Substituted amide compounds useful as farnesoid X receptor modulators

文档序号：277438 发布日期：2021-11-19 浏览：37次中文

阅读说明：本技术 可用作类法尼醇x受体调节剂的经取代的酰胺化合物 (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是具有1至4个独立地选自N、O和S的杂原子的5元杂环基或5元杂芳基,其被0至4个R～(1)取代；并且A、X～(1)、X～(2)、X～(3)、X～(4)、Z～(1)、Z～(2)、R～(1)、R～(2)、R～(3a)、R～(3b)、a、b和d是本文中定义的。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失调相关的疾病、障碍或病症,诸如病理性纤维化、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 a 5-membered heterocyclyl or 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S, interrupted by 0 to 4R 1 Substitution; and A, X 1 、X 2 、X 3 、X 4 、Z 1 、Z 2 、R 1 、R 2 、R 3a 、R 3b 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 CR^5aOr N;

X²is CR^5bOr N;

X³is CR^5cOr N;

X⁴is CR^5dOr N; provided that X is¹、X²、X³And X⁴0, 1 or 2 of are N;

Z¹and Z²Independently is CH₂Or O; provided that Z is¹And Z²Is CH₂；

a is 0 or 1;

b is 0, 1 or 2;

d is 0, 1 or 2; provided that when a, b and d are each 0, Z¹And Z²Each is CH₂；

Q is C_2-6Alkenyl or C_2-6Alkynyl, each with 0 to 2R¹Substitution;

each R¹Independently is-C (O) OR^x、-C(O)NR^xR^x、C_1-4Hydroxyalkyl, 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 0 to 3R^1aSubstitution;

each R^1aIndependently of each otherIs halo, oxo, cyano, hydroxy, -NH₂、C_1-6Alkyl radical, C_1-6Alkoxy, -NH (C)_1-6Alkyl), -N (C)_1-6Alkyl radical)₂or-NR^xC(O)(C_1-6Alkyl) wherein each of the alkyl and alkoxy is substituted with 0 to 6R^1bSubstitution;

each R^1bIndependently is halo, hydroxy, -NR^wR^wOxo, cyano, C_1-3Alkoxy radical, C_1-3Haloalkoxy, -C (O) OR^x、-C(O)NR^wR^wor-NR^xC(O)R^y；

Or when X is¹Is CR^5aWhen Q and R are^5aCan be combined together to form-CR^1a＝CR¹CH₂CH₂-a bridge;

R²The method comprises the following steps:

(i)C_1-6alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy, or-NR^vR^vWherein each of said alkyl, alkenyl, alkynyl and alkoxy is substituted with 0 to 6R^2aSubstitution;

(ii)C_3-8carbocyclyl, C_6-8Spirobicyclic group, 4-to 7-membered heterocyclyl group, phenyl, or 5-to 6-membered heteroaryl, wherein each of said carbocyclyl, spirobicyclic group, heterocyclyl group, phenyl, and heteroaryl is substituted with 0 to 3R^2bSubstitution; or

(iii)-CH₂(C_3-6Cycloalkyl), -CH₂(4-to 6-membered heterocyclyl), -NR^x(CH₂)_0-2(C_3-6Cycloalkyl), -NR-^x(CH₂)_0-2(C_5-8Bicycloalkyl), -NR^x(CH₂)_0-2(C_5-8Spiro bicyclic group), -NR^x(CH₂)_0-2(4-to 6-membered heterocyclyl), -NR^x(CH₂)_0-2(5-to 6-membered heteroaryl), -NR^x(CH₂)_0-2(phenyl), -O (CH)₂)_0-2(C_3-6Cycloalkyl), -O (CH)₂)_0-2(C_5-8Bicycloalkyl), -O (CH₂)_0-2(C_5-8Spiro bicyclic group), -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, spirobicyclyl, aryl, and heteroaryl is substituted with 0 to 3R^2bSubstitution;

each R^2aIndependently is halo, cyano, hydroxy, oxo, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy, -NR^xR^x、-C(O)(C_1-6Alkyl), -C (O) (C)_3-6Cycloalkyl), -NR-^xC(O)R^y、-C(O)(C_1-6Alkyl), -C (O) OR^x、-C(O)NR^wR^w、-S(O)₂R^y、-S(O)₂(C_1-3Fluoroalkyl group), -NR^xS(O)₂(C_1-3Alkyl), -NR-^xS(O)₂(C_3-6Cycloalkyl), -S (O)₂NR^zR^zor-P (O) R^yR^y；

Each R^2bIndependently is halo, cyano, hydroxy, oxo, C _1-6Alkyl radical, C_1-6Alkoxy, -NR^xR^x、-NR^xC(O)O(C_1-3Alkyl), -C (O) (C)_1-3Alkyl), or-S (O)₂(C_1-3Alkyl) wherein each of the alkyl and alkoxy is substituted with 0 to 6R^2aSubstitution;

R^3aand R^3bIndependently of each other is hydrogen, C_1-3Alkyl radical, C_1-3Haloalkyl, or C_3-6Cycloalkyl, or R^3aAnd R^3bTogether with the carbon atom to which they are attached form C_3-6A 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 0 to 3R^4aSubstitution; or

Each R^4aIndependently is halo, cyano, hydroxy, -NH₂、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy, - (CH)₂)_0-3NH(C_1-6Alkyl), - (CH)₂)_0-2N(C_1-6Alkyl radical)₂、-(CH₂)_0-3(C_3-6Cycloalkyl), or- (CH)₂)_0-3(4-to 6-membered heterocyclyl), wherein each of the alkyl, alkoxy, alkenyl, and alkynyl is substituted with 0 to 6R^4dAnd each of said cycloalkyl and heterocyclyl is substituted with 0 to 3R^4eSubstitution;

R^4bis C_1-6Alkyl, - (CH)₂)_0-3(C_3-6Cycloalkyl), or- (CH)₂)_0-3(4-to 6-membered heterocyclyl), wherein each of said alkyl groups is substituted with 0 to 6R^4dAnd each of said cycloalkyl and heterocyclyl is substituted with 0 to 3R^4eSubstitution;

each R^4cIndependently of each other is hydrogen, C_1-6Alkyl radical, C_3-6Cycloalkyl, 4-to 6-membered heterocyclyl, phenyl, or 5-to 6-membered heteroaryl;

Each R^4dIndependently is halo, hydroxy, -NR^xR^xOxo, cyano, C_1-3Alkoxy, or C_1-3A haloalkoxy group;

each R^4eIndependently is halo, oxo, cyano, hydroxy, -NH₂、C_1-6Alkyl radical, C_1-6Alkoxy, -NH (C)_1-6Alkyl), or-N (C)_1-6Alkyl radical)₂Wherein each of said alkyl and alkoxy groups is substituted with 0 to 6R^4dSubstitution;

R^5a、R^5b、R^5cand R^5dEach independently is hydrogen, halo, hydroxy, cyano, substituted with 0 to 6R^5eSubstituted C_1-6Alkyl, by 0 to 6R^5eSubstituted C_1-6Alkoxy, -C (O) OR^x、-C(O)NR^wR^w、-S(O)₂R^y、-S(O)₂NR^zR^zOr by 0 to 3R^5fA substituted phenyl group, which is substituted,

each R^5eIndependently is halo, hydroxy, -NR^xR^xOxo, cyano, C_1-3Alkoxy, or C_1-3A haloalkoxy group;

each R^5fIndependently is halo, oxo, cyano, hydroxy, -NH₂、C_1-6Alkyl radical, C_1-6Alkoxy, -NH (C)_1-6Alkyl), or-N (C)_1-6Alkyl radical)₂Wherein each of said alkyl and alkoxy groups is substituted with 0 to 6R^5eSubstitution;

each R^vIndependently of each other is hydrogen, C_1-6Alkyl or alternatively, two R^vTogether with the nitrogen atom to which they are attached form a 4-to 7-membered bicyclic or spirocyclic moiety containing 0 to 2 additional heteroatoms independently selected from N, O and S, wherein each ring may be interrupted by 0 to 6R^2aSubstitution;

each R^wIndependently of each other is hydrogen, C _1-6Alkyl, or C_3-6A cycloalkyl group; or alternatively, two R^wTogether with the nitrogen atom to which they are attached form a 4 to 7 membered ring moiety containing 0 to 2 additional heteroatoms independently selected from N, O and S;

each R^xIndependently of each other is hydrogen, C_1-6Alkyl, or C_3-6A cycloalkyl group;

R^yis C_1-6Alkyl or C_3-6A cycloalkyl group; and is

Each R^zIndependently of each other is hydrogen, C_1-6Alkyl, or C_3-6A cycloalkyl group; or alternatively, two R^zTogether with the nitrogen atom to which they are attached form a 4 to 7 membered ring moiety containing 0 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-CR^1c＝CR^1cR¹or-C.ident.CR¹；

R¹is-C (O) OR^x、-C(O)NR^xR^x、C_1-4Hydroxyalkyl, or a cyclic group selected from 5 to 6 membered heteroaryl, wherein the cyclic group is substituted with 0 to 3R^1aSubstitution;

each R^1aIndependently F, Cl, oxo, cyano, hydroxy, -NH₂、C_1-4Alkyl radical, C_1-4Alkoxy, -NH (C)_1-4Alkyl), -N (C)_1-4Alkyl radical)₂or-NR^xC(O)(C_1-4Alkyl) wherein each of the alkyl and alkoxy is substituted with 0 to 4R^1bSubstitution;

each R^1bIndependently F, Cl, hydroxy, -NR^wR^wCyano, C_1-3Alkoxy, or C_1-3A fluoroalkoxy group;

Each R^1cIndependently is H or-CH₃；

Or when X is¹Is CR^5a，X²Is CR^5b，X³Is CR^5c，X⁴Is CR^5dThen Q and R^5aCan be combined together to form-CR^1a＝CR¹CH₂CH₂-a bridge;

R²the method comprises the following steps:

(i)C_1-4alkyl radical, C_1-4Alkoxy, or-NR^vR^vWherein each of said alkyl and alkoxy groups is substituted with 0 to 4R^2aSubstitution;

(ii)C_3-8carbocyclyl, C_6-8Spirobicyclic group, phenyl, or 4-to 7-membered heterocyclyl, wherein each of said carbocyclic, spirobicyclic, and heterocyclyl is substituted with 0 to 3R^2bSubstitution; or

(iii)-CH₂(C_3-5Cycloalkyl), -CH₂(4-to 6-membered heterocyclyl), -NR^x(CH₂)_0-2(C_3-5Cycloalkyl), -NR-^x(CH₂)_0-2(4-to 6-membered heterocyclyl), -NR^x(CH₂)_0-2(phenyl), -O (phenyl), or-S (O)₂(C_3-6Cycloalkyl), wherein each of said cycloalkyl, heterocyclyl and phenyl is substituted with 0 to 3R^2bSubstitution;

each R^2aIndependently F, Cl, hydroxy, -NR^xR^xOxo, cyano, C_1-3Alkoxy radical, C_1-3Haloalkoxy, or-C (O) OH;

each R^2bIndependently F, Cl, cyano, hydroxy, C_1-4Alkyl radical, C_1-3Alkoxy, -NR^xR^x、-NR^xC(O)O(C_1-3Alkyl), -C (O) (C)_1-2Alkyl), or-S (O)₂(C_1-2Alkyl) wherein each of the alkyl and alkoxy is substituted with 0 to 4R^2aSubstitution;

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 0 to 3R ^4aSubstitution; or

Each R^4aIndependently F, Cl, cyano, hydroxy, -NH₂、C_1-4Alkyl radical, C_1-4Alkoxy, - (CH)₂)_0-3NH(C_1-6Alkyl), - (CH)₂)_0-3N(C_1-6Alkyl radical)₂、-(CH₂)_0-3(C_3-6Cycloalkyl), or- (CH)₂)_0-3(4-to 6-membered heterocyclyl), wherein each of the alkyl and alkoxy is substituted with 0 to 4R^4dAnd each of said cycloalkyl and heterocyclyl is substituted with 0 to 3R^4eSubstitution;

R^4bis C_1-4Alkyl, - (CH)₂)_0-3(C_3-6Cycloalkyl), or- (CH)₂)_0-3(4-to 6-membered heterocyclyl), wherein each of said alkyl groups is substituted with 0 to 4R^4dAnd each of said cycloalkyl and heterocyclyl is substituted with 0 to 3R^4eSubstitution;

each R^4cIndependently of each other is hydrogen, C_1-3Alkyl, or C_3-6A cycloalkyl group;

each R^4dIndependently F, Cl, hydroxy, -NR^xR^xOxo, cyano, C_1-3Alkoxy, or C_1-3A fluoroalkoxy group;

each R^4eIndependently F, Cl, oxo, cyano, hydroxy, -NH₂、C_1-4Alkyl radical, C_1-4Alkoxy, or-NH (C)_1-6Alkyl), or-N (C)_1-6Alkyl radical)₂Wherein each of said alkyl and alkoxy groups is substituted with 0 to 4R^4dSubstitution;

R^5a、R^5b、R^5cand R^5dEach of which is independently hydrogen, F, Cl, hydroxy, cyano, substituted with 0 to 4R^5eSubstituted C_1-3Alkyl, by 0 to 4R^5eSubstituted C_1-3Alkoxy, -C (O) OR^x、-C(O)NR^wR^w、-S(O)₂R^y、-S(O)₂NR^zR^zOr by 0 to 3R^5fSubstituted phenyl;

each R^wIndependently of each other is hydrogen, C _1-4Alkyl, or C_3-6A cycloalkyl group; or alternatively, two R^wTogether with the nitrogen atom to which they are attached form a 4 to 7 membered ring moiety containing 0 to 2 additional heteroatoms independently selected from N, O and S;

each R^xIndependently is H, C_1-4Alkyl, or C_3-6A cycloalkyl group;

R^yis C_1-4Alkyl or C_3-6A cycloalkyl group; and is

Each R^zIndependently of each other is hydrogen, C_1-4Alkyl, or C_3-6A cycloalkyl group; or alternatively, two R^zTogether with the nitrogen atom to which they are attached form a group containing 0 to 2 furtherAn outer 4 to 7 membered ring moiety of a heteroatom 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 CH;

a is 1;

b is 1;

d is 1;

q is-CH ═ CHC (O) OH, -CH ═ CHC (O) OCH₃、-C(CH₃)＝CHC(O)OCH₃、-CH＝CHC(O)N(CH₃)₂-CH-CH (methyloxadiazole), or-C.ident.CC (CH)₃)₂OH；

R²is-CH (CH)₃)₂Or a cyclic group selected from cyclobutyl, cyclohexyl, cycloheptyl, bicyclo [1.1.1]Pentyl, piperidinyl, and tetrahydropyranyl, each cyclic group being independently selected from F and-CH by 0 to 1₃Substituted with the substituent(s);

R^3ais hydrogen or-CH₃；

R^3bIs hydrogen;

a is oxadiazolyl, phenyl, indazolyl, or benzothiazolyl, each substituted with 0 to 1R ^4aSubstitution; and is

Each R^4aIndependently is-CH₃、-CH(CH₃)₂、-C(CH₃)₃、-CH(CH₃)₂、-CF₂CH₃、-OCH₃、-N(CH₃)₂、-N(CH₂CH₃)₂Or a cyclic group selected from cyclopropyl, azetidinyl, pyrrolidinyl, tetrahydropyranyl, and morpholinyl.

4. A compound according to claim 1 or a stereoisomer, tautomer, or salt or solvate thereofAn agent of formula wherein Z¹Is CH₂(ii) a And Z₂Is CH₂。

5. A compound according to claim 1, or a stereoisomer, tautomer, or salt or solvate thereof, wherein Z is¹And Z²One of them is CH₂And Z is¹And Z²Is O.

6. The compound of claim 1, 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 0 to 3R^4aAnd (4) substitution.

7. The compound according to claim 1, or a salt thereof, wherein the compound has the structure of formula (II):

wherein

R¹is-C (O) OR^x、-C(O)NR^xR^xOr C_1-4A hydroxyalkyl group; and is

Each R^xIndependently is hydrogen or-CH₃。

8. The compound of claim 1, or a stereoisomer, tautomer, or salt or solvate thereof, wherein A is oxadiazolyl or phenyl, each substituted with 0 to 1R ^4aAnd (4) substitution.

9. The compound of claim 1, or a stereoisomer, tautomer, or salt or solvate thereof, wherein the compound is:

(E) -methyl 3- (3- (N- ((4- (4- (dimethylamino) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate (1);

(E) -3- (3- (N- ((4- (4- (dimethylamino) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylic acid (2);

(E) -methyl 3- (3- (N- ((4- (4-morpholinophenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate (3);

(E) -methyl 3- (3- (N- ((4- (4- (pyrrolidin-1-yl) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate (4);

(E) -methyl 3- (3- (N- ((4- (4- (azetidin-1-yl) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate (5);

(E) -methyl 3- (3- (N- ((4- (4- (dimethylamino) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) tetrahydro-2H-pyran-4-carboxamido) phenyl) acrylate (6);

(E) -methyl 3- (3- (N- ((4-phenylbicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate (7);

(E) -methyl 3- (3- (N- ((1- (1-methyl-1H-indazol-5-yl) -2-oxabicyclo [2.2.2] oct-4-yl) methyl) tetrahydro-2H-pyran-4-carboxamido) phenyl) acrylate (8);

(E) -methyl 3- (3- (1-methyl-N- ((1- (1-methyl-1H-indazol-5-yl) -2-oxabicyclo [2.2.2] oct-4-yl) methyl) piperidine-4-carboxamido) phenyl) acrylate (9);

(E) -methyl 3- (3- (N- ((1- (4-methoxyphenyl) -2-oxabicyclo [2.2.2] oct-4-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate (10);

(E) -methyl 3- (3- (N- ((4- (4-morpholinophenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) but-2-enoate (14);

(E) -methyl 3- (3- (N- ((4- (4-methoxyphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate (15);

(E) -methyl 3- (3- (N- ((4- (4-methoxyphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) but-2-enoate (16);

(E) -methyl 3- (3- (N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) but-2-enoate (19);

(E) -methyl 3- (3- (N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate (20);

(E) -methyl 3- (3- (N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclopropanecarboxamido) phenyl) acrylate (21);

(E) -methyl 3- (3- (N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) isobutyramido) phenyl) acrylate (22);

(E) -methyl 3- (3- (N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) tetrahydro-2H-pyran-4-carboxamido) phenyl) acrylate (23);

(E) -methyl 3- (3- (N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cycloheptanecarboxamido) phenyl) acrylate (24);

(E) -methyl 3- (3- (3-fluoro-N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) bicyclo [1.1.1] pentane-1-carboxamido) phenyl) acrylate (25);

(E) -methyl 3- (3- (3, 3-difluoro-N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclobutane-1-carboxamido) phenyl) acrylate (26);

(E) -N- (3- (3- (dimethylamino) -3-oxoprop-1-en-1-yl) phenyl) -N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamide (27);

(E) -methyl 3- (3- (N- ((4- (4-cyclopropylphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclopropanecarboxamido) phenyl) acrylate (28);

(E) -methyl 3- (3- (N- ((4- (4-cyclopropylphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate (29);

(E) -methyl 3- (3- (N- ((4- (benzo [ d ] thiazol-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclopropanecarboxamido) phenyl) acrylate (33);

(E) -methyl 3- (3- (N- ((4- (benzo [ d ] thiazol-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate (34);

(E) -N- ((4- (4-methoxyphenyl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (2- (3-methyl-1, 2, 4-oxadiazol-5-yl) vinyl) phenyl) cyclohexanecarboxamide (35);

(E) -methyl 3- (3- (N- ((4- (4-cyclopropylphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclopropanecarboxamido) phenyl) but-2-enoate (36);

(E) -methyl 3- (3- (N- ((4- (4-cyclopropylphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) but-2-enoate (37);

(E) -methyl 3- (3- (N- ((4- (4-isopropylphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate (38);

(E) -methyl 3- (3- (N- ((4- (4-isopropylphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclopropanecarboxamido) phenyl) acrylate (39);

(E) -methyl 3- (3- (N- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate (41);

(E) -methyl 3- (3- (N- ((4- (3-morpholino-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate (42);

(E) -methyl 3- (3- (N- ((4- (3- (tetrahydro-2H-pyran-4-yl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate (43);

(E) -methyl 3- (3- (N- ((4- (5-methyl-1, 2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate (44);

(E) -methyl 3- (3- (N- (1- (4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) ethyl) cyclohexanecarboxamido) phenyl) acrylate (46-47);

n- ((4- (5- (tert-butyl) -1,3, 4-oxadiazol-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3- (3-hydroxy-3-methylbut-1-yn-1-yl) phenyl) bicyclo [1.1.1] pentane-1-carboxamide (48); or

N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3- (3-hydroxy-3-methylbut-1-yn-1-yl) phenyl) bicyclo [1.1.1] pentane-1-carboxamide (49).

10. The compound of claim 1, or a stereoisomer, tautomer, or salt or solvate thereof, wherein the compound is:

methyl 5- (N- ((4- (4-morpholinophenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamide) -3, 4-dihydronaphthalene-2-carboxylate (11);

methyl 5- (N- ((4- (4- (dimethylamino) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamide) -3, 4-dihydronaphthalene-2-carboxylate (12);

methyl 5- (N- ((4- (4- (diethylamino) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamide) -3, 4-dihydronaphthalene-2-carboxylate (13);

5- (N- ((4- (4-methoxyphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) -3, 4-dihydronaphthalene-2-carboxylic acid (17);

methyl 5- (N- ((4- (4-methoxyphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamide) -3, 4-dihydronaphthalene-2-carboxylate (18);

methyl 5- (N- ((4- (4-cyclopropylphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamide) -3, 4-dihydronaphthalene-2-carboxylate (30);

methyl 5- (N- ((4- (4-cyclopropylphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclopropanecarboxamido) -3, 4-dihydronaphthalene-2-carboxylate (31);

methyl 5- (N- ((4- (4-cyclopropylphenyl) bicyclo [2.2.2] oct-1-yl) methyl) isobutyramido) -3, 4-dihydronaphthalene-2-carboxylate (32);

methyl 5- (N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamide) -3, 4-dihydronaphthalene-2-carboxylate (40); or

Methyl 5- (N- ((1- (1-methyl-1H-indazol-5-yl) -2-oxabicyclo [2.2.2] oct-4-yl) methyl) cyclohexanecarboxamide) -3, 4-dihydronaphthalene-2-carboxylate (45).

11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any one of claims 1 to 10, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

12. A compound according to any one of claims 1 to 10, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, for use in therapy.

13. A compound according to any one of claims 1 to 10, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, for use in the treatment of pathological fibrosis, cancer, inflammatory disorders, metabolic or cholestatic disorders.

14. The compound for use according to claim 13, wherein the pathological fibrosis is liver fibrosis, kidney fibrosis, biliary fibrosis, or pancreatic fibrosis.

15. A compound according to any one of claims 1 to 10, 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).

16. A compound according to any one of claims 1 to 10, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, for use in the treatment of Idiopathic Pulmonary Fibrosis (IPF).

Background

FXR or NR1H4 (nuclear receptor subfamily 1, group H, member 4) is a nuclear receptor that can activate the expression of specific target genes in a ligand-dependent manner. FXR is expressed in the liver, the entire gastrointestinal tract, colon, ovary, adrenal gland, kidney, and 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 an inverted repeat of a consensus hexanucleotide sequence (AGGTCA) separated by a single nucleotide (i.e., an IR-1 sequence). 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). Activation of FXR regulates the expression of multiple genes encoding enzymes and transporters involved in bile acid synthesis, influx, and efflux from 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 cytokine fibroblast growth factor 15 (rodent) or 19 (primate), 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 in the treatment of diseases of bile acid disorders, including those which may lead to fibrosis, cirrhosisChemosis, cholangiocarcinoma, hepatocellular carcinoma, liver failure, and dead cholestatic diseases (e.g., primary biliary cirrhosis and primary sclerosing cholangitis). 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 injury, which may lead to bacterial translocation across mucosal barriers and systemic infection (Berg, Trends microbiol.1995; 3: 149-154). 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 can be eradicated by selective reactivation of FXR in the gut (Degirolamo et al, Hepatology 61: 161-170). Pharmacological activation of FXR or transgene expression of FXR in the gut with small molecule agonists normalizes bile acid concentrations, reduces cell proliferation in hepatobiliary ducts, and reduces inflammatory cell infiltration, necrotic regions and liver fibrosis in rodent models of cholestasis (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 also regulate liver expression of hundreds of genes encoding proteins involved in pathways for cholesterol and lipid metabolism and transport, glucose homeostasis, inflammation, chemotaxis, and apoptosis (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 (Crawley, Expert opin. ther. patents 2010; 20: 1047-.

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 The 2011; 34: 274-. Risk factors for developing 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 histological findings of hepatic steatosis, inflammation and ballooning degeneration with varying 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 liver biopsy histological analysis (Neuschwender-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 potentially show benefit to 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 for their pharmaceutical utility.

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 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 making the compounds of formula (I) and/or salts thereof.

The compounds of the present invention may be used to treat a disease, disorder or condition associated with the activity of Farnesoid X Receptors (FXR) in a patient in need of such treatment 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 invention may be used as single agents or in combination with other agents for the treatment of a disease, disorder or condition selected from the group consisting of nonalcoholic steatohepatitis (NASH), nonalcoholic steatohepatitis (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. In addition, the present application provides methods for treating a patient suffering from FXR modulated diseases or disorders, 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 CR^5aOr N;

X²is CR^5bOr N;

X³is CR^5cOr N;

X⁴is CR^5dOr N; provided that X is¹、X²、X³And X⁴0, 1 or 2 of are N;

Z¹and Z²Independently is CH₂Or O; provided that Z is¹And Z²Is CH₂；

a is 0 or 1;

b is 0, 1 or 2;

d is 0, 1 or 2; provided that when a, b and d are each 0, Z¹And Z²Each is CH₂；

Q is C_2-6Alkenyl or C_2-6Alkynyl, each with 0 to 2R¹Substitution;

each R^1aIndependently is halo, oxo, cyano, hydroxy, -NH₂、C_1-6Alkyl radical, C_1-6Alkoxy, -NH (C)_1-6Alkyl), -N (C)_1-6Alkyl radical)₂or-NR^xC(O)(C_1-6Alkyl) wherein each of the alkyl and alkoxy is substituted with 0 to 6R^1bSubstitution;

each R^1bIndependently is halo, hydroxy, -NR^wR^wOxo, cyano, C_1-3Alkoxy radical, C_1-3Haloalkoxy, -C (O) OR^x、-C(O)NR^wR^wor-NR^xC(O)R^y；

Or when X is¹Is CR^5aWhen Q and R are ^5aCan be combined together to form-CR^1a＝CR¹CH₂CH₂-a bridge;

R²the method comprises the following steps:

(i)C_1-6alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy, or-NR^vR^vWherein each of said alkyl, alkenyl, alkynyl and alkoxy is substituted with 0 to 6R^2aSubstitution;

(ii)C_3-8carbocyclyl, C_6-8Spirobicyclic group, 6-to 7-membered heterocyclyl group, phenyl, or 5-to 6-membered heteroaryl group, wherein each of said carbocyclyl, spirobicyclic group, heterocyclyl group, phenyl, and heteroaryl group is substituted with 0 to 3R^2bSubstitution; or

(iii)-CH₂(C_3-6Cycloalkyl), -CH₂(4-to 6-membered heterocyclyl), -NR^x(CH₂)_0-2(C_3-6Cycloalkyl), -NR-^x(CH₂)_0-2(C_5-8Bicycloalkyl), -NR^x(CH₂)_0-2(C_5-8Spiro bicyclic group), -NR^x(CH₂)_0-2(4-to 6-membered heterocyclyl), -NR^x(CH₂)_0-2(5-to 6-membered heteroaryl), -NR^x(CH₂)_0-2(phenyl), -O (CH)₂)_0-2(C_3-6Cycloalkyl), -O (CH)₂)_0-2(C_5-8Bicycloalkyl), -O (CH)₂)_0-2(C_5-8Spiro bicyclic group), -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, spirobicyclyl, aryl, and heteroaryl is substituted with 0 to 3R^2bSubstitution;

each R^2aIndependently is halo, alkyl, cyano, hydroxy, oxo, C_1-3Alkoxy radical, C_1-3Haloalkoxy, -NR^xR^x、C_1-3Haloalkyl, -C (O) (C)_1-6Alkyl), -C (O) (C)_3-6Cycloalkyl), -NR-^xC(O)R^y、-C(O)(C_1-6Alkyl), -C (O) OR^x、-C(O)NR^wR^w、-S(O)₂R^y、-S(O)₂(C_1-3Fluoroalkyl group), -NR^xS(O)₂(C_1-3Alkyl), -NR-^xS(O)₂(C_3-6Cycloalkyl), -S (O) ₂NR^zR^zor-P (O) R^yR^y；

Each R^2bIndependently is halo, cyano, hydroxy, oxo, C_1-6Alkyl radical, C_1-6Alkoxy, -NR^xR^x、-NR^xC(O)O(C_1-3Alkyl), -C (O) (C)_1-3Alkyl), or-S (O)₂(C_1-3Alkyl) wherein each of the alkyl and alkoxy is substituted with 0 to 6R^2aSubstitution;

a is:

(i) a cyano group;

(iii)

each R^4cIndependently of each other is hydrogen, C_1-6Alkyl radical, C_3-6Cycloalkyl, 4-to 6-membered heterocyclyl, phenyl, or 5-to 6-membered heteroaryl;

each R^4dIndependently is halo, hydroxy, -NR^xR^xOxo, oxoRadical, cyano radical, C_1-3Alkoxy, or C_1-3A haloalkoxy group;

each R^5eIndependently is halo, hydroxy, -NR^xR^xOxo, cyano, C_1-3Alkoxy, or C_1-3A haloalkoxy group;

each R^5fIndependently is halo, oxo, cyano, hydroxy, -NR^xR^xFrom 0 to 6R^5eSubstituted C_1-6Alkyl, by 0 to 6R^5eSubstituted C_1-6Alkoxy, or substituted by 0 to 6R^5eSubstituted (C)_1-6Alkyl) amino;

each R^wIndependently of each other is hydrogen, C_1-6Alkyl, or C_3-6A cycloalkyl group; or alternatively, two R^wTogether with the nitrogen atom to which they are attached form a 4 to 7 membered ring moiety containing 0 to 2 additional heteroatoms independently selected from N, O and S;

each R^xIndependently of each other is hydrogen, C_1-6Alkyl, or C_3-6A cycloalkyl group;

R^yis C_1-6Alkyl or C_3-6A cycloalkyl group; and is

In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein X¹Is CR^5a；X²Is CR^5b；X³Is CR^5c；X⁴Is CR^5d. The compounds of this embodiment have the structure of formula (Ia):

this embodiment includes wherein R^5a、R^5b、R^5cAnd R^5dAre each a compound of hydrogen.

In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein X¹Is CR^5aOr N; x²Is CR^5bOr N; x³Is CR^5cOr N; x⁴Is CR^5dOr N; and X¹、X²、X³And X⁴One is 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):

This embodiment includes wherein R^5a、R^5b、R^5cAnd R^5dEach of which isA compound of hydrogen.

In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein X¹Is CR^5aOr N; x²Is CR^5bOr N; x³Is CR^5cOr N; x⁴Is CR^5dOr 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):

this embodiment includes wherein R^5a、R^5b、R^5cAnd R^5dAre each a compound of hydrogen.

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):

this embodiment includes compounds wherein each of a, b, and d is 1. This embodiment also includes compounds wherein each of a, b, and d is 0. In addition, this embodiment also includes compounds wherein each of a, b, and d is 2.

In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein Z is ¹And Z²One of themIs CH₂And Z is¹And Z²Is O. The compounds of this embodiment have the structure of formula (Im) and the structure of formula (In):

In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein X¹Is CR^5aAnd Q and R^5aAre linked together to form-CR^1a＝CR¹CH₂CH₂-. The compounds of this embodiment have the structure of formula (II):

in this embodiment include wherein Z¹And Z²Each is CH₂The compound of (1). This embodiment also includes compounds wherein a, b, and d are each 1. This embodiment additionally includes compounds wherein R is¹is-C (O) OR^x、-C(O)NR^xR^xOr C_1-4A hydroxyalkyl group; and each R^xIndependently is hydrogen or-CH₃。

In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein Q is substituted with 0 to 2R¹Substituted C_2-6An alkenyl group. This embodiment includes compounds wherein Q is-CR ^1c＝CR^1cR¹And each R^1cIndependently is H or-CH₃. This embodiment also includes compounds wherein Q is-CH ═ chc (o) OH, -CH ═ chc (o) OCH₃、-C(CH₃)＝CHC(O)OCH₃、-CH＝CHC(O)N(CH₃)₂or-CH ═ CH (methyl oxadiazole).

In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein Q is-CR^1c＝CR^1cR¹And the compound has the structure of formula (Ip):

this embodiment includes compounds wherein R is¹is-C (O) OR^x、-C(O)NR^xR^x、C_1-4Hydroxyalkyl, or a cyclic group selected from 5 to 6 membered heteroaryl, wherein the cyclic group is substituted with 0 to 3R^1aAnd (4) substitution. This embodiment also includes compounds wherein each R is^xIndependently is H, C_1-4Alkyl, or C_3-6A cycloalkyl group.

In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein Q is substituted with 0 to 2R¹Substituted C_2-6Alkynyl. This embodiment includes compounds wherein Q is-C ≡ CR¹. This embodiment also includes compounds wherein Q is-C ≡ CC (CH)₃)₂OH。

In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein a is cyano. This embodiment includes compounds wherein X ¹、X²、X³And X⁴Each is CH. This embodiment also includes compounds wherein Z¹And Z²Each 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 containing 1 to 4 heteroatoms independently selected from N, O and S5 to 10 membered heteroaryl, wherein each of said phenyl and heteroaryl is substituted with 0 to 3R^4aSubstitution; or

(ii)

This embodiment includes compounds 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 0 to 3R^4aSubstitution; or

(ii)

This embodiment also includes compounds wherein each R is^4aIndependently F, Cl, cyano, hydroxy, -NH₂、C_1-4Alkyl radical, C_1-4Alkoxy, - (CH)₂)_0-3NH(C_1-6Alkyl), - (CH)₂)_0-3N(C_1-6Alkyl radical)₂、-(CH₂)_0-3(C_3-6Cycloalkyl), or- (CH)₂)_0-3(4-to 6-membered heterocyclyl), wherein each of the alkyl and alkoxy is substituted with 0 to 4R^4dSubstitution; and each of said cycloalkyl and heterocyclyl is substituted with 0 to 3R^4eSubstitution; r^4bIs C_1-4Alkyl, - (CH)₂)_0-3(C_3-6Cycloalkyl), or- (CH)₂)_0-3(4-to 6-membered heterocyclyl), wherein each of said alkyl groups is substituted with 0 to 4R ^4dAnd each of said cycloalkyl and heterocyclyl is substituted with 0 to 3R^4eSubstitution; each R^4cIndependently of each other is hydrogen, C_1-3Alkyl, or C_3-6A cycloalkyl group; each R^4dIndependently F, Cl, hydroxy, -NR^xR^xOxo, cyano, C_1-3Alkoxy, or C_1-3A fluoroalkoxy group; and each R^4eIndependently F, Cl, oxo, cyano, hydroxy, -NH₂、C_1-4Alkyl radical, C_1-4Alkoxy, or-NH (C)_1-6Alkyl), or-N (C)_1-6Alkyl radical)₂Wherein each of said alkyl and alkoxy groups is substituted with 0 to 4R^4dAnd (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, interrupted with 0 to 3R^4aAnd (4) substitution. This embodiment includes 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 substituted with 0 to 3R^4aAnd (4) substitution. This embodiment also includes compounds wherein a is oxadiazolyl, oxazolyl, phenyl, pyrazolyl, pyridyl, pyrimidinyl, or thiazolyl, each substituted with 0 to 2R ^4aSubstitution; and each R^4aIndependently is-CH₃、-CH(CH₃)₂、-C(CH₃)₃、-CH(CH₃)₂、-CF₂CH₃、-OCH₃、-N(CH₃)₂、-N(CH₂CH₃)₂Or a cyclic group selected from cyclopropyl, azetidinyl, pyrrolidinyl, tetrahydropyranyl, and morpholinyl. This embodiment also includes compounds wherein A is oxadiazolyl, phenyl, indazolyl, or benzothiazolyl, each substituted with 0 to 1R^4aSubstitution; and each R^4aIndependently is-CH₃、-CH(CH₃)₂、-C(CH₃)₃、-CH(CH₃)₂、-CF₂CH₃、-OCH₃、-N(CH₃)₂、-N(CH₂CH₃)₂Or a cyclic group selected from cyclopropyl, azetidinyl, pyrrolidinyl, tetrahydropyranyl, and morpholinyl.

In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein a is:

this embodiment includes compounds wherein R is^4bIs C_1-4Alkyl, - (CH)₂)_0-3(C_3-6Cycloalkyl), or- (CH)₂)_0-3(4-to 6-membered heterocyclyl), wherein each of said alkyl groups is substituted with 0 to 4R^4dAnd each of said cycloalkyl and heterocyclyl is substituted with 0 to 3R^4eSubstitution; each R^4cIndependently of each other is hydrogen, C_1-3Alkyl, or C_3-6A cycloalkyl group; each R^4dIndependently F, Cl, hydroxy, -NR^xR^xOxo, cyano, C_1-3Alkoxy, or C_1-3A fluoroalkoxy group; and each R^4eIndependently F, Cl, oxo, cyano, hydroxy, -NH ₂、C_1-4Alkyl radical, C_1-4Alkoxy, or-NH (C)_1-6Alkyl), or-N (C)_1-6Alkyl radical)₂Wherein each of said alkyl and alkoxy groups is substituted with 0 to 4R^4dAnd (4) substitution.

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: (i) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy, or-NR^vR^vWherein each of said alkyl, alkenyl, alkynyl and alkoxy is substituted with 0 to 6R^2aSubstitution; or (ii) C_3-8Carbocyclyl, C_6-8Spirobicyclic group, 4-to 7-membered heterocyclic group, phenyl group, or 5A to 6-membered heteroaryl, wherein each of said carbocyclyl, spirobicyclic, heterocyclyl, phenyl and heteroaryl is substituted with 0 to 3R^2bAnd (4) substitution. This embodiment includes compounds wherein R is²The method comprises the following steps: (i) c_1-4Alkyl radical, C_1-4Alkoxy, or-NR^vR^vWherein each of said alkyl and alkoxy groups is substituted with 0 to 4R^2aSubstitution; or (ii) C_3-8Carbocyclyl, C_6-8Spirobicyclic group, phenyl, or 4-to 7-membered heterocyclyl, wherein each of said carbocyclic, spirobicyclic, and heterocyclyl is substituted with 0 to 3R^2bAnd (4) substitution. This embodiment also includes compounds wherein R is₂Is a cyclic group selected from the group consisting of cyclobutyl, cyclohexyl, cycloheptyl, bicyclo [1.1.1 ]Pentyl, piperidinyl and tetrahydropyranyl, each cyclic group being independently selected from F and-CH by 0 to 1₃Is 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 is²is-CH₂(C_3-6Cycloalkyl), -CH₂(4-to 6-membered heterocyclyl), -NR^x(CH₂)_0-2(C_3-6Cycloalkyl), -NR-^x(CH₂)_0-2(C_5-8Bicycloalkyl), -NR^x(CH₂)_0-2(C_5-8Spiro bicyclic group), -NR^x(CH₂)_0-2(4-to 6-membered heterocyclyl), -NR^x(CH₂)_0-2(5-to 6-membered heteroaryl), -NR^x(CH₂)_0-2(phenyl), -O (CH)₂)_0-2(C_3-6Cycloalkyl), -O (CH)₂)_0-2(C_5-8Bicycloalkyl), -O (CH)₂)_0-2(C_5-8Spiro bicyclic group), -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, spirobicyclyl, aryl and heteroaryl is substituted with 0 to 3R^2bAnd (4) substitution. This embodiment includes compounds wherein R is²is-CH₂(C_3-5Cycloalkyl), -CH₂(4-to 6-membered heterocyclyl), -NR^x(CH₂)_0-2(C_3-5Cycloalkyl), -NR-^x(CH₂)_0-2(4-to 6-membered heterocyclyl), -NR^x(CH₂)_0-2(phenyl), -O (phenyl), or-S (O)₂(C_3-6Cycloalkyl), wherein each of said cycloalkyl, heterocyclyl, phenyl and pyridyl is substituted with 0 to 3R^2bAnd (4) substitution. This embodiment also includes compounds wherein R is²is-NR^x(C_3-8Cycloalkyl), -NR- ^x(phenyl), or-S (O)₂(C_3-6Cycloalkyl), wherein each of said phenyl and cycloalkyl is independently substituted with 0 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 is^3aAnd R^3bIndependently of each other is hydrogen, C_1-3Alkyl radical, C_1-3Fluoroalkyl group, or C_3-6A cycloalkyl group; or R^3aAnd R^3bTogether with the carbon atom to which they are attached form C_3-6A cycloalkyl group. This embodiment includes compounds wherein R is^3aAnd R^3bIndependently of each other is hydrogen, C_1-2Alkyl, -CH₂F、-CHF₂、-CF₃Or C_3-4A cycloalkyl group; or R^3aAnd R^3bTogether with the carbon atom to which they are attached form C_3-4A cycloalkyl group. This embodiment also includes compounds wherein R is^3aAnd R^3bIndependently of each other is hydrogen, -CH₃Or cyclopropyl; or R^3aAnd R^3bTogether with the carbon atom to which they are attached form a cyclopropyl group. In addition, this embodiment includes compounds wherein R is^3aAnd R^3bOne of which is hydrogen or-CH₃And R is^3aAnd R^3bIs hydrogen.

In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein:

q is-CR^1c＝CR^1cR¹or-C.ident.CR¹；

R¹is-C (O) OR^x、-C(O)NR^xR^x、C_1-4Hydroxyalkyl, or a cyclic group selected from 5 to 6 membered heteroaryl, wherein the cyclic group is substituted with 0 to 3R ^1aSubstitution;

each R^1bIndependently F, Cl, hydroxy, -NR^wR^wCyano, C_1-3Alkoxy, or C_1-3A fluoroalkoxy group;

each R^1cIndependently is H or-CH₃；

Or when X is¹Is CR^5a，X²Is CR^5b，X³Is CR^5c，X⁴Is CR^5dThen Q and R^5aCan be combined together to form-CR^1a＝CR¹CH₂CH₂-a bridge;

R²the method comprises the following steps:

(i)C_1-4alkyl radical, C_1-4Alkoxy, or-NR^vR^vWherein each of said alkyl and alkoxy groups is substituted with 0 to 4R^2aSubstitution;

each R^2aIndependently F, Cl, hydroxy, -NR^xR^xOxo, cyano, C_1-3Alkoxy radical, C_1-3Haloalkoxy, or-C (O) OH;

each R^2bIndependently F, Cl, cyano, hydroxy, C _1-4Alkyl radical, C_1-3Alkoxy, -NR^xR^x、-NR^xC(O)O(C_1-3Alkyl), -C (O) (C)_1-2Alkyl), or-S (O)₂(C_1-2Alkyl) wherein each of the alkyl and alkoxy is substituted with 0 to 4R^2aSubstitution;

a is:

(i) a cyano group;

(ii) phenyl or a 5 to 6 membered heteroaryl group containing 1 to 4 heteroatoms independently selected from N, O and S,

wherein each of said phenyl and heteroaryl is substituted with 0 to 3R^4aSubstitution; or

(iii)

each R^4cIndependently of each other is hydrogen, C_1-3Alkyl, or C_3-6A cycloalkyl group;

each R^4dIndependently F, Cl, hydroxy, -NR^xR^xOxo, cyano, C_1-3Alkoxy, or C_1-3A fluoroalkoxy group;

each R^4eIndependently F, Cl, oxo, cyano, hydroxy, -NH₂、C_1-4Alkyl radical, C_1-4Alkoxy, or-NH (C) _1-6Alkyl), or-N (C)_1-6Alkyl radical)₂Wherein each of said alkyl and alkoxy groups is substituted with 0 to 4R^4dSubstitution;

each R^wIndependently of each other is hydrogen, C_1-4Alkyl, or C_3-6A cycloalkyl group; or alternatively, two R^wTogether with the nitrogen atom to which they are attached form a 4 to 7 membered ring moiety containing 0 to 2 additional heteroatoms independently selected from N, O and S;

each R^xIndependently is H, C_1-4Alkyl, or C_3-6A cycloalkyl group;

R^yis C_1-4Alkyl or C_3-6A cycloalkyl group; and is

Each R^zIndependently of each other is hydrogen, C_1-4Alkyl, or C_3-6A cycloalkyl group;or alternatively, two R^zTogether with the nitrogen atom to which they are attached form a 4 to 7 membered ring moiety containing 0 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 CH; x²Is CH; x³Is CH; x⁴Is CH; a is 1; b is 1; d is 1; q is-CH ═ CHC (O) OH, -CH ═ CHC (O) OCH₃、-C(CH₃)＝CHC(O)OCH₃、-CH＝CHC(O)N(CH₃)₂-CH-CH (methyloxadiazole), or-C.ident.CC (CH) ₃)₂OH；R²is-CH (CH)₃)₂Or a cyclic group selected from cyclobutyl, cyclohexyl, cycloheptyl, bicyclo [1.1.1]Pentyl, piperidinyl, and tetrahydropyranyl, each cyclic group being independently selected from F and-CH by 0 to 1₃Substituted with the substituent(s); r^3aIs hydrogen or-CH₃；R^3bIs hydrogen; a is oxadiazolyl, phenyl, indazolyl, or benzothiazolyl, each substituted with 0 to 1R^4aSubstitution; and each R^4aIndependently is-CH₃、-CH(CH₃)₂、-C(CH₃)₃、-CH(CH₃)₂、-CF₂CH₃、-OCH₃、-N(CH₃)₂、-N(CH₂CH₃)₂Or a cyclic group selected from cyclopropyl, azetidinyl, pyrrolidinyl, tetrahydropyranyl, and morpholinyl.

In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein: wherein the compound is: (E) -methyl 3- (3- (N- ((4- (4- (dimethylamino) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate (1); (E) -3- (3- (N- ((4- (4-dimethylamino) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylic acid (2); (E) -methyl 3- (3- (N- ((4- (4-morpholinophenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate (3); (E) -methyl 3- (3- (N- ((4- (4- (pyrrolidin-1-yl) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate (4); (E) -methyl 3- (3- (N- ((4- (4- (azetidin-1-yl) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate (5); (E) -methyl 3- (3- (N- ((4- (4- (dimethylamino) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) tetrahydro-2H-pyran-4-carboxamido) phenyl) acrylate (6); (E) -methyl 3- (3- (N- ((4-phenylbicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate (7); (E) -methyl 3- (3- (N- ((1- (1-methyl-1H-indazol-5-yl) -2-oxabicyclo [2.2.2] oct-4-yl) methyl) tetrahydro-2H-pyran-4-carboxamido) phenyl) acrylate (8); (E) -methyl 3- (3- (1-methyl-N- ((1- (1-methyl-1H-indazol-5-yl) -2-oxabicyclo [2.2.2] oct-4-yl) methyl) piperidine-4-carboxamido) phenyl) acrylate (9); (E) -methyl 3- (3- (N- ((1- (4-methoxyphenyl) -2-oxabicyclo [2.2.2] oct-4-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate (10); (E) -methyl 3- (3- (N- ((4- (4-morpholinophenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) but-2-enoate (14); (E) -methyl 3- (3- (N- ((4- (4-methoxyphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate (15); (E) -methyl 3- (3- (N- ((4- (4-methoxyphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) but-2-enoate (16); (E) -methyl 3- (3- (N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) but-2-enoate (19); (E) -methyl 3- (3- (N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate (20); (E) -methyl 3- (3- (N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclopropanecarboxamido) phenyl) acrylate (21); (E) -methyl 3- (3- (N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) isobutyramido) phenyl) acrylate (22); (E) -methyl 3- (3- (N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) tetrahydro-2H-pyran-4-carboxamido) phenyl) acrylate (23); (E) -methyl 3- (3- (N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cycloheptanecarboxamido) phenyl) acrylate (24); (E) -methyl 3- (3- (3-fluoro-N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) bicyclo [1.1.1] pentane-1-carboxamido) phenyl) acrylate (25); (E) -methyl 3- (3- (3, 3-difluoro-N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclobutane-1-carboxamido) phenyl) acrylate (26); (E) -N- (3- (3- (dimethylamino) -3-oxoprop-1-en-1-yl) phenyl) -N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamide (27); (E) -methyl 3- (3- (N- ((4- (4-cyclopropylphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclopropanecarboxamido) phenyl) acrylate (28); (E) -methyl 3- (3- (N- ((4- (4-cyclopropylphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate (29); (E) -methyl 3- (3- (N- ((4- (benzo [ d ] thiazol-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclopropanecarboxamido) phenyl) acrylate (33); (E) -methyl 3- (3- (N- ((4- (benzo [ d ] thiazol-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate (34); (E) -N- ((4- (4-methoxyphenyl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (2- (3-methyl-1, 2, 4-oxadiazol-5-yl) vinyl) phenyl) cyclohexanecarboxamide (35); (E) -methyl 3- (3- (N- ((4- (4-cyclopropylphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclopropanecarboxamido) phenyl) but-2-enoate (36); (E) -methyl 3- (3- (N- ((4- (4-cyclopropylphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) but-2-enoate (37); (E) -methyl 3- (3- (N- ((4- (4-isopropylphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate (38); (E) -methyl 3- (3- (N- ((4- (4-isopropylphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclopropanecarboxamido) phenyl) acrylate (39); (E) -methyl 3- (3- (N- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate (41); (E) -methyl 3- (3- (N- ((4- (3-morpholino-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate (42); (E) -methyl 3- (3- (N- ((4- (3- (tetrahydro-2H-pyran-4-yl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate (43); (E) -methyl 3- (3- (N- ((4- (5-methyl-1, 2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate (44); (E) -methyl 3- (3- (N- (1- (4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) ethyl) cyclohexanecarboxamido) phenyl) acrylate (46-47); n- ((4- (5- (tert-butyl) -1,3, 4-oxadiazol-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3- (3-hydroxy-3-methylbut-1-yn-1-yl) phenyl) bicyclo [1.1.1] pentane-1-carboxamide (48); or N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3- (3-hydroxy-3-methylbut-1-yn-1-yl) phenyl) bicyclo [1.1.1] pentane-1-carboxamide (49).

In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, or salt or solvate thereof, wherein the compound is: methyl 5- (N- ((4- (4-morpholinophenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamide) -3, 4-dihydronaphthalene-2-carboxylate (11); methyl 5- (N- ((4- (4- (dimethylamino) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamide) -3, 4-dihydronaphthalene-2-carboxylate (12); methyl 5- (N- ((4- (4- (diethylamino) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamide) -3, 4-dihydronaphthalene-2-carboxylate (13); 5- (N- ((4- (4-methoxyphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) -3, 4-dihydronaphthalene-2-carboxylic acid (17); methyl 5- (N- ((4- (4-methoxyphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamide) -3, 4-dihydronaphthalene-2-carboxylate (18); methyl 5- (N- ((4- (4-cyclopropylphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamide) -3, 4-dihydronaphthalene-2-carboxylate (30); methyl 5- (N- ((4- (4-cyclopropylphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclopropanecarboxamido) -3, 4-dihydronaphthalene-2-carboxylate (31); methyl 5- (N- ((4- (4-cyclopropylphenyl) bicyclo [2.2.2] oct-1-yl) methyl) isobutyramido) -3, 4-dihydronaphthalene-2-carboxylate (32); methyl 5- (N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamide) -3, 4-dihydronaphthalene-2-carboxylate (40); or 5- (N- ((1- (1-methyl-1H-indazol-5-yl) -2-oxabicyclo [2.2.2] oct-4-yl) methyl) cyclohexanecarboxamide) -3, 4-dihydronaphthalene-2-carboxylic acid methyl ester (45).

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 the described embodiments is intended to describe additional embodiments in combination with any and all other elements from any embodiment.

Definition of

The features and advantages of the present invention will be more readily understood by those of ordinary skill in the art upon reading the following detailed description. It is to be understood that certain features of the invention, which are, for clarity, described 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 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.

According to the convention used in the art, used in the structural formulae herein

To depict bonds as attachment points for moieties or substituents to the core or backbone structure.

The terms "halo" and "halogen" as used herein refer to F, Cl, Br and I.

The term "cyano" refers to the group-CN.

The term "hydroxy" refers to the group-OH.

The term "amino" refers to the group-NH₂。

The term "oxo" refers to the group ═ O.

The term "alkyl" as used herein refers to both branched and straight chain saturated aliphatic hydrocarbon groups containing, for example, from 1 to 12 carbon atoms, from 1 to 6 carbon atoms, and from 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, sec-butyl, and tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl. When 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, "C_1-4Alkyl "denotes straight and branched chain alkyl groups having 1 to 4 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 include both branched and straight chain saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms. For example, "C_1-4Fluoroalkyl "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, "C_1-4Hydroxyalkyl "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, "C_2-6Alkenyl "denotes straight and branched chain alkenyl groups having 2 to 6 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 2 to 6 carbon atoms.

The term "alkoxy" as used herein, means an alkyl group attached to the parent molecular moiety through an oxygen atom, e.g., methoxy (-OCH)₃). For example, "C_1-3Alkoxy "means an alkoxy group having 1 to 3 carbon atoms.

The terms "haloalkoxy" and "-O (haloalkyl)" denote an alkyl halide as defined above attached through an oxygen linkage (-O-)And (4) a base. For example, "C_1-4Haloalkoxy "is intended to include C₁、C₂、C₃And C₄A haloalkoxy group.

The terms "fluoroalkoxy" and "-O (fluoroalkyl)" represent fluoroalkyl groups as defined above attached through an oxygen linkage (-O-). For example, "C_1-4Fluoroalkoxy "is intended to include C₁、C₂、C₃And C₄A fluoroalkoxy group.

The term "cycloalkyl" as used herein refers to a group derived from a non-aromatic monocyclic or polycyclic hydrocarbon molecule by the removal of one hydrogen atom from a saturated ring carbon atom. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. When a number appears in the subscript following the symbol "C," the subscript more specifically defines the number of carbon atoms that a particular cycloalkyl group may contain. For example, "C_3-6Cycloalkyl "denotes cycloalkyl having 3 to 6 carbon atoms.

The terms "carbocyclyl", "carbocyclic", 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 atoms of all rings 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.

The term "aryl" as used herein 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 "heterocyclyl" (heterocyclo), "heterocyclic" or "heterocyclyl" (heterocyclyl) are used interchangeably and refer to a cyclic group having at least a saturated or partially saturated non-aromatic ring and wherein one or more of the rings has at least one heteroatom (O, S or N), preferably 1 to 3 heteroatoms independently selected from O, S and/or N. The rings of such groups containing heteroatoms 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, isoxazolyl, tetrahydrothiazolyl, isothiazolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, 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 group" are used interchangeably and refer to a bicyclic group in which the two rings are attached to a single carbon atom that is a member of each of the two rings. The term includes both spirobicycloalkyl, in which both rings are cycloalkyl rings attached to a single carbon atom that is a member of each of the two rings, and spirobicycloheteroalkyl; in spirobicyclic heteroalkyl one ring is the ring of a heterocyclyl group and the other ring is the ring of a cycloalkyl group attached at a single carbon atom as a member of each of the two rings, or a heterocyclyl ring in which both rings are attached at a single carbon atom as 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. Heteroaryl groups containing heteroatoms may 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 that make up 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 contain only aromatic rings. The heteroaryl group may be attached to 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, thiophenyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl.

Exemplary bicyclic heteroaryls include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, and pyrrolopyridinyl.

As used herein, the term "tautomer" refers to each of two or more isomers of a compound that exist together in equilibrium 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, wherein when R is ^5cIs hydroxy and R^5a、R^5bAnd R^5dThe compound of formula (Ia) when each of (a) is hydrogen may exist in tautomeric forms:

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), e.g. when a 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 acceptable metal and amine salts, wherein the cation does not significantly contribute to the toxicity or biological activity of the salt. However, other salts may for example be used in isolation or purification steps that may be employed during preparation and are therefore encompassed 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 (such as an equivalent amount) of an acid or base in a medium (such as one in which a 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, Iston, 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 hydrogen bromide), hydroiodide salts, maleate salts (formed with maleic acid), 2-hydroxyethanesulfonate salts, lactate salts, methanesulfonate salts (formed with methanesulfonic acid), 2-naphthalenesulfonate salts, nicotinate salts, oxalate salts, pectate salts, persulfate salts, 3-phenylpropionate salts, Phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, tosylates (such as tosylate), undecanoates, 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 (such as triethylamine), procaine, dibenzylamine, N-benzyl- β -phenylethylamine, 1-diphenylhydrabamine (ephenamine), N' -dibenzylethylene-diamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine, or similar pharmaceutically acceptable amines; and salts with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups may be quaternized with the following 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 others. 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 used 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, Ch 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 the implementation of stable compounds.

A "therapeutically effective amount" is intended to include an amount of a compound of the invention alone or in amounts of the various compounds claimed or in combination with other active ingredients effective to act as an FXR agonist or to effectively treat or prevent a disorder associated with bile acid imbalance (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 of the same atomic number but different mass numbers. By way of general example, and not limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include¹³C and¹⁴C. isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of 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, 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 present invention provides a process for preparing a compound of the present invention.

In another embodiment, the present invention provides an intermediate useful in the preparation of the compounds of the present invention.

In another embodiment, the present invention provides a pharmaceutical composition as defined above further comprising one or more additional therapeutic agents.

Utility of

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 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, 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 present invention provides a method for inducing Farnesoid X Receptor (FXR) antagonism in a patient, comprising administering to said 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 is associated with FXR dysfunction including 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 (such as 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, hematological 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, cancer of the oral or nasal mucosa, 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 FXR activity 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, failure to regenerate, hypohepatia, 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, focal segmental glomerulosclerosis, IgA nephropathy, nephropathy induced by drug or transplantation, autoimmune nephropathy, lupus nephritis, liver fibrosis, kidney fibrosis, Chronic Kidney Disease (CKD), diabetic nephropathy (DKD), 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), myxoma, herniated disc, 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, age-related macular degeneration (AMD), glaucoma, viral-induced fibrosis, Idiopathic Pulmonary Fibrosis (IPF), interstitial lung disease, non-specific interstitial pneumonia (NSIP), radiation-induced fibrosis (UIP), radiation-induced fibrosis, radiation fibrosis, familial pulmonary fibrosis, airway fibrosis, chronic lymphocytic leukemia, kaposi's sarcoma, myocardial fibrosis, and solid tumors, Proliferative Vitreoretinopathy (PVR), cicatricial pemphigoid glaucoma filtration surgical scar, crohn's disease, or systemic lupus erythematosus; keloid formation resulting from abnormal wound healing; fibrosis, myelofibrosis, and myoma 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 in the treatment of 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 in 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 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 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 the treatment of a fibrotic disorder, an inflammatory disorder or a cell proliferative disorder.

The compounds of the present invention may be used 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, one or more additional therapeutic agents are used in a combination pharmaceutical composition or combination method or combination useOne or more, preferably one to three, therapeutic agents selected from the following: TGF β receptor inhibitors (e.g., galinisertib); 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-alpha_VA β 6 integrin monoclonal antibody (e.g., 3G 9); human recombinant transudatin-2; human recombinant serum amyloid P; recombinant human antibodies to TGF-beta 1, -2, and-3; endothelin receptor antagonists (e.g., macitentan); an interferon gamma; inhibitors of c-Jun amino terminal kinase (JNK) (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); tetrasubstituted porphyrin derivatives containing manganese (III); monoclonal antibodies targeting eotaxin-2; interleukin-13 (IL-13) antibodies (e.g., lebrikizumab (lebrikizumab), tralopyrizumab (tralokinumab); bispecific antibodies targeting interleukin-4 (IL-4) and interleukin-13 (IL-13); NK1 tachykinin receptor agonists (e.g., Sar) ⁹、Met(O₂)¹¹-substance P); cintredekin besedotox; human recombinant DNA-derived IgG1 kappa monoclonal antibodies to connective growth factor and fully human IgG1 kappa antibodies selective for CC-chemokine ligand 2 (e.g., carlumab, CCX 140); antioxidants (e.g., N-acetyl cysteine); 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); immunosuppressants (e.g., tacrolimus, rapamycin, pimecrolimus); and therapeutic agents useful in the treatment of fibrotic disorders such as liver, biliary and kidney fibrosis, nonalcoholic fatty liver disease (NALFD), nonalcoholic steatohepatitis (NASH), myocardial fibrosis, Idiopathic Pulmonary Fibrosis (IPF) and systemic sclerosis. Therapeutic agents useful for treating such fibrotic disorders include, but are not limited to, FXR agonists (e.g., OCA, amaurokinase, and amaurokinase),GS-9674 and LJN452), LOXL2 inhibitors (e.g., simtuzumab), LPA1 antagonists (e.g., BMS-986020 and SAR 100842), PPAR modulators (e.g., elafinilor, pioglitazone and saroglitazar), IVA337), SSAO/VAP-1 inhibitors (e.g., PXS-4728A and SZE5302), ASK-1 inhibitors (e.g., GS-4997 or selonesertib), ACC inhibitors (e.g., CP-640186 and NDI-010976 or GS-0976), FGF21 mimetics (e.g., LY2405319 and BMS-986036), caspase inhibitors (e.g., entikasan), NOX4 inhibitors (e.g., GKT137831), mg 2 inhibitors (e.g., BMS-963272), α V integrin inhibitors (e.g., azubi-abib) and bile acid/nacrocapyral conjugates (e.g., zamaamatsugamumab). 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., cenicriviroc), galectin-3 inhibitors (e.g., TD-139, GR-MD-02), leukotriene receptor antagonists (e.g., tylukast (tipelukast), montelukast), SGLT2 inhibitors (e.g., dapagliflozin, remogliflozin (remogliflozin)), gl1 receptor agonists (e.g., liraglutide and somaglutacotide), FAK inhibitors (e.g., GSK-2256098), CB1 inverse agonists (e.g., JD 371-5037), CB2 agonists (e.g., APD-101 and JBT-101), autotaxin inhibitors (e.g., GLPG1690), prolyl-synthetase inhibitors (e.g., clozine benzonitrile (halofurokinase)), (e.g., clo), 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 combined use are selected from one or more, preferably one to three, of the following: immunooncology agents such as alemtuzumab, altuzumab, primima, nivolumab, ofatumumab, pembrolizumab, and rituximab.

The compounds of the invention may be administered for any of the uses described herein by any of the following suitable means: for example, 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); intranasally, including application to nasal membranes, such as by inhalation spray; topically, such as 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 present 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 i.e., adjuvants, excipients, or vehicles, such as diluents, preservatives, fillers, flow-regulating agents, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, and dispersants, depending on the mode of administration and the nature of the dosage form. The pharmaceutically acceptable carrier is formulated according to a number of factors that are also within the scope 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 can 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., stabilizing the active agent, binders, etc.). Descriptions of suitable pharmaceutically acceptable carriers and the factors involved in their selection are found in a variety of readily available sources (e.g., such as 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 using a compound or composition of the 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 that are also within the scope 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 can 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., stabilizing the active agent, binders, etc.). A description of suitable pharmaceutically acceptable carriers and The factors involved in their selection are found in a variety of 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.

The dosage regimen for the compounds of the invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the 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 type of concurrent treatment, the frequency of treatment, the route of administration, the renal and hepatic function of the patient and the desired effect.

As a general guide, the daily oral dose 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, and most preferably between about 0.01 to about 250 mg/day. The most preferred dosage will range from about 0.01 to about 10 mg/kg/minute during a constant rate infusion, intravenously. 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 typically 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. In 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, autotaxin inhibitors, LPA1 receptor antagonists, or other pharmaceutically active materials).

When used in combination with the compounds of the present invention, the other therapeutic agents described above may be used, for example, in the amounts indicated in the Physicians' Desk Reference, as in the patents mentioned 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 active ingredient 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 involves the formulation of 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 known in the art, to further isolate the active components. 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 present invention, whether administered in a single dosage form or administered in separate forms (but administered in the same manner at the same time), will be readily apparent to those skilled in the art once the present disclosure has been incorporated.

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 accomplished, 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 can 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 in the combination may be administered by intravenous injection, while the other therapeutic agents in the combination may be administered orally. Alternatively, for example, the therapeutic agent may be administered orally or all of the therapeutic agent 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 the combination therapy further includes a 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 an article. 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 used to manufacture, hold, store, or dispense a pharmaceutical product.

The second container is a container for holding the first container and optionally the 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 bags. The package insert may be physically attached to the outside of the first container by tape, glue, staples, or other attachment methods, 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 outside the second container, the package insert is preferably physically attached by tape, glue, staples or other attachment methods. Alternatively, it may be adjacent to or in contact with the outside of the second container, rather than being physically attached.

The package insert is a label, indicia, etc. that lists information related to the pharmaceutical composition located in the first container. The information listed will typically be determined by a regulatory agency (e.g., the United States Food and Drug Administration) that governs the area in which 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. 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 that one skilled in the art can use to prepare 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, a homochiral compound can be prepared by separation of the racemic product or diastereomer by 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 being carried out. Furthermore, in the description of the synthetic methods given below, it is to be understood that all proposed reaction conditions (including choice of solvent, reaction atmosphere, reaction temperature, duration of 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 will be clear 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 one particular method scheme over another in order to obtain the desired compound of the invention. It will also be appreciated that another major consideration in the planning of any synthetic route in this field is the judicious choice of protecting groups for protecting the reactive functional groups present in the compounds described in the present invention. 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. The following defines examples and other abbreviations used elsewhere in this application. Commonly used 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 example compounds were 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 was 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. Often, one of ordinary skill in the art of synthesis can design alternatives that may be desirable based on one or more considerationsInstead of preparation, one or more considerations such as shorter reaction times, less expensive starting materials, ease of 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, some of the functional groups outlined in the examples and claims may be replaced by well known bioisosteric replacements (bioisosteric replacement) known in the art, such as replacing the carboxylic acid group with a tetrazole or phosphate moiety. Collected in deuterated dimethyl sulfoxide ¹H NMR data was suppressed using water in the 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

Abbreviations as used herein are defined as follows: "1 x" represents once, "2 x" represents twice, "3 x" represents three times, "° c" represents degrees celsius, "eq" represents equivalents, "g" grams, "mg" represents milligrams, "L" represents liters, "mL" represents milliliters, "μ L" represents microliters, "N" represents positive, "M" represents moles, "mmol" represents millimoles, "min" represents minutes, "h" represents hours, "rt" represents room temperature, "RBF" represents a round bottom flask, "atm" represents atmospheric pressure, "psi" represents pounds per square inch, "conc" represents concentration, "RCM" represents a closed-loop metathesis reaction, "sat" or "sat'd" represents saturated, "SFC" represents supercritical fluid chromatography, "MW" represents molecular weight, "mp" represents melting point, "ee" represents enantiomeric excess, "MS" or "mass spectrometry" represents mass spectrometry, "ESI" represents electrospray ionization mass spectrometry, "HR" represents high resolution, "HRMS" represents high resolution mass spectrometry, "LCMS" represents liquid chromatography mass spectrometry, "HPLC" represents high pressure liquid chromatography, "RP HPLC" represents reversed phase HPLC, "TLC" or "TLC" represents thin layer chromatography, "NMR" represents nuclear magnetic resonance spectroscopy, "nOe" represents nuclear Oligorson Effect spectroscopy, ")" ¹H "represents proton," delta "represents delta," s "representsTable singlet, "d" represents a doublet, "t" represents a triplet, "q" represents a quartet, "m" represents a multiplet, "br" represents a broad peak, "Hz" represents hertz, and "α", "β", "R", "S", "E" and "Z" are stereochemical designations familiar to those skilled in the art.

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 ═

DCE ═ 1, 2-dichloroethane

MeOH ═ methanol

HCl ═ hydrochloric acid

AcOH ═ acetic acid

Cs₂CO₃Cesium carbonate (MCH)

DMSO ═ dimethyl sulfoxide

TEA5 ═ triethylamine

BOP (BOP) tris (dimethylamino) phosphonium hexafluorophosphate

DMAc ═ dimethylacetamide

DMAP ═ 4-dimethylaminopyridine

2-DMAP ═ 2-dimethylaminopyridine

Pyridinium PCC (chlorochromate)

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 can 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 by the methods described below, along with synthetic methods known in the art of organic chemistry, or variations thereof as will be appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are 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 to be 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 will be readily recognized by the skilled artisan. 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 will be 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 may be synthesized by coupling intermediate 1 and intermediate 2 under reductive amination conditions, a method known to those skilled in the art to be recognizable. Imine synthesis can be carried out in the presence of an acid such as 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 methods):

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 using any number of reagents (e.g., phosphorus oxychloride, thionyl chloride, oxalyl chloride, methyl chloroformate, or ethyl chloroformate, etc.) as recognized by one skilled in the art in a polar aprotic solvent (e.g., DCM, THF, etc.) at a temperature ranging between-30 ℃ to 0 ℃. 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 in the presence of a base (e.g., Et)₃N, DIPEA, pyridine, etc.) in a polar aprotic solvent (e.g., DCM, DCE, etc.) at room temperature to afford the urea represented by formula I. Alternatively, the reaction can be carried out by reaction with a base (e.g., Et)₃N, DIPEA, etc.) in a solvent (e.g., DCM, DCE, etc.) at 0 ℃ to room temperature with triphosgene treatment to activate intermediate 3. Can then be in base (e.g., Et)₃N, DIPEA, etc.) in a solvent (e.g., DCM, DCE, etc.) at room temperature to treat activated intermediate 3 with a substituted alkyl or aryl or heteroaryl amine to provide a urea represented by formula I.

Carbamate ester: can be in the presence of a base (e.g., Et)₃N, DIPEA, pyridine, etc.) in a polar aprotic solvent (e.g., DCM, DCE, THF, etc.) at 0 ℃ to room temperature with a chloroformate (or alcohol, active)To a carbonate) to obtain a carbamate represented by formula I.

Intermediates 1(a-h) (scheme 1) can be obtained in various ways depicted in schemes 2-10 (including but not limited to the following methods) using a variety of known methods recognized by those skilled in the art.

Scheme 2

Scheme 2 describes the synthesis of intermediate 1 a. Intermediate 5 may be obtained from commercial sources or may be synthesized by known methods readily recognizable to those skilled in the art. Can be in the presence of a base (e.g., K) ₂CO₃、Na₂CO₃Etc.) in a polar protic solvent (e.g., water, methanol, ethanol, etc.) to afford intermediate 6. Intermediate 6 can be reduced to intermediate 1a in the presence of a reagent such as tin (II) chloride in a polar protic solvent (e.g., water) using conditions recognized by those skilled in the art (including, but not limited to, the conditions described, such as heating). The intermediate 1a thus obtained may be converted into a compound of formula I as depicted in scheme 1.

Scheme 3

Scheme 3 describes the synthesis of intermediate 1 b. Intermediate 1a, synthesized as described in scheme 2, can be subjected to hydrolysis with the methyl ester of an alkali metal hydroxide base to provide intermediate 7. Intermediate 7 can be coupled with various amidooximes (derived from the corresponding nitriles by reaction with hydroxylamine; see Hirawat, s. et al WO 2006/110483) using amide bond coupling agents (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 intermediate 7 with an amidoxime at elevated temperature (60 ℃ to 100 ℃) to give intermediate 1 b.

Scheme 4

Scheme 4 describes the synthesis of intermediate 1 c. Intermediate 8 may be obtained from commercial sources or may be synthesized by known methods readily recognizable to those skilled in the art. Metal Catalyzed Cross-Coupling Reactions (such as Heck reaction, described in Metal-Catalyzed Cross-Coupling Reactions, arnin de Meijere,diederich, Vol.2, second revision and supplement, 2004, ISBN:3-527-30518-1, Wiley-VCH and references cited therein) subjecting intermediate 8 to olefin synthesis. Can be carried out in the presence of a metal catalyst such as bis (tri-o-tolylphosphine) palladium (II) dichloride and tetrabutylammonium bromide in the presence of a base (Et)₃N, DIPEA, etc.) in a solvent (DMAc, DMF, etc.) under the application of heat, intermediate 8 is treated with an olefin coupling partner to afford intermediate 1 c.

Scheme 5

Scheme 5 describes an alternative synthesis of intermediate 1 c. Intermediate 9 may be obtained from commercial sources or may be synthesized by known methods readily recognizable to those skilled in the art. Metal Catalyzed Cross-Coupling Reactions (such as Heck reaction, described in Metal-Catalyzed Cross-Coupling Reactions, arnin de Meijere,diederich, Vol.2, second revision and supplement, 2004, ISBN:3-527-30518-1, Wiley-VCH and references cited therein) to subject intermediate 9 to olefin synthesis. Can be arranged in Metal catalysts such as bis (tri-o-tolylphosphine) palladium (II) dichloride and tetrabutylammonium bromide in the presence of a base (Et)₃N, DIPEA, etc.) in a solvent (DMAc, DMF, etc.) under the application of heat intermediate 9 is treated with an olefin coupling partner to give intermediate 10. Intermediate 10 can be reduced to intermediate 1c in the presence of a reagent such as tin (II) chloride in a polar protic solvent (e.g., water) using conditions recognized by those skilled in the art (including, but not limited to, the conditions described, such as heating). The intermediate 1c thus obtained may be converted into a compound of formula I as depicted in scheme 1.

Scheme 6

Scheme 6 describes the synthesis of intermediate 1 d. Intermediate 6 can be synthesized as described in scheme 2. Intermediate 6 may be subjected to hydrolysis with the methyl ester of an alkali metal hydroxide base to provide intermediate 11. Intermediate 11 may be activated for acylation using any number of reagents (e.g., phosphorus oxychloride, thionyl chloride, oxalyl chloride, methyl chloroformate or alkyl chloroformate, etc.) as recognized by one skilled in the art in a polar aprotic solvent (e.g., DCM, THF, etc.) at a temperature ranging between-30 ℃ to 0 ℃. The activated acid intermediate can then be reacted with intermediate 12 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 intermediate 13. Intermediate 12 may be obtained from commercial sources or may be synthesized by known methods readily recognizable to those skilled in the art. Intermediate 13 can be reduced to intermediate 1d in the presence of a reagent such as tin (II) chloride in a polar protic solvent (e.g., water) using conditions recognized by those skilled in the art (including, but not limited to, the conditions described, such as heating). The intermediate 1d thus obtained can be converted into a compound of formula I as depicted in scheme 1.

Scheme 7

Scheme 7 describes the synthesis of intermediate 1 e. Intermediate 10 may be synthesized as described in scheme 5. Intermediate 10 may be subjected to hydrolysis with the methyl ester of an alkali metal hydroxide base to provide intermediate 14. Intermediate 14 may be activated for acylation using any number of reagents (e.g., phosphorus oxychloride, thionyl chloride, oxalyl chloride, methyl chloroformate or alkyl chloroformate, etc.) as recognized by one skilled in the art in a polar aprotic solvent (e.g., DCM, THF, etc.) at a temperature ranging between-30 ℃ to 0 ℃. The activated acid intermediate can then be reacted with intermediate 12 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 intermediate 15. Intermediate 12 may be obtained from commercial sources or may be synthesized by known methods readily recognizable to those skilled in the art. Intermediate 15 can be reduced to intermediate 1e in the presence of a reagent such as tin (II) chloride in a polar protic solvent (e.g., water) using conditions recognized by those skilled in the art (including, but not limited to, the conditions described, such as heating). The intermediate 1e thus obtained may be converted into a compound of formula I as depicted in scheme 1.

Scheme 8

Scheme 8 describes the synthesis of intermediate 1 f. Intermediate 9 may be obtained from commercial sources or may be synthesized by known methods readily recognizable to those skilled in the art. Many known methods (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 methods described in the references cited therein)The intermediate 9 is subjected to a metal-catalyzed Sonogashira coupling reaction. Intermediate 9 may be subjected to conditions such as Et in a polar aprotic solvent such as DMF₃Reaction of N and a metal catalyst such as bis (triphenylphosphine) palladium (II) dichloride and copper (I) iodide with a suitable alkyne coupling partner under heating to give intermediate 16. Intermediate 16 can be reduced to intermediate 1f in the presence of iron with acetic acid and ammonium chloride in a polar protic solvent (e.g., water and isopropanol) using conditions recognized by those skilled in the art (including, but not limited to, the conditions described, such as heating). The intermediate 1f thus obtained may be converted into a compound of formula I as depicted in scheme 1.

Scheme 9

Scheme 9 describes the synthesis of intermediate 1 g. Intermediate 17 may be obtained from commercial sources or may be synthesized by known methods readily recognizable to those skilled in the art. Intermediate 17 may be subjected to AlCl with heating in the presence of bromine₃To give the corresponding bromo-substituted intermediate 18. Bromine intermediate 18 can be subjected to acylation in dry toluene in the presence of a base such as NaH and dimethyl carbonate under heating to afford intermediate 19. Intermediate 19 can be passed through a reducing agent (e.g., NaBH)₄DIBAL-H, etc.) in a polar protic solvent (e.g., MeOH, EtOH, etc.) to afford secondary alcohol 20, which is subjected to elimination by treatment with p-TSA under heated conditions to yield intermediate 21. Can be used in metal catalyst such as Pd₂(dba)₃And suitable ligands (including but not limited to ligands such as 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene) and coupling partners tert-butyl carbamate and Cs₂CO₃Intermediate 21 was subjected to a Buchwald (Buchwald) coupling in the presence of a base to give the Boc-protected aniline intermediate 22. Intermediate 22 can be deprotected with an acid (e.g., TFA, HCl in dioxane, etc.) in a solvent (e.g., DCM, THF, etc.) to afford intermediate 1 g.

Scheme 10

Scheme 10 depicts the synthesis of intermediate 1 h. Intermediate 21 may be synthesized as described in scheme 9. Intermediate 21 may be subjected to hydrolysis with the methyl ester of an alkali metal hydroxide base to provide intermediate 23. Intermediate 23 may be activated for acylation using any number of reagents (e.g., phosphorus oxychloride, thionyl chloride, oxalyl chloride, methyl chloroformate or alkyl chloroformate, etc.) as recognized by one skilled in the art in a polar aprotic solvent (e.g., DCM, THF, etc.) at a temperature ranging between-30 ℃ to 0 ℃. The activated acid intermediate may then be reacted with intermediate 12 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 intermediate 24. Intermediate 12 may be obtained from commercial sources or may be synthesized by known methods readily recognizable to those skilled in the art. Intermediate 24 can be converted to intermediate 1h using the conditions described in scheme 9, undergoing sequential amination and deprotection steps. The intermediate 1h thus obtained can be converted into a compound of formula I as depicted in scheme 1.

Intermediate 2 (scheme 1) can be obtained in various ways depicted in scheme 11, including but not limited to the following methods, using a variety of known methods recognized by those skilled in the art.

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 give the compound of intermediate 26.

Formation of heterocyclic ring (A). The carboxylic acid moiety of compound 25 can be converted to a variety of heterocycles (a) using a variety of known methods recognized by those skilled in the art, including but not limited to the following:

a ═ 1,2, 4-oxadiazole. Intermediate 25 can be coupled with various amidooximes (derived from the corresponding nitriles by reaction with hydroxylamine; see Hirawat, s. et al WO 2006/110483) using amide bond coupling agents (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 (described in WO 2014/071247, Bradner, j.e. et al) using amide bond coupling reagents (e.g., CDI, BOP, EDC, etc.) in polar aprotic solvents (e.g., THF, 1, 4-dioxane DMF, MeCN, etc.). 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.2010,51,4801-4805) or Laweson's (Laweson) reagent (Kitamura, S. et al PCT International application 2008011130,2008), respectively.

A ═ 3-substituted 5-alkyl-1-methyl-1H-pyrazole. The methyl ketone can be treated with a base and the acid chloride of intermediate 25 to provide a diketone which upon reaction with a substituted or unsubstituted hydrazonium salt in a polar protic solvent such as ethanol at reflux temperature affords 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 such as 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 a polar protic solvent such as ethanol at reflux temperature to give ester 26, where A is an alkyl substituted pyrazole.

A is substituted heteroaryl. Intermediate 25 can be subjected to a genissi (Minisci) reaction with substituted heteroaryl compounds such as pyridine, pyrimidine, pyridazine, pyrazine, quinoline, pyrazole, etc. in the presence of silver nitrate and potassium or ammonium persulfate as solvents at ambient temperature in a mixture of DCM (or any other condition that can be used to generate groups for carbon centers) and water to give ester 26 (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 with a substituted 2-aminothiophenol (see generally Chedekel, m.r. et al synth. commu.1980, 10, 167-173; synthesis of various 2-aminothiophenols) using amide bond coupling reagents (e.g., BOP, T3P, EDC, etc.) in a polar aprotic solvent (e.g., DCE, THF, etc.). The coupling reaction may be carried out at elevated temperatures (60 ℃ to 80 ℃) to effect the 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.) intermediate 25 is activated for acylation to couple intermediate 25 with a substituted 2-chloroaniline (commercially available). The resulting formamide can be treated with Lawesson's reagent at elevated temperature (120 ℃) to effect in-situ cyclization to 2-benzothiazole.

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 accomplished in refluxing toluene in the presence of toluene sulfonic 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) benzoate dihydrochloride (Pascal, r. et al eur.j.org.chem.2000,22, 3755-one 3761) using an amide bond coupling reagent (e.g., HBTU, EDC, PyBOP, etc.) in a polar aprotic solvent (e.g., MeCN, THF, etc.). The cyclization can be accomplished under acidic conditions (neat AcOH) at elevated temperature (115 ℃). The resulting dihydroquinazoline intermediate may be oxidized to 2-quinazoline using an oxidizing agent such as DDQ.

A is 1-triazole. Intermediate 25 can be converted to the corresponding amine via a cotisis (Curtius) rearrangement as described in Shioiri, t. et al, j.am.chem.soc.1972,94, 6203-6205. After treatment with a reagent such as p-toluenesulfonyl azide, the amine can be converted to the corresponding azide, which is reacted with the appropriate alkyne (as described in Boren, B.C. et al J.am. chem.Soc.,2008,130, 8923-one 8930) to provide the triazole.

A is substituted 1,2, 4-triazole. Intermediate 25 can be converted to the corresponding hydrazide and can be subjected to reaction with a substituted carboxamide in the presence of triflic anhydride and 2-fluoropyridine under heating as described in Charette, a.b. et al org.lett, 2015,17, 1184-propanal 1187.

'a' may be other heterocycles such as substituted and unsubstituted oxazoles, thiazoles, imidazoles, isoxazoles, triazoles, pyrazoles, and may be 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 using the methods and references described therein as described in schemes 2-9.

Can be reduced by a reducing agent (e.g., LAH, DIBAL-H, NaBH)₄Etc.) intermediate 26 is subjected to reduction in a chlorinated or ethereal solvent (e.g., DCM, ether, 1, 4-dioxane, THF, etc.) to afford intermediate 27. The oxidation strips can be used by methods recognized by those skilled in the artIntermediate 27 is oxidized (e.g., Dess-Martin periodinane, swern oxidation conditions, PDC, etc.) to provide intermediate 2.

Scheme 12

Scheme 12 describes an alternative synthesis of compounds of formula I with a modified sequence of steps. Commercially available 4- (methoxycarbonyl) bicyclo [2.2.2 ] can be used ]Octane-1-carboxylic acid 25 in hydride-based reducing agents (e.g., LAH, DIBAL-H, NaBH)₄Etc.) to yield intermediate 28. Oxidation of intermediate 28 to intermediate 29 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 29 can be reacted in the presence of an acid (such as 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 afford intermediate 30. Intermediate 4 may be activated for acylation using any number of reagents (e.g., thionyl chloride, phosphorus oxychloride, oxalyl chloride, methyl chloroformate, or ethyl chloroformate, etc.) as recognized by one skilled in the art in a polar aprotic solvent (e.g., DCM, THF, etc.) at a temperature ranging between-30 ℃ to reflux temperature. The activated acid intermediate may be reacted with intermediate 30 in the presence of a base to form the corresponding amide. Subsequent hydrolysis with the methyl ester of an alkali metal hydroxide base can provide intermediate 31. Intermediate 31 may be converted to various heterocycles (a) using a variety of known methods recognized by those skilled in the art, including but not limited to the methods described in scheme 11, to provide compounds of formula I.

Alternatively, intermediate 29 and intermediate 8 may be subjected to reductive amination using a variety of known methods as will be recognized by those skilled in the art. Imine synthesis is carried out in the presence of an acid (such as acetic acid) in a suitable polar protic solvent (e.g., MeOH, EtOH, etc.) at room or reflux temperature,the imine is then reduced with a reducing agent (e.g., sodium cyanoborohydride, sodium triacetoxyborohydride, etc.) to afford intermediate 30 a. Intermediate 4 may be activated for acylation using any number of reagents (e.g., thionyl chloride, phosphorus oxychloride, oxalyl chloride, methyl chloroformate, or ethyl chloroformate, etc.) as recognized by one skilled in the art in a polar aprotic solvent (e.g., DCM, THF, etc.) at a temperature ranging between-30 ℃ to reflux temperature. The activated acid intermediate may be reacted with intermediate 30a in the presence of a base to form the corresponding amide. Subsequent hydrolysis with the methyl ester of an alkali metal hydroxide base may provide intermediate 31 a. Intermediate 31a can be converted to various heterocycles (a) using a variety of known methods recognized by those skilled in the art, including but not limited to the methods described in scheme 11, to give intermediate 31 b. Many known methods (including but not limited to Metal-Catalyzed Cross-Coupling Reactions, Armin de Meijere, Diederich, Vol.2, second revision and supplement, 2004, ISBN:3-527-30518-1, Wiley-VCH and references cited therein) to subject intermediate 31b to a metal catalyzed cross-coupling reaction. The intermediate 31b can be subjected to a metal catalyzed sonogashira coupling. These coupling reactions can be carried out on a metal catalyst Pd (PPh)₃)₂Cl₂And CuI in the presence of a base such as triethylamine in a polar aprotic solvent such as DMF at 90 ℃. The coupling reaction of intermediate 31b may be carried out with various suitable coupling partners (such as substituted alkynes) to give compounds represented by formula I. Intermediate 31b may be subjected to a metal catalyzed heck coupling. These coupling reactions can be carried out in the presence of a metal catalyst such as bis (tri-o-tolylphosphine) palladium (II) dichloride and tetrabutylammonium bromide in the presence of a base (Et)₃N, DIPEA, etc.) in a solvent (DMAc, DMF, etc.) under heating. The coupling reaction of intermediate 31b may be carried out with various suitable coupling partners such as substituted alkenes, alkenyl halides or triflates to give compounds represented by formula I. May use bis (Pinacolato) diboron, bis (neopentylethanoate) diboron and the like over palladium catalysts such as Pd (dppf) Cl ₂And converting intermediate 31b to an organoboron reagent in the presence of a base such as potassium acetate in a solvent (e.g., dioxane, DMSO, etc.) at reflux temperature, which is coupled with a suitable coupling partner such as an alkene, alkenyl halide, or triflate in a Suzuki (Suzuki) coupling to afford the compound represented by formula I. Alternatively, intermediate 31b can be converted to an organotin reagent using hexamethylditin in the presence of a palladium catalyst and in a solvent (e.g., toluene, THF, etc.) at reflux temperature, which is coupled in a still coupling (sher, b. et al PCT international application, 2016/039734,2016) with a suitable coupling partner (such as an alkenyl halide or triflate, etc.) to afford the compound represented by formula I.

Scheme 13

Scheme 13 describes an alternative synthesis of compounds of formula I with a modified sequence of steps.

Intermediate 30 (as depicted in scheme 12) can be subjected to hydrolysis with the methyl ester of an alkali metal hydroxide base to provide intermediate 32. Intermediate 32 can be converted to the various heterocycles (a) using a variety 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. Intermediate 4 may be activated for acylation using any number of reagents (e.g., thionyl chloride, phosphorus oxychloride, oxalyl chloride, methyl chloroformate, or ethyl chloroformate, etc.) as recognized by one skilled in the art in a polar aprotic solvent (e.g., DCM, THF, etc.) at a temperature ranging between-30 ℃ to reflux temperature. The activated acid intermediate may be reacted with intermediate 33 in the presence of a base to produce a compound of formula I.

Intermediate 30a (described in scheme 12) may be subjected to hydrolysis with the methyl ester of an alkali metal hydroxide base to provide intermediate 32 a. A variety of known methods (including but not limited to scheme 11) recognized by those skilled in the art can be usedThe process described) converts intermediate 32a to various heterocycles (a) to give compounds of formula 33 a. Intermediate 4 may be activated for acylation using any number of reagents (e.g., thionyl chloride, phosphorus oxychloride, oxalyl chloride, methyl chloroformate, or ethyl chloroformate, etc.) as recognized by one skilled in the art in a polar aprotic solvent (e.g., DCM, THF, etc.) at a temperature ranging between-30 ℃ to reflux temperature. The activated acid intermediate may be reacted with intermediate 33a in the presence of a base to produce intermediate 33 b. Many known methods (including but not limited to Metal-Catalyzed Cross-Coupling Reactions, Armin de Meijere,diederich, Vol.2, second revision and supplement, 2004, ISBN:3-527-30518-1, Wiley-VCH and references cited therein) to subject intermediate 33b to a metal catalyzed cross-coupling reaction. The intermediate 33b can be subjected to a metal catalyzed sonogashira coupling. These coupling reactions can be carried out on a metal catalyst Pd (PPh) ₃)₂Cl₂And CuI in the presence of a base such as triethylamine in a polar aprotic solvent such as DMF at 90 ℃. The coupling reaction of intermediate 33b may be carried out with various suitable coupling partners (such as substituted alkynes) to give compounds represented by formula I. Intermediate 33b may be subjected to a metal catalyzed heck coupling. These coupling reactions can be carried out in the presence of a metal catalyst such as bis (tri-o-tolylphosphine) palladium (II) dichloride and tetrabutylammonium bromide in the presence of a base (Et)₃N, DIPEA, etc.) in a solvent (DMAc, DMF, etc.) under heating. The coupling reaction of intermediate 33b may be carried out with various suitable coupling partners such as substituted alkenes, alkenyl halides or triflates to give compounds represented by formula I. Bis (pinacolato) diboron, bis (neopentyl glycolate) diboron, and the like can be used in palladium catalysts such as Pd (dppf) Cl₂And a base such as potassium acetate in a solvent (e.g., dioxane, DMSO, etc.) at reflux temperature to convert intermediate 33b to an organoboron reagent, which is coupled with a suitable reagent in a Suzuki (Suzuki) couplingCoupling of a coupling partner such as an alkene, alkenyl halide, or triflate affords compounds represented by formula I. Alternatively, intermediate 33b can be converted to an organotin reagent using hexamethylditin in the presence of a palladium catalyst and in a solvent (e.g., toluene, THF, etc.) at reflux temperature, which is coupled in a still coupling (sher, b. et al PCT international application, 2016/039734,2016) with a suitable coupling partner (such as an alkenyl halide or triflate, etc.) to afford the compound represented by formula I.

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 solvent such as DCM, DMF and the like and in solvent such as Et₃N, DIPEA by treating commercially available 4- (methoxycarbonyl) bicyclo [2.2.2 ] 2 with an activator such as BOP, HATU or the like in the presence of an organic base such as ammonium chloride at ambient temperature in the presence of ammonium chloride]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 by using POCl₃And base treatment such as imidazole converts intermediate 34 to intermediate 35. Intermediate 36 may be synthesized by reacting intermediate 35 with hydroxylamine; see Hirawat, s. et al WO 2006/110483. Various substituted intermediates 37 are 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 used in a hydride-based reducing agent (e.g., LAH, DIBAL-H, NaBH) ₄Etc.) in the presence of a chlorinated or ethereal solvent (such as DCM, ether, 1, 4-dioxane, THF, etc.) to afford intermediate 38. Oxidation conditions can be used by methods recognized by those skilled in the art (e.g.,dessimutan oxidizer, schwent oxidation conditions, PDC or PCC, etc.) oxidizes intermediate 39 to intermediate 40. Intermediate 40 may be converted to a 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). Intermediates represented by formula 31 (the synthesis described in scheme 12) can be subjected to esterification. Intermediate 31 may be activated for acylation using any number of reagents (e.g., thionyl chloride, phosphorus oxychloride, oxalyl chloride, methyl chloroformate, or ethyl chloroformate, etc.) as recognized by one skilled in the art in a polar aprotic solvent (e.g., DCM, THF, etc.) at a temperature ranging between-30 ℃ to reflux temperature. 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 prepared by dissolving in a solvent (e.g., DCM, DMF, etc.) in a base (e.g., Et)₃N, DIPEA, etc.) in the presence of ammonium chloride or a substituted amine (e.g., alkyl, cycloalkyl, aryl, heteroaryl, etc.) at ambient temperature or with heating the acid is activated with an activator (e.g., BOP, CDI, HATU, etc.) to subject intermediate 31 to an amide synthesis to give an amide of formula Ib. Can be prepared by dissolving in a solvent (e.g., DCM, DMF, etc.) in a base (e.g., Et) ₃N, DIPEA, etc.) and ammonium chloride at ambient temperature with an activator (e.g., BOP, CDI, HATU, etc.) the intermediate 31 is subjected to the primary amide synthesis. The primary amide thus obtained can be reacted with i) trifluoroacetic anhydride in pyridine at 0 ℃ or ii) POCl₃And imidazole treatment to give the nitrile of formula Ic. Intermediate 31 may be activated in a polar aprotic solvent (e.g., DCM, THF, etc.) using any number of reagents (e.g., thionyl chloride, phosphorus oxychloride, oxalyl chloride, methyl chloroformate, or ethyl chloroformate, etc.) as recognized by one skilled in the art at a temperature ranging between-30 ℃ to reflux temperature. Can be dissolved in polar aprotic solvent in the presence of a base (e.g., pyridine, DMAP, 2- (dimethylamino) pyridine, N-methylmorpholine, etc.)The activated acid intermediate is reacted with a sulfonamide in an agent (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 in 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 in the presence of an alkali metal hydroxide base at an elevated temperature (70 ℃) to form intermediate 55. Any number of reagents (e.g., NCS, Hg (ClO) can be used ₄)₂DDQ, etc.) to afford an aldehyde, may be accomplished by using an oxidizing agent (NaClO)₂PCC or PDC, KMnO₄Etc.) to the acid, followed by subsequent esterification by reaction with methyl iodide to provide intermediate 56. Subsequent hydrolysis of intermediate 56 with an alkali hydroxide base can provide intermediate 57. Intermediates 57 can be converted to various heterocycles (a) using a variety of known methods recognized by those skilled in the art, including but not limited to those described in scheme 11, to provide compounds of intermediates 58. 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 elevated temperature (120 ℃) to provide the corresponding acetate salt, which is subsequently hydrolyzed under acidic conditions (HCl) to afford intermediate 59. Oxidation of intermediate 59 to give the compound of formula 2a may 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 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 in 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) can 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 alkali metal hydroxide base at elevated temperature (70 ℃) to afford 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 salt, which is subsequently hydrolyzed under acidic conditions (HCl) to afford 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 described in scheme 16) to give intermediate 64. Oxidation of intermediate 64 to aldehyde 65 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 1 and intermediate 1 are reacted in the presence of an acid (such as acetic acid) in a suitable polar protic solvent (e.g., MeOH, EtOH, etc.) at room or reflux temperature using a variety of known methods as will be appreciated by those skilled in the artBody 65 is subjected to reductive amination and the imine is reduced 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 salt, which is subsequently hydrolyzed under acidic conditions (HCl) to afford intermediate 67. Can be prepared by using an oxidizing agent (NaClO)₂PCC or PDC, KMnO₄Etc.) intermediate 67 is oxidized to the acid and then the various heterocycles (a) are synthesized using a number of known methods recognized by those skilled in the art, including but not limited to those described in scheme 11, to give intermediate 68. Intermediate 4 may be activated for acylation using any number of reagents (e.g., thionyl chloride, phosphorus oxychloride, oxalyl chloride, methyl chloroformate, or ethyl chloroformate, etc.) as recognized by one skilled in the art in a polar aprotic solvent (e.g., DCM, THF, etc.) at a temperature ranging between-30 ℃ to reflux temperature. 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) are subjected to reductive amination in the presence of an acid (such as acetic acid) in a suitable polar protic solvent (e.g., MeOH, EtOH, etc.) at room or reflux temperature using a variety of known methods as would be recognized by one skilled in the art, and the imine is reduced with a reducing agent (e.g., sodium cyanoborohydride, sodium triacetoxyborohydride, etc.) to afford intermediate 66 a. Intermediate 66a may 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 salt, which is subsequently hydrolyzed under acidic conditions (HCl) to afford intermediate 67 a. Can be prepared by using an oxidizing agent (NaClO)₂PCC or PDC, KMnO₄Etc.) intermediate 67a is oxidized to the acid, and thenVarious heterocycles (a) are synthesized using a variety of known methods recognized by those skilled in the art, including but not limited to those described in scheme 11, to afford intermediates 68 a. 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 in an ether solvent (such as Et)₂O, THF, etc.) is subjected to treatment with an organomagnesium reagent at a temperature varying between-78 ℃ and 0 ℃ to give intermediate 70. Oxidation of intermediate 70 to intermediate 71 can be carried out by methods recognized by those skilled in the art using an oxidant such as dessimutan oxidant, PDC or PCC under oxidation conditions. 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 intermediate of formula 72. Intermediate 4 may be activated for acylation using any number of reagents (e.g., thionyl chloride, phosphorus oxychloride, oxalyl chloride, methyl chloroformate, or ethyl chloroformate, etc.) as recognized by one skilled in the art in a polar aprotic solvent (e.g., DCM, THF, etc.) at a temperature ranging between-30 ℃ to reflux temperature. The activated acid intermediate may be reacted with intermediate 72 in the presence of a base to produce a 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). Can be used for To convert intermediate 25 to intermediate 73 via a cotisis rearrangement as described in Shioiri, t. et al j.am.chem.soc.1972,94, 6203-cake 6205. Can be used in a hydride-based reducing agent (e.g., LAH, DIBAL-H, NaBH)₄Etc.) to intermediate 73 to yield intermediate 74. Oxidation of intermediate 74 to aldehyde 75 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 1 and intermediate 75 can be subjected to reductive amination in the presence of an acid (such as acetic acid) in a suitable polar protic solvent (e.g., MeOH, EtOH, etc.) at room or reflux temperature using a variety 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 76. Intermediate 4 may be activated for acylation using any number of reagents (e.g., thionyl chloride, phosphorus oxychloride, oxalyl chloride, methyl chloroformate, or ethyl chloroformate, etc.) as recognized by one skilled in the art in a polar aprotic solvent (e.g., DCM, THF, etc.) at a temperature ranging between-30 ℃ to reflux temperature. The activated acid intermediate may be reacted with intermediate 76 in the presence of a base to form the corresponding amide. The amide intermediate can be subjected to Boc deprotection using trifluoroacetic acid in a polar aprotic solvent (e.g., DCM, THF, etc.) at room temperature to afford intermediate 77. A variety of different transformations of intermediate 77 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 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 an 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 ℃ to 90 ℃ to yield the sulfonamide of formula If.

Urea: intermediate 77 can be reacted in a base (e.g., Et)₃N, DIPEA, pyridine, etc.) in a polar aprotic solvent (e.g., DCM, DCE, etc.) at room temperature to give a urea represented by formula Ig. Alternatively, the reaction can be carried out by reaction with a base (e.g., Et)₃N, DIPEA, etc.) in a solvent (e.g., DCM, DCE, etc.) at 0 ℃ to room temperature with triphosgene treatment to activate intermediate 77. Can then be in base (e.g., Et)₃N, DIPEA, etc.) in a solvent (e.g., DCM, DCE, etc.) at room temperature to treat activated intermediate 77 with a substituted alkyl or aryl or heteroaryl amine to provide a urea represented by formula Ig.

Carbamate ester: can be in the presence of a base (e.g., Et)₃N, DIPEA, pyridine, t-BuOK, etc.) in a polar aprotic solvent (e.g., DCM, DCE, THF, etc.) at 0 ℃ to room temperature, intermediate 77 is treated with a chloroformate (or an alcohol, activated to a carbonate) to give the 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 (synthesized as described in scheme 12) can be base hydrolyzed with an alkali metal hydroxide to give intermediate 78. Can be prepared by dissolving in a polar aprotic solvent (DCM, DMF, etc.) in a base (e.g., Et)₃N, DIPEA, etc.) and activating the acid with an activator (BOP, CDI, HATU, etc.) in the presence of ammonium chloride at ambient temperature intermediate 78 is subjected to the primary amide synthesis to afford intermediate 79. Various methods recognized by those skilled in the art (including, but not limited to, use of reagents (POCl) can be used₃、SOCl₂TFAA, etc.) and bases (imidazole, Et)₃N, DIPEA, etc.) to convert intermediate 79 to intermediate 80. Intermediate 81 may be synthesized by reacting intermediate 80 with hydroxylamine; see Hirawat, s. et al WO 2006/110483. Intermediates 37 may be obtained from commercial sources or may be readily recognized by one of skill in the art The synthesis is carried out by a known method. Intermediate 37 is 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 afford oxadiazole 82. Intermediate 82 can be converted to compounds of formula I by sequential amide synthesis and coupling as depicted in scheme 13.

Scheme 22

Scheme 22 describes the synthesis of compounds of formula I (wherein 'a' is phenyl). Commercially available 4- (methoxycarbonyl) bicyclo [2.2.2 ] can be heated in the presence of mercury oxide in dibromomethane as a solvent under heating]Octane-1-carboxylic acid 25 is subjected to bromination with bromine to give intermediate 90 (as described in Owen et al PCT international application No. 2014113485,2014). Can be on AlCl₃Converting intermediate 90 to intermediate 91 in benzene in the presence of Piyasena et al, PCT international application, 2015005901,2015. Can be prepared in CHCl in the presence of silver trifluoroacetate and bromine ₃Intermediate 91 was subjected to bromination at room temperature to give intermediate 92 (described by pivasena et al PCT international application No. 2015005901,2015). Can be used in a hydride-based reducing agent (e.g., LAH, DIBAL-H, NaBH)₄Etc.) to intermediate 92 to yield intermediate 93. 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 subjected to reductive amination in the presence of an acid (such as acetic acid) in a suitable polar protic solvent (e.g., MeOH, EtOH, etc.) at room or reflux temperature using a variety of known methods as would be recognized by one skilled in the art, followed by reductive amination with a reducing agent (e.g., sodium cyanoborohydride, triacetoxyborohydride, etc.)Sodium, etc.) to yield intermediate 95. Intermediate 4 may be activated for acylation using any number of reagents (e.g., thionyl chloride, phosphorus oxychloride, oxalyl chloride, methyl chloroformate, or ethyl chloroformate, etc.) as recognized by one skilled in the art in a polar aprotic solvent (e.g., DCM, THF, etc.) at a temperature ranging between-30 ℃ to reflux temperature. The activated acid intermediate may be reacted with intermediate 95 in the presence of a base to produce intermediate 96. Can be used in metal catalysts (e.g., CuBr, Pd (OAc) ₂、Pd₂(dba)₃、Pd(PPh₃)₄、Pd(PPh₃)₂Cl₂、Pd(dppf)Cl₂Etc.) and an appropriate ligand (including but not limited to ligands such as tricyclohexylphosphine, dppf, etc.) (if necessary) subjecting intermediate 96 to various metal catalyzed reactions (including but not limited to reactions such as Ullmann coupling, suzuki coupling, buhward coupling, stele coupling, etc.). The Ullmann coupling and Buherwald coupling reactions of intermediate 96 may be carried out with various coupling partners such as alkyl or aryl or heteroaryl amines, thiols and alcohols, and the like. The suzuki, stele coupling reaction of intermediate 96 may be carried out with a variety of coupling partners such as alkenyl, aryl or heteroaryl boronic acids, boronic esters, organotin reagents and the like. May be in the presence of a base (whenever necessary) (including but not limited to Na)₂CO₃、K₂CO₃、NaHCO₃、K₃PO₄、NaO^tBu, 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 to obtain a compound of formula I.

Scheme 23

Scheme 23 depicts the synthesis of intermediate 99. Commercially available 4- (methoxycarbonyl) bicyclo [2.2.2 ] can be used]Octane-1-carboxylic acid 25 is subjected to bromination and then in the presence of an appropriately substituted aromatic hydrocarbon as described in scheme 22 Friedel-Crafts arylation was carried out to give intermediate 97. Alternatively, intermediate 97 may be synthesized via a decarboxylated root bank (Negishi) type or suzuki type cross-coupling reaction. Intermediate 25 can be activated to N-hydroxyphthalimide ester, N-hydroxybenzotriazole ester, or the like, activated to a redox active ester, and can be activated with a metal catalyst (e.g., Fe (acac))₃、FeCl₃、NiCl₂Glyme, etc.) with various substituted aryl groups or an organozinc or organoboronic acid or grignard reagent to afford intermediate 97. Can be used in a hydride-based reducing agent (e.g., LAH, DIBAL-H, NaBH)₄Etc.) to intermediate 97 to yield intermediate 98. Oxidation of intermediate 98 to aldehyde 99 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 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.) intermediate 67 (synthesized as described in scheme 18A) was oxidized to give intermediate 100. Intermediate 100 can be converted to intermediate 101 via a cotisis 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 give 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 those 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.) intermediate 67a (synthesized as described in scheme 18B) was oxidized to give intermediate 100 a. Intermediate 100a can be converted to intermediate 101a via a cotisis rearrangement (as described in Shioiri, t. et al, j.am. chem. soc.1972,94, 6203-6205). Intermediate 101a may be subjected to sequential amide synthesis and boc-deprotection as described in scheme 20 to give amine intermediate 102 a.

A variety of different transformations of intermediate 102a may be performed to obtain variants of formula I using a number of known methods recognized by those skilled in the art (including, but not limited to, the following methods):

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 ℃ to 90 ℃ to produce intermediate 104.

Urea: intermediate 102a can be reacted in a base (e.g., Et)₃N, DIPEA, pyridine, etc.) in a polar aprotic solvent (e.g., DCM, DCE, etc.) at room temperature to afford intermediate 105. Alternatively, the reaction can be carried out by reaction with a base (e.g., Et)₃N, DIPEA, etc.) in a solvent (e.g., DCM, DCE, etc.) at 0 ℃ to room temperature with triphosgene treatment to activate intermediate 102 a. Can then be in base (e.g., Et)₃N, DIPEA, etc.) in a solvent (e.g., DCM, DCE, etc.) at room temperature with a solvent The activated intermediate 102a is treated with a substituted alkyl or aryl or heteroaryl amine to provide intermediate 105.

Carbamate ester: can be in the presence of a base (e.g., Et)₃N, DIPEA, pyridine, t-BuOK, etc.) in a polar aprotic solvent (e.g., DCM, DCE, THF, etc.) at 0 ℃ to room temperature using a chloroformate (or alcohol, activated to carbonate) to afford intermediate 106.

Many known methods (including but not limited to Metal-Catalyzed Cross-Coupling Reactions, Armin de Meijere,diederich, Vol.2, second revised and revised edition, 2004, ISBN:3-527-30518-1, Wiley-VCH and references cited therein) intermediate 103-106 was subjected to a metal catalyzed cross-coupling reaction. The intermediate 103-. These coupling reactions can be carried out on a metal catalyst Pd (PPh)₃)₂Cl₂And CuI in the presence of a base such as triethylamine in a polar aprotic solvent such as DMF at 90 ℃. The coupling reaction of intermediate 103-106 can be carried out with various suitable coupling partners, such as substituted alkynes, to give compounds represented by formula I (I, j, k, m). The intermediate 103-106 can be subjected to metal catalyzed heck coupling. These coupling reactions can be carried out in the presence of a metal catalyst such as bis (tri-o-tolylphosphine) palladium (II) dichloride and tetrabutylammonium bromide in the presence of a base (Et) ₃N, DIPEA, etc.) in a solvent (DMAc, DMF, etc.) under heating. The coupling reaction of intermediate 103-106 can be carried out with various suitable coupling partners such as substituted alkenes, alkenyl halides or triflates to give compounds represented by formula I (I, j, k, m). Bis (pinacolato) diboron, bis (neopentyl glycolate) diboron, and the like can be used in palladium catalysts such as Pd (dppf) Cl₂And a base such as potassium acetate in a solvent (e.g., dioxane, DMSO, etc.) at reflux temperature to convert intermediate 103-106 to an organoboron reagent, which is combined in a Suzuki (Suzuki) couplingCoupling of suitable coupling partners such as alkenes, alkenyl halides or triflates gives compounds of formula I (I, j, k, m). Alternatively, intermediate 103-106 can be converted to an organotin reagent using hexamethylditin in the presence of a palladium catalyst and in a solvent (e.g., toluene, THF, etc.) at reflux temperature, which is coupled in a still coupling (sher, b. et al PCT international application, 2016/039734,2016) with a suitable coupling partner (such as an alkenyl halide or triflate, etc.) to provide the compound represented by formula I (I, j, k, m).

General remarks: the order of steps involving the mounting groups 'Q' and 'a' may be performed interchangeably as appropriate in the scheme. Oxadiazole regioisomers can be generated by using the sequences described in schemes 11 and 14 attached to an oxabicyclo system.

Examples 1 and 2

(E) -methyl 3- (3- (N- ((4- (4- (dimethylamino) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate (1) and (E) -3- (3- (N- ((4- (4- (dimethylamino) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate (2)

Step A. preparation of intermediate 1 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 (commercially available) (1g, 4.71mmol) in CH₂Br₂To a stirred solution (10mL) was added mercuric oxide (1.73g, 8.01 mmol). The reaction mixture was heated at 80 ℃. Bromine (0.36mL, 7.07mmol) was added dropwise to the reaction mixture at the same temperature and stirring was continued for 3 h. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure to give the title compound (1g, 4.05 mm)ol, 86% yield). This compound was used as such in the next step. 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 1 B.4-phenyl bicyclo [2.2.2] octane-1-methyl formate

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 the same temperature for 5 min. Intermediate 1A (1g, 4.05mmol) as a solution in benzene (12mL) was added to the reaction mixture at-10 ℃. 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 as such in the next step.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 1C.4- (4-bromophenyl) bicyclo [2.2.2] octane-1-carboxylic acid methyl ester

A stirred solution of intermediate 1B (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 CHCl₃(40mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was filtered through celite. The filtrate was evaporated under reduced pressure, the residue was washed with n-hexane and dried in vacuo to give the title compound (0.74g, 1.580mmol, 48% yield). MS (ESI)323(M + H). ¹H NMR (300MHz, chloroform-d) δ 7.43(d, J ═ 8.7Hz,2H),7.20(d, J ═ 8.7 Hz), 7.7,2H),3.69(s,3H),1.99-1.78(m,12H)。

Step D. preparation of intermediate 1D. (4- (4-bromophenyl) bicyclo [2.2.2] oct-1-yl) methanol)

A stirred solution of intermediate 1C (0.65g, 2.011mmol) in DCM (5mL) was cooled to-78 ℃. 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 organic layers were combined, dried over anhydrous sodium sulfate 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, 1.999mmol, 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 1E.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 for 15 min. A solution of intermediate 1D (0.3g, 1.016mmol) in DCM (5mL) was added to the reaction mixture over a period of 10 min. The reaction mixture was stirred at-78 ℃ for 3 h. Adding Et ₃N (0.85mL, 6.10mmol) was added to the reaction and stirring was continued at-78 ℃ for another 5 min. The reaction mixture was allowed to warm to 0 ℃ and stirred for 1 h. The reaction mixture was poured into crushed ice and diluted with cold water (20mL). The organic layer was separated and the aqueous layer was extracted with DCM (2 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (220mg, 0.750mmol, 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 F. preparation of intermediate 1F. (E) -methyl 3- (3-nitrophenyl) acrylate

To a stirred solution of methyl 2- (dimethoxyphosphoryl) acetate (commercially available) (1.29mL, 7.94mmol) in water (6mL) at room temperature was added K₂CO₃(1.82g, 13.23mmol) followed by the addition of 3-nitrobenzaldehyde (commercially available) (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 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 G preparation of intermediate 1G. (E) -methyl 3- (3-aminophenyl) acrylate

To a stirred solution of intermediate 1F (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. The reaction mixture was allowed to warm to room temperature. The reaction volume was halved under reduced pressure and the remaining solution was poured into crushed ice. The aqueous solution was saturated with Na₂CO₃The aqueous solution was neutralized (pH about 7) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a concentrated solutionThe title compound was obtained 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 H. preparation of intermediate 1H. (E) -methyl 3- (3- (((4- (4-bromophenyl) bicyclo [2.2.2] oct-1-yl) methyl) amino) phenyl) acrylate

To a stirred solution of intermediate 1E (150mg, 0.512mmol) in anhydrous MeOH (3mL) was added intermediate 1G (100mg, 0.563mmol) followed by acetic acid (0.015mL, 0.256mmol) and molecular sieves at room temperature(15 mg). The reaction mixture was heated at 60 ℃ overnight. The reaction mixture was cooled to 0 ℃ and sodium cyanoborohydride (96mg, 1.535mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure, the residue was diluted with water 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 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 (100mg, 0.178mmol, 35% yield). ¹H NMR(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 I. preparation of intermediate 1I (E) -methyl 3- (3- (N- ((4- (4-bromophenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate

To a stirred solution of intermediate 1H (100mg, 0.220mmol) in anhydrous DCM (2mL) at 0 deg.C was added Et₃N (0.123mL, 0.880mmol), then cyclohexanecarbonyl chloride (commercially available) (0.06mL, 0.440mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. The reaction mixture was diluted with water and extracted with DCM (2 × 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate 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 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 (120mg, 0.172mmol, 78% yield). MS (ESI)564(M + H).

Step j. examples 1 and 2 preparation of (E) -methyl 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 1I (100mg, 0.177mmol) in toluene (5mL) was added dimethylamine (0.094mL, 1.771mmol), 2-di-tert-butylphosphino-2 ',4',6' -triisopropylbiphenyl (7.52mg, 0.018mmol), and sodium tert-butoxide (51mg, 0.531mmol) at room temperature. The reaction mixture was degassed and backfilled with argon. Pd is added₂(dba)₃(8mg, 8.86. mu. mol) was added to the reaction and the vial was sealed (pressure release vial). The reaction mixture was heated at 80 ℃ 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: 10-mM 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). The fractions containing the desired product are combinedAnd, and dried via centrifugation to give the title compound (example 1); (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) and example 2(2.7mg, 4.98. mu. mol, 3% yield);¹H NMR(400MHz,DMSO-d₆)δ12.44(bs,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)。

the following compounds were prepared according to the procedure described for synthetic example 1 by substituting intermediate 1I and the corresponding amine.

Example 6

(E) -3- (3- (N- ((4- (4- (dimethylamino) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) tetrahydro-2H-

Pyran-4-carboxamido) phenyl) acrylic acid methyl ester

Step a. intermediate 6A preparation of (E) -methyl 3- (3- (N- ((4- (4-bromophenyl) bicyclo [2.2.2] oct-1-yl) methyl) tetrahydro-2H-pyran-4-carboxamido) phenyl) acrylate

To a stirred solution of tetrahydro-2H-pyran-4-carboxylic acid (commercially available) (100mg, 0.768mmol) in DCM (5mL) at 0 deg.C was added oxalyl chloride (0.13mL, 1.537mmol) followed by DMF (catalytic amount). The reaction mixture was stirred at the same temperature for 1 h. The reaction mixture was allowed to warm to room temperature and concentrated under reduced pressure to give the corresponding acid chloride. To a stirred solution of intermediate 1H (120mg, 0.264mmol) in DCM (20mL) was added TEA (0.64mL, 4.61mmol) and stirred for 5 min. The prepared acid chloride was added to the reaction mixture and stirred overnight. The reaction mixture was diluted with DCM (20mL), washed with water (2 × 20mL), brine solution (2 × 10mL) 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 45% B; flow rate ═ 30 mL/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound (50mg, 0.077mmol, 10% yield). MS (ESI)568(M + H).

Step B. preparation of intermediate 6B. (E) -3- (3- (N- ((4- (4- (dimethylamino) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) tetrahydro-2H-pyran-4-carboxamido) phenyl) acrylic acid

To a stirred solution of intermediate 6A (35mg, 0.062mmol) in toluene (2mL) was added dimethylamine (0.927mL, 0.927mmol), 2-di-tert-butylphosphino-2 ',4',6' -triisopropylbiphenyl (2.62mg, 6.18 μmol) and sodium tert-butoxide (17.81mg, 0.185mmol) at room temperature. The reaction mixture was degassed and backfilled with argon. Pd is added₂(dba)₃(2.8mg, 3.09. mu. mol) was added to the reaction and the vial was sealed (pressure release vial). The reaction mixture was heated at 80 ℃ for 4 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (2 × 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to giveThe title compound (30mg, 0.058mmol, 94% yield). MS (ESI)517(M + H).

EXAMPLE 6 preparation of methyl (E) -3- (3- (N- ((4- (4- (dimethylamino) phenyl) bicyclo [2.2.2] oct-1-yl) methyl) tetrahydro-2H-pyran-4-carboxamido) phenyl) acrylate

To a stirred solution of intermediate 6B (35mg, 0.068mmol) in DCM (5mL) was added (trimethylsilyl) diazomethane (0.17mL, 0.339mmol) at 0 ℃. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. The reaction was quenched with acetic acid (0.5mL) and the reaction mixture was concentrated under reduced pressure. The crude material was purified via preparative LC/MS using the following conditions: (column: InertsilODS, 19X250mM, 5- μm particles; mobile phase A: 10-mM ammonium acetate; mobile phase B: acetonitrile; gradient: 50% -100% B over 24 min, then hold at 0% B for 0 min; flow: 17 mL/min). Fractions containing the desired product were combined and dried via centrifugation evaporation to give the title compound as a gummy liquid (1.1mg, 1.886 μmol, 3% yield). ¹H NMR(400MHz,DMSO-d₆)δ7.82(s,1H),7.74-7.63(m,2H),7.55-7.44(m,2H),7.20(br.s.,2H),7.06(d,J＝8.6Hz,2H),6.77(d,J＝15.9Hz,1H),6.61(d,J＝8.8Hz,2H),3.74(s,6H),3.64-3.54(m,3H),3.07-2.91(m,2H),2.89-2.76(m,7H),1.60(d,J＝8.8Hz,9H),1.50-1.31(m,9H),1.23(s,2H),1.13(t,J＝7.5Hz,2H)。FXR EC₅₀(nM)＝212；MS(ESI)531(M+H)。

Example 7

(E) -3- (3- (N- ((4-phenylbicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylic acid methyl ester

Step A. preparation of intermediate 7A. (4-phenylbicyclo [2.2.2] oct-1-yl) methanol

According to the synthesis for intermediate 1DThe title compound was prepared by substituting intermediate 1B as appropriate. (0.2g, 0.925mmol, 64% yield) as an off-white solid.¹H NMR(400MHz,DMSO-d₆)δ7.39-7.21(m,4H),7.20-7.10(m,1H),4.36(t,J＝5.5Hz,1H),3.09(d,J＝5.6Hz,2H),1.83-1.66(m,6H),1.52-1.38(m,6H)。

Step B. preparation of intermediate 7 B.4-phenylbicyclo [2.2.2] octane-1-carbaldehyde

To a solution of intermediate 7A (0.1g, 0.462mmol) in DCM (5mL) was added dessimutane oxidant (0.196g, 0.462mmol) at 0 ℃ under a nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stirred for 30 min. The reaction mixture was diluted with dichloromethane (20mL) and 10% NaHCO₃The aqueous solution, brine solution (5mL) was washed, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.1g, 0.397mmol, 86% yield).¹H NMR(400MHz,DMSO-d₆)δ9.48(s,1H),7.36-7.25(m,4H),7.19-7.13(m,1H),1.85-1.78(m,6H),1.73-1.66(m,6H)。

Step C. preparation of intermediate 7℃ (E) -methyl 3- (3- (((4-phenylbicyclo [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 1H by substituting intermediate 1G and intermediate 7B as appropriate. (0.05g, 0.126mmol, 34% yield) as a pale yellow solid. ¹H NMR(400MHz,DMSO-d₆)δ7.53(d,J＝16.1Hz,1H),7.37-7.23(m,4H),7.19-7.05(m,2H),6.89(s,1H),6.81(d,J＝7.6Hz,1H),6.73(dd,J＝7.9,1.6Hz,1H),6.51(d,J＝15.9Hz,1H),5.58(t,J＝5.9Hz,1H),3.72(s,3H),2.87(d,J＝5.9Hz,2H),1.85-1.71(m,6H),1.65-1.52(m,6H)。MS(ESI)376(M+H)。

EXAMPLE 7 preparation of methyl (E) -3- (3- (N- ((4-phenylbicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate

The title compound was prepared according to the procedure described for the synthesis of intermediate 1I by substituting intermediate 7C and the corresponding acid chloride as appropriate. (9mg, 0.018mmol, 27% yield).¹H NMR(400MHz,DMSO-d₆)δ7.80(s,1H),7.75-7.63(m,2H),7.53-7.38(m,2H),7.32-7.18(m,4H),7.16-7.06(m,1H),6.76(d,J＝16.1Hz,1H),3.74(s,3H),3.59(br.s.,2H),2.20(br.s.,1H),1.73-1.54(m,10H),1.48(br.s.,1H),1.44-1.28(m,8H),1.09(d,J＝13.2Hz,1H),0.88(br.s.,2H)。FXR EC₅₀(nM)395；MS(ESI)486(M+H)。

Example 8

(E) -methyl 3- (3- (N- ((1- (1-methyl-1H-indazol-5-yl) -2-oxabicyclo [2.2.2] oct-4-yl) methyl) tetrahydro-2H-pyran-4-carboxamido) phenyl) acrylate

Step a. preparation of intermediates 8a1 and 8a2 (5-bromo-1-methyl-1H-indazole and 5-bromo-2-methyl-2H-indazole)

To a stirred solution of 5-bromo-1H-indazole (commercially available) (2g, 10.15mmol) in DMSO (20mL) was added methyl iodide (0.82mL, 13.20mmol) 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 and extracted with EtOAc (3 × 20). The organic layers were combined, 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 40% B; flow rate ═ 30 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to afford intermediate 8a1(1.2g, 5.40mmol, 53% yield) as a white solid and intermediate 8a2(0.6g, 2.70mmol, 27% yield) as an off-white solid. The NOE study confirmed the desired compound. MS (ESI)213(M + H).

Step B preparation of intermediate 8 B.5-iodo-1-methyl-1H-indazole

To a solution of intermediate 8a1(1g, 4.74mmol) in 1, 4-dioxane (5mL) under an argon atmosphere 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, 0.474 mmol). The reaction mixture was heated at 110 ℃ overnight. The reaction mixture was cooled to room temperature, diluted with water (30mL) and extracted with DCM (3 × 20 mL). The organic layers were combined, 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 30% B; flow rate ═ 30 mL/min). The pure fractions were combined, concentrated 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 8C (4-hydroxy-4- (1-methyl-1H-indazol-5-yl) cyclohexane-1, 1-diyl) bis (methylene) bis (4-methylbenzenesulfonate)

A stirred solution of intermediate 8B (0.3g, 1.163mmol) in tetrahydrofuran (5mL) was cooled to-78 ℃. n-BuLi in hexane (0.93mL, 2.325mmol) 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 dry THF was added to the reaction. The reaction mixture was allowed to warm to room temperature. The reaction mixture was quenched with saturated aqueous ammonium chloride solution. The reaction mixture was extracted with EtOAc (2 × 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate 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, 0.397mmol, 34% yield). MS (ESI)599(M + H).

Step D. preparation of intermediate 8 D.4-Methylbenzenesulfonic acid (1- (1-methyl-1H-indazol-5-yl) -2-oxabicyclo [2.2.2] oct-4-yl) methyl ester

To a stirred solution of intermediate 8C (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 the same temperature for 30min and then heated at reflux for 12 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution. The reaction mixture was extracted with EtOAc (2 × 10 mL). The organic layers were combined, 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 a white solid (0.18g, 0.401mmol, 96% yield). MS (ESI)427(M + H).

Step e. intermediate 8e preparation of (1- (1-methyl-1H-indazol-5-yl) -2-oxabicyclo [2.2.2] oct-4-yl) methyl acetate

To a solution of intermediate 8D (2.5g, 5.86mmol) in DMF (30mL) in pressure tube was added sodium acetate (2.88g, 35.2 mmol). The reaction mixture was heated at 120 ℃ overnight. The reaction mixture was cooled to room temperature and diluted with water (50 mL). The aqueous solution was extracted with EtOAc (2 × 20 mL). The organic layers were combined, 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 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 8F (1- (1-methyl-1H-indazol-5-yl) -2-oxabicyclo [2.2.2] oct-4-yl) methanol

To a stirred solution of intermediate 8E (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 stirred at room temperature 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 organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure and dried in vacuo to give the title compound as a white solid (0.45g, 1.570mmol, 82% yield). MS (ESI)273(M + H).

Step G. preparation of intermediate 8G.1- (1-methyl-1H-indazol-5-yl) -2-oxabicyclo [2.2.2] octane-4-carbaldehyde

To a stirred solution of intermediate 8F (0.4g, 1.469mmol) in dichloromethane (2mL) was added desselatin oxidant (0.748g, 1.762mmol) at 0 ℃. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM, washed with water (10mL), aqueous sodium bicarbonate (10mL), dried over anhydrous sodium sulfate 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 and dried in vacuo to give the title compound as a semi-solid (0.4g, 1.406mmol, 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. intermediate 8H preparation of methyl (E) -3- (3- (((1- (1-methyl-1H-indazol-5-yl) -2-oxabicyclo [2.2.2] oct-4-yl) methyl) amino) phenyl) acrylate

The title compound was prepared according to the procedure described for the synthesis of intermediate 1H by substituting intermediate 8G and intermediate 1G. (0.035g, 0.077mmol, 42% yield) as a black solid. MS (ESI)432(M + H).

EXAMPLE 8 preparation of methyl (E) -3- (3- (N- ((1- (1-methyl-1H-indazol-5-yl) -2-oxabicyclo [2.2.2] oct-4-yl) methyl) tetrahydro-2H-pyran-4-carboxamido) phenyl) acrylate

The title compound was prepared according to the procedure described for the synthesis of intermediate 6A by substituting intermediate 8H and the corresponding acid as appropriate. (4.5mg, 7.78. mu. mol, 10% yield).¹H NMR(400MHz,DMSO-d₆)δ7.94(s,1H),7.87(s,1H),7.69(s,1H),7.73(s,1H),7.64(s,1H),7.56-7.43(m,3H),7.39(dd,J＝8.9,1.6Hz,1H),6.78(d,J＝15.9Hz,1H),3.99(s,3H),3.80-3.71(m,6H),3.66(d,J＝15.9Hz,3H),2.99(t,J＝11.5Hz,2H),2.08-1.96(m,2H),1.81(d,J＝5.1Hz,2H),1.69-1.53(m,5H),1.47(d,J＝11.5Hz,4H)。FXR EC₅₀(nM)1595.92；MS(ESI)544(M+H)。

Example 9

(E) -methyl 3- (3- (1-methyl-N- ((1- (1-methyl-1H-indazol-5-yl) -2-oxabicyclo [2.2.2] oct-4-yl) methyl) piperidine-4-carboxamido) phenyl) acrylate

The titled compound was prepared according to the procedure described for the synthesis of intermediate 6A by substituting intermediate 8H and the corresponding acid as appropriateA compound (I) is provided. (1.5mg, 2.64. mu. mol, 6% yield).¹H NMR(400MHz,DMSO-d₆)δ8.05-7.92(m,2H),7.69(s,1H),7.73(s,1H),7.65(s,1H),7.50(d,J＝7.8Hz,3H),7.44-7.33(m,1H),6.79(d,J＝16.1Hz,1H),3.99(s,3H),3.74(s,3H),3.71-3.55(m,4H),2.65(br.s.,1H),2.12(br.s.,1H),2.02(s,5H),1.87-1.73(m,2H),1.68-1.50(m,9H),1.50-1.38(m,2H)。FXR EC₅₀(nM)4718；MS(ESI)557(M+H)。

Example 10

(E) -methyl 3- (3- (N- ((1- (4-methoxyphenyl) -2-oxabicyclo [2.2.2] oct-4-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate

Step A. preparation of intermediate 10A. (4-hydroxy-4- (4-methoxyphenyl) cyclohexane-1, 1-diyl) bis (methylene) bis (4-methylbenzenesulfonate)

To a stirred solution of (4-oxocyclohexane-1, 1-diyl) bis (methylene) bis (4-methylbenzenesulfonate) (0.5g, 1.072mmol) in THF (15mL) at-78 deg.C was added (4-methoxyphenyl) magnesium bromide (commercially available) (3.21mL, 3.21 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution. The reaction mixture was extracted with EtOAc (2 × 20 mL). The organic layers were combined, 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 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 a white solid (0.6g, 0.992mmol, 93% yield).¹H NMR (400MHz, chloroform-d) δ 7.81-7.71(m,4H),7.37(d, J ═ 8.5Hz,4H),7.27-7.24(m,2H),6.90-6.83(m,2H),4.00(s,1H),3.84-3.77(m,5H),2.49-2.44(m,6H),1.70-1.60(m,5H),1.58-1.48(m,2H),1.30-1.27(m, 1H).

Step B. preparation of intermediate 10 B.4-Methylbenzenesulfonic acid (1- (4-methoxyphenyl) -2-oxabicyclo [2.2.2] oct-4-yl) methyl ester

The title compound was prepared according to the procedure described for the synthesis of intermediate 8D by substituting intermediate 10A where appropriate. (0.4g, 0.944mmol, 90% yield) as a white solid. MS (ESI)403(M + H).

Step C. intermediate 10 preparation of (1- (4-methoxyphenyl) -2-oxabicyclo [2.2.2] oct-4-yl) methyl acetate

The title compound was prepared according to the procedure described for the synthesis of intermediate 8E by substituting intermediate 10B as appropriate. (0.3g, 0.982mmol, 99% yield) as an off-white solid. MS (ESI)291(M + H).

Step D. preparation of intermediate 10D. (1- (4-methoxyphenyl) -2-oxabicyclo [2.2.2] oct-4-yl) methanol)

The title compound was prepared according to the procedure described for the synthesis of intermediate 8F by substituting intermediate 10C as appropriate. (0.25g, 0.906mmol, 88% yield) as an off-white solid. MS (ESI)249(M + H).

Step E. preparation of intermediate 10E.1- (4-methoxyphenyl) -2-oxabicyclo [2.2.2] octane-4-carbaldehyde

By substituting intermediates where appropriate according to the method described for the synthesis of intermediate 8G10D preparation of the title compound. (0.1g, 0.386mmol, 96% yield) as an off-white solid.¹H NMR(400MHz,DMSO-d₆)δ9.51(s,1H),7.32-7.25(m,2H),6.89-6.81(m,2H),3.98(s,2H),3.73(s,3H),2.14-2.00(m,2H),1.93-1.83(m,6H)。

Step F. intermediate 10F. preparation of methyl (E) -3- (3- (((1- (4-methoxyphenyl) -2-oxabicyclo [2.2.2] oct-4-yl) methyl) amino) phenyl) acrylate

The title compound was prepared according to the procedure described for the synthesis of intermediate 1H by substituting intermediate 10E and intermediate 1G as appropriate. (0.25g, 0.386mmol, 96% yield) as a black solid. MS (ESI)408(M + H).

EXAMPLE 10 preparation of methyl (E) -3- (3- (N- ((1- (4-methoxyphenyl) -2-oxabicyclo [2.2.2] oct-4-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate

The title compound was prepared according to the procedure described for the synthesis of intermediate 1I by substituting intermediate 10F where appropriate. (13mg, 0.025mmol, 41% yield).¹H NMR(400MHz,DMSO-d₆)δ7.83(s,1H),7.76-7.64(m,2H),7.55-7.39(m,2H),7.22(d,J＝8.8Hz,2H),6.87-6.72(m,2H),3.74(s,3H),3.70(s,3H),3.62(d,J＝10.5Hz,4H),2.19(br.s.,1H),1.98-1.87(m,2H),1.75(br.s.,2H),1.58(br.s.,7H),1.49(br.s.,3H),1.33(d,J＝13.9Hz,2H),1.07(s,1H),0.88(br.s.,2H)；FXR EC₅₀(nM)318.73；MS(ESI)518(M+H)。

Example 11

5- (N- ((4- (4-Morpholinophenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) -3, 4-dihydronaphthalene-2-carboxylic acid methyl ester

Step A. preparation of intermediate 11 A.5-bromo-3, 4-dihydronaphthalen-1 (2H) -one

3, 4-Dihydronaphthalen-1 (2H) -one (commercially available) (8.5g, 58.1mmol) was added to aluminum chloride (19.38g, 145mmol) in a 2-neck 250mL flask at 0 deg.C under a nitrogen atmosphere. The reaction mixture was heated at 90 ℃ for 45 min. Bromine (3.6mL, 69.8mmol) was added dropwise to the reaction mixture at the same temperature and stirred for 1 h. The reaction mixture was poured into crushed ice and purified by using NaHCO₃Neutralizing with water solution. The aqueous solution was extracted with EtOAc (2 × 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated and dried in vacuo to give the title compound 3, 4-dihydronaphthalen-1 (2H) -one (8.5g, 58.1mmol) and the combined organic layers were dried over MgSO ₄Drying, filtration and concentration under reduced pressure gave the title compound (5.2g, 15.48mmol, 27% yield).¹H NMR(400MHz,DMSO-d₆)δ7.89(ddd,J＝9.2,7.7,1.3Hz,2H),7.31(t,J＝7.8Hz,1H),2.95(t,J＝6.0Hz,2H),2.67-2.57(m,2H),2.13-2.03(m,2H)。MS(ESI)225/227(M+H)。

Step B. preparation of intermediate 11 B.5-bromo-1-oxo-1, 2,3, 4-tetrahydronaphthalene-2-carboxylic acid methyl ester

To a stirred solution of NaH (0.88g, 22.21mmol) and dimethyl carbonate (4.53mL, 53.3mmol) in dry toluene (20mL) at 60 deg.C was added a solution of intermediate 11A (2g, 8.89mmol) in toluene (20 mL). The reaction mixture was stirred at the same temperature for 16 h. The reaction mixture was poured into crushed ice and extracted with EtOAc (3 × 30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure and dried in vacuo to give the title compound (2.4g, 7.63mmol, 86% yield).¹H NMR (400MHz, chloroform-d) δ 8.06-8.00(m,1H),7.81-7.75(m,1H),7.57(dd, J ═ 8.0,1.0Hz,1H),3.78(s,3H),3.62(dd, J ═ 10.3,4.8Hz,1H),2.59(t, J ═ 8.00Hz,2H),2.94(t, J ═ 8.00Hz, 2H). MS (ESI)283/285(M + H).

Step C. preparation of intermediate 11 C.5-bromo-1-hydroxy-1, 2,3, 4-tetrahydronaphthalene-2-carboxylic acid methyl ester

To a stirred solution of intermediate 11B (2.4g, 8.48mmol) in MeOH (20mL) at 0 deg.C was added NaBH₄(0.45g, 11.87 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 5 h. The reaction mixture was concentrated under reduced pressure and the residue was poured into crushed ice. The aqueous solution was extracted with EtOAc (2 × 150 mL). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure and dried in vacuo to give the title compound (1.7g, 5.60mmol, 66% yield). ¹H NMR (400MHz, chloroform-d) δ 7.55-7.48(m,1H),7.39(d, J ═ 7.5Hz,1H),7.17-7.06(m,1H),5.06-4.97(m,1H),3.78(s,3H),3.13(d, J ═ 5.0Hz,1H),3.01-2.94(m,1H),2.79(dt, J ═ 11.5,3.3Hz,1H),2.73-2.62(m,1H),2.36-2.21(m,1H),2.17(ddd, J ═ 6.8,3.3,1.0Hz, 1H). MS (ESI)304(M + NH)₃)。

Step D. preparation of intermediate 11 D.5-bromo-3, 4-dihydronaphthalene-2-carboxylic acid methyl ester

To a stirred solution of intermediate 11C (1.7g, 5.96mmol) in toluene (20mL) was added p-toluenesulfonic acid monohydrate (0.057g, 0.298mmol) at 0 ℃. The reaction mixture was heated at 110 ℃ for 3 h. The reaction mixture was diluted with DCM (100mL) and washed with water (2 × 50mL), dried over anhydrous sodium sulfate 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 (900mg, 3.37mmol, 56% yield).¹H NMR (300MHz, chloroform-d) delta 7.55-7.43(m,2H),7.20-7.04(m,2H),3.85(s,3H),3.09-2.95(m,2H),2.72-2.61(m, 2H). Ms (esi)284(M + H) NH3 adduct.

Step E. preparation of intermediate 11E.5- ((bookbutoxycarbonyl) amino) -3, 4-dihydronaphthalene-2-carboxylic acid methyl ester

To a solution of intermediate 11D (0.7g, 2.62mmol) in toluene was added tert-butyl carbamate (0.338g, 2.88mmol), cesium carbonate (2.56g, 7.86mmol) and 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (0.152g, 0.262 mmol). The reaction mixture was degassed and backfilled with argon. Pd is added₂(dba)₃(0.120g, 0.131mmol) was added to the reaction mass and the vial was sealed (pressure release vial). The reaction mixture was stirred at 100 ℃ overnight. The reaction mixture was diluted with water and extracted with EtOAc (2 × 30 mL). The organic layers were combined, 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 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 an off-white solid (0.42g, 1.315mmol, 50% yield). MS (ESI)304(M + H).

Step F. preparation of intermediate 11 F.5-amino-3, 4-dihydronaphthalene-2-carboxylic acid methyl ester

To a solution of intermediate 11E (0.42g, 1.385mmol) in dichloromethane (10mL) was added TFA (0.53mL, 6.92mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with DCM (10mL) and 10% NaHCO ₃The aqueous solution was washed, 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 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 an oil (0.28g, 1.309mmol, 95)% yield). MS (ESI)204(M + H).

Step G. preparation of intermediate 11G.5- (((4- (4-bromophenyl) bicyclo [2.2.2] oct-1-yl) methyl) amino) -3, 4-dihydronaphthalene-2-carboxylic acid methyl ester

The title compound was prepared according to the procedure described for the synthesis of intermediate 1H by substituting intermediate 11F and intermediate 1E. (0.21g, 0.415mmol, 61% yield) as an off-white solid. MS (ESI)482(M + H).

Step H. preparation of intermediate 11H.5- (methyl N- ((4- (4-bromophenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamide) -3, 4-dihydronaphthalene-2-carboxylate

The title compound was prepared according to the procedure described for the synthesis of intermediate 1I by substituting intermediate 11G and the corresponding acid chloride. (0.18g, 0.274mmol, 63% yield) as an off-white solid. MS (ESI)590(M + H).

EXAMPLE 11.5 preparation of methyl N- ((4- (4-morpholinophenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamide) -3, 4-dihydronaphthalene-2-carboxylate

To a stirred solution of intermediate 11H (0.02g, 0.034mmol) in toluene (1mL) and THF (0.2mL) was added cesium carbonate (0.03g, 0.102mmol), morpholine (5.9mg, 0.068mmol) and 2-di-tert-butylphosphino-2 ',4',6' -triisopropylbiphenyl (2.88mg, 6.77 μmol) at room temperature. The reaction mixture was degassed and backfilled with argon. Pd is added₂(dba)₃(3.1mg, 3.39 μmol) was added to the reaction and the vessel was sealed (pressure release vial). The reaction mixture was heated at 90 ℃ for 5 h. 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: 10-mM ammonium acetate; mobile phase B: acetonitrile; gradient: 15% over 20 minutes)55% B, then 5 minutes at 100% B; flow rate: 15 mL/min). Fractions containing the desired product were combined and dried via centrifugation evaporation to give the title compound (5.4mg, 8.60 μmol, 25% yield).¹H NMR(400MHz,DMSO-d₆)δ7.59(s,1H),7.44-7.40(m,2H),7.36-7.32(m,1H),7.12(d,J＝8.80Hz,2H),6.82(d,J＝8.80Hz,2H),3.81(d,J＝4.80Hz,1H),3.75(s,3H),3.72-3.69(m,4H),3.03-2.97(m,5H),2.74-2.70(m,1H),2.55-2.50(m,2H),2.43-2.40(m,1H),1.97(s,1H),1.67-1.60(m,9H),1.49-1.47(m,3H),1.41-1.38(m,4H),1.28-1.19(m,3H),1.06-1.05(m,1H),0.92-0.81(m,2H)。FXR EC₅₀(nM)2738；MS(ESI)597(M+H)。

The following compounds were prepared according to the procedure described for the synthesis of example 11 (step I) by substituting intermediate 11H and the corresponding amine as appropriate.

Example 14

(E) -3- (3- (N- ((4- (4-morpholinophenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) but-2-enoic acid methyl ester

Step A. preparation of intermediate 14A. (E) -methyl 3- (3-aminophenyl) but-2-enoate

To a stirred solution of 3-bromoaniline (commercially available) (1g, 5.81mmol) in DMF (10mL) was added (E) -methylbut-2-enoate (commercially available) (1.74g, 17.44mmol), tetrabutylammonium bromide (0.37g, 1.163mmol) and TEA (2.431mL, 17.44mmol) in a pressure release vial. The reaction mixture was degassed and backfilled with argon. Dichlorobis (tri-o-tolylphosphine) palladium (II) (0.457g, 0.581mmol) was added to the reaction and the vial was sealed. The reaction mixture was heated at 110 ℃ for 12 h. The reaction mixture was cooled to room temperature, diluted with water (30mL) and extracted with EtOAc (2 × 30 mL). The organic layers were combined, dried over anhydrous sodium sulfate 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 and dried in vacuo to give the title compound as a pale yellow oil (0.7g, 3.48mmol, 60% yield). MS (ESI)192(M + H).

Step B. preparation of intermediate 14B. (E) -methyl 3- (3- (((4- (4-bromophenyl) bicyclo [2.2.2] oct-1-yl) methyl) amino) phenyl) but-2-enoate

The title compound was prepared according to the procedure described for the synthesis of intermediate 1H by substituting intermediate 14A and intermediate 1E. (0.06g, 0.125mmol, 22% yield) as an off-white solid. MS (ESI)468(M + H).

Step C. preparation of intermediate 14℃ (E) -methyl 3- (3- (N- ((4- (4-bromophenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) but-2-enoate

The title compound was prepared according to the procedure described for the synthesis of intermediate 1I by substituting intermediate 14B. (0.045g, 0.070mmol, 54% yield) as an off-white solid. MS (ESI)578(M + H).

EXAMPLE 14 preparation of (E) -methyl 3- (3- (N- ((4- (4-morpholinophenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) but-2-enoate

The title compound was prepared according to the procedure described for the synthesis of example 11 by substituting intermediate 14C and morpholine. (12mg, 0.020mmol, 47% yield).¹H NMR(400MHz,DMSO-d₆)δ7.61-7.50(m,2H),7.48(t,J＝7.6Hz,1H),7.41(d, J ═ 7.6Hz,1H),7.18(d, J ═ 8.8Hz,2H),6.90(d, J ═ 8.8Hz,2H),6.23(s,1H),3.74-3.67(m,7H),3.59(br.s.,2H),3.07-2.98(m,4H),2.19(br.s.,1H),1.70-1.55(m,10H),1.50(d, J ═ 10.3Hz,1H),1.43-1.27(m,8H),1.16-0.97(m,1H),0.87(d, J ═ 13.7Hz, 2H). (methyl, 3 protons buried under the solvent peak). FXR EC ₅₀(nM)1153。MS(ESI)585(M+H)。

Example 15

(E) -3- (3- (N- ((4- (4-methoxyphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylic acid methyl ester

Step A. preparation of intermediate 15A. (4- (4-methoxyphenyl) bicyclo [2.2.2] oct-1-yl) methanol

To a stirred solution of intermediate 1D (0.15g, 0.508mmol) in methanol (1mL) and DMF (2mL) was added a solution of sodium methoxide (0.08g, 1.524mmol) in methanol at room temperature under a nitrogen atmosphere. The reaction mixture was heated at 110 ℃ for 1 h. The reaction mixture was cooled to room temperature and copper (I) bromide (0.073g, 0.508mmol) was added. The resulting reaction mixture was heated at 110 ℃ for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (3 × 25 mL). The organic layers were combined, dried over anhydrous sodium sulfate 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 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 (0.1g, 0.325mmol, 64% yield).¹H NMR(400MHz,DMSO-d₆)δ7.35-7.25(m,2H),7.25-7.21(m,1H),6.86-6.79(m,1H),4.36(q,J＝5.4Hz,1H),3.71(s,3H),3.08(dd,J＝5.3,4.3Hz,2H),1.80-1.65(m,6H),1.50-1.39(m,6H)。

Step B. preparation of intermediate 15B.4- (4-methoxyphenyl) bicyclo [2.2.2] octane-1-carbaldehyde

The title compound was prepared according to the procedure described for the synthesis of intermediate 8G by substituting intermediate 15A where appropriate. (0.09g, 0.295mmol, 86% yield).¹H NMR(400MHz,DMSO-d₆)δ9.48(s,1H),7.23(d,J＝9.0Hz,2H),6.84(d,J＝9.0Hz,2H),3.72(s,3H),1.80-1.70(m,12H)。

Step C. preparation of intermediate 15℃ (E) -methyl 3- (3- (((4- (4-methoxyphenyl) 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 1H by substituting intermediate 15B and intermediate 1G as appropriate. (0.03g, 0.078mmol, 30% yield) as a pale yellow solid. MS (ESI)406(M + H).

EXAMPLE 15 preparation of methyl (E) -3- (3- (N- ((4- (4-methoxyphenyl) 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 intermediate 1I by substituting intermediate 15C as appropriate. (25mg, 0.048mmol, 55% yield).¹H NMR(400MHz,DMSO-d₆)δ7.79(s,1H),7.75-7.60(m,2H),7.48(t,J＝7.7Hz,1H),7.42(d,J＝8.1Hz,1H),7.21-7.08(m,2H),6.86-6.65(m,3H),3.74(s,3H),3.71-3.66(m,3H),3.59(br.s.,2H),2.20(br.s.,1H),1.73-1.53(m,10H),1.48(br.s.,1H),1.43-1.26(m,8H),1.08(d,J＝12.2Hz,1H),0.88(br.s.,2H)。FXR EC₅₀(nM)243；MS(ESI)516(M+H)。

Example 16

(E) -3- (3- (N- ((4- (4-methoxyphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) but-2-enoic acid methyl ester

Step a. preparation of intermediate 16A. (E) -methyl 3- (3- (((4- (4-methoxyphenyl) bicyclo [2.2.2] oct-1-yl) methyl) amino) phenyl) but-2-enoate

The title compound was prepared according to the procedure described for the synthesis of intermediate 1H by substituting intermediate 14A and intermediate 15B as appropriate. (0.016g, 0.036mmol, 36% yield). MS (ESI)420(M + H).

Example 16 preparation of (E) -methyl 3- (3- (N- ((4- (4-methoxyphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) but-2-enoate

The title compound was prepared according to the procedure described for the synthesis of intermediate 1I by substituting intermediate 16A where appropriate. (2.8mg, 5.23. mu. mol, 15% yield).¹H NMR(400MHz,DMSO-d₆)δ7.62-7.51(m,2H),7.48(t,J＝7.6Hz,1H),7.45-7.37(m,1H),7.23(d,J＝8.8Hz,2H),6.87(d,J＝8.8Hz,2H),6.23(s,1H),3.69(s,6H),3.59(br.s.,2H),2.53(s,3H),2.17–2.15(m,1H),1.69-1.55(m,10H),1.52(br.s.,1H),1.44-1.26(m,8H),1.09(d,J＝11.0Hz,1H),0.87(d,J＝13.7Hz,2H)。FXR EC₅₀(nM)575.63MS(ESI)530(M+H)。

Example 17

5- (N- ((4- (4-methoxyphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) -3, 4-dihydronaphthalene-2-carboxylic acid

To a stirred solution of intermediate 11H (15mg, 0.025mmol) in toluene (0.5mL) at room temperature were added methanol (8.14mg, 0.254mmol), cesium carbonate (24mg, 0.076mmol) and 2-di-tert-butylphosphino-2 ',4',6' -triisopropylbiphenyl (2.1mg, 5%08 μmol). The reaction mixture was degassed and backfilled with argon. Pd is added₂(dba)₃(2.32mg, 2.54. mu. mol) was added to the reaction mixture and the vial was sealed (pressure release vial). The reaction mixture was heated at 75 ℃ for 6 h. 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, 19X150mM, 5- μm particles; mobile phase A: 10-mM ammonium acetate; mobile phase B: acetonitrile; gradient: 20% -80% B over 20 minutes and then held at 80% B for 10 minutes; flow rate: 15 mL/min). Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (3mg, 9% yield). FXR EC ₅₀(nM)2243。MS(ESI)528(M+H)。¹H NMR(400MHz,DMSO-d₆)δ7.47(s,1H),7.42-7.28(m,3H),7.21-7.16(m,2H),6.83-6.78(m,2H),4.32(br d,J＝4.0Hz,1H),3.87-3.74(m,2H),3.69(s,3H),3.00(d,J＝13.6Hz,1H),2.76-2.68(m,1H),2.46-2.33(m,1H),2.04(s,1H),1.74-1.54(m,9H),1.49(br d,J＝5.5Hz,4H),1.39(br d,J＝14.1Hz,5H),1.29(br s,2H),0.86(br d,J＝7.5Hz,2H)。

Example 18

5- (N- ((4- (4-methoxyphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) -3, 4-dihydronaphthalene-2-carboxylic acid methyl ester

To a stirred solution of intermediate 11H (18mg, 0.030mmol) in toluene (0.5mL) was added methanol (0.02mL, 0.494mmol), cesium carbonate (19mg, 0.061mmol), and 2-di-tert-butylphosphino-2 ',4',6' -triisopropylbiphenyl (2.5mg, 6.10 μmol) at room temperature. The reaction mixture was degassed and backfilled with argon. Pd is added₂(dba)₃(2.79mg, 3.05. mu. mol) was added to the reaction mixture and the vial was sealed (pressure release vial). The reaction mixture was heated at 75 ℃ for 3 h. The reaction mixture was cooled and the crude material was purified via preparative LC/MS using the following conditions: (column: Waters Xbridge C18, 19X150mM, 5- μm particles; mobile phase A: 10-mM acetic acidAmmonium; mobile phase B: acetonitrile; gradient: 25% -80% B over 20 minutes, then held at 80% B for 10 minutes; flow rate: 15 mL/min). Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (4mg, 9% yield).¹H NMR(400MHz,DMSO-d₆)δ7.59(s,1H),7.32-7.44(m,3H),7.17(d,J＝8.40Hz,2H),6.80(d,J＝8.80Hz,2H),3.80-3.84(m,1H),3.75(s,3H),3.70(s,3H),3.17(d,J＝5.20Hz,1H),3.00(d,J＝13.20Hz,1H),2.71-2.75(m,1H),1.98-1.99(m,1H),1.64-1.67(m,9H),1.28-1.56(m,12H),1.05-1.09(m,1H),0.85-0.91(m,2H)。FXR EC₅₀(nM)1805.MS(ESI)542(M+H)。

Example 19

(E) -3- (3- (N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) but-2-enoic acid methyl ester

Step A. preparation of intermediate 19A.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]To a stirred solution of octane-1-carboxylic acid (2g, 9.42mmol) in DMF (20mL) was added (E) -N' -hydroxyacetamidine (commercially available) (1.39g, 18.85mmol), BOP (4.17g, 9.42mmol) and TEA (3.94mL, 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 and extracted with EtOAc (2 × 30 mL). The organic layers were combined, 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 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, 2.277mmol, 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 B. preparation of intermediate 19B.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 19A (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 ℃ and the reaction was quenched with 1.5N aqueous HCl. The reaction mixture was extracted with EtOAc (2 × 25 mL). The organic layers were combined, dried over anhydrous sodium sulfate 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, 2.348mmol, 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 C. preparation of intermediate 19C.4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] octane-1-carbaldehyde

To a stirred solution of intermediate 19B (0.58g, 2.61mmol) in dichloromethane (10mL) at 0 ℃ under a nitrogen atmosphere was added dessimutane oxidant (2.21g, 5.22 mmol). The reaction mixture was stirred at the same temperature 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 and concentrated under reduced pressure. The crude material was purified by flash chromatography (24 g)A silica gel cartridge column; a ═ Hex, B ═ EtOAc; gradient for 30 min; 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,H),1.96-1.84(m,6H),1.73-1.66(m,6H)。

Step D. preparation of intermediate 19D.4- (3-methyl-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 1H by substituting intermediate 14A and intermediate 19C as appropriate. (50mg, 0.101mmol, 44% yield) as a pale yellow solid. MS (ESI)396(M + H).

EXAMPLE 19 preparation of (E) -methyl 3- (3- (N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) but-2-enoate

To a stirred solution of intermediate 19D (50mg, 0.126mmol) in dichloromethane (2mL) was added TEA (0.053mL, 0.379mmol) at room temperature. The reaction mixture was cooled to 0 ℃. Cyclohexanecarbonyl chloride (18mg, 0.126mmol) was added to the reaction mixture and stirred at the same temperature for 1 h. The reaction mixture was allowed to warm to room temperature 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: 10-mM ammonium acetate; mobile phase B: acetonitrile; gradient: 10% -45% B over 25 minutes and then held at 100% B for 5 minutes; flow: 15 mL/min). Fractions containing the desired product were combined and dried via centrifugation evaporation to give the title compound (42mg, 0.080mmol, 63% yield).¹H NMR(400MHz,DMSO-d₆)δ7.58(s,1H),7.56-7.51(m,1H),7.51-7.31(m,2H),6.24(s,1H),3.69(s,3H),3.60(br.s.,2H),2.53(s,4H),2.27(s,3H),2.18(br.s.,1H),1.87-1.70(m,6H),1.60(d,J＝11.0Hz,4H),1.50(d,J＝13.7Hz,1H),1.44-1.26(m,7H),1.16-1.01(m,1H),0.87(d,J＝10.8Hz,2H)。FXR EC₅₀(nM)551；MS(ESI)506(M+H)。

Example 20

(E) -methyl 3- (3- (N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate

Step a. intermediate 20A preparation of methyl (E) -3- (3- (((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) 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 1H by substituting intermediate 1G and intermediate 19C as appropriate. (0.18g, 0.236mmol, 26% yield) as a pale yellow solid. MS (ESI)382(M + H).

Example 20 preparation of methyl (E) -3- (3- (N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) 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 19 (step F) by substituting intermediate 20A and cyclohexanecarbonyl chloride as appropriate. (6mg, 0.012mmol, 22% yield) as a white solid.¹H NMR(400MHz,DMSO-d₆)δ7.80(s,1H),7.75-7.63(m,2H),7.54-7.37(m,2H),6.76(d,J＝16.1Hz,1H),3.74(s,3H),3.65-3.53(m,2H),2.26(s,3H),2.18(br.s.,1H),1.83-1.72(m,6H),1.59(d,J＝11.0Hz,4H),1.47(br.s.,1H),1.44-1.35(m,6H),1.35-1.21(m,2H),1.08(d,J＝12.7Hz,1H),0.87(br.s.,2H)。FXR EC₅₀(nM)56；MS(ESI)492(M+H)。

The following compounds were prepared according to the procedure described for synthetic example 19 (step F) by substituting intermediate 20A and the corresponding acid chloride as appropriate.

Example 23

(E) -3- (3- (N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) tetrahydro-2H-

Pyran-4-carboxamido) phenyl) acrylic acid methyl ester

To a stirred solution of intermediate 20A (0.02g, 0.052mmol) in dichloromethane (1mL) was added tetrahydro-2H-pyran-4-carboxylic acid (6.8mg, 0.052mmol) followed by pyridine (0.013mL, 0.157 mmol). The reaction mixture was cooled to 0 ℃ and POCl was added ₃(9.77. mu.L, 0.105 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction was quenched with water (5 mL). The reaction mixture was extracted with DCM (2 × 5 mL). The organic layers were combined, dried over anhydrous sodium sulfate 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: 10-mM ammonium acetate; mobile phase B: acetonitrile; gradient: 15% -52% B over 25 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 centrifugation evaporation to give the title compound (8.8mg, 0.017mmol, 33% yield).¹H NMR(400MHz,DMSO-d₆)δ7.83(s,1H),7.77-7.63(m,2H),7.55-7.41(m,2H),6.77(d,J＝16.4Hz,1H),3.74(s,5H),3.66-3.55(m,2H),2.98(t,J＝11.5Hz,2H),2.27(s,3H),1.85-1.73(m,7H),1.65-1.52(m,2H),1.50-1.31(m,8H)。FXREC₅₀(nM)920；MS(ESI)494(M+H)。

The following compounds were prepared according to the procedure described for the synthesis of example 23 by substituting intermediate 20A and the corresponding acid as appropriate.

Example 27

(E) -N- (3- (3- (dimethylamino) -3-oxoprop-1-en-1-yl) phenyl) -N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamide

Step a. intermediate 27A preparation of (E) -3- (3- (N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylic acid

To a stirred solution of example 24(0.06g, 0.122mmol) in methanol (2mL) was added a solution of LiOH (0.015g, 0.610mmol) in water (1 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was acidified to a pH of about 2 by using 1.5N aqueous HCl. The precipitated solid was filtered and dried in vacuo to give the title compound as an off-white solid (0.06g, 0.119mmol, 98% yield). MS (ESI)478(M + H).

EXAMPLE 27 preparation of (E) -N- (3- (3- (dimethylamino) -3-oxoprop-1-en-1-yl) phenyl) -N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamide

To a stirred solution of intermediate 27A (15mg, 0.031mmol) in dichloromethane (2mL) at 0 ℃ was added DIPEA (0.016mL, 0.094mmol) followed by isobutyl chloroformate (8.25 μ l, 0.063 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 30 min. Dimethylamine (7.08mg, 0.157mmol) was added to the reaction mixture and stirred for 5 min. 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: 10-mM ammonium acetate; mobile phase B: acetonitrile; gradient: 15% -55% B over 20 minutes and then held at 100% B for 5 minutes; flow: 20 mL/min). Fractions containing the desired product were combined and dried via centrifugation evaporation to give the title compound (5.5mg, 10.68 μmol, 34% yield). ¹H NMR(400MHz,DMSO-d₆)δ7.76(s,1H),7.67(d,J＝6.6Hz,1H),7.52-7.42(m,2H),7.41-7.35(m,1H),7.33-7.22(m,1H),3.60(br.s.,2H),3.17(s,3H),2.93(s,3H),2.27(s,3H),2.21(br.s.,1H),1.83-1.74(m,6H),1.59(br.s.,4H),1.48(br.s.,1H),1.44-1.26(m,8H),1.06(s,1H),0.86(br.s.,2H)。FXR EC₅₀(nM)4462；MS(ESI)505(M+H)。

Example 28

(E) -methyl 3- (3- (N- ((4- (4-cyclopropylphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclopropanecarboxamido) phenyl) acrylate

Step A. preparation of intermediate 28A.4- (4-cyclopropylphenyl) bicyclo [2.2.2] octane-1-carboxylic acid methyl ester

To a stirred solution of intermediate 1C (500mg, 1.547mmol) in 1, 4-dioxane (10mL) was added cyclopropylboronic acid (200mg, 2.320mmol), tripotassium phosphate (985mg, 4.64mmol), palladium (II) acetate (34.7mg, 0.155mmol) and tricyclohexylphosphine (87mg, 0.309 mmol). The reaction mixture was degassed and backfilled with argon. The reaction mixture was heated at 100 ℃ for 12 h. The reaction mixture was cooled to room temperature, diluted with water (20mL) and extracted with ethyl acetate (2 × 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate 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 (330mg, 0.580mmol, 37% yield). MS (ESI)285(M + H).

Step B. preparation of intermediate 28B. (4- (4-cyclopropylphenyl) bicyclo [2.2.2] oct-1-yl) methanol

The title compound was prepared according to the procedure described for the synthesis of intermediate 19B by substituting intermediate 28A where appropriate. (250mg, 0.975mmol, 84% yield).¹H NMR(400MHz,DMSO-d₆)δ7.17(d,J＝8.3Hz,2H),6.96(d,J＝8.3Hz,2H),4.34(d,J＝5.5Hz,1H),3.07(d,J＝5.4Hz,2H),1.91-1.79(m,1H),1.78-1.64(m,6H),1.49-1.36(m,6H),0.89(dd,J＝2.2,8.4Hz,2H),0.65-0.51(m,2H)。

Step C. preparation of intermediate 28C.4- (4-cyclopropylphenyl) bicyclo [2.2.2] octane-1-carbaldehyde

The title compound was prepared according to the procedure described for the synthesis of intermediate 8G by substituting intermediate 28B as appropriate. (200mg, 0.786mmol, 78% yield).¹H NMR (400MHz, chloroform-d) δ 9.61-9.42(m,1H),7.20(d, J ═ 8.3Hz,2H),7.02(d, J ═ 8.3Hz,2H),1.91-1.83(m,7H),1.81-1.73(m,6H),0.95-0.91(m,2H),0.67(dd, J ═ 1.6,5.0Hz, 2H).

Step D. preparation of intermediate 28D. (E) -methyl 3- (3- (((4- (4-cyclopropylphenyl) 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 1H by substituting intermediate 1G and intermediate 28C as appropriate. (40mg, 0.044mmol, 22% yield). MS (ESI)416(M + H).

EXAMPLE 28 preparation of methyl (E) -3- (3- (N- ((4- (4-cyclopropylphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclopropanecarboxamido) phenyl) acrylate

The title compound was prepared according to the procedure described for the synthesis of example 19 (step F) by substituting intermediate 28D and cyclopropanecarbonyl chloride as appropriate. (4.6mg, 9.42. mu. mol, 19% yield). ¹HNMR(400MHz,DMSO-d₆)δ7.84(s,1H),7.68(s,1H),7.72(s,1H),7.48(br.s.,2H),7.11(d,J＝8.1Hz,2H),6.93(d,J＝8.3Hz,2H),6.75(d,J＝16.1Hz,1H),3.74(s,3H),3.66(s,2H),1.86-1.76(m,1H),1.70-1.52(m,6H),1.48-1.30(m,7H),0.93-0.83(m,2H),0.78(d,J＝3.9Hz,2H),0.69-0.51(m,4H)。FXR EC₅₀(nM)947；MS(ESI)484(M+H)。

Example 29

(E) -methyl 3- (3- (N- ((4- (4-cyclopropylphenyl) 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 19 (step F) by substituting intermediate 28D and cyclohexanecarbonyl chloride as appropriate. (3.0mg, 5.68. mu. mol, 11% yield).¹HNMR(400MHz,DMSO-d₆)δ7.79(s,1H),7.74-7.60(m,2H),7.54-7.31(m,2H),7.17-7.06(m,J＝8.3Hz,2H),7.01-6.88(m,J＝8.3Hz,2H),6.76(d,J＝16.1Hz,1H),3.74(s,3H),3.58(br.s.,2H),2.19(br.s.,1H),1.87-1.77(m,1H),1.69-1.54(m,11H),1.48(br.s.,1H),1.42-1.28(m,8H),1.24(s,1H),1.07(br.s.,1H),0.97-0.75(m,4H),0.62-0.54(m,2H)。FXR EC₅₀(nM)161；MS(ESI)526(M+H)。

Example 30

5- (N- ((4- (4-cyclopropylphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) -3, 4-dihydronaphthalene-2-carboxylic acid methyl ester

Step A. preparation of intermediate 30A.5- (((4- (4-cyclopropylphenyl) bicyclo [2.2.2] oct-1-yl) methyl) amino) -3, 4-dihydronaphthalene-2-carboxylic acid methyl ester

The title compound was prepared according to the procedure described for the synthesis of intermediate 1H by substituting intermediate 11F and intermediate 28C as appropriate. (45mg, 0.043mmol, 22% yield). MS (ESI)442(M + H).

EXAMPLE 30.5 preparation of methyl N- ((4- (4-cyclopropylphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamide) -3, 4-dihydronaphthalene-2-carboxylate

The title compound was prepared according to the procedure described for the synthesis of example 19 (step F) by substituting intermediate 30A and cyclohexanecarbonyl chloride as appropriate. (7.0mg, 0.013mmol, 28% yield).¹HNMR(400MHz,DMSO-d₆)δ7.59(s,1H),7.49-7.38(m,2H),7.37-7.29(m,1H),7.21-7.06(m,J＝8.1Hz,2H),7.02-6.84(m,J＝8.3Hz,2H),3.83(d,J＝13.9Hz,1H),3.75(s,3H),2.99(d,J＝13.7Hz,1H),2.79-2.71(m,1H),2.62-2.54(m,2H),2.45-2.37(m,1H),2.00(br.s.,1H),1.89-1.78(m,1H),1.71-1.55(m,9H),1.49(d,J＝5.9Hz,4H),1.41(br.s.,5H),1.26(d,J＝18.3Hz,2H),1.07(d,J＝13.7Hz,1H),0.94-0.76(m,4H),0.63-0.53(m,2H)；FXR EC₅₀(nM)195；MS(ESI)552(M+H)。

The following compounds were prepared according to the procedure described for synthetic example 19 (step F) by substituting intermediate 30A and the corresponding acid chloride as appropriate.

Example 33

(E) -3- (3- (N- ((4- (benzo [ d ] thiazol-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclopropanecarboxamido) phenyl) acrylic acid methyl ester

Step A. preparation of intermediate 33A.4- (benzo [ d ] thiazol-2-yl) bicyclo [2.2.2] octane-1-carboxylic acid methyl ester

To a solution of 4- (methoxycarbonyl) bicyclo [2.2.2] octane-1-carboxylic acid (0.25g, 1.178mmol) in dichloromethane (10mL) and water (10mL) were added benzo [ d ] thiazole (commercially available) (0.16g, 1.178mmol), silver nitrate (0.040g, 0.236mmol) and potassium persulfate (1.27g, 4.71 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with DCM (10mL), washed with water (10mL), brine solution (10mL), dried over anhydrous sodium sulfate 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 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 pale yellow solid (0.07g, 0.232mmol, 20% yield). MS (ESI)302(M + H).

Step B. preparation of intermediate 33B (4- (benzo [ d ] thiazol-2-yl) bicyclo [2.2.2] oct-1-yl) methanol

The title compound was prepared according to the procedure described for the synthesis of intermediate 19B by substituting intermediate 33A where appropriate. (0.06g, 0.208mmol, 90% yield) as an off-white solid. MS (ESI)274(M + H).

Step C. preparation of intermediate 33C.4- (benzo [ d ] thiazol-2-yl) bicyclo [2.2.2] octane-1-carbaldehyde

The title compound was prepared according to the procedure described for the synthesis of intermediate 19C by substituting intermediate 33B as appropriate. (0.07g, 0.155mmol, 85% yield).¹H NMR(400MHz,DMSO-d₆)δ9.50(s,1H),7.65-7.73(m,2H),7.45-7.49(m,2H),1.95-2.12(m,6H),1.82-1.85(m,3H),1.79-1.81(m,3H)。

Step D. preparation of intermediate 33D (E) -methyl 3- (3- (((4- (benzo [ D ] thiazol-2-yl) 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 1H by substituting intermediate 1G and intermediate 33C as appropriate. (30mg, 0.069mmol, 47% yield) as a pale yellow solid. MS (ESI)433(M + H).

EXAMPLE 33 preparation of methyl (E) -3- (3- (N- ((4- (benzo [ d ] thiazol-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclopropanecarboxamido) phenyl) acrylate

The title compound was prepared according to the procedure described for the synthesis of example 19 (step F) by substituting intermediate 33D and cyclopropanecarbonyl chloride. (2.8mg, 5.59. mu. mol, 20% yield).¹H NMR(400MHz,DMSO-d₆)δ8.02(d,J＝7.8Hz,1H),7.94-7.81(m,2H),7.77-7.61(m,2H),7.50(d,J＝4.6Hz,2H),7.45(t,J＝7.7Hz,1H),7.40-7.32(m,1H),6.77(d,J＝16.1Hz,1H),3.74(s,3H),3.69(br.s.,2H),1.96-1.79(m,6H),1.52-1.40(m,6H),1.37(br.s.,1H),0.80(br.s.,2H),0.62(br.s.,2H)。FXR EC₅₀(nM)414；MS(ESI)501(M+H)。

Example 34

(E) -3- (3- (N- ((4- (benzo [ d ] thiazol-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylic acid methyl ester

The title compound was prepared according to the procedure described for the synthesis of example 19 (step F) by substituting intermediate 33D and cyclohexanecarbonyl chloride. (3.3mg, 6.08. mu. mol, 22% yield). ¹H NMR(400MHz,DMSO-d₆)δ8.02(d,J＝7.8Hz,1H),7.90(d,J＝8.1Hz,1H),7.82(s,1H),7.76-7.60(m,2H),7.55-7.42(m,3H),7.37(t,J＝7.8Hz,1H),6.77(d,J＝16.1Hz,1H),3.74(s,3H),3.62(br.s.,2H),2.19(br.s.,1H),1.92-1.87(d,J＝8.6Hz,6H),1.59(br.s.,4H),1.53-1.40(m,7H),1.39-1.27(m,2H),1.07(br.s.,1H),0.88(br.s.,2H)。FXR EC₅₀(nM)222；MS(ESI)543(M+H)。

Example 35

(E) -N- ((4- (4-methoxyphenyl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (2- (3-methyl-1, 2, 4-oxadiazol-5-yl) vinyl) phenyl) cyclohexanecarboxamide

Step A. preparation of intermediate 35A. (E) -3- (3-aminophenyl) acrylic acid

To a stirred solution of intermediate 1G (0.1G, 0.564mmol) in methanol (1mL), tetrahydrofuran (1mL) and water (1mL) was added LiOH (0.041G, 1.693 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water and acidified with saturated aqueous citric acid. The aqueous solution was extracted with EtOAc (2 × 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.08g, 0.466mmol, 83% yield).¹H NMR(400MHz,DMSO-d₆)δ12.32(s,1H),7.41(d,J＝16.00Hz,1H),7.06(t,J＝8.00Hz,1H),6.79(d,J＝6.00Hz,2H),6.61(d,J＝7.60Hz,1H),6.30(d,J＝15.60Hz,1H),5.20(br.s.,2H)。MS(ESI)164(M+H)。

Step B intermediate 35B preparation of (E) -3- (2- (3-methyl-1, 2, 4-oxadiazol-5-yl) ethenyl) aniline

To a stirred solution of intermediate 35A (0.08g, 0.490mmol) in DMF (2mL) was added (E) -N' -hydroxyacetamidine (0.073g, 0.981mmol), BOP (0.217g, 0.490mmol) and then TEA (0.205mL, 1.471 mmol). The reaction mixture was stirred at room temperature for 1h and at 100 ℃ for 12 h. The reaction mixture was cooled to room temperature, diluted with water (10mL) and extracted with EtOAc (2 × 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate 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 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 yellow solid (0.055g, 0.260mmol, 53% yield). ¹H NMR(400MHz,DMSO-d₆)δ7.65(d,J＝16.1Hz,1H),7.13-7.06(m,2H),6.97-6.86(m,2H),6.68-6.63(m,1H),5.21(s,2H),2.35(s,3H)。MS(ESI)164(M+H)。

Step C. preparation of intermediate 35℃ (E) -N- ((4- (4-methoxyphenyl) bicyclo [2.2.2] oct-1-yl) methyl) -3- (2- (3-methyl-1, 2, 4-oxadiazol-5-yl) vinyl) aniline

The title compound was prepared according to the procedure described for the synthesis of intermediate 1H by substituting intermediate 35B and intermediate 15B as appropriate. (0.03g, 0.035mmol, 28% yield) as a pale yellow solid. MS (ESI)430(M + H).

EXAMPLE 35 preparation of (E) -N- ((4- (4-methoxyphenyl) bicyclo [2.2.2] oct-1-yl) methyl) -N- (3- (2- (3-methyl-1, 2, 4-oxadiazol-5-yl) vinyl) phenyl) cyclohexanecarboxamide

The title compound was prepared according to the procedure described for the synthesis of example 19 (step F) by substituting intermediate 35C and cyclohexanecarbonyl chloride as appropriate. (2.8mg, 5.19. mu. mol, 18% yield).¹HNMR(400MHz,DMSO-d₆)δ7.96-7.83(m,2H),7.77(d,J＝7.1Hz,1H),7.57-7.35(m,3H),7.24(d,J＝8.8Hz,2H),6.89(d,J＝8.8Hz,2H),3.69(s,3H),3.60(br.s.,2H),2.37(s,3H),2.22(br.s.,1H),1.72-1.53(m,12H),1.48(br.s.,1H),1.40(d,J＝8.1Hz,6H),1.09(d,J＝12.5Hz,1H),0.87(d,J＝13.2Hz,2H)。FXR EC₅₀(nM)446；MS(ESI)540(M+H)。

Example 36

(E) -3- (3- (N- ((4- (4-cyclopropylphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclopropanecarboxamido) phenyl) but-2-enoic acid methyl ester

Step a. intermediate 36A preparation of (E) -methyl 3- (3- (((4- (4-cyclopropylphenyl) bicyclo [2.2.2] oct-1-yl) methyl) amino) phenyl) but-2-enoate

The title compound was prepared according to the procedure described for the synthesis of intermediate 1H by substituting intermediate 14A and intermediate 28C as appropriate. (30mg, 0.024mmol, 12% yield). MS (ESI)430(M + H).

EXAMPLE 36 preparation of (E) -methyl 3- (3- (N- ((4- (4-cyclopropylphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclopropanecarboxamido) phenyl) but-2-enoate

The title compound was prepared according to the procedure described for the synthesis of example 19 (step F) by substituting intermediate 36A and cyclopropanecarbonyl chloride as appropriate. (6.6mg, 0.013mmol, 37% yield).¹HNMR(400MHz,DMSO-d₆)δ7.63(s,1H),7.57-7.40(m,3H),7.11(d,J＝8.3Hz,2H),6.93(d,J＝8.3Hz,2H),6.24(s,1H),3.78-3.57(m,5H),2.53(s,3H),1.90-1.75(m,1H),1.71-1.53(m,6H),1.45-1.28(m,7H),1.24(s,1H),0.93-0.83(m,2H),0.80(d,J＝2.9Hz,2H),0.69-0.52(m,4H)；FXR EC₅₀(nM)1785；MS(ESI)498(M+H)。

Example 37

(E) -3- (3- (N- ((4- (4-cyclopropylphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) but-2-enoic acid methyl ester

The title compound was prepared according to the procedure described for the synthesis of example 19 (step F) by substituting intermediate 36A and cyclohexanecarbonyl chloride. (7.4mg, 0.014mmol, 39% yield).¹H NMR(400MHz,DMSO-d₆)δ7.60-7.40(m,4H),7.12(d,J＝8.3Hz,2H),6.94(d,J＝8.6Hz,2H),6.23(s,1H),3.69(s,3H),3.59(br.s.,2H),2.53(s,3H),2.19(br.s.,1H),1.89-1.75(m,1H),1.71-1.53(m,10H),1.48(br.s.,1H),1.44-1.28(m,8H),1.09(d,J＝13.9Hz,1H),0.95-0.74(m,4H),0.64-0.49(m,2H)；FXR EC₅₀(nM)498；MS(ESI)540(M+H)。

Example 38

(E) -3- (3- (N- ((4- (4-isopropylphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylic acid methyl ester

Step A. preparation of intermediate 38A.4- (4- (prop-1-en-2-yl) phenyl) bicyclo [2.2.2] octane-1-carboxylic acid methyl ester

To a stirred solution of intermediate 1C (0.35g, 1.083mmol) in 1, 4-dioxane (6mL) and water (1.5mL) was added 4,4,5, 5-tetramethyl-2- (prop-1-en-2-yl) -1,3, 2-dioxaneOxopentaneborane (0.72g, 4.33mmol), sodium carbonate (0.34g, 3.25 mmol). The reaction mixture was degassed and backfilled with argon. PdCl ₂(dppf)-CH₂Cl₂Adduct (0.088g, 0.108mmol) was added to the reaction and the vial was sealed (pressure release vial). The reaction mixture was heated at 90 ℃ for 12 h. The reaction mixture was cooled to room temperature and diluted with water (10mL) and extracted with ethyl acetate (2 × 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate 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 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 (0.25g, 0.791mmol, 73% yield).¹H NMR(400MHz,DMSO-d₆)δ7.39-7.47(m,2H),7.27-7.30(m,2H),5.37(d,J＝0.40Hz,1H),5.04(d,J＝1.60Hz,1H),3.60(s,3H),2.04(s,3H),1.72-1.83(m,12H)。

Step B. preparation of intermediate 38B.4- (4-isopropylphenyl) bicyclo [2.2.2] octane-1-carboxylic acid methyl ester

Intermediate 38A (0.2g, 0.703mmol) was degassed in a stirred solution in methanol (3mL) and backfilled with nitrogen. Palladium on carbon (0.075g, 0.070mmol) was added to the reaction mixture and hydrogenated under a hydrogen atmosphere (balloon pressure) at room temperature for 12 h. The reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure to give the title compound as an off-white solid (0.18g, 0.534mmol, 76% yield). MS (ESI)287(M + H).

Step C. preparation of intermediate 38℃ (4- (4-isopropylphenyl) bicyclo [2.2.2] oct-1-yl) methanol

By following the procedure described for the synthesis of intermediate 19BThe title compound was then prepared by substituting intermediate 38B. (0.13g, 0.478mmol, 95% yield) as a white solid.¹H NMR(400MHz,DMSO-d₆)δ7.21-7.24(m,2H),7.11-7.15(m,2H),4.30-4.34(m,1H),3.08(d,J＝5.20Hz,2H),2.80-2.84(m,1H),1.70-1.74(m,6H),1.43-1.46(m,6H),1.18(d,J＝17.60Hz,6H)。

Step D. preparation of intermediate 38D.4- (4-isopropylphenyl) bicyclo [2.2.2] octane-1-carbaldehyde

The title compound was prepared according to the procedure described for the synthesis of intermediate 19C by substituting intermediate 38C where appropriate. (0.1g, 0.390mmol, 78% yield) as an oil.¹H NMR(400MHz,DMSO-d₆)δ9.48(s,1H),7.21-7.29(m,2H),7.14-7.16(m,2H),2.80-2.84(m,1H),1.66-1.91(m,12H),1.17(d,J＝7.20Hz,6H)。

Step E. preparation of intermediate 38E. (E) -methyl 3- (3- (((4- (4-isopropylphenyl) 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 1H by substituting intermediate 1G and intermediate 38D as appropriate. (0.07g, 0.134mmol, 43% yield) as a pale yellow solid. MS (ESI)418(M + H).

EXAMPLE 38 preparation of methyl (E) -3- (3- (N- ((4- (4-isopropylphenyl) 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 19 (step F) by substituting intermediate 38E and cyclohexanecarbonyl chloride. (6.8mg, 0.012mmol, 23% yield). ¹H NMR(400MHz,DMSO-d₆)δ7.79(s,1H),7.76-7.64(m,2H),7.54-7.39(m,2H),7.16(d,J＝8.4Hz,2H),7.10(d,J＝8.4Hz,2H),6.76(d,J＝16Hz,1H),3.74(s,3H),3.59(br.s.,2H),2.80(dt,J＝13.7,6.8Hz,1H),2.20(br.s.,1H),1.76-1.75(m,1H),1.69-1.54(m,9H),1.43-1.34(m,7H),1.32(br.s.,2H),1.19(d,J＝8.4Hz,6H),1.09(d,J＝9.8Hz,1H),0.85(br.s.,2H)。FXR EC₅₀(nM)196；MS(ESI)528(M+H)。

Example 39

(E) -3- (3- (N- ((4- (4-isopropylphenyl) bicyclo [2.2.2] oct-1-yl) methyl) cyclopropanecarboxamido) phenyl) acrylic acid methyl ester

The title compound was prepared according to the procedure described for the synthesis of example 19 (step F) by substituting intermediate 38E and cyclopropanecarbonyl chloride. (2.3mg, 4.64. mu. mol, 9% yield).¹H NMR(400MHz,DMSO-d₆)δ7.84(s,1H),7.76-7.58(m,2H),7.48(d,J＝5.4Hz,2H),7.16(d,J＝8.4Hz,2H),7.09(d,J＝8.4Hz,2H),6.75(d,J＝16Hz,1H),3.74(s,3H),3.66(br.s.,2H),2.80(dt,J＝13.9,6.9Hz,1H),1.73-1.58(m,6H),1.48-1.27(m,7H),1.15(d,J＝6.8Hz,6H),0.84-0.74(m,2H),0.62(br.s.,2H)。FXR EC₅₀(nM)1427；MS(ESI)486(M+H)。

Example 40

5- (N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamide) -3, 4-dihydronaphthalene-2-carboxylic acid methyl ester

Step A. preparation of intermediate 40A.5- (((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) amino) -3, 4-dihydronaphthalene-2-carboxylic acid methyl ester

The title compound was prepared according to the procedure described for the synthesis of intermediate 1H by substituting intermediate 11F and intermediate 19C. (50mg, 0.086mmol, 38% yield) as a pale yellow solid. MS (ESI)408(M + H).

EXAMPLE 40.5 preparation of methyl N- ((4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamide) -3, 4-dihydronaphthalene-2-carboxylate

The title compound was prepared according to the procedure described for the synthesis of example 19 (step F) by substituting intermediate 40A and cyclohexanecarbonyl chloride. (27mg, 0.051mmol, 69% yield). ¹H NMR(400MHz,DMSO-d₆)δ7.58(s,1H),7.51-7.38(m,2H),7.37-7.29(m,1H),3.84(d,J＝13.7Hz,1H),3.75(s,3H),3.17(d,J＝5.4Hz,1H),2.99(d,J＝13.9Hz,1H),2.78-2.68(m,1H),2.61-2.53(m,2H),2.43-2.33(m,1H),2.27(s,3H),1.99(br.s.,1H),1.81(t,J＝7.9Hz,6H),1.71-1.53(m,4H),1.53-1.44(m,3H),1.40(br.s.,3H),1.36-1.17(m,2H),1.07(d,J＝12.2Hz,1H),0.93-0.74(m,2H)。FXR EC₅₀(nM)1069；MS(ESI)518(M+H)。

EXAMPLE 41

(E) -methyl 3- (3- (N- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate

Step A. preparation of intermediate 41A.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 19A by substituting 4- (methoxycarbonyl) bicyclo [2.2.2] octane-1-carboxylic acid and (Z) -N' -hydroxycyclopropanecarboxamidine. (490mg, 1.667mmol, 71% yield). MS (ESI)277(M + H).

Step B. preparation of intermediate 41B. (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 19B by substituting intermediate 41A where appropriate. (500mg, 1.087mmol, 61% yield). MS (ESI)249(M + H).

Step C. preparation of intermediate 41C.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 8G by substituting intermediate 41B as appropriate. (350mg, 1.421mmol, 71% yield). MS (ESI)247(M + H).

Step D. intermediate 41D. preparation of methyl (E) -3- (3- (((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) 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 1H by substituting intermediate 1G and intermediate 41C as appropriate. (130mg, 0.319mmol, 79% yield) as a yellow gummy liquid. MS (ESI)408(M + H).

EXAMPLE 41 preparation of (E) -methyl 3- (3- (N- ((4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) 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 19 (step F) by substituting intermediate 41D and cyclohexanecarbonyl chloride as appropriate. (22mg, 0.042mmol, 58% yield);¹HNMR(400MHz,DMSO-d₆)δ7.79(s,1H),7.74-7.59(m,2H),7.54-7.33(m,2H),6.76(d,J＝16.1Hz,1H),3.74(s,3H),3.58(s,2H),2.17(br.s.,1H),2.08-1.98(m,1H),1.84-1.68(m,6H),1.59(d,J＝9.0Hz,4H),1.47(br.s.,1H),1.42-1.23(m,8H),1.15-0.97(m,3H),0.93-0.75(m,4H)。FXR EC₅₀(nM)＝47；MS(ESI)518(M+H)。

example 42

(E) -methyl 3- (3- (N- ((4- (3-morpholino-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate

Step A. preparation of intermediate 42A. (Z) -N' -hydroxymorpholine-4-carboxamidine

To a stirred solution of morpholine-4-carbonitrile (commercially available) (0.902mL, 8.92mmol) in ethanol (12mL) was added hydroxylamine (2.73mL, 44.6 mmol). The reaction mixture was stirred at reflux temperature for 1.5 h. The reaction mixture was cooled to room temperature and diluted with water (20mL) and extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (500mg, 3.41mmol, 38% yield) as a gummy liquid. MS (ESI)146(M + H).

Step B. preparation of intermediate 42B.4- (3-morpholino-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 19A by substituting intermediate 42A where appropriate. (450mg, 1.400mmol, 93% yield) with small amounts of impurities. MS (ESI)322(M + H).

Step C. preparation of intermediate 42℃ (4- (3-morpholino-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 19B by substituting intermediate 42B as appropriate. (200mg, 0.443mmol, 57% yield) as a yellow solid. MS (ESI)294(M + H).

Step D. preparation of intermediate 42D.4- (3-morpholino-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] octane-1-carbaldehyde

To a stirred solution of intermediate 42C (170mg, 0.579mmol) in DCM (3mL) at 0 ℃ was added DMP (295mg, 0.695 mmol). The reaction mixture was stirred at 0 ℃ for 1 h. The reaction mixture was allowed to warm to room temperature, diluted with DCM (10mL), washed with aqueous sodium bicarbonate solution (10mL), dried over anhydrous sodium sulfate 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 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 gummy liquid (90mg, 0.238mmol, 41% yield). MS (ESI)292(M + H).

Step e. intermediate 42E preparation of methyl (E) -3- (3- (((4- (3-morpholino-1, 2, 4-oxadiazol-5-yl) 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 1H by substituting intermediate 1G and intermediate 42D as appropriate. (100mg, 0.208mmol, 67% yield). MS (ESI)453(M + H).

EXAMPLE 42 preparation of (E) -methyl 3- (3- (N- ((4- (3-morpholino-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate

According to the procedure for Synthesis example 19The title compound was prepared by substituting intermediate 42E and cyclohexanecarbonyl chloride in the procedure described (step F). (11.56mg, 0.021mmol, 31% yield).¹H NMR(400MHz,DMSO-d₆)δ7.80(s,1H),7.74-7.62(m,2H),7.54-7.37(m,2H),6.76(d,J＝16.1Hz,1H),3.74(s,3H),3.68-3.61(m,4H),3.58(s,2H),3.28-3.20(m,4H),2.17(br.s.,1H),1.82-1.70(m,6H),1.59(d,J＝11.0Hz,4H),1.42-1.18(m,9H),1.08(d,J＝12.0Hz,1H),0.85(d,J＝11.5Hz,2H)FXR EC₅₀(nM)＝118.MS(ESI)563(M+H)。

Example 43

(E) -methyl 3- (3- (N- ((4- (3- (tetrahydro-2H-pyran-4-yl) -1,2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate

Step A. preparation of intermediate 43A. N' -hydroxytetrahydro-2H-pyran-4-carboxamidine

To a stirred solution of tetrahydro-2H-pyran-4-carbonitrile (commercially available) (0.988mL, 9.00mmol) in ethanol (12mL) was added hydroxylamine (2.7mL, 45.0mmol) at room temperature. The reaction mixture was stirred at reflux temperature for 2 h. The reaction was cooled to room temperature and concentrated under reduced pressure, the residue was diluted with water (20mL) and stirred for 5 min. The precipitated solid was filtered, washed with water and dried in vacuo to give the title compound as a white solid (1280mg, 6.21mmol, 69% yield). MS (ESI)145(M + H).

Step B. preparation of intermediate 43B.4- (3- (tetrahydro-2H-pyran-4-yl) -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 19A by substituting intermediate 43A where appropriate. (350mg, 0.983mmol, 42% yield). MS (ESI)320(M + H).

Step C. preparation of intermediate 43c. (4- (3- (tetrahydro-2H-pyran-4-yl) -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 19B by substituting intermediate 43B as appropriate. (160mg, 0.465mmol, 43% yield) as a white solid. MS (ESI)293(M + H).

Step D. preparation of intermediate 43D.4- (3- (tetrahydro-2H-pyran-4-yl) -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 28C by substituting intermediate 43C as appropriate. (230mg, 0.776mmol, 76% yield). MS (ESI)291(M + H).

Step e. intermediate 43E preparation of (E) -methyl 3- (3- (((4- (3- (tetrahydro-2H-pyran-4-yl) -1,2, 4-oxadiazol-5-yl) 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 1H by substituting intermediate 1G and intermediate 43D as appropriate. (220mg, 0.487mmol, 61% yield) as a pale yellow solid. MS (ESI)453(M + H).

EXAMPLE 43 preparation of methyl (E) -3- (3- (N- ((4- (3- (tetrahydro-2H-pyran-4-yl) -1,2, 4-oxadiazol-5-yl) 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 19 (step F) by substituting intermediate 43E and cyclohexanecarbonyl chloride as appropriate. (26mg, 0.046mmol, 69% yield).¹HNMR(400MHz,DMSO-d₆)δ7.80(s,1H),7.76-7.62(m,2H),7.55-7.32(m,2H),6.76(d,J＝15.9Hz,1H),3.91-3.79(m,2H),3.74(s,3H),3.59(s,2H),3.49-3.38(m,2H),3.00(tt,J＝11.5,3.8Hz,1H),2.18(br.s.,1H),1.88-1.72(m,8H),1.71-1.53(m,6H),1.49(d,J＝11.5Hz,1H),1.44-1.24(m,8H),1.08(d,J＝13.0Hz,1H),0.86(d,J＝11.7Hz,2H)；FXR EC₅₀(nM)＝107.MS(ESI)562(M+H)。

Example 44

(E) -methyl 3- (3- (N- ((4- (5-methyl-1, 2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) cyclohexanecarboxamido) phenyl) acrylate

Step A. preparation of intermediate 44 A.4-carbamoylbicyclo [2.2.2] octane-1-carboxylic acid methyl ester

4- (methoxycarbonyl) bicyclo [2.2.2] n under nitrogen atmosphere at room temperature]To a stirred solution of octane-1-carboxylic acid (0.5g, 2.356mmol) in DMF (10mL) were added ammonium chloride (1.26g, 23.56mmol), TEA (1.3mL, 9.42mmol) and BOP (1.04g, 2.356 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water (30mL) and extracted with EtOAc (2 × 30 mL). The organic layers were combined, 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 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 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 44 B.4-cyanobicyclo [2.2.2] octane-1-carboxylic acid methyl ester

To a stirred solution of intermediate 44A (0.35g, 1.657mmol) in pyridine (7mL) was added trifluoroacetic anhydride (1.74g, 8.28mmol) dropwise at 0 ℃. The reaction mixture was stirred at the same temperature for 30 min. The reaction was run with 10% NaHCO₃And (4) quenching the aqueous solution. The reaction mixture was extracted with EtOAc (2 × 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate 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 (0.25g, 1.23mmol, 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 44 C.4-cyanobicyclo [2.2.2] octane-1-carboxylic acid methyl ester

To a stirred solution of intermediate 44B (0.25g, 1.294mmol) in ethanol (5mL) was added hydroxylamine (0.319mL, 5.17mmol) in water at room temperature. The reaction mixture was heated at reflux for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (5mL) and stirred for 5 min. The precipitated solid was filtered, washed with water, and dried in vacuo to give the title compound as a white solid (0.28g, 1.17mmol, 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 44D.4- (5-methyl-1, 2, 4-oxadiazol-3-yl) bicyclo [2.2.2] octane-1-carboxylic acid methyl ester

A stirred solution of intermediate 44C (0.23g, 1.016mmol) in acetic anhydride (1.91mL, 20.33mmol) was heated at 120 ℃ for 30 min. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (5mL) and stirred for 5 min. Such as to the residue. The precipitated solid was filtered, washed with water, and dried in vacuo to give the title compound as an off-white solid (0.21g, 0.79mmol, 78% yield).¹H NMR(400MHz,DMSO-d₆)δ3.59(s,3H),2.53(s,3H),1.87-1.77(m,12H)。MS(ESI)251(M+H)。

Step E. preparation of intermediate 44e. (4- (5-methyl-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 19B by substituting intermediate 44D where appropriate. (0.155g, 0.66mmol, 79% yield) as a white solid.¹H NMR(400MHz,DMSO-d₆)δ4.37(t,J＝5.5Hz,1H),3.07(d,J＝5.5Hz,2H),2.52(s,3H),1.82-1.73(m,6H),1.48-1.38(m,6H)。

Preparation of intermediate 44F.4- (5-methyl-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 19C by substituting intermediate 44E where appropriate. (0.12g, 0.218mmol, 44% yield) as an off-white solid. ¹H NMR(400MHz,DMSO-d₆)δ9.45(s,1H),2.54(s,3H),1.79-1.87(m,6H),1.66-1.70(m,6H)。

Step G. intermediate 44G preparation of methyl (E) -3- (3- (((4- (5-methyl-1, 2, 4-oxadiazol-3-yl) 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 1H by substituting intermediate 1G and intermediate 44F as appropriate. (20mg, 0.050mmol, 23% yield) as an off-white solid. MS (ESI)382(M + H).

EXAMPLE 44 preparation of methyl (E) -3- (3- (N- ((4- (5-methyl-1, 2, 4-oxadiazol-3-yl) 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 19 (step F) by substituting intermediate 44G and cyclohexanecarbonyl chloride. (9.3mg, 0.019mmol, 36% yield).¹H NMR(400MHz,DMSO-d₆) δ 7.80(s,1H),7.75-7.60(m,2H),7.54-7.37(m,2H),6.76(d, J ═ 16.1Hz,1H),3.74(s,3H),3.58(br.s.,2H),2.18(br.s.,1H),1.78-1.66(m,6H),1.59(d, J ═ 9.8Hz,4H),1.48(br.s.,1H),1.42-1.25(m,8H),1.08(d, J ═ 14.4Hz,1H),0.87(br.s.,2H), (3 protons of the methyl group are buried under the solvent peak). FXREC₅₀(nM)87；MS(ESI)492(M+H)。

Example 45

5- (N- ((1- (1-methyl-1H-indazol-5-yl) -2-oxabicyclo [ 2.2.2)]Oct-4-yl) methyl) cyclohexanecarboxamido) -3, 4-dihydronaphthalene-2-carboxylic acid methyl ester

Step a. preparation of intermediate 45a.5- (((1- (1-methyl-1H-indazol-5-yl) -2-oxabicyclo [2.2.2] oct-4-yl) methyl) amino) -3, 4-dihydronaphthalene-2-carboxylic acid methyl ester

The title compound was prepared according to the procedure described for the synthesis of intermediate 1H by substituting intermediate 11F and intermediate 8G as appropriate. (0.12g, 0.249mmol, 33% yield) as a black solid. MS (ESI)458(M + H).

Example 45.5 preparation of methyl N- ((1- (1-methyl-1H-indazol-5-yl) -2-oxabicyclo [2.2.2] oct-4-yl) methyl) cyclohexanecarboxamide) -3, 4-dihydronaphthalene-2-carboxylate

The title compound was prepared according to the procedure described for the synthesis of example 19 (step F) by substituting intermediate 45A and cyclohexanecarbonyl chloride. (0.06g, 0.100mmol, 92% yield) as an off-white solid.¹H NMR(400MHz,DMSO-d₆)δ7.95(s,1H),7.66(s,1H),7.60(s,1H),7.52-7.48(m,2H),7.40-7.34(m,3H),3.99(s,3H),3.95-3.90(m,1H),3.84-3.81(m,1H),3.76(s,3H),3.69-3.67(m,1H),2.97-2.93(m,1H),2.67-2.68(m,1H),2.56-2.55(m,2H),2.45-2.36(m,2H),2.05-2.02(m,4H),1.83-1.25(m,10H),1.12-1.05(m,1H),0.89-0.83(m,3H)。FXR EC₅₀(nM)1150；MS(ESI)568.3(M+H)。

Examples 46 and 47

(E) -3- (3- (N- (1- (4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) ethyl) cyclohexanecarboxamido) phenyl) acrylic acid methyl ester

Step A. preparation of intermediate 46A.1- (4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) ethan-1-ol

A stirred solution of intermediate 19C (0.5g, 2.270mmol) in dry tetrahydrofuran (15mL) was cooled to-78 ℃. Methyl magnesium bromide in ether (1.135mL, 3.40mmol) was added to the reaction under nitrogen. The reaction mixture was stirred at the same temperature for 1 h. The reaction mixture was allowed to warm to 0 ℃. Reacting with saturated NH ₄And (4) quenching by using a Cl aqueous solution. The reaction mixture was washed with EtOAc (2 × 10 m)L) extracting. The organic layers were combined, dried over anhydrous sodium sulfate 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 an oil (0.51g, 2.050mmol, 90% yield).¹H NMR(400MHz,DMSO-d₆)δ4.28(d,J＝5.20Hz,1H),3.24-3.26(m,1H),2.29(s,3H),1.83-1.87(m,6H),1.40-1.55(m,6H),0.96(d,J＝6.40Hz,3H)。

Step B. preparation of intermediate 46B.1- (4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) ethan-1-one

To a stirred solution of intermediate 46A (0.4g, 1.693mmol) in dichloromethane (5mL) was added dessimutane oxidant (1.79g, 4.23mmol) at 0 ℃. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was diluted with DCM (10mL) and 10% NaHCO₃Aqueous solution (10mL), brine solution (10mL), dried over anhydrous sodium sulfate 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 as a white solid (0.3g, 1.216mmol, 72% yield). ¹H NMR(400MHz,DMSO-d₆)δ2.31(s,3H),2.00(s,3H),1.89-1.93(m,6H),1.74-1.78(m,6H)。

Step C. preparation of intermediate 46℃ (E) -methyl 3- (3- ((1- (4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) ethyl) amino) phenyl) acrylate

The title compound was prepared according to the procedure described for the synthesis of intermediate 1H by substituting intermediate 1G and intermediate 46B as appropriate. (100mg, 0.152mmol, 47% yield) as a pale yellow oil. MS (ESI)396(M + H).

Examples 46 and 47 preparation of (E) -methyl 3- (3- (N- (1- (4- (3-methyl-1, 2, 4-oxadiazol-5-yl) bicyclo [2.2.2] oct-1-yl) ethyl) cyclohexanecarboxamido) phenyl) acrylate

To a stirred solution of intermediate 46A (70mg, 0.177mmol) in pyridine (2mL) was added DMAP (23mg, 0.177mmol) at room temperature followed by cyclohexane carbonyl chloride (130mg, 0.885 mmol). The reaction mixture was heated at 90 ℃ for 3 days. The reaction mixture was diluted with DCM (10mL) and 10% NaHCO₃Aqueous solution (10mL), brine solution (10mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by reverse phase, followed by chiral HPLC using the following conditions: (column: DAD-1Cellulose-2(250X4.6)5.0 μm; isocratic mode, mobile phase: MeOH, column temperature: 30 ℃ C.; total flow: 2 mL/min). Enantiomer 1(RT ═ 7.97min.) example-46 (7.5mg, 0.015mmol, 8% yield); ¹H NMR(400MHz,DMSO-d₆)δ7.83-7.27(m,5H),6.76(dd,J＝16.3,7.2Hz,1H),4.80(br.s.,1H),3.75(d,J＝2.7Hz,3H),2.29(s,3H),1.83(br.s.,7H),1.61(br.s.,3H),1.53(br.s.,6H),1.45(br.s.,2H),1.41-1.28(m,2H),1.07(d,J＝12.2Hz,2H),0.97(br.s.,2H),0.78(br.s.,2H)。FXR EC₅₀(nM) 302; MS (ESI)506(M + H); and enantiomer 2(RT ═ 9.7min) example-47 (9.1mg, 0.018mmol, 10% yield).¹H NMR(400MHz,DMSO-d₆)δ7.83-7.27(m,5H),6.76(dd,J＝16.3,7.2Hz,1H),4.80(br.s.,1H),3.75(d,J＝2.7Hz,3H),2.29(s,3H),1.83(br.s.,7H),1.61(br.s.,3H),1.53(br.s.,6H),1.45(br.s.,2H),1.41-1.28(m,2H),1.07(d,J＝12.2Hz,2H),0.97(br.s.,2H),0.78(br.s.,2H)。FXR EC₅₀(nM)152.MS(ESI)506(M+H)。

Example 48

N- ((4- (5- (tert-butyl) -1,3, 4-oxadiazol-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3- (3-hydroxy-3-methylbut-1-yn-1-yl) phenyl) bicyclo [1.1.1] pentane-1-carboxamide

Step A. preparation of intermediate 48A.4- (2-pivaloylhydrazine-1-carbonyl) bicyclo [2.2.2] octane-1-carboxylic acid methyl ester

To 4- (methoxycarbonyl) bicyclo [2.2.2] at 0 DEG C]To a stirred solution of octane-1-carboxylic acid (1g, 4.71mmol) and pivalohydrazide (commercially available) (0.602g, 5.18mmol) in DMF (10mL) were added HATU (2.329g, 6.12mmol) and DIPEA (2.469mL, 14.13mmol) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was poured into ice water and extracted with ethyl acetate (2 × 150 mL). The combined organic layers were dried over MgSO₄Dried and concentrated under reduced pressure. The crude residue thus obtained was purified by flash silica gel column chromatography (30% EtOAc in hexanes as eluent, 40g column) to give the title compound (900mg, 2.90mmol, 62% yield).¹H NMR(300MHz,DMSO-d₆)δ9.21(d,J＝0.90Hz,1H),9.15(s,1H),3.57(s,3H),1.85-1.60(m,12H),1.12(s,9H)。MS(ESI)311(M+H)。

Step B. preparation of intermediate 48B.4- (5- (tert-butyl) -1,3, 4-oxadiazol-2-yl) bicyclo [2.2.2] octane-1-carboxylic acid methyl ester

To a stirred solution of intermediate 48A (700mg, 2.255mmol) in MeCN (1mL) was added triphenylphosphine (1242mg, 4.74mmol) and CCl at room temperature₄(0.239mL, 2.481mmol) and the reaction mixture was stirred at 90 ℃ for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with EtOAc (50mL) and washed with water (30 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (24g silica gel column, EtOAc/PE, 0-60% EA, gradient elution) to give the title compound (650mg,2.223mmol, 99% yield).¹H NMR(300MHz,DMSO-d₆)δ3.60(s,3H),1.89-1.80(m,12H),1.32(s,9H)。MS(ESI)293(M+H)。

Step C. preparation of intermediate 48℃ (4- (5- (tert-butyl) -1,3, 4-oxadiazol-2-yl) bicyclo [2.2.2] oct-1-yl) methanol

The title compound was prepared according to the procedure described for the synthesis of intermediate 19B by substituting intermediate 48B as appropriate. (720mg, 2.72mmol, 100% yield).¹H NMR(400MHz,DMSO-d₆)δ4.40(t,J＝5.5Hz,1H),3.08(d,J＝5.5Hz,2H),1.89-1.75(m,6H),1.51-1.37(m,6H),1.38(s,9H)。

Step D. preparation of intermediate 48D.4- (5- (tert-butyl) -1,3, 4-oxadiazol-2-yl) bicyclo [2.2.2] octane-1-carbaldehyde

The title compound was prepared according to the procedure described for the synthesis of intermediate 19C by substituting intermediate 48C as appropriate. (600mg, 2.287mmol, 86% yield).¹H NMR(400MHz,DMSO-d₆)δ9.46(s,1H),1.96-1.83(m,6H),1.75-1.63(m,6H),1.33(s,9H)。MS(ESI)263(M+H)。

Step E. preparation of intermediate 48 E.3-bromo-N- ((4- (5- (tert-butyl) -1,3, 4-oxadiazol-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 1H by substituting intermediate 48D as appropriate. (200mg, 0.478mmol, 33% yield).¹H NMR(300MHz,DMSO-d₆)δ7.00-6.93(m,1H),6.76(d,J＝2.3Hz,1H),6.60(dd,J＝8.1,2.1Hz,2H),5.76(d,J＝2.6Hz,1H),2.80(d,J＝5.9Hz,2H),1.90-1.80(m,6H),1.60-1.50(m,6H),1.32(s,9H)。MS(ESI)418(M+H)。

Step F. preparation of intermediate 48F.N- (3-bromophenyl) -N- ((4- (5- (tert-butyl) -1,3, 4-oxadiazol-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide

Intermediate 48E (300mg, 0.717mmol) and 3-fluorobicyclo [1.1.1] are added at room temperature]To a stirred solution of pentane-1-carboxylic acid (112mg, 0.860mmol) in DCM (5mL) was added pyridine (0.290mL, 3.59mmol) and POCl₃(0.134mL, 1.434 mmol). The reaction mixture was stirred at room temperature for 2h and poured into ice water. The aqueous layer was extracted with EtOAc (2 × 150mL) and the combined organic layers were extracted over MgSO₄And (5) drying. The solvent was removed under reduced pressure. The residue was purified via flash silica gel column chromatography using 50% EtOAC in hexanes as eluent (24g column) to give the title compound (250mg, 0.471mmol, 66% yield).¹H NMR(300MHz,DMSO-d₆)δ7.71(s,1H),7.61(d,J＝7.6Hz,1H),7.42(d,J＝8.9Hz,2H),1.87(br.s.,6H),1.80-1.72(m,6H),1.45-1.36(m,6H),1.30(s,9H)。MS(ESI)530(M+H)。

Step G. example 48 preparation of N- ((4- (5- (tert-butyl) -1,3, 4-oxadiazol-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3- (3-hydroxy-3-methylbut-1-yn-1-yl) phenyl) bicyclo [1.1.1] pentane-1-carboxamide

To a stirred solution of intermediate 48F (20mg, 0.038mmol) in DMF (1mL) at room temperature was added 2-methylbut-3-yn-2-ol (3.81mg, 0.045mmol) and Et ₃N (0.016mL, 0.113 mmol). The reaction mixture was degassed with argon for 5min and bis (triphenylphosphine) palladium (II) dichloride (2.65mg, 3.77 μmol) was added followed by copper (I) iodide (0.359mg, 1.885 μmol). The reaction mixture was stirred at 90 ℃ for 12 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue thus obtained 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 10-mM ammonium acetate; mobile phase B: 95:5 acetonitrile, water containing 10-mM ammonium acetate; gradient: hold at 10% B for 0 min, 10% -40% B over 25 min, then hold at 100% B for 5 min; flow rate: 15 mL/min; column temperature: and 25C. Fraction collection is triggered by a signal. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (3.7mg, 18% yield).¹H NMR(400MHz,DMSO-d₆)δ7.56-7.27(m,4H),5.51(s,1H),3.72-3.55(m,1H),3.50-3.39(m,1H),1.97-1.63(m,12H),1.54-1.34(m,12H),1.30(s,9H)。FXREC₅₀(nM)＝30.MS(ESI)534(M+H)。

Example 49

N- ((4- (5- (1, 1-difluoroethyl) -1,2, 4-oxadiazol-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -3-fluoro-N- (3- (3-hydroxy-3-methylbut-1-yn-1-yl) phenyl) bicyclo [1.1.1] pentane-1-carboxamide

Step A. preparation of intermediate 49A.4- (hydroxymethyl) bicyclo [2.2.2] octane-1-carboxylic acid methyl ester

To 4- (methoxycarbonyl) bicyclo [2.2.2] at 0 DEG C]To a stirred solution of octane-1-carboxylic acid (1.5g,7.1mmol) in THF (17mL) was added borane dimethyl sulfide complex (2.0mL, 21 mmol). The reaction mixture was warmed to room temperature and stirred. After 4h, the reaction was quenched with MeOH (added dropwise over 15 min under cooling). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and the crude product was purified by flash silica gel column chromatography (80g silica cartridge; a ═ PE, B ═ EtOAc; 25min gradient; 0% to 50% B; flow rate ═ 60 mL/min; with KMnO; (r); with a solvent)₄TLC visualization). The pure fractions were combined, concentrated and dried in vacuo to give the title compound as a white solid (1.3g, 6.6mmol, 93% yield).¹H NMR(400MHz,DMSO-d₆)δ3.56(s,3H),3.36(s,2H),3.05(s,1H),1.78-1.64(m,6H),1.37-1.27(m,6H)。

Step B. preparation of intermediate 49 B.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 19C by substituting intermediate 49A where appropriate. (0.070g, 0.34mmol, 67% yield) as a colorless oil.¹H NMR(400MHz,CHCl₃-d)δ9.4(s,1H),3.66(s,3H),1.86-1.82(m,7H),1.69-1.66(m,5H)

Step C. preparation of intermediate 49C.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 1H by substituting intermediate 49B and 3-bromoaniline as appropriate. (900mg, 2.55mmol, 44% yield). MS (ESI)353(M + H).

Step D. preparation of intermediate 49D.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 procedure described for the synthesis of example 23 by substituting intermediate 49C where appropriate. (850mg, 1.830mmol, 71.6% yield). MS (ESI)464(M + H).

Step E. preparation of intermediate 49E.4- ((N- (3-bromophenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamido) methyl) bicyclo [2.2.2] octane-1-carboxylic acid

Intermediate 49D (850mg, 1.830mmol) in THF (5mL), MeOH (5mL) and H at room temperature₂To a stirred solution in O (5mL) was added LiOH (263mg, 10.98 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure to give the crude product. To this residue ice water was added and the aqueous layer was acidified with aqueous HCl until the pH of the solution was about 2. The product was extracted with EtOAc (2 × 50mL) and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the title compound (750mg, 1.649mmol, 90% yield). MS (ESI)450(M + H).

Step F. preparation of intermediate 49F.4- ((N- (3-bromophenyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamido) methyl) bicyclo [2.2.2] octane-1-carboxamide

To a stirred solution of intermediate 49E (1.65g, 3.66mmol) in DMF (15mL) was added ammonium chloride (235mg, 4.40mmol), TEA (1.5mL, 10.99mmol) and BOP (1.78g, 4.03 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water (50mL) and extracted with ethyl acetate (2 × 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure and dried in vacuo to give the title compound (1.6g, 3.56mmol, 97% yield). MS (ESI)449(M + H).

Step G preparation of intermediate 49G.N- (3-bromophenyl) -N- ((4-cyanobicyclo [2.2.2] oct-1-yl) methyl) -3-fluorobicyclo [1.1.1] pentane-1-carboxamide

A stirred solution of intermediate 49F (1.6g, 3.56mmol) in pyridine (15mL) was cooled to 0 ℃. TFAA (2.51mL, 17.80mmol) was added dropwise to the reaction mixture. The reaction mixture was allowed to warm to room temperature and stirred for 30 min. The reaction mixture was diluted with ice-cold water (50mL) and extracted with ethyl acetate (2 × 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate 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 and dried in vacuo to give the title compound as a light brown gummy oil (850mg, 1.97mmol, 55% yield). MS (ESI)431(M + H).

Step H. preparation of intermediate 49h. (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

To a stirred solution of intermediate 49G (0.47G, 1.090mmol) in ethanol (10mL) was added hydroxylamine (0.336mL, 5.45mmol) at room temperature. The reaction mixture was heated to 90 ℃ for 3 h. The reaction mixture was concentrated under reduced pressure to give the crude product. To this residue ice water was added and the aqueous layer was extracted with EtOAc (2 × 50mL) and the combined organic layers were extracted over MgSO₄And (5) drying. The solvent was removed under reduced pressure to give the title compound (400mg, 0.844mmol, 77% yield). MS (ESI)464(M + H).

Step I. preparation of intermediate 49I.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

To a stirred solution of intermediate 49H (300mg, 0.646mmol) in DMF (10mL) was added 2, 2-difluoropropionic acid (71.1mg, 0.646mmol), TEA (0.360mL, 2.58mmol) at room temperature, followed by BOP (314mg, 0.711 mmol). After stirring at room temperature for 3h, the reaction mixture was heated at 110 ℃ overnight. The reaction mixture was concentrated under reduced pressure, washed with water (20mL) Diluted and 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 product was purified by flash column chromatography (4g silica cartridge, 0-40% EtOAc/petroleum ether) to give the title compound as a brown solid (250mg, 0.464mmol, 72% 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)。MS(ESI)538(M+H)。

Step J. example 49 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- (3-hydroxy-3-methylbut-1-yn-1-yl) phenyl) bicyclo [1.1.1] pentane-1-carboxamide

The title compound was prepared according to the procedure described for the synthesis of example 48 by substituting intermediate 49I where appropriate. (13mg, 0.024mmol, 51.2% yield).¹H NMR(400MHz,DMSO-d₆)δ7.50-7.35(m,4H),5.52(s,1H),3.70-3.61(m,1H),3.46(br s,1H),2.14(t,J＝19.7Hz,3H),1.97-1.67(m,12H),1.45-1.33(m,6H)。FXR EC₅₀(nM)＝39.MS(ESI)452(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.

The Gal4-hFXR fusion construct reporter system was used as the primary assay for characterizing compound activity. Constructs comprising 5 copies of the Gal4 promoter response element upstream of the firefly luciferase reporter cDNA were stably expressed in HEK293 cells. The reporter cell line was maintained in Duchen modified eagle' S medium (DMEM; Gibco) supplemented with 1% penicillin-streptomycin (P/S) solution, 500. mu.g/ml bleomycin (Zeocin), and 10% charcoal/dextran treated fetal bovine serum (cs-FBS) at 37 ℃ in humidified 5% CO ₂In an atmosphere. Construction of another plasmid in which the human cytomegalovirus promoter in the pcDNA3.1 vector directs the expression of the cDNA encoding the fusion protein from which it was derivedDNA binding domain from Gal4 transcription factor fused from the ligand binding domain of 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: separately, 25. mu.g of pcDNA3.1-Gal4-FXR plasmid was diluted into 1.87mL of Opti-MEM (Thermo-Fisher) and 40. mu.L of Lipofectamine 2000(Thermo-Fisher) was diluted into 1.87mL of Opti-MEM, and then the diluted DNA solution was added to the diluted Lipofectamine 2000 solution and incubated at room temperature for 15-20 minutes. Immediately prior to cell transfer, the mixture was further diluted with 10ml of a solution consisting of DMEM, 10% cs-FBS and 1% P/S. The maintenance medium was aspirated from the cells and the final transfection mixture was added, then the cells were humidified at 37 ℃ with 5% CO₂Incubate under atmosphere overnight. 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 Corning/Costar clear bottom 384 well white plate using an Echo acoustic dispenser (Labcyte). Transfected cells were harvested, counted and diluted so that 10-25,000 cells in 25 μ L were plated into each well of a 384-well compound assay plate. Compound treated cells were humidified 5% CO at 37 deg.C₂Incubate under atmosphere overnight. 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 the luminescence was measured on an envision (perkin elmer) plate reader. The background counts of DMSO-treated cells alone were subtracted from all the raw counts and the corrected values were converted to the percentage of the control reaction obtained with 8 μ M GW-4064. These data were fitted 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 weighing 25-28g were purchased from Taconic Labs (Hadamson, N.Y.) and maintained at Teklad Global 18%Protein rodent diet (Harlan Laboratories). After 1 week of adaptation, mice were grouped based on 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 leaves of the liver were divided, half of which were homogenized and assayed 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 (which encodes the small heterodimer partner SHP); abcb11 (which encodes bile salt excretion pump BSEP); cyp7a1 and Cyp8b1 (in the liver) and Fgf15, Fabp6 (which encodes the ileal bile acid binding protein I-BABP); slc51a (which encodes the organic solute transporter α subunit OSTA) and Slc51b (which encodes the organic solute transporter β subunit OSTB) (in the ileum). Statistically significant changes in FGF15 gene expression were expressed as fold increase and CYP relative to vehicle control_7A1Expressed as a percentage reduction.

Other features of the present invention should become apparent in the course of the above description of exemplary embodiments given for the purpose of illustrating the invention and not for the purpose of limiting the same. 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 as indicated 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 separate element of an embodiment is an independent embodiment of its own. Moreover, any element of an embodiment is intended to be combined with any and all other elements from any embodiment to describe another embodiment.

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