2000。MS(ESI)564(M+H)。
Example 124
(1S,3S) -N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-N- (3-isopropoxyphenyl) -3- (trifluoromethyl) cyclobutane-1-carboxamide
The title compound was synthesized according to the procedure described for the synthesis of example 1, substituting intermediate 123A and the corresponding acid where appropriate. (12mg, 0.024mmol, 47% yield).1HNMR(400MHz,DMSO-d6)δ7.37-7.28(m,1H),6.99-6.85(m,3H),4.68(quin,J＝6.0Hz,1H),3.59(br s,1H),3.48-3.40(m,1H),1.94-1.71(m,12H),1.53-1.36(m,6H),1.27(s,15H)。FXR EC50(nM)＝2000。MS(ESI)510(M+H)。
Example 125
(1S,3S) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-N- (3-isopropoxyphenyl) -3-methylcyclobutane-1-carboxamide
Step A. intermediate 125A. preparation of N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-isopropoxyaniline
The title compound was synthesized according to the procedure described for the synthesis of intermediate 1G by substituting intermediate 1F and 3-isopropoxyaniline where appropriate. (60mg, 0.141mmol, 76% yield) as an off-white solid. MS (ESI)406(M + H).
Step B. example 125 preparation of (1S,3S) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-hydroxy-N- (3-isopropoxyphenyl) -3-methylcyclobutane-1-carboxamide
The title compound was synthesized according to the procedure described for the synthesis of example 1, substituting intermediate 125A and the corresponding acid where appropriate. (5.2mg, 9.34. mu. mol, 19% yield).1H NMR(400MHz,DMSO-d6)δ7.29(t,J＝8.1Hz,1H),6.95-6.80(m,3H),4.90(s,1H),4.73-4.60(m,1H),3.63-3.53(m,2H),2.55(br d,J＝3.7Hz,1H),2.21-2.04(m,5H),1.84-1.72(m,6H),1.67-1.57(m,2H),1.50-1.36(m,6H),1.26(d,J＝5.9Hz,6H),1.10-0.85(m,3H)。FXR EC50(nM)＝1525。MS(ESI)518(M+H)。
The following examples were synthesized according to the method described for the synthesis of example 1, by substituting intermediate 125A and the corresponding acid where appropriate.
Example 128
N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (4-fluoro-3- (2-hydroxypropan-2-yl) phenyl) bicyclo [1.1.1] pentane-1-carboxamide
To a solution of intermediate 121B (25mg, 0.047mmol) in THF (2mL) at 0 ℃ was added 3M methylmagnesium bromide in diethyl ether (0.032mL, 0.095 mmol). The reaction mixture was allowed to warm slowly to room temperature and stirred for 1 h. The reaction mixture was washed with saturated NH 4Aqueous Cl (5mL) was quenched and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (5mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via preparative LC/MS using the following conditions: column: waters XBridge C18, 150mm x 19mm, 5 μm particles; mobile phase A: 5:95 acetonitrile, water containing 10mM ammonium acetate; mobile phase B: 95:5 acetonitrile, water containing 10mM ammonium acetate; gradient: hold at 15% B for 2 minutes, 15% -57% B over 25 minutes, then hold at 100% B for 5 minutes; flow rate: 15 mL/min; column temperature: at 25 ℃. The collection of fractions is triggered by a signal. Will contain the desired productFractions of material were combined and dried via centrifugal evaporation to give the title compound (10.4mg, 0.020mmol, 42% yield).1H NMR(400MHz,DMSO-d6)δ7.49(dd,J＝2.8,7.5Hz,1H),7.34-7.27(m,1H),7.20(dd,J＝8.6,11.2Hz,1H),5.46(s,1H),3.60-3.53(m,1H),3.50-3.43(m,1H),1.91-1.76(m,12H),1.50(br d,J＝10.0Hz,6H),1.46-1.37(m,6H),1.27(s,9H)。FXR EC50(nM)＝4000。MS(ESI)528(M+H)。
Example 129
N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3-methoxyphenyl) bicyclo [1.1.1] pentane-1-carboxamide
Step a. intermediate 129a. preparation of n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-methoxyaniline
The title compound was synthesized according to the procedure described for the synthesis of intermediate 1G, substituting intermediate 1F and 3-methoxyaniline where appropriate. (25mg, 0.063mmol, 57% yield) as an off-white solid. MS (ESI)378(M + H).
Step B. example 129 preparation of N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3-methoxyphenyl) bicyclo [1.1.1] pentane-1-carboxamide
The title compound was synthesized according to the procedure described for the synthesis of example 1, substituting intermediate 129A and the corresponding acid where appropriate. (11mg, 0.022mmol, 42% yield).1H NMR(400MHz,DMSO-d6)δ7.36(t,J＝8.3Hz,1H),7.04–6.88(m,3H),3.80(s,3H),3.68-3.56(m,1H),3.52-3.40(m,1H),2.14(t,J＝19.7Hz,3H),1.97-1.70(m,12H),1.57-1.34(m,6H)。FXR EC50(nM)＝73。MS(ESI)490(M+H)。
Example 130
N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-ethoxyphenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
Step a. intermediate 130a. preparation of n- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-ethoxyaniline
The title compound was synthesized according to the procedure described for the synthesis of intermediate 1G, substituting intermediate 1F and 3-ethoxyaniline where appropriate. (30mg, 0.073mmol, 66% yield) as an off-white solid. MS (ESI)392(M + H).
Step B. example 130 preparation of N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3-ethoxyphenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
The title compound was synthesized according to the procedure described for the synthesis of example 1, substituting intermediate 130A and the corresponding acid where appropriate. (12mg, 0.024mmol, 47% yield). 1HNMR(400MHz,DMSO-d6)δ7.39-7.29(m,1H),7.00-6.88(m,3H),4.14-4.00(m,2H),3.65-3.56(m,1H),3.51-3.42(m,1H),2.14(t,J＝19.6Hz,3H),1.95-1.82(m,6H),1.82-1.70(m,6H),1.51-1.40(m,6H),1.34(t,J＝6.9Hz,3H)。FXR EC50(nM)＝91。MS(ESI)504(M+H)。
Example 131
(S) -1- (3-bromophenyl) -1- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- (2-fluoro-3-hydroxy-3-methylbutyl) urea
The title compound was prepared according to the procedure described for the synthesis of example 30 by substituting intermediate 30A and (S) -4-amino-3-fluoro-2-methylbutan-2-ol where appropriate: (1.2mg, 2.093. mu. mol, 9% yield).1H NMR(400MHz,DMSO-d6)δ7.54(s,1H),7.43(td,J＝2.1,6.5Hz,1H),7.38-7.29(m,2H),7.24-6.92(m,1H),5.91(t,J＝5.5Hz,1H),4.66(br.s.,1H),4.26-4.11(m,1H),3.61-3.49(m,2H),3.20-3.08(m,1H),2.13(t,J＝19.7Hz,3H),1.82-1.70(m,6H),1.45-1.33(m,6H),1.08(s,6H)。FXR EC50(nM)＝228。MS(ESI)573(M+H)。
Example 132
N- (3-bromophenyl) -N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.1] hept-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
Step A. intermediate 132A. preparation of bicyclo [2.2.1] heptane-1, 4-dicarboxylic acid dimethyl ester
A solution of diisopropylamine (24.52mL, 172mmol) in THF (230mL) was cooled to-20 deg.C and a 2.5M solution of n-butyllithium in hexane (45.3mL, 113mmol) was added dropwise. The mixture was stirred at-20 ℃ for 20min and then cooled to-78 ℃. To this solution was added dropwise anhydrous hexamethylphosphoramide (63.0mL, 362 mmol). A solution of dimethyl cyclopentane-1, 3-dicarboxylate (8.43g, 45.3mmol) in THF (40mL) was added dropwise over a period of 20min and the reaction mixture was allowed to warm to 0 ℃ and stir for 20 min. The reaction mixture was cooled again to 78 ℃ and 1-bromo-2-chloroethane (6.78mL, 81mmol) was added over a 20min period. The cooling bath was removed and the mixture was allowed to warm to room temperature over a period of 6 h. The reaction mixture was then washed with saturated NH 4Dissolving Cl in waterThe solution (100mL) was quenched, concentrated under reduced pressure to 1/5 volumes and washed with H2Dilution with O (120 mL). The aqueous phase was separated and extracted with EtOAc (3 × 100 mL). The combined organic extracts were washed with water (100mL), brine (100mL) and dried over MgSO4Filtered, and concentrated under reduced pressure. The crude compound was purified by flash chromatography (80g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 70% B; flow rate ═ 40 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound as an off-white semi-solid (4.2g, 19.79mmol, 44% yield). MS (ESI)213(M + H).
Step B preparation of intermediate 132B.4- (methoxycarbonyl) bicyclo [2.2.1] heptane-1-carboxylic acid
Intermediate 132A (3.5g, 16.49mmol) was dissolved in THF (100mL) and a solution of sodium hydroxide (0.660g, 16.49mmol) in MeOH (10mL) was added dropwise. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure without heating. The residue was dissolved in water (20mL) and washed with CH2Cl2(3 × 15 mL). The aqueous layer was acidified with 6N HCl until pH 3. The resulting aqueous solution was extracted with DCM (4 × 50 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as an off-white semi-solid (2.6g, 13.12mmol, 80% yield). MS (ESI)197 (M-H).
Step C. preparation of intermediate 132C.4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.1] heptane-1-carboxylic acid methyl ester
The title compound was prepared according to the procedure described for the synthesis of intermediate 1D by substituting intermediate 132B and N' -hydroxypivalimide amide where appropriate. (900mg, 3.23mmol, 51% yield). MS (ESI)279(M + H).
Step D. intermediate 132D preparation of (4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.1] hept-1-yl) methanol
The title compound was prepared according to the procedure described for the synthesis of intermediate 1E, by substituting intermediate 132C where appropriate. (0.9g, 3.60mmol, 77% yield) as an off-white solid.1H NMR(400MHz,DMSO-d6)δ4.53(t,J＝6.40Hz,1H),3.49(d,J＝5.60Hz,2H),1.98-2.02(m,2H),1.81-1.84(m,5H),1.71-1.79(m,2H),1.24-1.37(m,10H)。
Step E. preparation of intermediate 132E 4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.1] heptane-1-carbaldehyde
The title compound was prepared according to the procedure described for the synthesis of intermediate 1F, by substituting intermediate 132D where appropriate. (0.4g, 1.611mmol, 58% yield).1H NMR(400MHz,CDCl3)δ9.89(s,1H),2.16-2.29(m,4H),1.96-2.01(m,4H),1.67-1.69(m,2H),1.40(s,9H)。
Step F. preparation of intermediate 132F 3-bromo-N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.1] hept-1-yl) methyl) aniline
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G by substituting intermediate 132E and 3-bromoaniline where appropriate: (320mg, 0.791mmol, 66% yield). MS (ESI)404(M + H).
Step G. example 132 preparation of N- (3-bromophenyl) -N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.1] hept-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide.
The title compound was prepared according to the procedure described for the synthesis of example 1, substituting intermediate 132F and the corresponding acid where appropriate: (5.6mg, 10.84. mu. mol, 22% yield).1HNMR(400MHz,DMSO-d6)δ7.74(s,1H),7.66-7.58(m,1H),7.49-7.33(m,2H),4.05-3.72(m,2H),2.05-1.79(m,8H),1.78-1.69(m,2H),1.67-1.49(m,4H),1.42-1.31(m,2H),1.28(s,9H)。FXR EC50(nM)＝498。MS(ESI)516(M+H)。
Example 133
(1s,3s) -N- (3-bromophenyl) -N- ((4- (3- (tert-butyl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.1] hept-1-yl) methyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamide
The title compound was prepared according to the procedure described for the synthesis of example 1, substituting intermediate 132F where appropriate: (2mg, 3.51. mu. mol, 10% yield).1H NMR(400MHz,DMSO-d6)δ7.73(s,1H),7.61-7.52(m,1H),7.48-7.34(m,2H),6.54(s,1H),3.96(s,2H),3.17(d,J＝5.1Hz,1H),2.72(br t,J＝8.9Hz,1H),2.37-2.30(m,2H),2.11-2.03(m,2H),2.00-1.90(m,2H),1.76-1.67(m,2H),1.66-1.56(m,2H),1.53(s,2H),1.40-1.23(m,12H)。FXR EC50(nM)＝4000。MS(ESI)570(M+H)。
Example 134
N- (3-bromophenyl) -N- ((4- (5- (2-fluoropropan-2-yl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- (2-hydroxypropan-2-yl) bicyclo [1.1.1] pentane-1-carboxamide
Step a. preparation of intermediate 134 a.3-bromo-N- ((4- (5- (2-fluoroprop-2-yl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) aniline
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G by substituting intermediate 95C and 3-bromoaniline where appropriate: (650mg, 1.539mmol, 82% yield). MS (ESI)422(M + H).
Step b. preparation of intermediate 134b.3- ((3-bromophenyl) ((4- (5- (2-fluoropropan-2-yl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) carbamoyl) bicyclo [1.1.1] pentane-1-carboxylic acid methyl ester
The title compound was prepared according to the procedure described for the synthesis of example 1, by substituting intermediate 134A and the corresponding acid where appropriate: (290mg, 0.505mmol, 71% yield). MS (ESI)574(M + H).
Step C. example 134 preparation of N- (3-bromophenyl) -N- ((4- (5- (2-fluoropropan-2-yl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3- (2-hydroxypropan-2-yl) bicyclo [1.1.1] pentane-1-carboxamide
To a solution of intermediate 134B (30mg, 0.052mmol) in THF (5mL) at-78 deg.C was added dropwise Et23M methyl magnesium chloride in O (0.174mL, 0.522 mmol). The reaction mixture was stirred at-78 ℃ for 30 min. By addition of saturated NH4The reaction mixture was quenched with aqueous Cl (10 mL). The resulting aqueous solution was extracted with ethyl acetate (2 × 10 mL). The combined organic extracts were washed with brine solution (15mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via preparative LC/MS using the following conditions: column: waters XBridge C18, 150mm x 19mm, 5 μm particles; mobile phase A: 5:95 acetonitrile, water containing 10mM ammonium acetate; mobile phase B: 95:5 acetonitrile, water containing 10mM ammonium acetate; gradient: hold at 15% B for 2 minutes, 15% -57% B over 25 minutes, then hold at 100% B for 5 minutes; flow rate: 15 mL/min; column temperature: at 25 ℃. The collection of fractions is triggered by a signal. Fractions containing the desired product were combined and passed Evaporation to dryness by centrifugation gave the title compound as an off-white solid (4mg, 6.96. mu. mol, 13% yield).1H NMR(400MHz,DMSO-d6)δ7.66-7.63(m,1H),7.57(dt,J＝6.9,1.7Hz,1H),7.46-7.35(m,2H),4.03(s,1H),3.62-3.43(m,2H),1.82-1.70(m,12H),1.46-1.34(m,12H),0.86(s,6H)。FXR EC50(nM)＝434。MS(ESI)574(M+H)。
Example 135
N- (3-cyano-5-fluorophenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
Step A. preparation of intermediate 135A.3- (((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) amino) -5-fluorobenzonitrile
The title compound was prepared according to the procedure described for the synthesis of intermediate 1G by substituting intermediate 1F and commercially available 3-amino-5-fluorobenzonitrile where appropriate: (80mg, 0.205mmol, 56% yield). MS (ESI)391(M + H).
Step B. example 135 preparation of N- (3-cyano-5-fluorophenyl) -N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide
The title compound was prepared according to the procedure described for the synthesis of example 1, substituting intermediate 135A where appropriate: (7.3mg, 0.015mmol, 28% yield).1H NMR(400MHz,DMSO-d6)δ7.98(s,1H),7.95-7.87(m,2H),3.65-3.47(m,2H),2.14(t,J＝19.7Hz,3H),1.93(br s,6H),1.84-1.66(m,6H),1.47-1.35(m,6H)。FXR EC50(nM)＝18,MS(ESI)503(M+H)。
The following examples were synthesized according to the method described for the synthesis of example 1, by substituting intermediate 135A and the corresponding acid where appropriate.
Example 139
3- (4- (((1S,3S) -N- (3-bromophenyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamido) methyl) bicyclo [2.2.2] oct-1-yl) -1,2, 4-oxadiazole-5-carboxamide
Step A. preparation of intermediate 139A.4- (((3-bromophenyl) amino) methyl) bicyclo [2.2.2] octane-1-carboxylic acid
The title compound was synthesized according to the procedure described for the synthesis of intermediate 28C, by substituting intermediate 33C where appropriate: (1.9g, 5.62mmol, 99% yield) as a white solid. MS (ESI)338(M + H).
Step B. preparation of intermediate 139B.4- (((3-bromophenyl) amino) methyl) bicyclo [2.2.2] octane-1-carboxamide
The title compound was synthesized according to the procedure described for the synthesis of intermediate 1A, by substituting intermediate 139A where appropriate: (2.0g, 5.93mmol, 100% yield). MS (ESI)338(M + H).
Step C. preparation of intermediate 139C.4- (((3-bromophenyl) amino) methyl) bicyclo [2.2.2] octane-1-carbonitrile
To a stirred solution of intermediate 139B (2.0g, 5.93mmol) in pyridine (50mL) was added imidazole (1.009g, 14.83mmol) and cooled to 0 ℃. Dropwise addition of POCl to the cooled solution3(0.608mL, 6.52mmol) and the reaction mixture was allowed to gradually warm to room temperature over 5 h. The reaction mixture was diluted with cold water (100mL) and extracted with ethyl acetate (2 × 70 mL). The combined organic layers were washed with 1.5N aqueous HCl (4 × 50mL), water (100mL), and saturated aqueous brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (24g silica cartridge; a ═ Hex, B ═ EtOAc; 30min gradient; 0% B to 30% B; flow rate ═ 30 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound as a white solid (1.0g, 3.13mmol, 53% yield). MS (ESI)336(M +18) (NH) 4An adduct).
Step D. preparation of intermediate 139D. (Z) -4- (((3-bromophenyl) amino) methyl) -N' -hydroxybicyclo [2.2.2] octane-1-carboximidamide
The title compound was synthesized according to the procedure described for the synthesis of intermediate 1C, substituting intermediate 139C where appropriate: (1.0g, 2.84mmol, 91% yield) as a white solid. MS (ESI)352(M + H).
Step E. intermediate 139 E.preparation of intermediate 3- (4- (((3-bromophenyl) amino) methyl) bicyclo [2.2.2] oct-1-yl) -1,2, 4-oxadiazole-5-carboxamide
The title compound was synthesized according to the procedure described for the synthesis of intermediate 1D, by substituting intermediate 139D and 2-amino-2-oxoacetic acid where appropriate: (210mg, 52% yield) as an off-white solid. MS (ESI)405(M + H).
EXAMPLE 139.preparation of 3- (4- (((1S,3S) -N- (3-bromophenyl) -3-hydroxy-3- (trifluoromethyl) cyclobutane-1-carboxamido) methyl) bicyclo [2.2.2] oct-1-yl) -1,2, 4-oxadiazole-5-carboxamide
The title compound was prepared according to the procedure described for the synthesis of example 1, substituting intermediate 139E and the corresponding acid where appropriate: (12.8mg, 0.02mmol, 99% yield).1H NMR(400MHz,DMSO-d6)δ8.56(br d,J＝2.9Hz,1H),8.40-8.23(m,1H),7.71(s,1H),7.55(br d,J＝7.6Hz,1H),7.48-7.30(m,2H),6.63-6.48(m,1H),3.69-3.53(m,2H),3.18(s,1H),2.79-2.67(m,1H),2.39-2.27(m,2H),2.14-1.97(m,2H),1.86-1.69(m,6H),1.50-1.29(m,6H)。FXR EC50(nM)＝1450,MS(ESI)573(M+H)。
Example 140
3- (4- ((N- (3-bromophenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamido) methyl) bicyclo [2.2.2] oct-1-yl) -1,2, 4-oxadiazole-5-carboxamide
The title compound was prepared according to the procedure described for the synthesis of example 1, substituting intermediate 139E and the corresponding acid where appropriate: (28mg, 0.05mmol, 44% yield).1H NMR(400MHz,DMSO-d6)δ8.60-8.49(m,1H),8.32(br d,J＝1.2Hz,1H),7.71(s,1H),7.65-7.56(m,1H),7.49-7.36(m,2H),3.63-3.49(m,2H),1.97-1.67(m,10H),1.52-1.29(m,6H)。FXR EC50(nM)＝721,MS(ESI)519(M+H)。
Biological evaluation
Exemplary compounds of the invention were tested in a transient human FXR/Gal 4-luciferase reporter assay, and the assay results are reported in table 1 and examples 1 to 3, along with other analytical data.
Gal4-hFXR fusion construct reporter System was used as a preliminary assay to tabulateAnd (4) characterizing the activity of the compound. Stably expressing in HEK293 cells a construct comprising 5 copies of the Gal4 promoter response element upstream of the firefly luciferase reporter cDNA. The reporter cell line was humidified 5% CO2Maintained in Dulbecco 'S Modified Eagle' S medium (DMEM; Gibco) supplemented with 1% penicillin-streptomycin (P/S) solution, 500. mu.g/mL giberellin, and 10% charcoal/dextran treated fetal bovine serum (cs-FBS) at 37 ℃ in an atmosphere. Another plasmid was constructed in which the human cytomegalovirus promoter in the pcdna3.1 vector directed the expression of the cDNA encoding the fusion protein consisting of the DNA binding domain from Gal4 transcription factor fused to the ligand binding domain from human FXR.
The day before transfection, the reporter cells in culture were detached from the plates with trypsin and plated into T75 flasks at sufficient density to reach approximately 90% confluence the next morning. Transfection reagents were prepared by: mu.g of pcDNA3.1-Gal4-FXR plasmid was diluted to 1.87mL of Opti-MEM (Thermo-Fisher) and 40. mu.L of Lipofectamine 2000(Thermo-Fisher) was diluted to 1.87mL of Opti-MEM, respectively, and then the diluted DNA solution was added to the diluted Lipofectamine 2000 solution and incubated at room temperature for 15-20 minutes. The mixture was further diluted with 10mL of a solution consisting of DMEM, 10% cs-FBS and 1% P/S and immediately transferred to cells. The maintenance medium was aspirated from the cells and the final transfection mixture was added, then the cells were humidified in 5% CO2Incubate overnight at 37 ℃ under atmosphere. This protocol can be scaled up and transiently transfected cells can be cryopreserved in an assay ready format.
For compound testing, 100nL of compound (serial dilutions in DMSO) was dispensed into the wells of a 384-well white plate with Corning/Costar clear bottom using an Echo acoustic dispenser (Labcyte). Transfected cells were harvested, counted and diluted so that 10-25,000 cells in 25 μ Ι _ were plated into each well of a 384 well compound assay plate. Compound-treated cells in humidified 5% CO 2Incubate overnight at 37 ℃ under atmosphere.The following morning, 25 μ L of Steady-glo (promega) was added to each well of the plate, the mixture was incubated for 15min with shaking, and luminescence was measured on an envision (perkin elmer) plate reader. Background counts from cells treated with DMSO alone were subtracted from all raw counts and the correction values were converted to the percentage of control reactions obtained with 8 μ M GW-4064. Fitting these data to a 4 parameter log agonist-response equation to calculate EC50The value is obtained.
In vivo test examples: acute mouse PK/PD
Male C57BL6/NTac mice (body weight 25-28g) were purchased from Taconic Laboratories (Hadamson, N.Y.) and maintained on a Teklad Global 18% protein rodent diet (Harlan Laboratories). After 1 week of acclimation, mice were sorted into groups according to body weight. Mice were administered a single oral dose of vehicle or test compound. Systemic compound exposure was evaluated in plasma derived from blood collected via the inframandibular vein 1 hour after dosing and at the end of the study (6 h). At the end of the study, animals were euthanized and dissected rapidly. The inner lobe of the liver was divided, half of which was homogenized and analyzed for compound exposure, and the other half was stored in RNAlater (Thermo-Fisher Scientific). The ileum was also dissected and stored in RNAlater. Tissue samples from RNAlater were homogenized with MP Biomedicals beads. RNA was extracted using a MagMax-96 Total RNA isolation kit (Thermo-Fisher Scientific) according to the manufacturer's protocol. RNA concentration was determined using a Nano-Drop 8000 spectrophotometer (Thermo Fisher). According to the manufacturer's protocol, with Invitrogen Reverse transcription was performed with VILO cDNA synthesis kit. Real-time PCR was performed using Taqman PCR master mix from Applied Biosystems according to the manufacturer's protocol. All primers were purchased from Thermo-Fisher Scientific. The mouse genes analyzed included Nr0b2 in the liver (which encodes the small heterodimer partner SHP), Abcb11 (which encodes the bile salt excretion pump BSEP), Cyp7a1 and Cyp8b1, as well as Fgf15, Fabp6 (which encodes the ileal bile acid binding protein I-BABP), and Slc51a (which encodes the organic proteinSolute transporter alpha subunit OSTA) and Slc51b (which encodes organic solute transporter beta subunit OSTB). Statistically significant changes in FGF15 gene expression were expressed as fold increase and CYP as percent reduction relative to vehicle control7A1And (4) expressing.
Other features of the present invention should become apparent during the course of the above description of exemplary embodiments, which are given for the purpose of illustration and are not intended to limit the invention. The present invention may be embodied in other specific forms without departing from its spirit or essential attributes. The present invention encompasses all combinations of the preferred aspects of the invention described herein. It is to be understood that any and all embodiments of the present invention may be combined with any one or more other embodiments to describe additional embodiments. It is also to be understood that each individual element of an embodiment is an independent embodiment of its own. Moreover, any element of an embodiment is intended to describe additional embodiments in combination with any and all other elements from any embodiment.
- 上一篇：一种医用注射器针头装配设备
- 下一篇：用于治疗帕金森病的新儿茶酚胺前药