Compounds useful as immunomodulators

Abstract

The present disclosure generally relates to compounds useful as immunomodulators. Provided herein are compounds, compositions comprising such compounds, and methods of their use. The disclosure further pertains to pharmaceutical compositions comprising at least one compound according to the disclosure that are useful for the treatment of various diseases, including cancer and infectious diseases.

Claims

1. A compound of formula (I) ##STR00434## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 and R.sup.5 are independently selected from hydrogen, CH.sub.3, cyano, halo, halomethyl, dihalomethyl, and trihalomethyl; R.sup.2 and R.sup.3 are independently selected from hydrogen, O(CH.sub.2).sub.mPh, (CH.sub.2).sub.mOPh, O(CH.sub.2).sub.nNR.sup.aR.sup.b, (CH.sub.2).sub.mPh, -(alkenylene)Ph, S(O).sub.2NH(CH.sub.2).sub.nNR.sup.aR.sup.b, S(O).sub.2NH(CH.sub.2).sub.nCO.sub.2H, O(CH.sub.2)piperidinyl, O(CH.sub.2).sub.mpyridinyl, (CH.sub.2).sub.mNH(CH.sub.2).sub.nNR.sup.aR.sup.b, NH(CH.sub.2).sub.nNR.sup.aR.sup.b, C(O)NH(CH.sub.2).sub.nNR.sup.aR.sup.b, NHC(O)(CH.sub.2).sub.nNR.sup.aR.sup.b, NHC(O)NH(CH.sub.2).sub.nNR.sup.aR.sup.b, and NHC(O)NH(CH.sub.2).sub.nCO.sub.2H; wherein each piperidinyl group is optionally substituted with a C.sub.1-C.sub.3alkyl group; and wherein the pyridinyl group is optionally substituted with a cyano group; and wherein each Ph group is optionally substituted with one, two, or three groups independently selected from C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3alkylcarbonyl, amino, carboxy, (C.sub.3-C.sub.6cycloalkyl)alkoxy, cyano, halo, hydroxy, hydroxymethyl, CHO, C(O)NR.sup.aR.sup.b, (CH.sub.2).sub.mNR.sup.aR.sup.b; OCH.sub.2phenyl wherein the phenyl is optionally substituted with one or two halo groups, and OCH.sub.2pyridinyl optionally substituted with a cyano group, aminocarbonyl group, or a pyrazole ring; or R.sup.2 and R.sup.3, together with the atoms to which they are attached, form a 1,4-dioxane ring optionally substituted with O(CH.sub.2).sub.nNR.sup.aR.sup.b; R.sup.4 is selected from hydrogen, O(CH.sub.2).sub.mPh, (CH.sub.2).sub.mOPh, O(CH.sub.2).sub.nNR.sup.aR.sup.b, (CH.sub.2).sub.mPh, -(alkenylene)Ph, S(O).sub.2NH(CH.sub.2).sub.nNR.sup.aR.sup.b, S(O).sub.2NH(CH.sub.2).sub.nCO.sub.2H, O(CH.sub.2)piperidinyl, O(CH.sub.2).sub.mpyridinyl, NH(CH.sub.2).sub.nNR.sup.aR.sup.b, C(O)NH(CH.sub.2).sub.nNR.sup.aR.sup.b, NHC(O)(CH.sub.2).sub.nNR.sup.aR.sup.b, NHC(O)NH(CH.sub.2).sub.nNR.sup.aR.sup.b, and NHC(O)NH(CH.sub.2).sub.nCO.sub.2H, wherein each piperidinyl group is optionally substituted with a C.sub.1-C.sub.3alkyl group; and wherein the pyridinyl group is optionally substituted with a cyano group; and wherein each Ph group is optionally substituted with one, two, or three groups independently selected from C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3alkylcarbonyl, amino, carboxy, cyano, (C.sub.3-C.sub.6cycloalkyl)alkoxy, halo, hydroxy, hydroxymethyl, C(O)NR.sup.aR.sup.b, (CH.sub.2).sub.mNR.sup.aR.sup.b; OCH.sub.2phenyl wherein the phenyl is optionally substituted with one or two halo groups, and OCH.sub.2pyridinyl optionally substituted with a cyano group, aminocarbonyl group, or a pyrazole ring; R.sup.6 and R.sup.7 are independently selected from hydrogen; O(CH.sub.2).sub.mPh, (CH.sub.2).sub.mOPh, O(CH.sub.2).sub.nNR.sup.aR.sup.b, (CH.sub.2).sub.mPh, -(alkenylene)Ph, S(O).sub.2NH(CH.sub.2).sub.nNR.sup.aR.sup.b, S(O).sub.2NH(CH.sub.2).sub.nCO.sub.2H, O(CH.sub.2)piperidinyl, O(CH.sub.2).sub.mpyridinyl, (CH.sub.2).sub.mNH(CH.sub.2).sub.nNR.sup.aR.sup.b, NH(CH.sub.2).sub.nNR.sup.aR.sup.b, C(O)NH(CH.sub.2).sub.nNR.sup.aR.sup.b, NHC(O)(CH.sub.2).sub.nNR.sup.aR.sup.b, NHC(O)NH(CH.sub.2).sub.nNR.sup.aR.sup.b, and NHC(O)NH(CH.sub.2).sub.nCO.sub.2H, wherein the piperidinyl group is optionally substituted with a C.sub.1-C.sub.3alkyl group; and wherein the pyridinyl group is optionally substituted with a cyano group; and wherein each Ph group is optionally substituted with one, two, or three groups independently selected from C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3alkylcarbonyl, amino, carboxy, cyano, (C.sub.3-C.sub.6cycloalkyl)alkoxy, halo, hydroxy, hydroxymethyl, C(O)NR.sup.aR.sup.b, (CH.sub.2).sub.mNR.sup.aR.sup.b; OCH.sub.2phenyl wherein the phenyl is optionally substituted with one or two halo groups; and OCH.sub.2pyridinyl optionally substituted with a cyano group, aminocarbonyl group, or a pyrazole ring; or R.sup.6 and R.sup.7, together with the atoms to which they are attached, form a 1,4-dioxane ring optionally substituted with O(CH.sub.2).sub.nNR.sup.aR.sup.b; provided that at least two of R.sup.2, R.sup.3, R.sup.4, R.sup.6, and R.sup.7 are other than hydrogen; and provided that when R.sup.2 is (CH.sub.2).sub.mOPh, (CH.sub.2).sub.mPh, or -(alkenylene)Ph then R.sup.6 is selected from (CH.sub.2).sub.mOPh, (CH.sub.2).sub.mPh, and -(alkenylene)Ph; m is 1, 2, or 3; n is 2, 3, 4, 5; R.sup.a and R.sup.b are independently selected from hydrogen, C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3alkylsulfonylC.sub.1-C.sub.3alkyl, aminocarbonylC.sub.1-C.sub.6alkyl, carboxyC.sub.2-C.sub.6alkenyl, carboxyC.sub.1-C.sub.6alkyl, (carboxyC.sub.1-C.sub.3alkyl)carbonyl, cyanoC.sub.1-C.sub.3alkyl, (C.sub.3-C.sub.6cycloalkyl)C.sub.1-C.sub.3alkyl, C.sub.3-C.sub.6cycloalkyl, haloC.sub.1-C.sub.3alkyl, hydroxyC.sub.1-C.sub.6alkyl, (hydroxyC.sub.1-C.sub.6alkyl)carbonyl, imidazolylC.sub.1-C.sub.3alkyl, morpholinylC.sub.1-C.sub.3alkyl, oxeranyl, phenyl, phenylC.sub.1-C.sub.3alkyl, piperidinyl, piperidinylC.sub.1-C.sub.3alkyl, pyridinylC.sub.1-C.sub.3alkyl, pyrimidinylC.sub.1-C.sub.3alkyl, pyrazolylC.sub.1-C.sub.3alkyl, tetrahydrofurylC.sub.1-C.sub.3alkyl, thiazolyl, thiazolylC.sub.1-C.sub.3alkyl, (NR.sup.cR.sup.d)C.sub.1-C.sub.3alkyl, ##STR00435## wherein the alkyl part of the carboxyC.sub.1-C.sub.3alkyl is further optionally substituted with one or two groups selected from C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3alkylsulfanyl, cyano, hydroxy, indolyl, phenylC.sub.1-C.sub.3alkoxy, phenyl optionally substituted with one halo, and pyridinyl; and wherein the alkyl part of the (C.sub.3-C.sub.6cycloalkyl)C.sub.1-C.sub.3alkyl, the haloC.sub.1-C.sub.3alkyl, the imidazolylC.sub.1-C.sub.3alkyl, and the phenylC.sub.1-C.sub.3alkyl is optionally substituted with a aminocarbonyl or carboxy group; wherein the alkyl part of, the is optionally substituted with an aminocarbonyl group; wherein the C.sub.3-C.sub.6cycloalkyl and the cycloalkyl part of the (C.sub.3-C.sub.6cycloalkyl)C.sub.1-C.sub.3alkyl is optionally substituted with one, two, or three groups independently selected from hydroxy and hydroxyC.sub.1-C.sub.3alkyl; and wherein the alkyl part of the hydroxyC.sub.1-C.sub.6alkyl is further optionally substituted with one group selected from C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.6alkoxycarbonyl, C.sub.3-C.sub.6cycloalkyl, phenylC.sub.1-C.sub.3alkoxycarbonyl, tetrahydrofuryl, imidazolyl optionally substituted with one or two groups independently selected from C.sub.1-C.sub.3alkyl and halo, pyridinyl, phenyl optionally substituted with two halo groups, and thiazolyl; and wherein the imidazolyl part of the imidazolylC.sub.1-C.sub.3alkyl, the piperidinyl, the piperidinyl part of the piperidinylC.sub.1-C.sub.3alkyl, the pyrazolyl part of the pyrazolylC.sub.1-C.sub.3alkyl, and the pyridinyl part of the pyridinylC.sub.1-C.sub.3alkyl are optionally substituted with one, two, or three groups independently selected from C.sub.1-C.sub.3alkyl, cyano, halo, and hydroxyC.sub.1-C.sub.3alkyl; and wherein the phenyl and the phenyl part of the phenylC.sub.1-C.sub.3alkyl is optionally substituted with one or two groups independently selected from C.sub.1-C.sub.3alkoxy, amino and halo; or R.sup.a and R.sup.b, together with the nitrogen atom to which they are attached, form a four-, five-, or six-membered ring optionally containing one additional heteroatom selected from nitrogen, oxygen, and sulfur; wherein the ring is optionally fused to a phenyl group to form a bicyclic structure and wherein the ring and bicyclic structure are optionally substituted with one or two groups selected from C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3alkoxycarbonyl, C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3alkylcarbonyl, aminocarbonyl, carboxy, carboxyC.sub.1-C.sub.3alkyl, halo, hydroxy, hydroxyC.sub.1-C.sub.3alkyl, NR.sup.cR.sup.d, (NR.sup.cR.sup.d)carbonyl, (NR.sup.cR.sup.d)carbonylC.sub.1-C.sub.3alkyl, oxo, pyridinyl, and phenyl optionally substituted with a halo or methoxy group; and R.sup.c and R.sup.d are independently selected from hydrogen, C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3alkylcarbonyl; and ##STR00436##

2. A compound of claim 1 wherein R.sup.4 is hydrogen.

3. A compound of claim 2 wherein R.sup.1 and R.sup.5 are selected from CH.sub.3 and halo.

4. A compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein: one of R.sup.2 and R.sup.3 is hydrogen and the other is selected from O(CH.sub.2).sub.mPh, (CH.sub.2).sub.mOPh, O(CH.sub.2).sub.nNR.sup.aR.sup.b, S(O).sub.2NH(CH.sub.2).sub.nNR.sup.aR.sup.b, S(O).sub.2NH(CH.sub.2).sub.nCO.sub.2H, O(CH.sub.2).sub.mpyridinyl, (CH.sub.2).sub.mNH(CH.sub.2).sub.nNR.sup.aR.sup.b, C(O)NH(CH.sub.2).sub.nNR.sup.aR.sup.b, NHC(O)(CH.sub.2).sub.nNR.sup.aR.sup.b, NHC(O)NH(CH.sub.2).sub.nNR.sup.aR.sup.b; and NHC(O)NH(CH.sub.2).sub.nCO.sub.2H; wherein each piperidinyl group is optionally substituted with a C.sub.1-C.sub.3alkyl group; and wherein the pyridinyl group is optionally substituted with a cyano group; and wherein each Ph group is optionally substituted with one, two, or three groups independently selected from C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3alkylcarbonyl, amino, carboxy, (C.sub.3-C.sub.6cycloalkyl)alkoxy, cyano, halo, hydroxy, hydroxymethyl, CHO, C(O)NR.sup.aR.sup.b, (CH.sub.2).sub.mNR.sup.aR.sup.b, OCH.sub.2phenyl wherein the phenyl is optionally substituted with one or two halo groups, and OCH.sub.2pyridinyl optionally substituted with a cyano group, aminocarbonyl group, or a pyrazole ring; and one of R.sup.6 and R.sup.7 is hydrogen and the other is selected from O(CH.sub.2).sub.mPh, (CH.sub.2).sub.mOPh, O(CH.sub.2).sub.nNR.sup.aR.sup.b, S(O).sub.2NH(CH.sub.2).sub.nNR.sup.aR.sup.b, S(O).sub.2NH(CH.sub.2).sub.nCO.sub.2H, O(CH.sub.2).sub.mpyridinyl, (CH.sub.2).sub.mNH(CH.sub.2).sub.nNR.sup.aR.sup.b, C(O)NH(CH.sub.2).sub.nNR.sup.aR.sup.b, NHC(O)(CH.sub.2).sub.nNR.sup.aR.sup.b, NHC(O)NH(CH.sub.2).sub.nNR.sup.aR.sup.b, and NHC(O)NH(CH.sub.2).sub.nCO.sub.2H, wherein the pyridinyl group is optionally substituted with a cyano group; and wherein each Ph group is optionally substituted with one, two, or three groups independently selected from C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3alkylcarbonyl, amino, carboxy, cyano, (C.sub.3-C.sub.6cycloalkyl)alkoxy, halo, hydroxy, hydroxymethyl, C(O)NR.sup.aR.sup.b, (CH.sub.2).sub.mNR.sup.aR.sup.b; OCH.sub.2phenyl wherein the phenyl is optionally substituted with one or two halo groups; and OCH.sub.2pyridinyl optionally substituted with a cyano group, aminocarbonyl group, or a pyrazole ring.

5. A compound selected from 2,2-((((2-chloro-2-methyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(3-hydroxypyrrolidine-1,3-diyl))diacetic acid; 1,1-(((2-chloro-2-methyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(4-hydroxypiperidine-4-carboxylic acid); (2S,2S,4R,4R)-1,1-(((2-chloro-2-methyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(4-hydroxypyrrolidine-2-carboxylic acid); (3R,3R)-1,1-(((2,6-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol); (R)-1-(4-(3-((3-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)piperazin-1-yl)ethan-1-one; (R)-1-(3-((3-(3-(3-(dimethylamino)azetidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (3R)-1-(3-((3-(3-(3-(hydroxymethyl)piperidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((3-(3-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((2,2-dimethyl-3-(3-((2-morpholinoethyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((2,2-dimethyl-3-(3-((pyridin-4-ylmethyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((3-(3-((2-(dimethylamino)ethyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((3-(3-((2-(1H-pyrazol-1-yl)ethyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((2,2-dimethyl-3-(3-((2-(3-methyl-1H-pyrazol-1-yl)ethyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((2,2-dimethyl-3-(3-((2-(methylsulfonyl)ethyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (S)-3-((3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)amino)propane-1,2-diol; (3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)-L-serine; (S)-3-hydroxy-2-((3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)amino)-2-methylpropanoic acid; (R)-1-(3-((3-(3-((2-hydroxyethyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; 3-((3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)(methyl)amino)propane-1,2-diol, 2.0 TFA; 2-hydroxy-3-((3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)amino)propanoic acid; (R)-1-(3-((3-(3-(((1r,4r)-4-hydroxycyclohexyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; N((R)-1-(3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-yl)acetamide; 1-(3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)piperidine-3-carboxamide; (R)-1-(3-((3-(3-((3-(1H-imidazol-1-yl)propyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((2,2-dimethyl-3-(3-((3-morpholinopropyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((2,2-dimethyl-3-(3-((2-(pyridin-3-yl)ethyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; N,N-diethyl-1-(3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)piperidine-3-carboxamide; (R)-1-(3-((2,2-dimethyl-3-(3-((pyridin-2-ylmethyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (3R)-1-(3-((3-(3-(2-(hydroxymethyl)piperidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; ((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(piperidine-1,3-diyl))dimethanol, 2.0 TFA; 2,2-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(azanediyl))bis(ethan-1-ol); 3,3-((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(N-(2-(pyridin-4-yl)ethyl)propan-1-amine); 4,4-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(azanediyl))bis(2-methylbutane-2,3-diol); 3,3-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(methylazanediyl))bis(propan-1-ol); (2S,2S)-3,3-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(methylazanediyl))bis(propane-1,2-diol); (R)-1-(3-((3-(3-((2-(dimethylamino)ethyl)(methyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (3S,4R)-4-(hydroxymethyl)-1-(3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)piperidin-3-ol; (R)-1-(3-((3-(3-((2-hydroxyethyl)(methyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((2,2-dimethyl-3-(3-((2-(pyridin-4-yl)ethyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-4-(3-((3-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)-1-methylpiperazin-2-one; (S)-2-((3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)amino)-3-(pyridin-4-yl)propanoic acid; (R)-3-((3-((3-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)amino)propanamide; (2S,4R)-4-hydroxy-1-(3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidine-2-carboxylic acid; (3R)-1-(3-((3-(3-((2-hydroxy-2-(pyridin-3-yl)ethyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((2,2-dimethyl-3-(3-(phenethylamino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((3-(3-((3-hydroxypropyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((2,2-dimethyl-3-(3-((2-(1-methyl-1H-imidazol-4-yl)ethyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((2,2-dimethyl-3-(3-(((1-methylpiperidin-4-yl)methyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (S)-2-hydroxy-3-((3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)amino)propanoic acid; (R)-1-(3-((3-(3-((3-hydroxy-2,2-dimethylpropyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (3R)-1-(3-((3-(3-((2-hydroxy-1-(pyridin-4-yl)ethyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)N-(2-((3-((3-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)amino)ethyl)acetamide; (R)-1-(3-((2,2-dimethyl-3-(3-(methyl(pyridin-3-ylmethyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((2,2-dimethyl-3-(3-((pyridin-3-ylmethyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (2S,4R)-4-hydroxy-1-(3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidine-2-carboxylic acid; (R)-3-((3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)amino)propane-1,2-diol; (R)-1-(3-((3-(3-((2-hydroxyethyl)(propyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-3-((3-((3-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)(methyl)amino)propanamide; (R)-1-(3-((3-(3-(((R)-1-hydroxy-3-methylbutan-2-yl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((3-(3-(bis(pyridin-2-ylmethyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((3-(3-(((S)-2-hydroxy-1-phenylethyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((3-(3-(((S)-1-hydroxy-3-methylbutan-2-yl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; 3-((3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)amino)propane-1,2-diol; (R)-1-(3-((3-(3-((2-(4-chloro-1H-pyrazol-1-yl)ethyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((3-(3-((2-(4-chloro-1H-pyrazol-1-yl)ethyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((2,2-dimethyl-3-(3-(methyl(pyridin-2-ylmethyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((3-(3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((2,2-dimethyl-3-(3-(methyl(pyridin-4-ylmethyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((3-(3-((4-aminophenethyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((2,2-dimethyl-3-(3-((1-methylpiperidin-4-yl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((3-(3-((1-(2-hydroxyethyl)piperidin-4-yl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-2,2-((3-((3-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)azanediyl)bis(ethan-1-ol); (R)-1-(3-((3-(3-(((R)-2-hydroxy-1-phenylethyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((3-(3-(4-(dimethylamino)piperidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((3-(3-(((R)-1-(5-chloro-1-methyl-1H-imidazol-4-yl)-3-hydroxypropan-2-yl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((3-(3-(benzyl(2-hydroxyethyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((3-(3-((2-hydroxyethyl)(isopentyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)piperidine-3-carboxylic acid; (R)-1-(3-((3-(3-(((S)-2-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; 3,3-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(methylazanediyl))dipropanamide; 2,2,2,2-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(azanetriyl))tetrakis(ethan-1-ol); 3,3-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(methylazanediyl))bis(propane-1,2-diol); (2S,2S)-3,3-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(azanediyl))bis(propane-1,2-diol); (S)-3-((3-((3-(3-((3-hydroxypropyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)amino)propane-1,2-diol; (S)-1-(3-((3-(3-(((S)-2,3-dihydroxypropyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)piperidine-3-carboxylic acid; (3S,3S)-1,1-(((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(piperidine-3-carboxylic acid); 3,3-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(azanediyl))bis(propane-1,2-diol); (3S,3S,4S,4S)-1,1-(((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(piperidine-3,4-diol); 2,2-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(piperazine-4,1-diyl))bis(ethan-1-ol); 3,3-((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(N-(2-(pyridin-3-yl)ethyl)propan-1-amine); 1,1-(((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(N,N-dimethylazetidin-3-amine); (1S,1S,2R,2R,3R,3R,5R,5R)-5,5-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(azanediyl))bis(3-(hydroxymethyl)cyclopentane-1,2-diol); (1R,2S,3R,5R)-3-((3-((2,2-dimethyl-3-(3-((2-(pyridin-4-yl)ethyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)amino)-5-(hydroxymethyl)cyclopentane-1,2-diol; 3,3-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(methylazanediyl))bis(cyclobutan-1-ol); (2S,3S)-3-((3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)amino)-3-phenylpropane-1,2-diol; (R)-1-(3-((3-(3-((R)-2-(hydroxymethyl)morpholino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (3R,3R)-1,1-((((((propane-1,3-diylbis(methylazanediyl))bis(propane-3,1-diyl))bis(oxy))bis(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl))bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol); 3,3-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(azanediyl))bis(1-methoxypropan-2-ol); (3R,3R)-1,1-(((((((oxybis(ethane-2,1-diyl))bis(methylazanediyl))bis(propane-3,1-diyl))bis(oxy))bis(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl))bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol); (R)-1-(3-((2,2-dimethyl-3-(3-(methyl(2-(2-(methylamino)ethoxy)ethyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (1R,1R,2R,2R)-2,2-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(azanediyl))bis(1-phenylpropane-1,3-diol); (S)-3-((3-((3-(3-(((1R,2R)-1,3-dihydroxy-1-phenylpropan-2-yl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)amino)propane-1,2-diol; 5,5-(((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(((S)-2,3-dihydroxypropyl)azanediyl))bis(methylene))dinicotinonitrile; 2,2-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(((S)-2,3-dihydroxypropyl)azanediyl))diacetonitrile; (2S,2S)-3,3-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis((2-(pyridin-2-yl)ethyl)azanediyl))bis(propane-1,2-diol); (2S,2S)-3,3-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis((2-(pyridin-3-yl)ethyl)azanediyl))bis(propane-1,2-diol); (S)-3-((3-((3-(3-(((S)-2,3-dihydroxypropyl)(2-(pyridin-3-yl)ethyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)amino)propane-1,2-diol; 3,3-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(azanediyl))bis(2-methylpropane-1,2-diol); (R)-1-(3-((2,2-dimethyl-3-(3-(piperidin-1-yl)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((3-(3-(4-(hydroxymethyl)piperidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; N-(1-(3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-yl)acetamide; (R)-1-(3-((2,2-dimethyl-3-(3-(4-(pyridin-2-yl)piperazin-1-yl)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-2-(4-(3-((3-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)piperazin-1-yl)-N-isopropylacetamide; (R)-1-(3-((2,2-dimethyl-3-(3-(methyl(phenethyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((3-(3-(4-(2-methoxyphenyl)piperazin-1-yl)prop oxy)-2, 2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((3-(3-(((R)-2-hydroxy-2-phenylethyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((3-(3-(((S)-2-hydroxy-2-phenylethyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)piperidin-3-ol; (S)-1-(3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)piperidin-3-ol; (S)-2-((3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)amino)-3-(pyridin-2-yl)propanoic acid; (S)-2-((3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)amino)-3-(pyridin-3-yl)propanoic acid; (R)-1-(3-((2,2-dimethyl-3-(3-((2-(pyridin-2-yl)ethyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (2S,2S)-1,1-(((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4,1-phenylene))bis(methylene))bis(piperidine-2-carboxylic acid); (S)-1-(5-chloro-4-((3-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-(hydroxymethyl)phenoxy)methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methoxy)-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid; (2R,2R)-2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4,1-phenylene))bis(methylene))bis(azanediyl))bis(3-hydroxy-2-methylpropanoic acid); 2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-methoxy-4,1-phenylene))bis(methylene))bis(azanediyl))bis(propane-1,3-diol); (2S,2S)-2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4,1-phenylene))bis(methylene))bis(azanediyl))bis(3-hydroxy-2-methylpropanoic acid); (S)-2-((5-chloro-4-((3-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-(hydroxymethyl)phenoxy)methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methoxy)-2-((5-cyanopyridin-3-yl)methoxy)benzyl)amino)-3-hydroxy-2-methylpropanoic acid; 5,5-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(4-chloro-6-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-3,1-phenylene))bis(oxy))bis(methylene))dinicotinonitrile; (R)-5-((4-chloro-5-((3-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-((3-hydroxypyrrolidin-1-yl)methyl)phenoxy)methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methoxy)-2-(hydroxymethyl)phenoxy)methyl)nicotinonitrile; 5,5-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(4-chloro-6-((((S)-2,3-dihydroxypropyl)amino)methyl)-3,1-phenylene))bis(oxy))bis(methylene))dinicotinonitrile; 5,5-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(4-chloro-6-(((1,3-dihydroxypropan-2-yl)amino)methyl)-3,1-phenylene))bis(oxy))bis(methylene))dinicotinonitrile; 5-((4-chloro-5-((3-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-(((1,3-dihydroxypropan-2-yl)amino)methyl)phenoxy)methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methoxy)-2-(hydroxymethyl)phenoxy)methyl)nicotinonitrile; 5,5-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(4-chloro-6-(((1,3-dihydroxypropan-2-yl)((S)-2,3-dihydroxypropyl)amino)methyl)-3,1-phenylene))bis(oxy))bis(methylene))dinicotinonitrile; (3R,3R)-1,1-(((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol); (R)-1-(3-((3-(4-((R)-3-hydroxypyrrolidin-1-yl)butoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl) pyrrolidin-3-ol; (R)-1-(3-((3-((5-((R)-3-hydroxypyrrolidin-1-yl)pentyl)oxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((3-(4-((R)-3-hydroxypyrrolidin-1-yl)butoxy)-2,2-dimethyl-[1,1-biphenyl]-4-yl)oxy)propyl) pyrrolidin-3-ol; (R)-1-(3-((3-((5-((R)-3-hydroxypyrrolidin-1-yl)pentyl)oxy)-2,2-dimethyl-[1,1-biphenyl]-4-yl)oxy)propyl)pyrrolidin-3-ol; (3R,3R)-1,1-(((2,2-dimethyl-[1,1-biphenyl]-3,4-diyl)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol); (R)-1-(3-((3-(3-(dimethylamino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; N-(4-((R)-3-hydroxypyrrolidin-1-yl)butyl)-3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-carboxamide; 3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-N-(3-((R)-3-hydroxypyrrolidin-1-yl)propyl)-2,2-dimethyl-[1,1-biphenyl]-3-carboxamide; (R)N-(3-(dimethylamino)propyl)-3-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-sulfonamide; (R)-5-(((3-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)methylnicotinonitrile; (3R,3R)-1,1-(((2,2-dimethyl-[1,1-biphenyl]-4,4-diyl)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol); 3-((R)-3-hydroxypyrrolidin-1-yl)-N-(3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)propanamide; (R)-3-(3-(3-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)ureido)propanoic acid; N-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)-3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-carboxamide; N-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)-3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-sulfonamide; 1-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)-3-(3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)urea; (R)-1-(3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)amino)propyl)pyrrolidin-3-ol; (R)-3-(((3-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)methyl)benzonitrile; (R)-3-(3-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-ylsulfonamido)propanoic acid; (3S,3S)-1,1-(((2-methyl-[1,1-biphenyl]-3,4-diyl)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol); (3S,3S)-1,1-(((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2-methyl-[1,1-biphenyl]-3,4-diyl)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol); (3R,3R)-1,1-(((2-methyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol); (3R,3R)-1,1-(((2-chloro-2-methyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol); 3,3-bis(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2-methyl-[1,1-biphenyl]-2-carbonitrile; (3R,3R)-1,1-(((2-methyl-2-(trifluoromethyl)-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol), 2 TFA; (R)-1-(3-((2-methyl-3-(3-phenylpropoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; 1-(3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)-3-phenylpyrrolidin-3-ol, 2 TFA; (3R)-1-(3-((2,2-dimethyl-3-((1-methylpiperidin-3-yl)methoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (3R)-1-(3-(3-(3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenoxy)propyl)pyrrolidin-3-ol; (3R)-1-(3-(3-(3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenoxy)propyl)pyrrolidin-3-ol; and (3R,3R)-1,1-((2,2,3,3-tetrahydro-[6,6-bibenzo[b][1,4]dioxine]-3,3-diyl)bis(ethane-2,1-diyl))bis(pyrrolidin-3-ol); or a pharmaceutically acceptable salt thereof.

6. A compound selected from (1R,2S,5R)-3-((3-((3-(3-(((1R,2S,3R,4R)-2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)amino)-5-(hydroxymethyl)cyclopentane-1,2-diol; 5,5-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(4-chloro-6-((4-(hydroxymethyl)-2-oxooxazolidin-3-yl)methyl)-3,1-phenylene))bis(oxy))bis(methylene))dinicotinonitrile; 3,3-((2,2-dichloro-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propan-1-amine); N,N-(((2,2-dichloro-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(2,3-dihydroxypropanamide); (3R,3R)-4,4-((((2,2-dichloro-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(azanediyl))bis(3-hydroxy-4-oxobutanoic acid); (R)-1-(3-((3-((3-aminobenzyl)oxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; (R)-1-(3-((3-(3-((R)-3-fluoropyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol; 2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(2,5-dimethyl-4,1-phenylene))bis(methylene))bis(azanediyl))bis(2-methylpropane-1,3-diol; (2S,2S)-1,1-(((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(2,5-dimethyl-4,1-phenylene))bis(methylene))bis(piperidine-2-carboxylic acid); 2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-((3,5-difluorobenzyl)oxy)-4,1-phenylene))bis(methylene))bis(azanediyl))bis(propane-1,3-diol); 2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(2,5-dimethyl-4,1-phenylene))bis(methylene))bis(azanediyl))bis(propane-1,3-diol); 2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-((3,5-difluorobenzyl)oxy)-4,1-phenylene))bis(methylene))bis(methylazanediyl))bis(propane-1,3-diol); (2S,2S)-1,1-(((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-((3,5-difluorobenzyl)oxy)-4,1-phenylene))bis(methylene))bis(piperidine-2-carboxylic acid); 2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-((3,5-difluorobenzyl)oxy)-4,1-phenylene))bis(methylene))bis(azanediyl))bis(2-methylpropane-1,3-diol); (2S,2S)-2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-((3,5-difluorobenzyl)oxy)-4,1-phenylene))bis(methylene))bis(azanediyl))bis(3-hydroxypropanoic acid); (2S,2S)-2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-((3,5-difluorobenzyl)oxy)-4,1-phenylene))bis(methylene))bis(azanediyl))bis(3-hydroxy-2-methylpropanoic acid); 2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-((3,5-difluorobenzyl)oxy)-4,1-phenylene))bis(methylene))bis(methylazanediyl))bis(2-methylpropane-1,3-diol); (2S,2S)-2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-((3,5-difluorobenzyl)oxy)-4,1-phenylene))bis(methylene))bis(methylazanediyl))bis(3-hydroxypropanoic acid); (2S,2S)-2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-((3,5-difluorobenzyl)oxy)-4,1-phenylene))bis(methylene))bis(methylazanediyl))bis(3-hydroxy-2-methylpropanoic acid); (2S,2S)-2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-((3,5-difluorobenzyl)oxy)-4,1-phenylene))bis(methylene))bis(methylazanediyl))bis(3-methylbutanoic acid); (2S,2S)-2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-((3,5-difluorobenzyl)oxy)-4,1-phenylene))bis(methylene))bis(methylazanediyl))dipentanoic acid; (2S,2S)-2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-((3,5-difluorobenzyl)oxy)-4,1-phenylene))bis(methylene))bis(methylazanediyl))bis(4-methylpentanoic acid); (2S,2S,3R,3R)-2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(2-((6-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-5-chloro-4,1-phenylene))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid); 2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(2-((6-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-5-chloro-4,1-phenylene))bis(methylene))bis(azanediyl))bis(propane-1,3-diol); 2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(2-((6-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-5-chloro-4,1-phenylene))bis(methylene))bis(azanediyl))bis(2-methylpropane-1,3-diol; (2S,2S)-1,1-(((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(2-((6-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-5-chloro-4,1-phenylene))bis(methylene))bis(piperidine-2-carboxylic acid); (2S,2S)-2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(2-((6-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-5-chloro-4,1-phenylene))bis(methylene))bis(azanediyl))bis(3-hydroxy-2-methylpropanoic acid); 2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(2-((6-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-5-chloro-4,1-phenylene))bis(methylene))bis(methylazanediyl))bis(2-methylpropane-1,3-diol); 2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(2-((6-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-5-chloro-4,1-phenylene))bis(methylene))bis(methylazanediyl))bis(2-methylpropanoic acid); (2S,2S)-2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(2-((6-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-5-chloro-4,1-phenylene))bis(methylene))bis(methylazanediyl))bis(4-hydroxybutanoic acid); (2S,2S)-2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(2-((6-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-5-chloro-4,1-phenylene))bis(methylene))bis(methylazanediyl))dipentanoic acid; (2S,2S)-2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(2-((6-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-5-chloro-4,1-phenylene))bis(methylene))bis(methylazanediyl))bis(3-hydroxy-2-methylpropanoic acid); 2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(2-((6-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-5-chloro-4,1-phenylene))bis(methylene))bis(methylazanediyl))bis(propane-1,3-diol); (2S,2S,3R,3R)-2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(2-((6-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-5-chloro-4,1-phenylene))bis(methylene))bis(methylazanediyl))bis(3-hydroxybutanoic acid); N-(4-((3-((4-((((S)-1-carboxy-3-hydroxypropyl)(methyl)amino)methyl)-2-chloro-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methoxy)-5-chloro-2-methoxybenzyl)-N-methyl-L-homoserine; 3-((4-((3-((4-(((2-carboxyethyl)(methyl)amino)methyl)-2-chloro-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methoxy)-5-chloro-2-methoxybenzyl)(methyl)amino)propanoic acid; 1,1-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-methoxy-4,1-phenylene))bis(N-((1H-pyrazol-3-yl)methyl)methanamine); 1,1-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-methoxy-4,1-phenylene))bis(N-(pyrimidin-5-ylmethyl)methanamine); 1,1-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-methoxy-4,1-phenylene))bis(N-(thiazol-5-ylmethyl)methanamine); 3,3-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-methoxy-4,1-phenylene))bis(methylene))bis(azanediyl))dipropionic acid; (2S,2S)-2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-methoxy-4,1-phenylene))bis(methylene))bis(azanediyl))bis(4-hydroxybutanoic acid); 1,1-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-methoxy-4,1-phenylene))bis(N-((1H-pyrazol-3-yl)methyl)-N-methylmethanamine); 1,1-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-methoxy-4,1-phenylene))bis(N-methyl-N-(pyrimidin-5-ylmethyl)methanamine); 1,1-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-methoxy-4,1-phenylene))bis(N-methyl-N-(thiazol-5-ylmethyl)methanamine); (2S,2S)-1,1-(((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(3-methyl-4,1-phenylene))bis(methylene))bis(piperidine-2-carboxylic acid); (2S,2S)-1,1-(((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-methyl-4,1-phenylene))bis(methylene))bis(piperidine-2-carboxylic acid); 3,3-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-methyl-4,1-phenylene))bis(methylene))bis(azanediyl))dipropionic acid; (S)-1-(4-((3-((4-(((S)-2-carboxypiperidin-1-yl)methyl)-2-chloro-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methoxy)-5-chloro-2-methylbenzyl)piperidine-2-carboxylic acid; 3-((4-((3-((4-(((2-carboxyethyl)amino)methyl)-2-chloro-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methoxy)-5-chloro-2-methylbenzyl)amino)propanoic acid; N-(4-((3-((4-((((S)-1-carboxy-3-hydroxypropyl)(methyl)amino)methyl)-2-chloro-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methoxy)-5-chloro-2-methylbenzyl)-N-methyl-L-homoserine; and (S)-2-((4-((3-((4-((((S)-2-carboxy-1-hydroxypropan-2-yl)amino)methyl)-2-chloro-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methoxy)-5-chloro-2-methylbenzyl)amino)-3-hydroxy-2-methylpropanoic acid; or a pharmaceutically acceptable salt thereof.

7. A compound selected from ##STR00437## ##STR00438## ##STR00439## ##STR00440## ##STR00441## ##STR00442## ##STR00443## ##STR00444## ##STR00445## ##STR00446## ##STR00447## ##STR00448## ##STR00449## ##STR00450## ##STR00451## ##STR00452## ##STR00453## ##STR00454## ##STR00455## ##STR00456## ##STR00457## ##STR00458## ##STR00459## ##STR00460## ##STR00461## ##STR00462## ##STR00463## ##STR00464## ##STR00465## ##STR00466## ##STR00467## ##STR00468## ##STR00469## ##STR00470## ##STR00471## ##STR00472## ##STR00473## ##STR00474## ##STR00475## ##STR00476## ##STR00477## ##STR00478## ##STR00479## ##STR00480## ##STR00481## ##STR00482## ##STR00483## ##STR00484## or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Description

EXAMPLES

(1) The invention is further defined in the following Examples. It should be understood that the Examples are given by way of illustration only. From the above discussion and the Examples, one skilled in the art can ascertain the essential characteristics of the invention, and without departing from the spirit and scope thereof, can make various changes and modifications to adapt the invention to various uses and conditions. As a result, the invention is not limited by the illustrative examples set forth hereinbelow, but rather is defined by the claims appended hereto.

(2) As used in the present specification, the following terms have the meanings indicated: DCM for dichloromethane; DMF for N,N-dimethylformamide; THF for tetrahydrofuran; EtOAc for ethyl acetate; n-BuLi for n-butyllithium; O.sup.iPr for isopropyloxy; h or hr or hrs for hours; min or mins for minutes; sec for seconds; TFA for trifluoroacetic acid; MeOH for methanol; ACN or MeCN for acetonitrile; sat. or satd. for saturated; RT or rt for room temperature or retention time (context will dictate); R.sub.t for retention time; evap'd for evaporated; DIAD for diisorpropyl azodicarboxylate; DMSO for dimethylsulfoxide; NMP for N-methylpyrrolidinone; HATU for (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidhexafluorophosphate); dppf for 1,1-bis(diphenylphosphino)ferrocene; OAc for acetate; RBF for round-bottomed flask; DIEA or iPr.sub.2NEt for diisopropylethylamine; EDC for 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; DCE for 1,2-dichloroethane; NCS for N-chlorosuccinimide; Et.sub.3N for triethylamine; EtOH for ethanol; HCTU for (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidhexafluorophosphate); and HOBt for hydroxybenzotriazole.

(3) Examples 1001 to 1004 were prepared as described below:

(4) LC-MS conditions P-1: Column: Phenomenex LUNA C18, 302, 3 u; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 40 C.; Gradient: 0% B, 0-100% B over 2 minutes, then a 1.0-minute hold at 100% B; Flow rate: 1 mL/min; Detection: UV at 254 nm.

Preparation of 2-chloro-3,3-bis(3-chloropropoxy)-2-methyl-1,1-biphenyl

(5) ##STR00007##

(6) A mixture of 3-bromo-2-methylphenol (0.374 g, 2.000 mmol) and 2-chloro-3-ethoxyphenylboronic acid (0.401 g, 2 mmol) in THF (10 mL) and 0.5 M aq. potassium phosphate, tribasic (12.00 mL, 6.00 mmol) was stirred under nitrogen sparging for 10 min and then added 2nd gen. XPhos precatalyst (0.047 g, 0.060 mmol) and sparging was continued for another 5 min. The reaction mixture was stirred at rt under nitrogen for 16 h and diluted with EtOAc, washed with water, brine, dried (Na.sub.2SO.sub.4), concentrated and purified by silica gel FCC (flash column chromatography) (0-20% EtOAc-hexanes) to yield 2-chloro-3-ethoxy-2-methyl-[1,1-biphenyl]-3-ol (0.5 g, 95% yield) as a white solid. LC-MS (method P-1): R.sub.t (Retention time)=1.748 min, m/z 261.1 (MH).sup.; .sup.1H NMR (400 MHz, CHLOROFORM-d) 7.28-7.23 (m, 1H), 7.14 (t, J=7.8 Hz, 1H), 6.96 (dd, J=8.3, 1.3 Hz, 1H), 6.88-6.83 (m, 2H), 6.80-6.75 (m, 1H), 4.81 (s, 1H), 4.20-4.14 (m, 2H), 2.03 (s, 3H), 1.53 (t, J=7.0 Hz, 3H).

(7) To a cold (78 C.) stirred solution of 2-chloro-3-ethoxy-2-methyl-[1,1-biphenyl]-3-ol (0.5 g) in DCM (12 mL) was added a solution of boron tribromide (4.40 mL, 4.40 mmol) in DCM under nitrogen. The mixture was allowed to warm to rt and stirred for 2-3 h and then quenched with ice and neutralized with satd. NaHCO.sub.3. The organic layer was separated and washed with water, brine, dried (MgSO.sub.4) and concentrated to afford 2-chloro-2-methyl-[1,1-biphenyl]-3,3-diol (0.41 g, 1.747 mmol, 87% yield) as a tan solid. LC-MS (method P-1): R.sub.t=1.407 min, m/z 233.1 (MH).sup.; .sup.1H NMR (400 MHz, CHLOROFORM-d) 7.24 (t, J=7.8 Hz, 1H), 7.15 (t, J=7.8 Hz, 1H), 7.07 (dd, J=8.2, 1.6 Hz, 1H), 6.86 (d, J=7.8 Hz, 1H), 6.83 (dd, J=7.7, 1.6 Hz, 1H), 6.80-6.77 (m, 1H), 5.71 (s, 1H), 4.79 (s, 1H), 2.03 (s, 3H).

(8) Neat potassium carbonate (0.353 g, 2.56 mmol) was added to a stirred solution of 2-chloro-2-methyl-[1,1-biphenyl]-3,3-diol (0.25 g, 1.065 mmol) and 1-bromo-3-chloropropane (0.419 mL, 4.26 mmol) in DMF (4 mL), and the mixture heated at 65 C. overnight. The reaction mixture was cooled to rt and diluted with ether and water. The organic phase was separated and washed with water, brine, dried (Na.sub.2SO.sub.4), concentrated and purified by silica gel chromatography (0-10% EtOAc/hexane) to yield 2-chloro-3,3-bis(3-chloropropoxy)-2-methyl-1,1-biphenyl (0.351 g, 0.905 mmol, 85% yield, contains 10% mono-bromopropoxy and bis-bromopropoxy isomers) as a clear viscous oil which was used in subsequent steps as a mixture without further purification.

Preparation of 3,5-bis(3-chloropropoxy)-2,2-dimethyl-1,1-biphenyl and 3-chloropropoxy-5-bromopropoxy-2,2-dimethyl-1,1-biphenyl

(9) ##STR00008##

(10) Neat potassium carbonate (0.829 g, 6.00 mmol) was added to a stirred solution of 3-bromo-4-methylphenol (0.935 g, 5 mmol) and 1-bromo-3-chloropropane (0.590 mL, 6.00 mmol) in DMF (10 mL), and the mixture heated at 50 C. overnight. The reaction mixture was cooled to rt and diluted with ether and added water. The organic phase was washed with water, brine, dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by silica gel chromatography (0-10% EtOAc/hexane) to yield a mixture of 2-bromo-4-(3-chloropropoxy)-1-methylbenzene and 2-bromo-4-(3-bromopropoxy)-1-methylbenzene in 7:3 ratio as a clear viscous oil (1.3 g). .sup.1H NMR (500 MHz, CHLOROFORM-d) 7.16-7.12 (m, 2H), 6.79 (dd, J=8.4, 2.6 Hz, 1H), 4.10 (t, J=5.7 Hz, 2H), 3.75 (t, J=6.3 Hz, 2H), 2.35 (s, 3H), 2.28-2.18 (m, 2H).

(11) n-Butyllithium (0.442 mL, 1.106 mmol) in hexanes was added to a cold (78 C.) stirred solution of 1-bromo-3-(3-chloropropoxy)-2-methylbenzene (0.265 g, 1.005 mmol) in THF (3 mL) and the mixture was stirred at 78 C. for 15 min. A solution of triisopropyl borate (0.277 mL, 1.207 mmol) in THF (1 mL) was then added, and the mixture was stirred at 78 C. for 2 h and then allowed to warm to 0 C. The reaction mixture was evaporated to dryness under reduced pressure to afford crude isopropyl (3-(3-chloropropoxy)-2-methylphenyl)boronate (0.23 g) which was dissolved in dioxane (5 ml) and added 6N HCl (5 mL), and the mixture was heated at 65 C. for 1 h. The reaction mixture was evaporated to dryness and azeotroped with toluene to afford crude (3-(3-chloropropoxy)-2-methylphenyl)boronic acid (0.195 g, 0.853 mmol, 85% yield) as a light brown semi-solid which was used in the next step without further purification.

(12) A mixture of (3-(3-chloropropoxy)-2-methylphenyl)boronic acid (0.195 g, 0.853 mmol) and 2-bromo-4-(3-chloropropoxy)-1-methylbenzene/2-bromo-4-(3-bromopropoxy)-1-methylbenzene (0.225 g) in THF (6 mL)/dioxane (2 mL) and 0.5 M aq potassium phosphate, tribasic (5.12 mL, 2.56 mmol) was stirred under N.sub.2 sparging for 15 min. 2nd gen. XPhos precatalyst (0.020 g, 0.026 mmol) was then added to the mixture, and sparging was continued for another 10 min. The reaction mixture was stirred at rt under N.sub.2 for 16 h, and diluted with EtOAc, washed with water, brine, dried (Na.sub.2SO.sub.4) and concentrated. The crude isolate was purified by silica gel chromatography (10-30% EtOAc-hex) to yield a mixture of 3,5-bis(3-chloropropoxy)-2,2-dimethyl-1,1-biphenyl and 3-chloropropoxy-5-bromopropoxy-2,2-dimethyl-1,1-biphenyl (0.276 g) which was used in the next step as a mixture. .sup.1H NMR (400 MHz, CHLOROFORM-d) 7.20 (d, J=7.5 Hz, 1H), 7.16 (d, J=2.8 Hz, 1H), 7.14-7.12 (m, 1H), 6.88 (d, J=7.8 Hz, 1H), 6.82 (dd, J=11.2, 2.6 Hz, 1H), 6.70 (d, J=2.8 Hz, 1H), 4.15-4.06 (m, 4H), 3.82-3.73 (m, 4H), 2.35 (s, 3H), 2.34-2.27 (m, 2H), 2.27-2.23 (m, 2H), 2.01 (s, 3H).

(13) The following preparative HPLC method was used for the purification of Examples 1001 to 1004:

(14) Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 5-40% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation.

(15) The following two analytical LC-MS conditions were used to determine the final purity:

(16) LC-MS conditions-1: Column: Waters Acquity UPLC BEH C18, 2.150 mm, 1.7-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm.

(17) LC-MS conditions-2: Column: Waters Acquity UPLC BEH C18, 2.150 mm, 1.7-m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm.

Example 1001: 2,2-((((2-chloro-2-methyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(3-hydroxypyrrolidine-1,3-diyl))diacetic acid

(18) ##STR00009##

(19) A stirred mixture of 2-chloro-3,3-bis(3-chloropropoxy)-2-methyl-1,1-biphenyl (27.6 mg, 0.071 mmol), ethyl 2-(3-hydroxypyrrolidin-3-yl)acetate, TFA (45 mg, 0.157 mmol), potassium carbonate (49.2 mg, 0.356 mmol) and sodium iodide (10.67 mg, 0.071 mmol) in DMF (2 mL) was heated at 65 C. overnight. The reaction mixture was cooled and diluted with EtOAc, washed with water, brine, dried (MgSO.sub.4) and concentrated to afford diethyl 2,2-(1,1-(((2-chloro-2-methyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(3-hydroxypyrrolidine-3,1-diyl))diacetate (55 mg) as a clear oil which was saponified (LiOH.H.sub.2O, THF-MeOHH.sub.2O) and purified by prep. HPLC to afford 2,2-((((2-chloro-2-methyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(3-hydroxypyrrolidine-1,3-diyl))diacetic acid. LC-MS (conditions-1): R.sub.t=1.455 min, m/z 605.1 [M+H].sup.+

Example 1002: 1,1-(((2-chloro-2-methyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(4-hydroxypiperidine-4-carboxylic acid)

(20) ##STR00010##

(21) A stirred mixture of 2-chloro-3,3-bis(3-chloropropoxy)-2-methyl-1,1-biphenyl (39.6 mg, 0.102 mmol), methyl 4-hydroxypiperidine-4-carboxylate (35.8 mg, 0.225 mmol), potassium carbonate (70.6 mg, 0.511 mmol) and sodium iodide (15.31 mg, 0.102 mmol) in DMF (2 mL) was heated at 65 C. overnight. The reaction mixture was cooled and diluted with EtOAc, washed with water, brine, dried (MgSO.sub.4), concentrated to afford dimethyl 1,1-(((2-chloro-2-methyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(4-hydroxypiperidine-4-carboxylate) (59 mg) as a clear oil which was saponified (LiOH.H.sub.2O, THF-MeOHH.sub.2O) and purified by prep. HPLC to afford 1,1-(((2-chloro-2-methyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(4-hydroxypiperidine-4-carboxylic acid). LC-MS (conditions-1): R.sub.t=1.059 min, m/z 605.10 [M+H].sup.+

Example 1003: (2S,2S,4R,4R)-1,1-(((2-chloro-2-methyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(4-hydroxypyrrolidine-2-carboxylic acid)

(22) ##STR00011##

(23) A stirred mixture of 2-chloro-3,3-bis(3-chloropropoxy)-2-methyl-1,1-biphenyl (36.6 mg, 0.094 mmol), (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate, HCl (44.6 mg, 0.245 mmol), potassium carbonate (65.2 mg, 0.472 mmol) and sodium iodide (14.15 mg, 0.094 mmol) in DMF (1 mL) was heated at 65 C. overnight. The reaction mixture was cooled and diluted with EtOAc, washed with water, brine, dried (MgSO.sub.4) and concentrated to afford (2S,2S,4R,4R)-dimethyl 1,1-(((2-chloro-2-methyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(4-hydroxypyrrolidine-2-carboxylate) (53 mg) as a clear oil which was saponified (LiOH.H.sub.2O, THF-MeOHH.sub.2O) and purified by prep. HPLC to afford (2S,2S,4R,4R)-1,1-(((2-chloro-2-methyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(4-hydroxypyrrolidine-2-carboxylic acid). LC-MS (conditions-1): R.sub.t=1.008 min, m/z 577.1 [M+H].sup.+

Example 1004: (3R,3R)-1,1-(((2,6-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol)

(24) ##STR00012##

(25) A stirred mixture of 3,5-bis(3-chloropropoxy)-2,2-dimethyl-1,1-biphenyl/3-chloropropoxy-5-bromopropoxy-2,2-dimethyl-1,1-biphenyl (0.050 g, 0.136 mmol, based on Cl isomer), (R)-pyrrolidin-3-ol, HCl (0.050 g, 0.408 mmol), potassium carbonate (0.113 g, 0.817 mmol) and sodium iodide (0.041 g, 0.272 mmol) in DMF (2 mL) was heated at 75 C. for 16 h. The reaction mixture was cooled, diluted with EtOAc, washed with water, brine, dried (MgSO.sub.4), concentrated and purified by prep. HPLC to afford (3R,3R)-1,1-(((2,6-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol). LC-MS (conditions-1): R.sub.t=1.201 min, m/z 469.2 [M+H].sup.+

(26) Examples 2001 to 2131 were prepared as described below, and the HPLC LC/MS conditions employed for these examples were listed below:

(27) LC/MS Condition A:

(28) Column=Waters Aquity UPLC BEH C18, 2.150 mm, 1.7 m

(29) Start % B=2; Final % B=98

(30) Gradient time=1.5 min; Stop time=2 or 2.5 min

(31) Flow Rate=0.8 mL/min; Wavelength=220 nm or 254 nm

(32) Solvent A=100% water/0.05% TFA

(33) Solvent B=100% ACN/0.05% TFA

(34) Oven temp.=40 C.

(35) LC/MS Condition B:

(36) Column=Phenomenex-Luna C18, 2.050 mm, 3 m

(37) Start % B=0; Final % B=100

(38) Gradient time=4 min; Stop time=5 or 6 min

(39) Flow Rate=0.8 mL/min; Wavelength=220 nm or 254 nm

(40) Solvent A=5% ACN/95% water/10 mM NH.sub.4OAc

(41) Solvent B=95% ACN/5% water/10 mM NH.sub.4OAc

(42) Oven temp.=40 C.

(43) LC/MS Condition C:

(44) Column=Phenomenex-Luna C18, 2.050 mm, 3 m

(45) Start % B=0; Final % B=100

(46) Gradient time=4 min; Stop time=5 or 6 min

(47) Flow Rate=0.8 mL/min; Wavelength=220 nm or 254 nm

(48) Solvent A=10% MeOH/90% H2O/0.1% TFA

(49) Solvent B=90% MeOH/10% H.sub.2O/0.1% TFA

(50) Oven temp.=40 C.

(51) LC/MS Condition D:

(52) Column=Waters Aquity UPLC BEH C18, 2.150 mm, 1.7 m

(53) Start % B=2; Final % B=98

(54) Gradient time=1.5 min; Stop time=1.6 min

(55) Flow Rate=0.8 mL/min; Wavelength=220 nm or 254 nm

(56) Solvent A=100% water/0.05% TFA

(57) Solvent B=100% ACN/0.05% TFA

(58) Oven temp.=50 C.

(59) LC/MS Condition E:

(60) Column=Waters Acquity UPLC BEH C18, 2.150 mm, 1.7-m

(61) Start % B=0; Final % B=100

(62) Gradient time=3 min; Stop time=3.75 min

(63) Flow rate=1.0 mL/min: Wavelength=220 nm

(64) Solvent A=5% ACN/95% water/10 mM NH.sub.4OAc

(65) Solvent B=95% ACN/5% water/10 mM NH.sub.4OAc

(66) Oven temp.=50 C.

(67) LC/MS Condition F:

(68) Column=Waters Acquity UPLC BEH C18, 2.150 mm, 1.7-m

(69) Start % B=0; Final % B=100

(70) Gradient time=3 min; Stop time=3.75 min

(71) Flow rate=1.0 mL/min: Wavelength=220 nm

(72) Solvent A=5% ACN/95% water/0.1% TFA

(73) Solvent B=95% ACN/5% water/0.1% TFA

(74) Oven temp.=50 C.

Intermediate: 1-bromo-3-(3-bromopropoxy)-2-methylbenzene

(75) ##STR00013##

(76) A magnetically stirred solution of 1,3-dibromopropane (61 g, 302 mmol) and 3-bromo-2-methylphenol (5.00 g, 26.7 mmol) in acetone (200 mL) is treated with potassium carbonate (9.8 g, 70.9 mmol). The mixture was stirred at rt for seven days. The solids were filtered and washed with acetone (800 mL), and the filtrate evap'd (evaporated) in vacuo and then on high vacuum to remove excess 1,3-dibromopropane. The crude liquid was applied to the head of a 330 g Teledyne Isco Silica Flash Column (some hexanes, very little DCM mixed with mostly hexanes used to apply) and purified on Biotage using a gradient from 100% hexanes to 100% CH.sub.2Cl.sub.2 over 10 col vols (column volumes). The fractions containing the product were evaporated in vacuo then dried on high vacuum to give 13.35 g (92%) of the pure title compound as a colorless liquid. .sup.1H NMR (400 MHz, CHLOROFORM-d) 7.18 (dd, J=8.0, 0.8 Hz, 1H), 7.02 (t, J=8.2 Hz, 1H), 6.81 (d, J=8.3 Hz, 1H), 4.11 (t, J=5.8 Hz, 2H), 3.64 (t, J=6.4 Hz, 2H), 2.36 (t, J=5.9 Hz, 2H), 2.33 (s, 3H).

Intermediate: 2-(3-(3-bromopropoxy)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

(77) ##STR00014##

(78) An oven dried 150 mL pressure bottle is charged with 1-bromo-3-(3-bromopropoxy)-2-methylbenzene (5.3 g, 17.21 mmol) (5.30 g, 17.2 mmol), 4,4,4,4,5,5,5,5-octamethyl-2,2-bi(1,3,2-dioxaborolane) (7.3 g, 28.7 mmol), and potassium acetate (5.3 g, 54.0 mmol). After adding dioxane (100 mL), argon was bubbled into the mixture for 10 min, and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (825 mg, 1.128 mmol) then added to the mixture. The reaction is sealed and heated in a 80 C. oil bath for 21 h. The reaction was treated with water (300 mL) and EtOAc (250 L), and filtered through diatomaceous earth (Celite) to remove some dark solids. The pad was washed with ethyl acetate (300 mL). The layers were partitioned. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated to a dark oily solid. The crude product dissolved in CH.sub.2Cl.sub.2/hexane was applied to the head of a 330 g Teledyne Isco Silica Flash Column and purified on Biotage using a gradient from 100% hexanes to 100% CH.sub.2Cl.sub.2 over 11 col vols. The fractions containing the product were evaporated in vacuo and dried on high vacuum to give 4.36 g (71%) of the pure title compound as a white solid. .sup.1H NMR (500 MHz, CHLOROFORM-d) 7.38 (d, J=7.3 Hz, 1H), 7.16 (t, J=7.8 Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 4.11 (t, J=5.7 Hz, 2H), 3.66 (t, J=6.5 Hz, 2H), 2.44 (s, 3H), 2.36 (quin, J=6.1 Hz, 2H), 1.37 (s, 12H).

Intermediate: (R)-1-(3-(3-bromo-2-methylphenoxy)propyl)pyrrolidin-3-ol

(79) ##STR00015##

(80) A magnetically stirred solution of 1-bromo-3-(3-bromopropoxy)-2-methylbenzene (3.00 g, 9.74 mmol) and (R)-pyrrolidin-3-ol, HCl (2.41 g, 19.50 mmol) in MeOH (40 mL) under N.sub.2 in a 150 mL pressure bottle was treated with Hunig's base (6 ml, 34.4 mmol), sealed, and placed in a 70 C. oil bath overnight. The solvent was evaporated and the residue was partitioned with EtOAc (250 mL) and sat. aq NaHCO.sub.3 (200 mL). The layers was separated, the organic layer washed with water (75 mL) and brine (50 mL). This first extract was dried over Na.sub.2SO.sub.4, filtered and evapd to give 2.81 g of the title compound. The non-brine aqueous layers were combined and again extracted with fresh EtOAc (250 mL). This was washed with 50 mL water, 50 mL brine, dried over Na.sub.2SO.sub.4 and evapd separately to give 180 mg of the pure title compound. .sup.1H NMR (500 MHz, CHLOROFORM-d) 7.20-7.14 (m, 1H), 7.01 (t, J=8.2 Hz, 1H), 6.79 (d, J=8.2 Hz, 1H), 4.38 (ddt, J=7.2, 4.9, 2.3 Hz, 1H), 4.04 (t, J=6.3 Hz, 2H), 2.96 (td, J=8.6, 5.2 Hz, 1H), 2.76 (d, J=10.1 Hz, 1H), 2.69 (t, J=7.4 Hz, 2H), 2.58 (dd, J=10.1, 5.2 Hz, 1H), 2.40-2.34 (m, 1H), 2.22 (dddd, J=13.8, 8.7, 7.1, 5.2 Hz, 1H), 2.10-1.99 (m, 2H), 1.87-1.73 (m, 1H). LC/MS Condition B: ret time (retention time) 2.53 min; m/e=314 (M+H).sup.+.

Intermediate: (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(81) ##STR00016##

(82) To a solution of 2-(3-(3-bromopropoxy)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.82 g, 5.13 mmol) and (R)-1-(3-(3-bromo-2-methylphenoxy)propyl)pyrrolidin-3-ol (1.74 g, 5.54 mmol) in THF (110 mL) was added aqueous potassium phosphate tribasic 0.5M (25.4 mL, 12.70 mmol) (degassed with N.sub.2 for 1 h before use) and then flushed with argon and added 2nd Generation XPhos Precatalyst (200 mg, 0.254 mmol). The resulting mixture was flushed with argon for a few min, sealed, and stirred at rt overnight. The mixture was partioned with CH.sub.2Cl.sub.2 (350 mL) and water (200 mL). The organic layer was washed with brine (100 mL), dried with Na.sub.2SO.sub.4, filtered, and evap'd in vacuo, and then dried 5 min on high vacuum to a weight of 3.3 g and immediately froze at 20 C. LCMS showed about 60-70% product. The product was dissolved in a total of 90 mL MeOH in a 100 mL round bottomed flask and used 1 mL for most of the reactions indicated below: LC/MS Condition A: ret time 1.32 min; m/e=462 (M+H).sup.+.

Intermediate: 3,3-bis(3-bromopropoxy)-2,2-dimethyl-1,1-biphenyl

(83) ##STR00017##

(84) To a solution of 2-(3-(3-bromopropoxy)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (600 mg, 1.690 mmol) and 1-bromo-3-(3-bromopropoxy)-2-methylbenzene (521 mg, 1.692 mmol) in anhydrous THF (40 mL) was added potassium phosphate tribasic 0.5 M (8.5 mL, 4.25 mmol). The reaction mixture was flushed well with argon, treated with 2.sup.nd generation xphos precatalyst (66 mg, 0.084 mmol). The mixture was flushed with argon again, securely capped and stirred at room temperature for 8 h. The reaction was diluted with dichloromethane (300 mL) and water (150 mL). The organic layer was washed with brine (1100 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness to give 600 mg (78%) of the crude title compound that was used without further purification.

(85) LC/MS condition B: ret time=4.45 min; m/e=457 (M+H).sup.+

Intermediate: (2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)dimethanol

(86) ##STR00018##

(87) To a solution of (2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (5.0 g, 20.15 mmol) and (3-bromo-2-methylphenyl)methanol (4.05 g, 20.15 mmol) in THF (350 mL) was added potassium phosphate tribasic 0.5 M (100 mL, 50.0 mmol). The reaction mixture was flushed well with argon, treated with 2.sup.nd generation xphos precatalyst (420 mg, 0.534 mmol). The mixture was flushed with argon again and stirred at rt overnight. The mixture was diluted with dichloromethane (600 mL) and water (75 mL), and the organic layer was drained off. The water layer was extracted with dichloromethane (2150 mL). The organic layers were combined, dried over Na.sub.2SO.sub.4/MgSO.sub.4, filtered and evaporated to dryness. The crude residue was dissolved in dichloromethane (35 mL) and the white precipitate was collected by filtration to give 3.58 g (73%) of the pure title compound as a white solid.

(88) .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.39 (d, J=7.2 Hz, 2H), 7.22 (t, J=7.6 Hz, 2H), 6.97-6.92 (m, 2H), 5.11 (t, J=5.4 Hz, 2H), 4.55 (d, J=5.3 Hz, 4H), 1.90 (s, 6H).

Intermediate: 4,4-(((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-hydroxybenzaldehyde)

(89) ##STR00019##

(90) To a magnetically stirred ice cold mixture of (2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)dimethanol (2.1 g, 8.67 mmol), 5-chloro-2,4-dihydroxybenzaldehyde (3.1 g, 17.96 mmol), and triphenylphosphine (5.0 g, 19.06 mmol) in THF (150 mL) under continuos argon flush is slowly added over 35 min DIAD (3.6 mL, 18.52 mmol). After the addition was complete, the cooling bath is removed and the reaction flask was securely capped and the mixture allowed to stir overnight at room temperature. The solvent was removed in vacuo, and the residue suspended in dichloromethane (30 mL) and evaporated to dryness. Ice cold THF (25 mL) was added to the residue which was then placed in a 20 C. freezer for 15 min, and during which time much solid precipitated out. The solid was collected by filtration to give 3.46 g (72%) of the pure title compound as a white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 10.04 (s, 2H), 7.72 (s, 2H), 7.53 (d, J=8.7 Hz, 2H), 7.33 (t, J=7.6 Hz, 2H), 7.17-7.11 (m, 2H), 6.88 (s, 2H), 5.34 (s, 4H), 2.02 (s, 6H).

Intermediate: 5,5-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(4-chloro-6-formyl-3,1-phenylene))bis(oxy))bis(methylene))dinicotinonitrile

(91) ##STR00020##

(92) To a rapidly stirred solution of 4,4-(((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-hydroxybenzaldehyde) (1.25 g, 2.267 mmol), and 5-(chloromethyl)nicotinonitrile (0.866 g, 5.68 mmol) in anhydrous DMF (8 mL) was added cesium carbonate (1.87 g, 5.74 mmol), and sodium iodide (77 mg, 0.514 mmol). The reaction mixture was flushed well with argon, securely capped, and placed in a 75 C. oil bath with good magnetic stirring for 2 h 45 min. The reaction mixture was poured into ice water and the resulting yellow precipitate was collected by filtration to give 1.47 g (83%) of the pure title compound as a yellow solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 10.24 (s, 2H), 9.05-9.03 (m, 4H), 8.56 (t, J=2.0 Hz, 2H), 7.74 (s, 2H), 7.56 (d, J=7.0 Hz, 2H), 7.34 (t, J=7.6 Hz, 2H), 7.30 (s, 2H), 7.17 (d, J=6.9 Hz, 2H), 5.50 (s, 4H), 5.48-5.42 (m, 4H), 2.05 (s, 6H).

Intermediate: 4,4-(((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-methoxybenzaldehyde)

(93) ##STR00021##

(94) To a rapidly stirred solution of 4,4-(((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-hydroxybenzaldehyde) (250 mg, 0.453 mmol) in DMF (2.0 mL) was added cesium carbonate (370 mg, 1.136 mmol), followed by iodomethane (85 L, 1.365 mmol). The reaction mixture was flushed briefly with N.sub.2, securely capped and stirred at room temp overnight. The mixture was diluted with dichloromethane (225 mL) and water (25 mL). The organic layer was washed with water (520 mL), brine (120 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness. The crude residue was dissolved in dichloromethane (25 mL), applied to the head of a 80 g Teledyne Isco Silica Flash Column and purified on Biotage using a gradient from 100% dichloromethane to 15% ethyl acetate/dichloromethane over 12 column volumes. The fractions containing the product were evaporated in vacuo and then dried on high vacuum to give 187.6 mg (71%) of the pure title compound as a white solid. .sup.1H NMR (500 MHz, CHLOROFORM-d) 10.29 (s, 2H), 7.90 (s, 2H), 7.53 (d, J=6.9 Hz, 2H), 7.33 (t, J=7.6 Hz, 2H), 7.20 (dd, J=7.6, 1.1 Hz, 2H), 6.63 (s, 2H), 5.29 (s, 4H), 3.96 (s, 6H), 2.10 (s, 6H).

Example 2001: (R)-1-(4-(3-((3-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)piperazin-1-yl)ethan-1-one

(95) ##STR00022##

(96) To a reaction vial containing 1-acetylpiperazine (40 mg, 0.312 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) dissolved in methanol (1.0 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 18-36 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-65% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (10.9 mg, 47%). LC/MS Condition E: ret time 1.46 min; m/e=510 (M+H).sup.+; LC/MS Condition F: ret time 1.16 min; m/e=510 (M+H).sup.+.

Example 2002: (R)-1-(3-((3-(3-(3-(dimethylamino)azetidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(97) ##STR00023##

(98) To a reaction vial containing 3-(dimethylamino)azetidine dihydrochloride (60 mg, 0.347 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) dissolved in methanol (1.0 mL) and N,N-diisopropylethylamine (150 L, 0.859 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 18-36 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-50% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (15.5 mg, 74%). LC/MS Condition E: ret time 1.23 min; m/e=482 (M+H).sup.+; LC/MS Condition F: ret time 1.1 min; m/e=482 (M+H).sup.+.

Example 2003: (3R)-1-(3-((3-(3-(3-(hydroxymethyl)piperidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(99) ##STR00024##

(100) To a reaction vial containing 3-piperidinemethanol (34.1 L, 0.304 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) dissolved in methanol (1.0 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 18-36 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-50% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound as a mixture of diastereomers: (11.8 mg, 55%). LC/MS Condition E: ret time 1.2 min; m/e=497 (M+H).sup.+; LC/MS Condition F: ret time 1.2 min; m/e=497 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.18 (t, J=7.9 Hz, 2H), 6.93 (d, J=8.1 Hz, 2H), 6.64 (d, J=7.7 Hz, 2H), 4.22 (br s, 1H), 4.05 (br d, J=8.4 Hz, 4H), 3.29 (br dd, J=10.6, 5.1 Hz, 1H), 3.25-3.19 (m, 1H), 2.93 (br s, 1H), 2.81 (br s, 2H), 2.75-2.62 (m, 3H), 2.60-2.55 (m, 1H), 2.49-2.41 (m, 1H), 2.07-1.88 (m, 8H), 1.83 (s, 6H), 1.79-1.68 (m, 1H), 1.62 (br d, J=9.2 Hz, 4H), 1.46 (br d, J=11.7 Hz, 1H), 0.91 (br d, J=9.9 Hz, 1H).

Example 2004: (R)-1-(3-((3-(3-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(101) ##STR00025##

(102) To a reaction vial containing 3-piperidinemethanol (34.1 L, 0.304 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) dissolved in methanol (1.0 mL) and N,N-diisopropylethylamine (100 L, 0.573 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 18-36 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 30-70% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (23.5 mg, 94%). LC/MS Condition E: ret time 1.64 min; m/e=575 (M+H).sup.+. LC/MS Condition F: ret time 1.31 min; m/e=575 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.17 (td, J=7.7, 4.4 Hz, 2H), 6.94 (dd, J=8.4, 4.4 Hz, 2H), 6.69-6.61 (m, 4H), 4.21 (br s, 1H), 4.13-3.97 (m, 4H), 3.70 (d, J=5.1 Hz, 6H), 3.50 (s, 2H), 2.81-2.69 (m, 3H), 2.69-2.59 (m, 6H), 2.42 (br s, 1H), 2.07-1.97 (m, 3H), 1.96-1.88 (m, 4H), 1.84 (d, J=6.6 Hz, 6H), 1.56 (br s, 1H)

Example 2005: (R)-1-(3-((2,2-dimethyl-3-(3-((2-morpholinoethyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(103) ##STR00026##

(104) To a reaction vial containing 4-(2-aminoethyl)morpholine (85 L, 0.646 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) dissolved in methanol (1.0 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 18-36 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-55% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (21.4 mg, 96%). LC/MS Condition E: ret time 1.17 min; m/e=512 (M+H).sup.+. LC/MS Condition F: ret time 1.07 min; m/e=512 (M+H).sup.+.

Example 2006: (R)-1-(3-((2,2-dimethyl-3-(3-((pyridin-4-ylmethyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(105) ##STR00027##

(106) To a reaction vial containing added pyridin-4-ylmethanamine (66 mg, 0.610 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) dissolved in methanol (1.0 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 18-36 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-60% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (10.0 mg, 46%). LC/MS Condition E: ret time 1.32 min; m/e=490 (M+H).sup.+. LC/MS Condition F: ret time 1.08 min; m/e=490 (M+H).sup.+.

Example 2007: (R)-1-(3-((3-(3-((2-(dimethylamino)ethyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(107) ##STR00028##

(108) To a reaction vial containing N,N-dimethylethylenediamine (57 L, 0.522 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) dissolved in methanol (1.0 mL) and N,N-diisopropylethylamine (57 L, 0.522 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 18-36 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 40-80% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (12.8 mg, 61%). LC/MS Condition E: ret time 1.20 min; m/e=470 (M+H).sup.+. LC/MS Condition F: ret time 1.08 min; m/e=470 (M+H).sup.+.

Example 2008: (R)-1-(3-((3-(3-((2-(1H-pyrazol-1-yl)ethyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(109) ##STR00029##

(110) To a reaction vial containing 2-(1H-pyrazol-1-yl)ethanamine (60 mg, 0.540 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) dissolved in methanol (1.0 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 18-36 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 40-80% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (12.5 mg, 59%). LC/MS Condition E: ret time 1.29 min; m/e=493 (M+H).sup.+. LC/MS Condition F: ret time 1.23 min; m/e=493 (M+H).sup.+.

Example 2009: (R)-1-(3-((2,2-dimethyl-3-(3-((2-(3-methyl-1H-pyrazol-1-yl)ethyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(111) ##STR00030##

(112) To a reaction vial containing 3-(3-methyl-1H-pyrazol-1-yl)propan-1-amine (75 mg, 0.539 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) dissolved in methanol (1.0 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 18-36 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-50% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (14.9 mg, 63%). LC/MS Condition E: ret time 1.28 min; m/e=521 (M+H).sup.+. LC/MS Condition F: ret time 1.28 min; m/e=521 (M+H).sup.+.

Example 2010: (R)-1-(3-((2,2-dimethyl-3-(3-((2-(methylsulfonyl)ethyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(113) ##STR00031##

(114) To a reaction vial containing 2-(methylsulfonyl)ethanamine, 1.0 HCl (75 mg, 0.470 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) dissolved in methanol (1.0 mL) and N,N-diisopropylethylamine (100 L, 0.573 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 18-36 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-50% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (15.9 mg, 48%). LC/MS Condition E: ret time 1.32 min; m/e=505 (M+H).sup.+. LC/MS Condition F: ret time 1.14 min; m/e=505 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.21 (t, J=7.9 Hz, 2H), 6.95 (d, J=8.4 Hz, 2H), 6.66 (d, J=7.3 Hz, 2H), 4.45 (br s, 1H), 4.09 (br dd, J=9.5, 6.2 Hz, 4H), 3.58-3.49 (m, 2H), 3.47-3.32 (m, 9H), 3.27-3.15 (m, 3H), 3.13 (s, 3H), 2.22-2.06 (m, 4H), 1.85 (s, 6H)

Example 2011: (S)-3-((3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)amino)propane-1,2-diol

(115) ##STR00032##

(116) To a reaction vial containing (S)-3-aminopropane-1,2-diol, 1.0 HCl (58 mg, 0.455 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) dissolved in methanol (1.0 mL) and N,N-diisopropylethylamine (100 L, 0.573 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 18-36 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-50% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (19.0 mg, 92%). LC/MS Condition E: ret time 1.08 min; m/e=473 (M+H).sup.+. LC/MS Condition F: ret time 1.12 min; m/e=473 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.18 (td, J=7.8, 4.2 Hz, 2H), 6.93 (dd, J=8.1, 3.7 Hz, 2H), 6.64 (t, J=7.3 Hz, 2H), 4.19 (br s, 1H), 4.12-3.99 (m, 4H), 3.61 (br s, 1H), 3.39-3.26 (m, 3H), 2.86 (br t, J=6.8 Hz, 2H), 2.78 (dd, J=12.1, 3.7 Hz, 1H), 2.72 (br dd, J=15.0, 6.2 Hz, 1H), 2.63-2.56 (m, 3H), 2.55 (s, 2H), 2.44 (br d, J=6.6 Hz, 1H), 2.33 (br d, J=6.2 Hz, 1H), 2.03-1.94 (m, 3H), 1.83 (d, J=3.3 Hz, 6H), 1.61-1.47 (m, 1H)

Example 2012: (3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)-L-serine

(117) ##STR00033##

(118) To a reaction vial containing L-serine (55 mg, 0.523 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) dissolved in methanol (1.0 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 18-36 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-50% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (12.3 mg, 54%). LC/MS Condition E: ret time 1.10 min; m/e=487 (M+H).sup.+. LC/MS Condition F: ret time 1.11 min; m/e=487 (M+H).sup.+.

Example 2013: (S)-3-hydroxy-2-((3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)amino)-2-methylpropanoic acid

(119) ##STR00034##

(120) To a reaction vial containing 2-methyl-L-serine (62 mg, 0.520 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) dissolved in methanol (1.0 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 18-36 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-60% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (9.0 mg, 40%). LC/MS Condition E: ret time 1.12 min; m/e=501 (M+H).sup.+. LC/MS Condition F: ret time 1.15 min; m/e=501 (M+H).sup.+.

Example 2014: (R)-1-(3-((3-(3-((2-hydroxyethyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(121) ##STR00035##

(122) To a reaction vial containing ethanolamine (32 mg, 0.524 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) dissolved in methanol (1.0 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 18-36 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-60% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (22.4 mg, quantitative yield). LC/MS Condition E: ret time 1.09 min; m/e=443 (M+H).sup.+. LC/MS Condition F: ret time 1.13 min; m/e=443 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.23-7.13 (m, 2H), 6.94 (dd, J=8.3, 3.9 Hz, 2H), 6.64 (t, J=7.9 Hz, 2H), 4.19 (br s, 1H), 4.14-3.98 (m, 4H), 3.53 (t, J=5.3 Hz, 2H), 2.87 (br t, J=7.0 Hz, 2H), 2.80-2.66 (m, 3H), 2.63-2.54 (m, 5H), 2.44 (br d, J=8.1 Hz, 1H), 2.33 (br d, J=6.2 Hz, 1H), 1.98 (br s, 3H), 1.83 (d, J=3.3 Hz, 6H), 1.54 (br d, J=3.7 Hz, 1H)

Example 2015: 3-((3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)(methyl)amino)propane-1,2-diol, 2.0 TFA

(123) ##STR00036##

(124) To a reaction vial containing 3-methylamino-1,2-propanediol (30 l, 0.311 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) dissolved in methanol (1.0 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 18-36 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% TFA; Mobile Phase B: 95:5 acetonitrile: water with 0.1% TFA; Gradient: 15-55% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound as a TFA salt and as a mixture of diastereomers: (29.9 mg, 98%). LC/MS Condition E: ret time 1.11 min; m/e=487 (M+H).sup.+. LC/MS Condition F: ret time 1.10 min; m/e=487 (M+H).sup.+.

Example 2016: 2-hydroxy-3-((3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)amino)propanoic acid

(125) ##STR00037##

(126) To a reaction vial containing DL-isoserine (55 mg, 0.523 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) dissolved in methanol (1.0 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 18-36 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-50% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (7.3 mg, 34%). LC/MS Condition E: ret time 1.10 min; m/e=487 (M+H).sup.+. LC/MS Condition F: ret time 1.13 min; m/e=487 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.23-7.12 (m, 2H), 6.93 (br d, J=8.1 Hz, 2H), 6.65 (dd, J=12.7, 7.5 Hz, 2H), 4.21 (br s, 1H), 4.06 (br dd, J=17.2, 8.1 Hz, 4H), 3.71 (br t, J=6.6 Hz, 1H), 3.11 (br t, J=7.2 Hz, 2H), 2.97 (br d, J=3.3 Hz, 2H), 2.76 (br dd, J=15.0, 9.5 Hz, 1H), 2.71-2.60 (m, 3H), 2.42 (br d, J=8.8 Hz, 1H), 2.14-2.04 (m, 2H), 2.04-1.97 (m, 1H), 1.95-1.90 (m, 3H), 1.84 (d, J=6.6 Hz, 6H), 1.57 (br s, 1H)

Example 2017: (R)-1-(3-((3-(3-(((1r,4r)-4-hydroxycyclohexyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(127) ##STR00038##

(128) To a reaction vial containing trans-4-aminocyclohexanol hydrochloride (80 mg, 0.528 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) dissolved in methanol (1.0 mL) and N,N-diisopropylethylamine (125 L, 0.716 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 18-36 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-50% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (15.0 mg, 70%). LC/MS Condition E: ret time 1.13 min; m/e=497 (M+H).sup.+. LC/MS Condition F: ret time 1.16 min; m/e=497 (M+H).sup.+.

Example 2018: N((R)-1-(3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-yl)acetamide

(129) ##STR00039##

(130) To a reaction vial containing (3R)-(+)-3-acetamidopyrrolidine (40 mg, 0.312 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) dissolved in methanol (1.0 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 18-36 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-55% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (18.0 mg, 80%). LC/MS Condition E: ret time 1.22 min; m/e=510 (M+H).sup.+. LC/MS Condition F: ret time 1.15 min; m/e=510 (M+H).sup.+.

Example 2019: 1-(3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)piperidine-3-carboxamide

(131) ##STR00040##

(132) To a reaction vial containing nipecotamide (40 mg, 0.312 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) dissolved in methanol (1.0 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol). The reaction was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 18-36 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 45-85% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (11.4 mg, 51%). LC/MS Condition E: ret time 1.24 min; m/e=510 (M+H).sup.+. LC/MS Condition F: ret time 1.14 min; m/e=510 (M+H).sup.+.

Example 2020: (R)-1-(3-((3-(3-((3-(1H-imidazol-1-yl)propyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(133) ##STR00041##

(134) To a reaction vial containing 1-(3-aminopropyl)imidazole (80 l, 0.670 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) dissolved in methanol (1.0 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 18-36 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-55% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (19.0 mg, 86%). LC/MS Condition E: ret time 1.15 min; m/e=507 (M+H).sup.+. LC/MS Condition F: ret time 1.07 min; m/e=507 (M+H).sup.+.

Example 2021: (R)-1-(3-((2,2-dimethyl-3-(3-((3-morpholinopropyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(135) ##STR00042##

(136) To a reaction vial containing N-(3-aminopropyl)morpholine (95 l, 0.646 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) dissolved in methanol (1.0 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 18-36 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-55% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (21.3 mg, 94%). LC/MS Condition E: ret time 1.17 min; m/e=526 (M+H).sup.+. LC/MS Condition F: ret time 1.07 min; m/e=526 (M+H).sup.+.

Example 2022: (R)-1-(3-((2,2-dimethyl-3-(3-((2-(pyridin-3-yl)ethyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(137) ##STR00043##

(138) To a reaction vial containing 3-(2-aminoethyl)pyridine (76 l, 0.647 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) dissolved in methanol (1.0 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 18-36 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-55% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (16.2 mg, 72%). LC/MS Condition E: ret time 1.22 min; m/e=504 (M+H).sup.+. LC/MS Condition F: ret time 1.08 min; m/e=504 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.47 (s, 1H), 8.43 (d, J=3.7 Hz, 1H), 7.67 (br d, J=8.1 Hz, 1H), 7.32 (dd, J=7.7, 4.8 Hz, 1H), 7.24-7.14 (m, 2H), 6.93 (d, J=8.4 Hz, 2H), 6.64 (dd, J=10.3, 8.1 Hz, 2H), 4.22 (br s, 1H), 4.06 (br dd, J=14.3, 8.1 Hz, 4H), 3.05-2.97 (m, 2H), 2.93 (br t, J=7.0 Hz, 2H), 2.86-2.76 (m, 3H), 2.65 (br s, 3H), 2.44 (br d, J=9.9 Hz, 1H), 2.05-1.96 (m, 3H), 1.96-1.89 (m, 3H), 1.82 (s, 6H), 1.57 (br s, 1H)

Example 2023: N,N-diethyl-1-(3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)piperidine-3-carboxamide

(139) ##STR00044##

(140) To a reaction vial containing N,N-diethylnipecotamide (60 mg, 0.326 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) dissolved in methanol (1.0 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 18-36 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-55% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound as a mixture of diastereomers: (19.9 mg, 81%). LC/MS Condition E: ret time 1.42 min; m/e=566 (M+H).sup.+. LC/MS Condition F: ret time 1.37 min; m/e=566 (M+H).sup.+.

Example 2024: (R)-1-(3-((2,2-dimethyl-3-(3-((pyridin-2-ylmethyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(141) ##STR00045##

(142) To a reaction vial containing 2-(aminomethyl)pyridine (61 L, 0.587 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) dissolved in methanol (1.0 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 18-36 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 45-85% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (14.9 mg, 65%). LC/MS Condition E: ret time 1.28 min; m/e=490 (M+H).sup.+. LC/MS Condition F: ret time 1.25 min; m/e=490 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.52 (d, J=4.4 Hz, 1H), 7.77 (t, J=7.7 Hz, 1H), 7.45 (d, J=7.3 Hz, 1H), 7.33-7.26 (m, 1H), 7.18 (t, J=7.9 Hz, 2H), 6.94 (br d, J=8.8 Hz, 2H), 6.64 (dd, J=7.2, 4.6 Hz, 2H), 4.23 (br s, 1H), 4.15-3.97 (m, 6H), 2.90 (br t, J=7.2 Hz, 2H), 2.81 (br s, 1H), 2.76-2.65 (m, 3H), 2.58 (br s, 1H), 2.07-1.98 (m, 3H), 1.98-1.93 (m, 2H), 1.91 (s, 2H), 1.83 (s, 3H), 1.79 (s, 3H), 1.59 (br s, 1H)

Example 2025: (3R)-1-(3-((3-(3-(2-(hydroxymethyl)piperidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(143) ##STR00046##

(144) To a reaction vial containing 2-piperidinemethanol (35 mg, 0.304 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) dissolved in methanol (1.0 mL) and N,N-diisopropylethylamine (50 L, 0.286 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 18-36 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 45-85% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound as a mixture of diastereomers: (28.0 mg, quantitative yield). LC/MS Condition E: ret time 1.22 min; m/e=497 (M+H).sup.+. LC/MS Condition F: ret time 1.24 min; m/e=497 (M+H).sup.+.

Example 2026: ((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(piperidine-1,3-diyl))dimethanol, 2.0 TFA

(145) ##STR00047##

(146) To a reaction vial containing 3,3-bis(3-bromopropoxy)-2,2-dimethyl-1,1-biphenyl (20 mg, 0.044 mmol) was added 3-piperidinemethanol (103 L, 0.920 mmol), DMF (0.5 mL) and MeOH (0.5 mL) and N,N-diisopropylethylamine (35 L, 0.200 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 18 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.1% TFA; Gradient: 15-55% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound as a TFA salt and as a mixture of diastereomers: (32.0 mg, 96%). LC/MS Condition E: ret time 1.29 min; m/e=525 (M+H).sup.+. LC/MS Condition F: ret time 1.25 min; m/e=525 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.21 (t, J=7.9 Hz, 2H), 6.96 (d, J=8.1 Hz, 2H), 6.66 (d, J=7.7 Hz, 2H), 4.09 (td, J=10.1, 5.1 Hz, 4H), 3.52 (br d, J=10.6 Hz, 4H), 3.33-3.21 (m, 6H), 2.84 (br d, J=11.0 Hz, 2H), 2.73-2.61 (m, 2H), 2.25-2.12 (m, 4H), 1.94-1.81 (m, 10H), 1.76-1.62 (m, 4H), 1.25-1.09 (m, 2H)

Example 2027: 2,2-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(azanediyl))bis(ethan-1-ol)

(147) ##STR00048##

(148) To a reaction vial containing 3,3-bis(3-bromopropoxy)-2,2-dimethyl-1,1-biphenyl (20 mg, 0.044 mmol) was added ethanolamine (55 mg, 0.900 mmol), DMF (0.5 mL) and MeOH (0.5 mL) and N,N-diisopropylethylamine (31 L, 0.177 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 18 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 5-45% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (17.9 mg, 98%). LC/MS Condition E: ret time 1.09 min; m/e=417 (M+H).sup.+. LC/MS Condition F: ret time 1.14 min; m/e=417 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.19 (t, J=7.9 Hz, 2H), 6.95 (d, J=8.1 Hz, 2H), 6.65 (d, J=7.3 Hz, 2H), 4.15-4.02 (m, 4H), 3.59 (t, J=5.3 Hz, 4H), 2.99 (br t, J=7.3 Hz, 4H), 2.91-2.86 (m, 4H), 2.10-1.99 (m, 4H), 1.84 (s, 6H)

Example 2028: 3,3-((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(N-(2-(pyridin-4-yl)ethyl)propan-1-amine)

(149) ##STR00049##

(150) To a reaction vial containing 3,3-bis(3-bromopropoxy)-2,2-dimethyl-1,1-biphenyl (20 mg, 0.044 mmol) was added 4-(2-aminoethyl)pyridine (106 l, 0.878 mmol), MeOH (0.5 mL) and N,N-diisopropylethylamine (31 L, 0.177 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 18 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-50% B over 22 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (22.1 mg, 85%). LC/MS Condition E: ret time 1.30 min; m/e=539 (M+H).sup.+. LC/MS Condition F: ret time 1.05 min; m/e=539 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.45 (br d, J=5.1 Hz, 4H), 7.26 (d, J=5.1 Hz, 4H), 7.19 (t, J=7.9 Hz, 2H), 6.93 (d, J=8.1 Hz, 2H), 6.64 (d, J=7.7 Hz, 2H), 4.06 (q, J=6.4 Hz, 4H), 3.00-2.91 (m, 4H), 2.90-2.85 (m, 4H), 2.80 (br t, J=7.5 Hz, 4H), 2.02-1.92 (m, 4H), 1.82 (s, 6H)

Example 2029: 4,4-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(azanediyl))bis(2-methylbutane-2,3-diol)

(151) ##STR00050##

(152) To a reaction vial containing 3,3-bis(3-bromopropoxy)-2,2-dimethyl-1,1-biphenyl (20 mg, 0.044 mmol) was added 1-amino-3-methyl-2,3-butanediol (105 mg, 0.881 mmol), MeOH (1.5 mL) and N,N-diisopropylethylamine (25 L, 0.143 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 18 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-50% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound as a mixture of diastereomers: (22.1 mg, 85%). LC/MS Condition E: ret time 1.11 min; m/e=533 (M+H).sup.+. LC/MS Condition F: ret time 1.43 min; m/e=533 (M+H).sup.+.

Example 2030: 3,3-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(methylazanediyl))bis(propan-1-ol)

(153) ##STR00051##

(154) To a reaction vial containing 3,3-bis(3-bromopropoxy)-2,2-dimethyl-1,1-biphenyl (20 mg, 0.044 mmol) was added 3-(methylamino)-1-propanol (80 mg, 0.898 mmol), MeOH (1.5 mL) and N,N-diisopropylethylamine (25 L, 0.143 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 18 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-50% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (20.9 mg, 100%). LC/MS Condition E: ret time 1.15 min; m/e=473 (M+H).sup.+. LC/MS Condition F: ret time 1.18 min; m/e=473 (M+H).sup.+.

Example 2031: (2S,2S)-3,3-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(methylazanediyl))bis(propane-1,2-diol)

(155) ##STR00052##

(156) To a reaction vial containing 3,3-bis(3-bromopropoxy)-2,2-dimethyl-1,1-biphenyl (20 mg, 0.044 mmol) was added (S)-3-(methylamino)propane-1,2-diol (100 mg, 0.951 mmol), MeOH (1.5 mL) and N,N-diisopropylethylamine (25 L, 0.143 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 18 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 5-45% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (22.5 mg, 100%). LC/MS Condition E: ret time 1.21 min; m/e=505 (M+H).sup.+. LC/MS Condition F: ret time 1.03 min; m/e=505 (M+H).sup.+.

Example 2032: (R)-1-(3-((3-(3-((2-(dimethylamino)ethyl)(methyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(157) ##STR00053##

(158) To a reaction vial containing N,N,N-trimethylethylenediamine (40 L, 0.313 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) dissolved in methanol (1.0 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 18-36 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 30-70% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (17.5 mg, 84%). LC/MS Condition E: ret time 1.12 min; m/e=484 (M+H).sup.+. LC/MS Condition F: ret time 1.06 min; m/e=484 (M+H).sup.+.

Example 2033: (3S,4R)-4-(hydroxymethyl)-1-(3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)piperidin-3-ol

(159) ##STR00054##

(160) To a reaction vial containing (3S,4R)-4-(hydroxymethyl)piperidin-3-ol, HCl (58 mg, 0.346 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (25 mg, 0.054 mmol) dissolved in methanol (2.0 mL) and N,N-diisopropylethylamine (80 L, 0.458 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 18-48 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 5-45% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (20.2 mg, 50%). LC/MS Condition E: ret time 1.07 min; m/e=513 (M+H).sup.+. LC/MS Condition F: ret time 1.12 min; m/e=513 (M+H).sup.+.

Example 2034: (R)-1-(3-((3-(3-((2-hydroxyethyl)(methyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(161) ##STR00055##

(162) To a reaction vial containing 2-(methylamino)ethanol (35 L, 0.436 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (29 mg, 0.063 mmol) dissolved in methanol (2.0 mL). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 70 C. sand bath with shaking for 24 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 5-45% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min, to give the pure title compound as a TFA salt: (17.3 mg, 40%). LC/MS Condition E: ret time 1.08 min; m/e=457 (M+H).sup.+. LC/MS Condition F: ret time 1.13 min; m/e=457 (M+H).sup.+.

Example 2035: (R)-1-(3-((2,2-dimethyl-3-(3-((2-(pyridin-4-yl)ethyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(163) ##STR00056##

(164) To a reaction vial containing 2-(pyridin-4-yl)ethanamine (64.4 mg, 0.527 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (29 mg, 0.063 mmol) dissolved in methanol (2.0 mL). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 70 C. sand bath with shaking for 72 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-50% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min, to give the pure title compound as a TFA salt: (4.9 mg, 10%). LC/MS Condition E: ret time 1.30 min; m/e=504 (M+H).sup.+. LC/MS Condition F: ret time 1.12 min; m/e=504 (M+H).sup.+.

Example 2036: (R)-4-(3-((3-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)-1-methylpiperazin-2-one

(165) ##STR00057##

(166) To a reaction vial containing 1-methylpiperazin-2-one, HCl (47.2 mg, 0.313 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (25 mg, 0.054 mmol) dissolved in methanol (1 mL). N,N-diisopropylethylamine (80 L, 0.458 mmol) was added and the reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 70 C. sand bath with shaking for 72 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-50% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min, to give the pure title compound as a TFA salt: (4.2 mg, 11%). LC/MS Condition E: ret time 1.36 min; m/e=496 (M+H).sup.+. LC/MS Condition F: ret time 1.13 min; m/e=496 (M+H).sup.+.

Example 2037: (S)-2-((3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)amino)-3-(pyridin-4-yl)propanoic acid

(167) ##STR00058##

(168) To a reaction vial containing (S)-2-amino-3-(pyridin-4-yl)propanoic acid (65 mg, 0.391 mmol) in MeOH (1.5 mL) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (29 mg, 0.063 mmol) dissolved in methanol (2.0 mL). N,N-diisopropylethylamine (90 L, 0.515 mmol) was added followed by DMF (0.2 mL) and water (0.15 mL). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 70 C. sand bath with shaking for 72 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-50% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min, to give the pure title compound as a TFA salt: (4.3 mg, 8%). LC/MS Condition E: ret time 1.13 min; m/e=548 (M+H).sup.+. LC/MS Condition F: ret time 1.18 min; m/e=548 (M+H).sup.+.

Example 2038: (R)-3-((3-((3-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)amino)propanamide

(169) ##STR00059##

(170) To a reaction vial containing 3-aminopropanamide, HCl (55 mg, 0.442 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) dissolved in methanol (1.0 mL) and N,N-diisopropylethylamine (90 L, 0.515 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 24 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-50% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. to give the pure title compound: (9.7 mg, 48%). LC/MS Condition E: ret time 1.11 min; m/e=470 (M+H).sup.+. LC/MS Condition F: ret time 1.124 min; m/e=470 (M+H).sup.+.

Example 2039: (2S,4R)-4-hydroxy-1-(3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidine-2-carboxylic acid

(171) ##STR00060##

(172) To a reaction vial containing (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid (35 mg, 0.267 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) dissolved in methanol (1.0 mL) and N,N-diisopropylethylamine (65 L, 0.372 mmol). Then DMF (0.2 mL) and water (0.18 mL) were added to the mixture. The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 24 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-50% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. to give the pure title compound: (7.4 mg, 33%). LC/MS Condition E: ret time 1.11 min; m/e=513 (M+H).sup.+. LC/MS Condition F: ret time 1.15 min; m/e=513 (M+H).sup.+.

Example 2040: (3R)-1-(3-((3-(3-((2-hydroxy-2-(pyridin-3-yl)ethyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(173) ##STR00061##

(174) To a reaction vial containing 2-amino-1-(pyridin-3-yl)ethanol, oxalic acid salt (70 mg, 0.307 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) dissolved in methanol (1.0 mL) and N,N-diisopropylethylamine (120 L, 0.687 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 24 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 5-40% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound as a TFA salt as a mixture of epimers: (4.1 mg, 10%). LC/MS Condition E: ret time 1.21 min; m/e=520 (M+H).sup.+.

(175) LC/MS Condition F: ret time 1.09 min; m/e=520 (M+H).sup.+.

Example 2041: (R)-1-(3-((2,2-dimethyl-3-(3-(phenethylamino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(176) ##STR00062##

(177) To a reaction vial containing 2-phenylethanamine (65 mg, 0.536 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) dissolved in methanol (1.0 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol). The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 24 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-60% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. to give the pure title compound: (20.7 mg, 93%). LC/MS Condition E: ret time 1.52 min; m/e=503 (M+H).sup.+. LC/MS Condition F: ret time 1.37 min; m/e=503 (M+H).sup.+.

Example 2042: (R)-1-(3-((3-(3-((3-hydroxypropyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(178) ##STR00063##

(179) A mixture of 3-aminopropan-1-ol (40 mg, 0.533 mmol), (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1.0 mL) and N,N-diisopropylethylamine (65 L, 0.372 mmol) was heated at 65 C. for 24 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 40-80% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. to give the pure title compound: (19.6 mg, 99%). LC/MS Condition E: ret time 1.11 min; m/e=457 (M+H).sup.+. LC/MS Condition F: ret time 1.16 min; m/e=457 (M+H).sup.+.

Example 2043: (R)-1-(3-((2,2-dimethyl-3-(3-((2-(1-methyl-1H-imidazol-4-yl)ethyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(180) ##STR00064##

(181) A mixture of 2-(1-methyl-1H-imidazol-4-yl)ethanamine (62 mg, 0.495 mmol), and (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1.0 mL) and N,N-diisopropylethylamine (60 L, 0.344 mmol) was heated at 70 C. for 24 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-50% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. to give the pure title compound: (20.4 mg, 92%). LC/MS Condition E: ret time 1.16 min; m/e=507 (M+H).sup.+. LC/MS Condition F: ret time 1.08 min; m/e=507 (M+H).sup.+.

Example 2044: (R)-1-(3-((2,2-dimethyl-3-(3-(((1-methylpiperidin-4-yl)methyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(182) ##STR00065##

(183) A mixture of (1-methylpiperidin-4-yl)methanamine (53.3 mg, 0.416 mmol) and (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1.0 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol) was heated at 70 C. for 24 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 5-45% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. to give the pure title compound: (15.8 mg, 70%). LC/MS Condition E: ret time 1.08 min; m/e=510 (M+H).sup.+. LC/MS Condition F: ret time 1.08 min; m/e=510 (M+H).sup.+.

Example 2045: (S)-2-hydroxy-3-((3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)amino)propanoic acid

(184) ##STR00066##

(185) A mixture of L-Isoserine (50 mg, 0.48 mmol) and (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1.0 mL), DMF (0.1 mL) and N,N-diisopropylethylamine (90 L, 0.515 mmol) was heated at 60-70 C. for 48 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 5-45% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. to give the pure title compound: (15.6 mg, 73%). LC/MS Condition E: ret time 1.09 min; m/e=487 (M+H).sup.+. LC/MS Condition F: ret time 1.14 min; m/e=487 (M+H).sup.+.

Example 2046: (R)-1-(3-((3-(3-((3-hydroxy-2,2-dimethylpropyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(186) ##STR00067##

(187) A mixture of 3-amino-2,2-dimethylpropan-1-ol (55 mg, 0.533 mmol) and (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1.0 mL) and N,N-diisopropylethylamine (50 L, 0.286 mmol) was heated at 70 C. for 24 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-50% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. to give the pure title compound: (23 mg, 97%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.26-7.13 (m, 2H), 6.93 (dd, J=8.1, 4.4 Hz, 2H), 6.67-6.60 (m, 2H), 4.21-4.17 (m, 1H), 4.11-4.00 (m, 4H), 3.20 (s, 2H), 2.84-2.68 (m, 3H), 2.63-2.54 (m, 5H), 2.47-2.43 (m, 1H), 2.37-2.33 (m, 1H), 2.03-1.88 (m, 5H), 1.83 (s, 3H), 1.82 (s, 3H), 1.59-1.50 (m, 1H), 0.83 (s, 6H). LC/MS Condition E: ret time 1.21 min; m/e=485 (M+H).sup.+. LC/MS Condition F: ret time 1.22 min; m/e=485 (M+H).sup.+.

Example 2047: (3R)-1-(3-((3-(3-((2-hydroxy-1-(pyridin-4-yl)ethyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(188) ##STR00068##

(189) A mixture of 2-amino-2-(pyridin-4-yl)ethanol, 2 HCl (77.7 mg, 0.368 mmol) and (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1.0 mL) and N,N-diisopropylethylamine (130 L, 0.744 mmol) was heated at 65-70 C. for 48 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-55% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. to give the pure title compound: (5.4 mg, 23%). LC/MS Condition E: ret time 1.44 min; m/e=520 (M+H).sup.+. LC/MS Condition F: ret time 1.05 min; m/e=520 (M+H).sup.+.

Example 2048: (R)N-(2-((3-((3-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)amino)ethyl)acetamide

(190) ##STR00069##

(191) A mixture of N-(2-aminoethyl)acetamide (56 mg, 0.548 mmol) and (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1.0 mL) and N,N-diisopropylethylamine (40 L, 0.229 mmol) was heated at 70 C. for 48 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-50% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound as a TFA salt: (26.1 mg, 85%). LC/MS Condition E: ret time 1.11 min; m/e=484 (M+H).sup.+; LC/MS Condition F: ret time 1.13 min; m/e=484 (M+H).sup.+.

Example 2049: (R)-1-(3-((2,2-dimethyl-3-(3-(methyl(pyridin-3-ylmethyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(192) ##STR00070##

(193) A mixture of N-methyl-1-(pyridin-3-yl)methanamine (38 mg, 0.311 mmol) and (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1.0 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol) was heated at 70 C. for 48 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-50% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound as a TFA salt: (15.8 mg, 41.4%). LC/MS Condition E: ret time 1.59 min; m/e=504 (M+H).sup.+. LC/MS Condition F: ret time 1.10 min; m/e=504 (M+H).sup.+.

Example 2050: (R)-1-(3-((2,2-dimethyl-3-(3-((pyridin-3-ylmethyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(194) ##STR00071##

(195) A mixture of pyridin-3-ylmethanamine (80 mg, 0.740 mmol) and (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1.0 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol) was heated at 65-70 C. for 48 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-50% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (11.9 mg, 55%). LC/MS Condition E: ret time 1.29 min; m/e=490 (M+H).sup.+. LC/MS Condition F: ret time 1.10 min; m/e=490 (M+H).sup.+.

Example 2051: (2S,4R)-4-hydroxy-1-(3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidine-2-carboxylic acid

(196) ##STR00072##

(197) To a reaction vial containing (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid (35 mg, 0.267 mmol) was added a solution of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) dissolved in methanol (1.0 mL) and N,N-diisopropylethylamine (65 L, 0.372 mmol). Then DMF (0.2 mL) and water (0.18 mL) were added to the mixture. The reaction mixture was briefly flushed with N.sub.2, securely capped, sonicated for 10 sec, and placed in a 65 C. sand bath with shaking for 24 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 40-80% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. to give the pure title compound: (21.7 mg, 97%). LC/MS Condition E: ret time 1.11 min; m/e=513 (M+H).sup.+; LC/MS Condition F: ret time 1.15 min; m/e=513 (M+H).sup.+.

Example 2052: (R)-3-((3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)amino)propane-1,2-diol

(198) ##STR00073##

(199) A mixture of (R)-3-aminopropane-1,2-diol, HCl (62.4 mg, 0.489 mmol) and (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1.0 mL) and N,N-diisopropylethylamine (170 L, 0.973 mmol) was heated at 65-70 C. for 48 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-50% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (20.2 mg, 98%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.18 (td, J=7.9, 3.3 Hz, 2H), 6.94 (dd, J=7.9, 5.3 Hz, 2H), 6.64 (dd, J=7.3, 5.1 Hz, 2H), 4.21-4.17 (m, 1H), 4.12-3.99 (m, 4H), 3.53-3.34 (m, 6H), 2.96-2.85 (m, 2H), 2.77-2.66 (m, 2H), 2.64-2.56 (m, 3H), 2.49-2.44 (m, 1H), 2.37-2.33 (m, 1H), 2.03-1.93 (m, 3H), 1.83 (s, 3H), 1.82 (s, 3H), 1.57-1.52 (m, 1H). LC/MS Condition E: ret time 1.09 min; m/e=473 (M+H).sup.+. LC/MS Condition F: ret time 1.12 min; m/e=473 (M+H).sup.+.

Example 2053: (R)-1-(3-((3-(3-((2-hydroxyethyl)(propyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(200) ##STR00074##

(201) A mixture of 2-(propylamino)ethanol (41 mg, 0.397 mmol) and (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1.0 mL) and N,N-diisopropylethylamine (40 L, 0.229 mmol) was heated at 65-70 C. for 72 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-60% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (12.5 mg, 59%). LC/MS Condition E: ret time 1.27 min; m/e=485 (M+H).sup.+; LC/MS Condition F: ret time 1.22 min; m/e=485 (M+H).sup.+.

Example 2054: (R)-3-((3-((3-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)(methyl)amino)propanamide

(202) ##STR00075##

(203) A mixture of 2-(propylamino)ethanol (41 mg, 0.397 mmol) and (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1.0 mL) and N,N-diisopropylethylamine (40 L, 0.229 mmol) was heated at 65-70 C. for 72 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-50% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (10 mg, 47%). LC/MS Condition E: ret time 1.18 min; m/e=484 (M+H).sup.+; LC/MS Condition F: ret time 1.12 min; m/e=484 (M+H).sup.+.

Example 2055: (R)-1-(3-((3-(3-(((R)-1-hydroxy-3-methylbutan-2-yl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(204) ##STR00076##

(205) A mixture of (R)-2-amino-3-methylbutan-1-ol (50 mg, 0.485 mmol) and (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1.0 mL) and N,N-diisopropylethylamine (40 L, 0.229 mmol) was heated at 65-70 C. for 72 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-50% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (14.4 mg, 62%). LC/MS Condition E: ret time 1.24 min; m/e=485 (M+H).sup.+; LC/MS Condition F: ret time 1.23 min; m/e=485 (M+H).sup.+.

Example 2056: (R)-1-(3-((3-(3-(bis(pyridin-2-ylmethyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(206) ##STR00077##

(207) A mixture of bis(pyridin-2-ylmethyl)amine (52 mg, 0.261 mmol) and (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1.0 mL) and N,N-diisopropylethylamine (40 L, 0.229 mmol) was heated at 65-70 C. for 72 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 45-85% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (18.4 mg, 66%). LC/MS Condition E: ret time 1.78 min; m/e=581 (M+H).sup.+; LC/MS Condition F: ret time 1.28 min; m/e=581 (M+H).sup.+.

Example 2057: (R)-1-(3-((3-(3-(((S)-2-hydroxy-1-phenylethyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(208) ##STR00078##

(209) A mixture of (S)-2-amino-2-phenylethanol (55 mg, 0.401 mmol) and (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1.0 mL) and N,N-diisopropylethylamine (40 L, 0.229 mmol) was heated at 70 C. for 72 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-65% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (8.3 mg, 34%). LC/MS Condition E: ret time 1.46 min; m/e=519 (M+H).sup.+; LC/MS Condition F: ret time 1.29 min; m/e=519 (M+H).sup.+.

Example 2058: (R)-1-(3-((3-(3-(((S)-1-hydroxy-3-methylbutan-2-yl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(210) ##STR00079##

(211) A mixture of (S)-2-amino-3-methylbutan-1-ol (45 mg, 0.436 mmol) and (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (0.8 mL) and N,N-diisopropylethylamine (40 L, 0.229 mmol) was heated at 70 C. for 72 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-55% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (4.7 mg, 91%). LC/MS Condition E: ret time 1.25 min; m/e=485 (M+H).sup.+; LC/MS Condition F: ret time 1.24 min; m/e=485 (M+H).sup.+.

Example 2059: 3-((3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)amino)propane-1,2-diol

(212) ##STR00080##

(213) A mixture of 3-aminopropane-1,2-diol (61 mg, 0.670 mmol) and (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1 mL) and N,N-diisopropylethylamine (70 L, 0.401 mmol) was heated at 60-70 C. for 48 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-50% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound as a mixture of diastereomers: (19.2 mg, 93%). LC/MS Condition E: ret time 1.09 min; m/e=473 (M+H).sup.+. LC/MS Condition F: ret time 1.11 min; m/e=473 (M+H).sup.+.

Example 2060: (R)-1-(3-((3-(3-((2-(4-chloro-1H-pyrazol-1-yl)ethyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(214) ##STR00081##

(215) A mixture of 2-(4-chloro-1H-pyrazol-1-yl)ethanamine, HCl (75 mg, 0.412 mmol) and (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1 mL) and N,N-diisopropylethylamine (100 L, 0.573 mmol) was heated at 70 C. for 72 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-65% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (11 mg, 46%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.96 (s, 1H), 7.51 (s, 1H), 7.18 (t, J=7.9 Hz, 2H), 6.93 (t, J=7.5 Hz, 2H), 6.64 (d, J=7.3 Hz, 2H), 4.27-4.24 (m, 1H), 4.17 (t, J=6.1 Hz, 2H), 4.09-3.99 (m, 4H), 3.43-3.36 (m, 2H), 2.98 (t, J=6.2 Hz, 2H), 2.93-2.65 (m, 7H), 2.62-2.57 (m, 1H), 2.07-1.94 (m, 3H), 1.93-1.86 (m, 2H), 1.83 (s, 3H), 1.82 (s, 3H), 1.67-1.60 (m, 1H).

(216) LC/MS Condition E: ret time 1.48 min; m/e=527 (M+H).sup.+.

(217) LC/MS Condition F: ret time 1.31 min; m/e=527 (M+H).sup.+.

Example 2061: (R)-1-(3-((3-(3-((2-(4-chloro-1H-pyrazol-1-yl)ethyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(218) ##STR00082##

(219) A mixture of 2-(5-chloro-1-methyl-1H-imidazol-4-yl)ethanamine, 2 HCl (95 mg, 0.409 mmol) and (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1 mL) and N,N-diisopropylethylamine (160 L, 0.916 mmol) was heated at 70 C. for 48 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-50% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (4 mg, 17%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.68 (s, 1H), 7.18 (q, J=7.7 Hz, 2H), 6.93 (d, J=7.3 Hz, 2H), 6.64 (dd, J=13.0, 7.5 Hz, 2H), 4.21 (br. s., 1H), 4.12-4.00 (m, 4H), 3.08-2.97 (m, 4H), 2.78 (dd, J=9.4, 5.7 Hz, 1H), 2.74-2.61 (m, 6H), 2.43 (d, J=8.8 Hz, 1H), 2.07-1.97 (m, 3H), 1.95-1.87 (m, 2H), 1.89 (s, 3H), 1.82 (s, 6H), 1.63-1.53 (m, 1H). LC/MS Condition E: ret time 1.27 min; m/e=541 (M+H).sup.+; LC/MS Condition F: ret time 1.12 min; m/e=541 (M+H).sup.+.

Example 2062: (R)-1-(3-((2,2-dimethyl-3-(3-(methyl(pyridin-2-ylmethyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(220) ##STR00083##

(221) A mixture of N-methyl-1-(pyridin-2-yl)methanamine (53.6 mg, 0.439 mmol) and (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol) was heated at 70 C. for 48 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-60% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (18.5 mg, 76%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.44 (d, J=4.8 Hz, 1H), 7.64 (s, 1H), 7.39 (d, J=7.7 Hz, 1H), 7.20-7.15 (m, 3H), 6.93 (dd, J=8.3, 3.9 Hz, 2H), 6.63 (dd, J=11.9, 7.5 Hz, 2H), 4.38-4.25 (m, 1H), 4.12-3.99 (m, 4H), 3.64 (br. s., 2H), 3.12-2.84 (m, 5H), 2.60-2.55 (m, 3H), 2.24 (s, 3H), 2.11-1.92 (m, 5H), 1.83 (s, 3H), 1.71 (s, 3H), 1.71-1.69 (m, 1H). LC/MS Condition E: ret time 1.50 min; m/e=504 (M+H).sup.+. LC/MS Condition F: ret time 1.23 min; m/e=504 (M+H).sup.+.

Example 2063: (R)-1-(3-((3-(3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(222) ##STR00084##

(223) A mixture of 2-(piperazin-1-yl)ethanol (45.3 mg, 0.348 mmol) and (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol) was heated at 70 C. for 24 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 5-45% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (20.1 mg, 89%). LC/MS Condition E: ret time 1.21 min; m/e=512 (M+H).sup.+. LC/MS Condition F: ret time 1.07 min; m/e=512 (M+H).sup.+.

Example 2064: (R)-1-(3-((2,2-dimethyl-3-(3-(methyl(pyridin-4-ylmethyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(224) ##STR00085##

(225) A mixture of N-methyl-1-(pyridin-4-yl)methanamine, 2 HCl (39.7 mg, 0.203 mmol) and (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1 mL) and N,N-diisopropylethylamine (80 L, 0.458 mmol) was heated at 70 C. for 72 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 60-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (28.8 mg, 40%). LC/MS Condition E: ret time 1.71 min; m/e=504 (M+H).sup.+. LC/MS Condition F: ret time 1.12 min; m/e=504 (M+H).sup.+.

Example 2065: (R)-1-(3-((3-(3-((4-aminophenethyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(226) ##STR00086##

(227) A mixture of 4-(2-aminoethyl)aniline (40.8 mg, 0.300 mmol) and (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol) was heated at 70 C. for 48 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 40-80% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (14.2 mg, 63%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.25-7.13 (m, 2H), 6.94 (d, J=8.4 Hz, 2H), 6.88 (d, J=8.4 Hz, 2H), 6.66 (d, J=7.3 Hz, 1H), 6.63 (d, J=7.7 Hz, 1H), 6.50 (d, J=8.1 Hz, 2H), 4.19 (br. s., 1H), 4.10-4.00 (m, 4H), 3.00-2.87 (m, 4H), 2.78-2.70 (m, 1H), 2.67-2.56 (m, 5H), 2.46 (d, J=7.0 Hz, 1H), 2.37 (br. s., 1H), 2.05-1.96 (m, 3H), 1.93-1.89 (m, 2H), 1.86 (s, 3H), 1.80 (s, 3H), 1.63-1.48 (m, 1H). LC/MS Condition E: ret time 1.2 min; m/e=518 (M+H).sup.+. LC/MS Condition F: ret time 1.14 min; m/e=518 (M+H).sup.+.

Example 2066: (R)-1-(3-((2,2-dimethyl-3-(3-((1-methylpiperidin-4-yl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(228) ##STR00087##

(229) A mixture of 1-methylpiperidin-4-amine (56.2 mg, 0.492 mmol) and (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol) was heated at 65-70 C. for 72 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 40-85% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (10.1 mg, 47%). LC/MS Condition E: ret time 1.06 min; m/e=496 (M+H).sup.+. LC/MS Condition F: ret time 1.10 min; m/e=496 (M+H).sup.+.

Example 2067: (R)-1-(3-((3-(3-((1-(2-hydroxyethyl)piperidin-4-yl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(230) ##STR00088##

(231) A mixture of 2-(4-aminopiperidin-1-yl)ethanol (82 mg, 0.569 mmol) and (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol) was heated at 65 C. for 72 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 5-45% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (7.7 mg, 34%). LC/MS Condition E: ret time 1.14 min; m/e=526 (M+H).sup.+. LC/MS Condition F: ret time 1.09 min; m/e=526 (M+H).sup.+.

Example 2068: (R)-2,2-((3-((3-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)azanediyl)bis(ethan-1-ol)

(232) ##STR00089##

(233) A mixture of 2,2-azanediyldiethanol (26 mg, 0.247 mmol) and (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol) was heated at 65-70 C. for 72 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-55% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (10.5 mg, 49%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.19 (td, J=7.8, 4.2 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 6.65 (dd, J=13.0, 7.5 Hz, 2H), 4.37-4.33 (m, 1H), 4.13-3.97 (m, 4H), 3.53-3.48 (m, 3H), 3.43-3.37 (m, 3H), 3.17-2.63 (m, 10H), 2.12-2.03 (m, 3H), 1.97-1.92 (m, 2H), 1.84 (s, 3H), 1.83 (s, 3H), 1.79-1.72 (m, 1H). LC/MS Condition E: ret time 1.18 min; m/e=487 (M+H).sup.+. LC/MS Condition F: ret time 1.16 min; m/e=487 (M+H).sup.+.

Example 2069: (R)-1-(3-((3-(3-(((R)-2-hydroxy-1-phenylethyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(234) ##STR00090##

(235) A mixture of (R)-2-amino-2-phenylethanol (58 mg, 0.423 mmol) and (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1 mL) and N,N-diisopropylethylamine (40 L, 0.229 mmol) was heated at 70 C. for 72 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 60-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (11 mg, 47%). LC/MS Condition E: ret time 1.44 min; m/e=519 (M+H).sup.+. LC/MS Condition F: ret time 1.33 min; m/e=519 (M+H).sup.+.

Example 2070: (R)-1-(3-((3-(3-(4-(dimethylamino)piperidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(236) ##STR00091##

(237) A mixture of N,N-dimethylpiperidin-4-amine (42 mg, 0.328 mmol) and (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol) was heated at 70 C. for 24 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 5-45% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (20.1 mg, 89%). LC/MS Condition E: ret time 1.22 min; m/e=510 (M+H).sup.+. LC/MS Condition F: ret time 1.05 min; m/e=510 (M+H).sup.+.

Example 2071: (R)-1-(3-((3-(3-(((R)-1-(5-chloro-1-methyl-1H-imidazol-4-yl)-3-hydroxypropan-2-yl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(238) ##STR00092##

(239) A mixture of (R)-2-amino-3-(5-chloro-1-methyl-1H-imidazol-4-yl)propan-1-ol, 2 HCl (110 mg, 0.419 mmol) and (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1 mL) and N,N-diisopropylethylamine (150 L, 0.859 mmol) was heated at 70 C. for 48 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-55% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (9.1 mg, 19%). LC/MS Condition E: ret time 1.35 min; m/e=571 (M+H).sup.+. LC/MS Condition F: ret time 1.13 min; m/e=571 (M+H).sup.+.

Example 2072: (R)-1-(3-((3-(3-(benzyl(2-hydroxyethyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(240) ##STR00093##

(241) A mixture of 2-(benzylamino)ethanol (47 mg, 0.311 mmol) and (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1 mL) and N,N-diisopropylethylamine (40 L, 0.229 mmol) was heated at 65-70 C. for 72 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 40-80% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (12.0 mg, 52%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.34-7.13 (m, 7H), 6.92 (dd, J=16.3, 8.3 Hz, 2H), 6.63 (dd, J=15.0, 7.7 Hz, 2H), 4.30 (br. s., 1H), 4.14-3.96 (m, 4H), 3.62 (s, 2H), 3.52-3.47 (m, 2H), 3.09-2.72 (m, 6H), 2.65-2.61 (m, 2H), 2.57-2.53 (m, 2H), 2.15-2.00 (m, 3H), 1.92-1.88 (m, 2H), 1.83 (s, 3H), 1.73-1.68 (m, 1H), 1.70 (s, 3H). LC/MS Condition E: ret time 1.71 min; m/e=533 (M+H).sup.+. LC/MS Condition F: ret time 1.28 min; m/e=533 (M+H).sup.+.

Example 2073: (R)-1-(3-((3-(3-((2-hydroxyethyl)(isopentyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(242) ##STR00094##

(243) A mixture of 2-(isopentylamino)ethanol (44 mg, 0.335 mmol) and (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1 mL) and N,N-diisopropylethylamine (50 L, 0.286 mmol) was heated at 65-70 C. for 120 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 5-45% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (14.4 mg, 63%). LC/MS Condition E: ret time 1.43 min; m/e=513 (M+H).sup.+. LC/MS Condition F: ret time 1.31 min; m/e=513 (M+H).sup.+.

Example 2074: (R)-1-(3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)piperidine-3-carboxylic acid

(244) ##STR00095##

(245) A mixture of (S)-piperidine-3-carboxylic acid (10 mg, 0.07 mmol) and (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (22 mg, 0.047 mmol) in DMF (0.5 mL), methanol (0.5 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol) was heated at 70 C. for 24 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 40-80% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (1.7 mg, 7%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) 7.23-7.15 (m, 2H), 6.95 (t, J=8.1 Hz, 2H), 6.69 (dd, J=7.5, 2.8 Hz, 2H), 4.57-4.47 (m, 1H), 4.15 (s, 4H), 3.40-3.15 (m, 12H), 2.68-2.60 (m, 1H), 2.35-2.15 (m, 5H), 2.00-1.90 (m, 4H), 1.92 (s, 3H), 1.90 (s, 3H), 1.86-1.81 (m, 1H). LC/MS Condition E: ret time 1.14 min; m/e=511 (M+H).sup.+. LC/MS Condition F: ret time 1.21 min; m/e=511 (M+H).sup.+.

Example 2075: (R)-1-(3-((3-(3-(((S)-2-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(246) ##STR00096##

(247) A mixture of (S)-2-amino-1-(3-chloro-4-fluorophenyl)ethanol, HCl (94.2 mg, 0.417 mmol) and (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1 mL) and N,N-diisopropylethylamine (100 L, 0.573 mmol) was heated at 70 C. for 72 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 30-70% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (15.5 mg, 62%). LC/MS Condition E: ret time 1.48 min; m/e=571 (M+H).sup.+. LC/MS Condition F: ret time 1.43 min; m/e=571 (M+H).sup.+.

Example 2076: 3,3-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(methylazanediyl))dipropanamine

(248) ##STR00097##

(249) A mixture of 3-(methylamino)propanamide (90 mg, 0.88 mmol) and 3,3-bis(3-bromopropoxy)-2,2-dimethyl-1,1-biphenyl (20 mg, 0.044 mmol) in DMF (0.5 mL), methanol (0.5 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol) was heated at 65 C. for 24 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 10-40% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (16.8 mg, 75%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.39 (br. s., 2H), 7.17 (t, J=7.9 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 6.78 (br. s., 2H), 6.63 (d, J=7.7 Hz, 2H), 4.09-3.97 (m, 4H), 2.67-2.53 (m, 8H), 2.29-2.19 (m, 10H), 1.94-1.88 (m, 4H), 1.82 (s, 6H). LC/MS Condition E: ret time 1.24 min; m/e=499 (M+H).sup.+. LC/MS Condition F: ret time 1.08 min; m/e=499 (M+H).sup.+.

Example 2077: 2,2,2,2-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(azanetriyl))tetrakis(ethan-1-ol)

(250) ##STR00098##

(251) A mixture of 2,2-azanediyldiethanol (80 mg, 0.761 mmol) and 3,3-bis(3-bromopropoxy)-2,2-dimethyl-1,1-biphenyl (20 mg, 0.044 mmol) in methanol (0.5 mL), DMF (0.5 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol) was heated at 65 C. for 24 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 10-50% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (16.5 mg, 89%). LC/MS Condition E: ret time 1.25 min; m/e=505 (M+H).sup.+. LC/MS Condition F: ret time 1.13 min; m/e=505 (M+H).sup.+.

Example 2078: 3,3-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(methylazanediyl))bis(propane-1,2-diol)

(252) ##STR00099##

(253) A mixture of 3-(methylamino)propane-1,2-diol (99 mg, 0.942 mmol) and 3,3-bis(3-bromopropoxy)-2,2-dimethyl-1,1-biphenyl (20 mg, 0.044 mmol) in methanol (0.5 mL), THF (0.5 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol) was heated at 65 C. for 72 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-50% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound as a mixture of diastereoisomers: (21.6 mg, 98%). LC/MS Condition E: ret time 1.06 min; m/e=505 (M+H).sup.+. LC/MS Condition F: ret time 1.06 min; m/e=505 (M+H).sup.+.

Example 2079: (2S,2S)-3,3-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(azanediyl))bis(propane-1,2-diol)

(254) ##STR00100##

(255) A mixture of (S)-3-aminopropane-1,2-diol (2 g, 21.95 mmol) and 3,3-bis(3-bromopropoxy)-2,2-dimethyl-1,1-biphenyl (500 mg, 1.096 mmol) in methanol (11 mL) and N,N-diisopropylethylamine (600 L, 3.44 mmol) was heated at 65 C. for 20 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 30200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 5-45% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 50 mL/min to give the pure title compound: (440 mg, 83%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.19 (t, J=7.9 Hz, 2H), 6.94 (d, J=8.1 Hz, 2H), 6.65 (d, J=7.7 Hz, 2H), 4.16-4.01 (m, 4H), 3.72-3.64 (m, 2H), 3.45-3.28 (m, 4H), 2.95 (t, J=7.2 Hz, 4H), 2.92-2.87 (m, 2H), 2.69 (dd, J=12.1, 8.4 Hz, 2H), 2.08-1.99 (m, 4H), 1.84 (s, 6H). LC/MS Condition E: ret time 1.06 min; m/e=477 (M+H).sup.+. LC/MS Condition F: ret time 1.08 min; m/e=477 (M+H).sup.+.

Example 2080: (S)-3-((3-((3-(3-((3-hydroxypropyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)amino)propane-1,2-diol

(256) ##STR00101##

(257) A mixture of (S)-3-aminopropane-1,2-diol (66.7 mg, 0.73 mmol), 3-aminopropan-1-ol (42 mg, 0.56 mmol), and 3,3-bis(3-bromopropoxy)-2,2-dimethyl-1,1-biphenyl (20 mg, 0.044 mmol) in methanol (0.5 mL), DMF (0.5 mL) and N,N-diisopropylethylamine (100 L, 0.573 mmol) was heated at 65 C. for 24 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-45% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound as a TFA salt: (6.8 mg, 22%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.20 (t, J=7.9 Hz, 2H), 6.95 (d, J=8.1 Hz, 2H), 6.65 (d, J=7.7 Hz, 2H), 4.20-4.01 (m, 4H), 3.75 (d, J=5.5 Hz, 1H), 3.49 (t, J=6.1 Hz, 2H), 3.45-3.30 (m, 2H), 3.12-3.03 (m, 5H), 2.98 (t, J=7.5 Hz, 2H), 2.81 (dd, J=12.3, 9.4 Hz, 1H), 2.10 (d, J=5.5 Hz, 4H), 1.85 (s, 6H), 1.78-1.70 (m, 2H). LC/MS Condition E: ret time 1.01 min; m/e=461 (M+H).sup.+. LC/MS Condition F: ret time 1.08 min; m/e=461 (M+H).sup.+.

Example 2081: (S)-1-(3-((3-(3-(((S)-2,3-dihydroxypropyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)piperidine-3-carboxylic acid

(258) ##STR00102##

(259) A mixture of (S)-piperidine-3-carboxylic acid (11.2 mg, 0.087 mmol) and 3,3-bis(3-bromopropoxy)-2,2-dimethyl-1,1-biphenyl (20 mg, 0.044 mmol) in methanol (0.5 mL), DMF (0.5 mL) and N,N-diisopropylethylamine (170 L, 0.975 mmol) was heated at 65 C. for 2 h. Then (S)-3-aminopropane-1,2-diol, HCl (53 mg, 0.415 mmol), N,N-diisopropylethylamine (90 L, 0.52 mmol), and more (S)-piperidine-3-carboxylic acid (35 mg, 0.27 mmol) were added and the mixture was heated at 65 C. for 24 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-50% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. to give the pure title compound as a TFA salt: (8.5 mg, 38%). LC/MS Condition E: ret time 1.11 min; m/e=515 (M+H).sup.+. LC/MS Condition F: ret time 1.18 min; m/e=515 (M+H).sup.+.

Example 2082: (3S,3S)-1,1-(((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(piperidine-3-carboxylic acid)

(260) ##STR00103##

(261) Isolated from the reaction mixture for Example 2081. The pure title compound was also obtained as a TFA salt: (11.7 mg, 43%). LC/MS Condition E: ret time 1.13 min; m/e=553 (M+H).sup.+. LC/MS Condition F: ret time 1.25 min; m/e=553 (M+H).sup.+.

Example 2083: 3,3-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(azanediyl))bis(propane-1,2-diol)

(262) ##STR00104##

(263) A mixture of 3-aminopropane-1,2-diol (84 mg, 0.922 mmol) and 3,3-bis(3-bromopropoxy)-2,2-dimethyl-1,1-biphenyl (20 mg, 0.044 mmol) in methanol (0.5 mL), THF (0.5 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol) was heated at 65 C. for 72 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 2-42% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound as a mixture of diastereoisomers: (19.4 mg, 90%). LC/MS Condition E: ret time 1.07 min; m/e=477 (M+H).sup.+. LC/MS Condition F: ret time 1.10 min; m/e=477 (M+H).sup.+.

Example 2084: (3S,3S,4S,4S)-1,1-(((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(piperidine-3,4-diol)

(264) ##STR00105##

(265) A mixture of (3S,4S)-piperidine-3,4-diol, HCl (40 mg, 0.260 mmol) and 3,3-bis(3-bromopropoxy)-2,2-dimethyl-1,1-biphenyl (20 mg, 0.044 mmol) in methanol (1 mL) and N,N-diisopropylethylamine (60 L, 0.344 mmol) was heated at 65 C. for 24 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-50% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (9.9 mg, 43%). LC/MS Condition E: ret time 1.27 min; m/e=529 (M+H).sup.+. LC/MS Condition F: ret time 1.07 min; m/e=529 (M+H).sup.+.

Example 2085: 2,2-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(piperazine-4,1-diyl))bis(ethan-1-ol)

(266) ##STR00106##

(267) A mixture of 2-(piperazin-1-yl)ethanol (99 mg, 0.760 mmol) and 3,3-bis(3-bromopropoxy)-2,2-dimethyl-1,1-biphenyl (20 mg, 0.044 mmol) in methanol (1 mL) and N,N-diisopropylethylamine (25 L, 0.143 mmol) was heated at 65 C. for 72 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-50% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound as a TFA salt: (45.9 mg, 99%). LC/MS Condition E: ret time 1.28 min; m/e=555 (M+H).sup.+. LC/MS Condition F: ret time 1.05 min; m/e=555 (M+H).sup.+.

Example 2086: 3,3-((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(N-(2-(pyridin-3-yl)ethyl)propan-1-amine)

(268) ##STR00107##

(269) A mixture of 2-(pyridin-3-yl)ethanamine (100.7 mg, 0.824 mmol) and 3,3-bis(3-bromopropoxy)-2,2-dimethyl-1,1-biphenyl (20 mg, 0.044 mmol) in methanol (1.5 mL) and N,N-diisopropylethylamine (25 L, 0.143 mmol) was heated at 65 C. for 72 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 5-45% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound as a TFA salt: (26 mg, 59%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.80 (br. s., 2H), 8.60 (d, J=1.5 Hz, 2H), 8.57 (dd, J=4.8, 1.5 Hz, 2H), 7.91 (d, J=7.7 Hz, 2H), 7.54 (dd, J=7.9, 5.0 Hz, 2H), 7.21 (t, J=7.9 Hz, 2H), 6.96 (d, J=8.1 Hz, 2H), 6.66 (d, J=7.3 Hz, 2H), 4.15-4.07 (m, 4H), 3.33-3.27 (m, 4H), 3.22-3.15 (m, 4H), 3.05-2.99 (m, 4H), 2.16-2.10 (m, 4H), 1.85 (s, 6H). LC/MS Condition E: ret time 1.30 min; m/e=539 (M+H).sup.+. LC/MS Condition F: ret time 1.07 min; m/e=539 (M+H).sup.+.

Example 2087: 1,1-(((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(N,N-dimethylazetidin-3-amine)

(270) ##STR00108##

(271) A mixture of N,N-dimethylazetidin-3-amine, 2 HCl (110 mg, 0.636 mmol) and 3,3-bis(3-bromopropoxy)-2,2-dimethyl-1,1-biphenyl (20 mg, 0.044 mmol) in methanol (3 mL) and N,N-diisopropylethylamine (220 L, 1.26 mmol) was heated at 65 C. for 48 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-55% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (16.6 mg, 77%). LC/MS Condition E: ret time 1.59 min; m/e=495 (M+H).sup.+. LC/MS Condition F: ret time 1.68 min; m/e=495 (M+H).sup.+.

Example 2088: (1S,1S,2R,2R,3R,3R,5R,5R)-5,5-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(azanediyl))bis(3-(hydroxymethyl)cyclopentane-1,2-diol)

(272) ##STR00109##

(273) A mixture of (1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diol, HCl (40 mg, 0.218 mmol) and 3,3-bis(3-bromopropoxy)-2,2-dimethyl-1,1-biphenyl (20 mg, 0.044 mmol) in methanol (1 mL) and N,N-diisopropylethylamine (70 L, 0.40 mmol) was heated at 65 C. for 24 h. Then 2-(pyridin-4-yl)ethanamine (50 mg, 0.409 mmol) was added, and the mixture heated at 65 C. for 48 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 5-45% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (2.3 mg, 9%). LC/MS Condition E: ret time 1.40 min; m/e=589 (M+H).sup.+. LC/MS Condition F: ret time 1.45 min; m/e=589 (M+H).sup.+.

Example 2089: (1R,2S,3R,5R)-3-((3-((2,2-dimethyl-3-(3-((2-(pyridin-4-yl)ethyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)amino)-5-(hydroxymethyl)cyclopentane-1,2-diol

(274) ##STR00110##

(275) From Example 2088: The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 5-45% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. A second purification via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 20-60% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min gave the pure title compound as a TFA salt: (3.2 mg, 9%). LC/MS Condition E: ret time 1.52 min; m/e=564 (M+H).sup.+. LC/MS Condition F: ret time 1.43 min; m/e=564 (M+H).sup.+.

Example 2090: 3,3-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(methylazanediyl))bis(cyclobutan-1-ol)

(276) ##STR00111##

(277) A mixture of 3-(methylamino)cyclobutanol (73.2 mg, 0.724 mmol) and 3,3-bis(3-bromopropoxy)-2,2-dimethyl-1,1-biphenyl (20 mg, 0.044 mmol) in methanol (1 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol) was heated at 65 C. for 24 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-55% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (20.8 mg, 90%). LC/MS Condition E: ret time 1.49 min; m/e=497 (M+H).sup.+. LC/MS Condition F: ret time 1.22 min; m/e=497 (M+H).sup.+.

Example 2091: (2S,3S)-3-((3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)amino)-3-phenylpropane-1,2-diol

(278) ##STR00112##

(279) A mixture of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) and (2S,3S)-3-amino-3-phenylpropane-1,2-diol, HCl (42.8 mg, 0.210 mmol) in methanol (1 mL) and N,N-diisopropylethylamine (60 L, 0.344 mmol) was heated at 65 C. for 48 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-60% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (9.9 mg, 41%). LC/MS Condition E: ret time 1.79 min; m/e=549 (M+H).sup.+. LC/MS Condition F: ret time 1.66 min; m/e=549 (M+H).sup.+.

Example 2092: (R)-1-(3-((3-(3-((R)-2-(hydroxymethyl)morpholino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(280) ##STR00113##

(281) A mixture of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) and (R)-morpholin-2-ylmethanol, HCl (39 mg, 0.254 mmol) in methanol (1 mL) and N,N-diisopropylethylamine (60 L, 0.344 mmol) was heated at 65 C. for 24 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-60% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (19.7 mg, 91%). LC/MS Condition E: ret time 1.71 min; m/e=499 (M+H).sup.+. LC/MS Condition F: ret time 1.51 min; m/e=499 (M+H).sup.+.

Example 2093: (3R,3R)-1,1-((((((propane-1,3-diylbis(methylazanediyl))bis(propane-3,1-diyl))bis(oxy))bis(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl))bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol)

(282) ##STR00114##

(283) A mixture of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) and N1,N3-dimethylpropane-1,3-diamine (2.6 mg, 0.025 mmol) in methanol (3 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol) was heated at 65 C. for 72 h. More N.sub.1,N.sub.3-dimethylpropane-1,3-diamine (7.5 mg, 0.072 mmol) was added, and the mixture heated at 65 C. for 48 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-65% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (1.3 mg, 3%). LC/MS Condition E: ret time 1.99 min; m/e=865 (M+H).sup.+. LC/MS Condition F: ret time 1.69 min; m/e=865 (M+H).sup.+.

Example 2094: 3,3-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(azanediyl))bis(1-methoxypropan-2-ol)

(284) ##STR00115##

(285) A mixture of 1-amino-3-methoxypropan-2-ol (95 mg, 0.904 mmol) and 3,3-bis(3-bromopropoxy)-2,2-dimethyl-1,1-biphenyl (20 mg, 0.044 mmol) in methanol (1 mL) and N,N-diisopropylethylamine (70 L, 0.401 mmol) was heated at 65 C. for 72 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-50% B over 18 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound as a mixture of diasteromers: (21.8 mg, 98%). LC/MS Condition E: ret time 1.13 min; m/e=505 (M+H).sup.+. LC/MS Condition F: ret time 1.15 min; m/e=505 (M+H).sup.+.

Example 2095: (3R,3R)-1,1-(((((((oxybis(ethane-2,1-diyl))bis(methylazanediyl))bis(propane-3,1-diyl))bis(oxy))bis(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl))bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol)

(286) ##STR00116##

(287) A mixture of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) and 2,2-oxybis(N-methylethanamine) (2.7 mg, 0.020 mmol) in methanol (1.5 mL) and N,N-diisopropylethylamine (40 L, 0.229 mmol) was heated at 65 C. for 72 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-65% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (4.2 mg, 10%). LC/MS Condition E: ret time 1.94 min; m/e=895 (M+H).sup.+. LC/MS Condition F: ret time 1.77 min; m/e=895 (M+H).sup.+.

Example 2096: (R)-1-(3-((2,2-dimethyl-3-(3-(methyl(2-(2-(methylamino)ethoxy)ethyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(288) ##STR00117##

(289) From the above describing the preparation of Example 2095, (3R,3R)-1,1-(((((((oxybis(ethane-2,1-diyl))bis(methylazanediyl))bis(propane-3,1-diyl))bis(oxy))bis(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl))bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol), Example 2096 was also obtained: (5.2 mg, 21%). LC/MS Condition E: ret time 1.60 min; m/e=514 (M+H).sup.+. LC/MS Condition F: ret time 1.55 min; m/e=514 (M+H).sup.+.

Example 2097: (1R,1R,2R,2R)-2,2-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diylbis)bis(bis(propane-3,1-diyl))bis(azanediyl))bis(1-phenylpropane-1,3-diol)

(290) ##STR00118##

(291) A mixture of (1R,2R)-2-amino-1-phenylpropane-1,3-diol (119 mg, 0.712 mmol) and 3,3-bis(3-bromopropoxy)-2,2-dimethyl-1,1-biphenyl (20 mg, 0.044 mmol) in methanol (1 mL) and N,N-diisopropylethylamine (55 L, 0.315 mmol) was heated at 65 C. for 24 h. (S)-3-aminopropane-1,2-diol (50 mg, 0.549 mmol) and more N,N-diisopropylethylamine (50 ul) were added, and the mixture was continued heating at 65 C. overnight. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 12-52% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (15.0 mg, 54%). LC/MS Condition E: ret time 1.95 min; m/e=629 (M+H).sup.+. LC/MS Condition F: ret time 1.58 min; m/e=629 (M+H).sup.+.

Example 2098: (S)-3-((3-((3-(3-(((1R,2R)-1,3-dihydroxy-1-phenylpropan-2-yl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)amino)propane-1,2-diol

(292) ##STR00119##

(293) From the above describing the preparation of Example 2097, (1R,1R,2R,2R)-2,2-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(azanediyl))bis(1-phenylpropane-1,3-diol), Example 2098 was also obtained: (4.1 mg, 17%). LC/MS Condition E: ret time 1.67 min; m/e=553 (M+H).sup.+. LC/MS Condition F: ret time 1.42 min; m/e=553 (M+H).sup.+.

Example 2099: 5,5-(((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(((S)-2,3-dihydroxypropyl)azanediyl))bis(methylene))dinicotinonitrile

(294) ##STR00120##

(295) A mixture of (2S,2S)-3,3-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(azanediyl))bis(propane-1,2-diol) (Example 2079, 20 mg, 0.042 mmol) and 5-(chloromethyl)nicotinonitrile (51 mg, 0.334 mmol) in methanol (1 mL) and N,N-diisopropylethylamine (130 L, 0.744 mmol) was heated at 65 C. for 24 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 40-80% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (15.0 mg, 45%). LC/MS Condition E: ret time 2.43 min; m/e=709 (M+H).sup.+. LC/MS Condition F: ret time 1.84 min; m/e=709 (M+H).sup.+.

Example 2100: 2,2-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(((S)-2,3-dihydroxypropyl)azanediyl))diacetonitrile

(296) ##STR00121##

(297) A mixture of (2S,2S)-3,3-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(azanediyl))bis(propane-1,2-diol) (Example 2079, 20 mg, 0.042 mmol) and 2-iodoacetonitrile (20 l, 0.276 mmol) in methanol (1 mL) and N,N-diisopropylethylamine (50 L, 0.286 mmol) was heated at 65 C. for 4 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-65% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (16.1 mg, 64%). LC/MS Condition E: ret time 1.65 min; m/e=555 (M+H).sup.+. LC/MS Condition F: ret time 1.45 min; m/e=555 (M+H).sup.+.

Example 2101: (2S,2S)-3,3-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis((2-(pyridin-2-yl)ethyl)azanediyl))bis(propane-1,2-diol)

(298) ##STR00122##

(299) A solution of (2S,2S)-3,3-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(azanediyl))bis(propane-1,2-diol) (Example 2079, 22 mg, 0.046 mmol), 2-(2-bromoethyl)pyridine, hydrobromide (151 mg, 0.336 mmol) in NMP (0.9 mL) was treated with N,N-diisopropylethylamine (180 l, 1.03 mmol), and heated at 80 C for 5.5 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-60% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (10.3 mg, 32%). LC/MS Condition E: ret time 1.39 min; m/e=687 (M+H).sup.+. LC/MS Condition F: ret time 1.20 min; m/e=687 (M+H).sup.+.

Example 2102: (2S,2S)-3,3-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis((2-(pyridin-3-yl)ethyl)azanediyl))bis(propane-1,2-diol)

(300) ##STR00123##

(301) A solution of (2S,2S)-3,3-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(azanediyl))bis(propane-1,2-diol) (Example 2079, 10 mg, 0.021 mmol), 3-(2-bromoethyl)pyridine, hydrobromide (18 mg, 0.067 mmol) in DMF (0.5 mL) was treated with N,N-diisopropylethylamine (30 l, 0.172 mmol), and placed in a 65-70 C sand bath shaker for 72 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-70% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (0.7 mg, 4%). LC/MS Condition E: ret time 1.58 min; m/e=687 (M+H).sup.+. LC/MS Condition F: ret time 0.98 min; m/e=344 (M+2H).sup.2+.

Example 2103: (S)-3-((3-((3-(3-(((S)-2,3-dihydroxypropyl)(2-(pyridin-3-yl)ethyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)amino)propane-1,2-diol

(302) ##STR00124##

(303) From the above describing the purification of Example 2102, (2S,2S)-3,3-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis((2-(pyridin-3-yl)ethyl)azanediyl))bis(propane-1,2-diol), Example 2103 was also isolated: (3.2 mg, 24%). LC/MS Condition E: ret time 1.33 min; m/e=582 (M+H).sup.+. LC/MS Condition F: ret time 1.04 min; m/e=582 (M+H).sup.+.

Example 2104: 3,3-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(azanediyl))bis(2-methylpropane-1,2-diol)

(304) ##STR00125##

(305) A mixture of 3,3-bis(3-bromopropoxy)-2,2-dimethyl-1,1-biphenyl (20 mg, 0.044 mmol) and 3-amino-2-methylpropane-1,2-diol (60 mg, 0.571 mmol) in methanol (1 mL) and N,N-diisopropylethylamine (30 L, 0.172 mmol) was heated at 65 C. for 24 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-50% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound as a mixture of diastereomers: (10.3 mg, 32%). LC/MS Condition E: ret time 1.13 min; m/e=505 (M+H).sup.+. LC/MS Condition F: ret time 1.17 min; m/e=505 (M+H).sup.+.

Example 2105: (R)-1-(3-((2,2-dimethyl-3-(3-(piperidin-1-yl)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(306) ##STR00126##

(307) A mixture of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) and piperidine (36.8 mg, 0.433 mmol) was treated with MeOH (1 mL) and Hunig's base (100 l, 0.573 mmol). The resulting mixture was stirred at 60 C. for 16 h. The reaction mixture was filtered and the filtrate was purified via preparative LC/MS with the following conditions: ColumnXBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-70% B over 22 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired products were combined and dried via centrifugal evaporation to give the pure title compound: (19.1 mg, 95%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.18 (t, J=7.9 Hz, 2H), 6.94 (d, J=8.1 Hz, 2H), 6.64 (d, J=7.3 Hz, 2H), 4.26 (br. s., 1H), 4.11-3.97 (m, 4H), 3.36 (br. s., 2H), 2.93-2.52 (m, 10H), 1.98 (br. s., 5H), 1.83 (s, 6H), 1.64 (br. s., 1H), 1.55 (br. s., 4H), 1.42 (br. s., 2H). LC/MS Condition E: RT (Retention Time)=1.28 min; m/e=467 (M+H).sup.+.

Example 2106: (R)-1-(3-((3-(3-(4-(hydroxymethyl)piperidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(308) ##STR00127##

(309) A mixture of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) and piperidin-4-ylmethanol (49.8 mg, 0.433 mmol) was treated with MeOH (1 mL) and Hunig's base (100 l, 0.573 mmol). The resulting mixture was stirred at 60 C. for 16 h. The reaction mixture was filtered and the filtrate was purified via preparative LC/MS with the following conditions: ColumnXBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-70% B over 22 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired products were combined and dried via centrifugal evaporation to give the pure title compound: (19.9 mg, 93%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.18 (t, J=7.9 Hz, 2H), 6.93 (d, J=8.1 Hz, 2H), 6.64 (d, J=7.3 Hz, 2H), 4.22 (br. s., 1H), 4.08-3.94 (m, 4H), 3.37 (br. s., 3H), 3.24 (d, J=5.9 Hz, 2H), 2.94 (br. s., 2H), 2.85-2.63 (m, 4H), 2.55 (s, 2H), 2.06-1.92 (m, 6H), 1.83 (s, 6H), 1.69-1.55 (m, 3H), 1.37 (br. s., 1H), 1.22-1.05 (m, 2H).

(310) LC/MS Condition E: RT=1.15 min; m/e=497 (M+H).sup.+.

Example 2107: N-(1-(3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-yl)acetamide

(311) ##STR00128##

(312) A mixture of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) and N-(pyrrolidin-3-yl)acetamide (55.4 mg, 0.433 mmol) was treated with MeOH (1 mL) and Hunig's base (100 l, 0.573 mmol). The resulting mixture was stirred at 60 C. for 16 h. The reaction mixture was filtered and the filtrate was purified via preparative LC/MS with the following conditions: ColumnXBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-70% B over 22 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired products were combined and dried via centrifugal evaporation to give the pure title compound: (18 mg, 77%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.99 (d, J=6.6 Hz, 1H), 7.18 (t, J=7.9 Hz, 2H), 6.93 (d, J=8.1 Hz, 2H), 6.64 (dd, J=7.3, 4.0 Hz, 2H), 4.25 (br. s., 1H), 4.13 (br. s., 1H), 4.10-3.97 (m, 4H), 2.93-2.73 (m, 4H), 2.71-2.57 (m, 5H), 2.43 (d, J=6.2 Hz, 1H), 2.38-2.32 (m, 1H), 2.14-1.91 (m, 7H), 1.83 (d, J=2.9 Hz, 6H), 1.78 (s, 3H), 1.63 (br. s., 1H), 1.54 (dd, J=13.2, 6.2 Hz, 1H). LC/MS Condition E: RT=1.15 min; m/e=510 (M+H).sup.+.

Example 2108: (R)-1-(3-((2,2-dimethyl-3-(3-(4-(pyridin-2-yl)piperazin-1-yl)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(313) ##STR00129##

(314) A mixture of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) and 1-(pyridin-2-yl)piperazine (70.6 mg, 0.433 mmol) was treated with MeOH (1 mL) and Hunig's base (100 l, 0.573 mmol). The resulting mixture was stirred at 60 C. for 16 h. The reaction mixture was filtered and the filtrate was purified via preparative LC/MS with the following conditions: ColumnXBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-70% B over 22 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired products were combined and dried via centrifugal evaporation to give the pure title compound: (23.5 mg, 97%).

(315) .sup.1H NMR (500 MHz, METHANOL-d.sub.4) 8.11 (d, J=4.8 Hz, 1H), 7.59 (t, J=7.7 Hz, 1H), 7.22-7.13 (m, 2H), 6.94 (d, J=8.1 Hz, 2H), 6.85 (d, J=8.4 Hz, 1H), 6.74-6.63 (m, 3H), 4.52 (br. s., 1H), 4.15 (d, J=5.9 Hz, 4H), 3.57 (d, J=4.8 Hz, 4H), 3.39 (d, J=8.4 Hz, 1H), 3.23 (d, J=4.0 Hz, 3H), 3.20-3.09 (m, 2H), 2.75-2.68 (m, 6H), 2.29-2.19 (m, 3H), 2.15-2.09 (m, 2H), 1.97 (br. s., 1H), 1.91 (d, J=8.4 Hz, 6H).

(316) LC/MS Condition E: RT=1.12 min; m/e=545 (M+H).sup.+.

Example 2109: (R)-2-(4-(3-((3-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)piperazin-1-yl)-N-isopropylacetamide

(317) ##STR00130##

(318) A mixture of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) and N-isopropyl-2-(piperazin-1-yl)acetamide (80 mg, 0.433 mmol) was treated with MeOH (1 mL) and Hunig's base (100 l, 0.573 mmol). The resulting mixture was stirred at 60 C. for 16 h. The reaction mixture was filtered and the filtrate was purified via preparative LC/MS with the following conditions: ColumnXBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-70% B over 22 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired products were combined and dried via centrifugal evaporation to give the pure title compound: (21.6 mg, 85%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.39 (d, J=8.4 Hz, 1H), 7.18 (t, J=7.7 Hz, 2H), 6.93 (d, J=8.1 Hz, 2H), 6.64 (d, J=8.1 Hz, 2H), 4.22 (br. s., 1H), 4.10-3.99 (m, 4H), 3.88 (dd, J=14.1, 6.8 Hz, 1H), 2.80 (br. s., 1H), 2.75-2.62 (m, 3H), 2.55 (s, 3H), 2.50-2.31 (m, 10H), 2.06-1.87 (m, 6H), 1.83 (s, 6H), 1.58 (br. s., 1H), 1.06 (d, J=6.6 Hz, 6H). LC/MS Condition E: RT=1.20 min; m/e=567 (M+H).sup.+.

Example 2110: (R)-1-(3-((2,2-dimethyl-3-(3-(methyl(phenethyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(319) ##STR00131##

(320) A mixture of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) and N-methyl-2-phenylethanamine (58.5 mg, 0.433 mmol) was treated with MeOH (1 mL) and Hunig's base (100 l, 0.573 mmol). The resulting mixture was stirred at 60 C. for 16 h. The reaction mixture was filtered and the filtrate was purified via preparative LC/MS with the following conditions: ColumnXBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-70% B over 22 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired products were combined and dried via centrifugal evaporation to give the pure title compound: (12.5 mg, 46%).

(321) .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.21 (td, J=15.4, 7.3 Hz, 7H), 6.92 (dd, J=17.8, 8.3 Hz, 2H), 6.64 (dd, J=7.2, 5.0 Hz, 2H), 4.33 (br. s., 1H), 4.11-3.95 (m, 4H), 3.16-2.82 (m, 5H), 2.79-2.59 (m, 6H), 2.34 (br. s., 3H), 2.13-1.99 (m, 3H), 1.97-1.88 (m, 2H), 1.83 (s, 6H), 1.73 (br. s., 1H). LC/MS Condition E: RT=1.58 min; m/e=517 (M+H).sup.+.

Example 2111: (R)-1-(3-((3-(3-(4-(2-methoxyphenyl)piperazin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(322) ##STR00132##

(323) A mixture of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) and 1-(2-methoxyphenyl)piperazine (83 mg, 0.433 mmol) was treated with MeOH (1 mL) and Hunig's base (100 l, 0.573 mmol). The resulting mixture was stirred at 60 C. for 16 h. The reaction mixture was filtered and the filtrate was purified via preparative LC/MS with the following conditions: ColumnXBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-70% B over 22 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired products were combined and dried via centrifugal evaporation to give the pure title compound: (16.3 mg, 66%).

(324) .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.18 (t, J=7.9 Hz, 2H), 6.98-6.90 (m, 4H), 6.88 (s, 2H), 6.65 (t, J=7.0 Hz, 2H), 4.26 (br. s., 1H), 4.12-3.99 (m, 4H), 3.77 (s, 3H), 2.97 (br. s., 4H), 2.92-2.75 (m, 4H), 2.55 (s, 8H), 2.08-1.93 (m, 5H), 1.84 (s, 6H), 1.65 (br. s., 1H). LC/MS Condition E: RT=1.39 min; m/e=574 (M+H).sup.+.

Example 2112: (R)-1-(3-((3-(3-(((R)-2-hydroxy-2-phenylethyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(325) ##STR00133##

(326) A mixture of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) and (R)-2-amino-1-phenylethanol (59.3 mg, 0.433 mmol) was treated with MeOH (1 mL) and Hunig's base (100 l, 0.573 mmol). The resulting mixture was stirred at 60 C. for 16 h. The reaction mixture was filtered and the filtrate was purified via preparative LC/MS with the following conditions: ColumnXBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-70% B over 22 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired products were combined and dried via centrifugal evaporation to give the pure title compound: (10.7 mg, 47%).

(327) .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.38-7.30 (m, 4H), 7.27-7.22 (m, 1H), 7.21-7.14 (m, 2H), 6.93 (d, J=8.1 Hz, 2H), 6.64 (t, J=7.9 Hz, 2H), 4.72 (dd, J=8.8, 3.7 Hz, 1H), 4.19 (br. s., 1H), 4.05 (dd, J=13.8, 7.5 Hz, 4H), 2.93-2.69 (m, 5H), 2.67-2.57 (m, 3H), 2.47 (d, J=7.3 Hz, 1H), 2.36 (d, J=8.4 Hz, 1H), 2.04-1.95 (m, 3H), 1.91-1.87 (m, 2H), 1.83 (s, 6H). LC/MS Condition E: RT=1.36 min; m/e=519 (M+H).sup.+.

Example 2113: (R)-1-(3-((3-(3-(((S)-2-hydroxy-2-phenylethyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(328) ##STR00134##

(329) A mixture of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) and (S)-2-amino-1-phenylethanol (59.3 mg, 0.433 mmol) was treated with MeOH (1 mL) and Hunig's base (100 l, 0.573 mmol). The resulting mixture was stirred at 60 C. for 16 h. The reaction mixture was filtered and the filtrate was purified via preparative LC/MS with the following conditions: ColumnXBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-70% B over 22 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired products were combined and dried via centrifugal evaporation to give the pure title compound: (9.0 mg, 37%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.39-7.28 (m, 7H), 7.25 (d, J=7.0 Hz, 2H), 7.21-7.15 (m, 2H), 6.93 (d, J=8.4 Hz, 2H), 6.64 (t, J=7.3 Hz, 2H), 4.70 (dd, J=8.6, 3.9 Hz, 1H), 4.19 (br. s., 1H), 4.05 (dd, J=12.7, 7.2 Hz, 4H), 2.89-2.71 (m, 5H), 2.64-2.56 (m, 3H), 2.46 (d, J=6.6 Hz, 1H), 2.35 (d, J=7.0 Hz, 1H), 2.04-1.94 (m, 3H), 1.90-1.87 (m, 1H), 1.83 (s, 6H), 1.55 (d, J=3.7 Hz, 1H). .sup.1H NMR showed some extra protons in the aromatic region that might came from the sm/amine). LC/MS Condition E: RT=1.34 min; m/e=519 (M+H).sup.+.

Example 2114: (R)-1-(3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)piperidin-3-ol

(330) ##STR00135##

(331) A mixture of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) and (R)-piperidin-3-ol, HCl (59.5 mg, 0.433 mmol) was treated with MeOH (1 mL) and Hunig's base (100 l, 0.573 mmol). The resulting mixture was stirred at 60 C. for 16 h. The reaction mixture was filtered and the filtrate was purified via preparative LC/MS with the following conditions: ColumnXBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-70% B over 22 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired products were combined and dried via centrifugal evaporation to give the pure title compound: (17.3 mg, 79%).

(332) .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.18 (t, J=7.9 Hz, 2H), 6.93 (d, J=8.4 Hz, 2H), 6.64 (dd, J=7.2, 3.1 Hz, 2H), 4.23 (br. s., 1H), 4.09-3.96 (m, 4H), 3.48 (br. s., 1H), 2.91-2.56 (m, 8H), 2.05-1.86 (m, 8H), 1.83 (s, 6H), 1.78 (d, J=7.3 Hz, 2H), 1.61 (br. s., 2H), 1.41 (d, J=11.7 Hz, 1H), 1.10 (br. s., 1H). LC/MS Condition E: RT=1.17 min; m/e=483 (M+H).sup.+.

Example 2115: (S)-1-(3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)piperidin-3-ol

(333) ##STR00136##

(334) A mixture of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) and (S)-piperidin-3-ol, HCl (59.5 mg, 0.433 mmol) was treated with MeOH (1 mL) and Hunig's base (100 l, 0.573 mmol). The resulting mixture was stirred at 60 C. for 16 h. The reaction mixture was filtered and the filtrate was purified via preparative LC/MS with the following conditions: ColumnXBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-70% B over 22 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired products were combined and dried via centrifugal evaporation to give the pure title compound: (15.9 mg, 71%).

(335) .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.18 (t, J=7.7 Hz, 2H), 6.93 (d, J=8.1 Hz, 2H), 6.67-6.61 (m, 2H), 4.25 (br. s., 1H), 4.10-3.98 (m, 4H), 3.49 (br. s., 1H), 3.37 (br. s., 2H), 2.95-2.60 (m, 8H), 2.08-1.92 (m, 6H), 1.79 (br. s., 2H), 1.63 (br. s., 2H), 1.42 (d, J=13.2 Hz, 1H), 1.11 (br. s., 1H). LC/MS Condition E: RT=1.22 min; m/e=483 (M+H).sup.+.

Example 2116: (S)-2-((3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)amino)-3-(pyridin-2-yl)propanoic acid

(336) ##STR00137##

(337) A mixture of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) and (S)-2-amino-3-(pyridin-2-yl)propanoic acid (71.9 mg, 0.433 mmol) was treated with MeOH (1 mL) and Hunig's base (100 l, 0.573 mmol). The resulting mixture was stirred at 60 C. for 16 h. The reaction mixture was filtered and the filtrate was purified via preparative LC/MS with the following conditions: ColumnXBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-70% B over 22 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired products were combined and dried via centrifugal evaporation to give the pure title compound: (4.8 mg, 20%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.30 (br. s., 1H), 7.69 (t, J=7.5 Hz, 1H), 7.31 (d, J=7.7 Hz, 1H), 7.24-7.15 (m, 3H), 6.92 (t, J=7.5 Hz, 2H), 6.69-6.59 (m, 2H), 4.24 (br. s., 1H), 4.11-3.99 (m, 4H), 3.68 (dd, J=7.2, 5.0 Hz, 1H), 3.28 (dd, J=15.4, 4.4 Hz, 1H), 3.14-2.94 (m, 3H), 2.90-2.58 (m, 5H), 2.55 (s, 1H), 2.15-1.93 (m, 5H), 1.84-1.76 (m, 6H), 1.62 (br. s., 1H).

(338) LC/MS Condition E: RT=1.24 min; m/e=548 (M+H).sup.+.

Example 2117: (S)-2-((3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)amino)-3-(pyridin-3-yl)propanoic acid

(339) ##STR00138##

(340) A mixture of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) and (S)-2-amino-3-(pyridin-3-yl)propanoic acid, 2 HCl (103 mg, 0.433 mmol) was treated with MeOH (1 mL) and Hunig's Base (100 l, 0.573 mmol). The resulting mixture was stirred at 60 C. for 16 h. The reaction mixture was filtered and the filtrate was purified via preparative LC/MS with the following conditions: ColumnXBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-70% B over 22 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired products were combined and dried via centrifugal evaporation to give the pure title compound: (7.9 mg, 32%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.45 (s, 1H), 8.39 (d, J=4.8 Hz, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.29-7.23 (m, 1H), 7.18 (t, J=7.7 Hz, 2H), 6.93 (d, J=8.1 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 6.64 (t, J=6.8 Hz, 2H), 4.21 (br. s., 1H), 4.09-3.97 (m, 4H), 3.03-2.91 (m, 3H), 2.79 (d, J=7.0 Hz, 2H), 2.66 (br. s., 3H), 2.55 (s, 2H), 2.44 (d, J=8.1 Hz, 1H), 2.04-1.91 (m, 5H), 1.81 (d, J=11.7 Hz, 6H), 1.57 (br. s., 1H).

(341) LC/MS Condition E: RT=1.13 min; m/e=548 (M+H).sup.+.

Example 2118: (R)-1-(3-((2,2-dimethyl-3-(3-((2-(pyridin-2-yl)ethyl)amino)propoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(342) ##STR00139##

(343) A mixture of (R)-1-(3-((3-(3-bromopropoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) and 2-(pyridin-2-yl)ethanamine, 2 HCl (84 mg, 0.433 mmol) was treated with MeOH (1 mL) and Hunig's Base (100 l, 0.573 mmol). The resulting mixture was stirred at 60 C. for 16 h. The reaction mixture was filtered and the filtrate was purified via preparative LC/MS with the following conditions: ColumnXBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 10-70% B over 22 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired products were combined and dried via centrifugal evaporation to give the pure title compound: (16.5 mg, 73.5%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.46 (d, J=4.4 Hz, 1H), 7.70 (t, J=7.5 Hz, 1H), 7.29 (d, J=7.7 Hz, 1H), 7.24-7.20 (m, 1H), 7.20-7.13 (m, 2H), 6.93 (d, J=8.4 Hz, 2H), 6.64 (dd, J=12.3, 7.5 Hz, 2H), 4.19 (br. s., 1H), 4.12-3.98 (m, 4H), 3.39 (br. s., 5H), 3.13-3.05 (m, 2H), 2.99-2.88 (m, 4H), 2.76-2.68 (m, 1H), 2.66-2.54 (m, 3H), 2.46 (d, J=6.6 Hz, 1H), 2.36 (d, J=8.8 Hz, 1H), 2.04-1.94 (m, 3H), 1.82 (s, 6H), 1.59-1.47 (m, 1H). LC/MS Condition E: RT=1.24 min; m/e=504 (M+H).sup.+.

Example 2119: (2S,2S)-1,1-(((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4,1-phenylene))bis(methylene))bis(piperidine-2-carboxylic acid)

(344) ##STR00140##

(345) To a reaction vial containing 5,5-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(4-chloro-2-formyl-5,1-phenylene))bis(oxy))bis(methylene))dinicotinonitrile (45 mg, 0.057 mmol), and L-pipecolic acid (70 mg, 0.542 mmol), was added 1,2-dichloroethane (1.13 mL), ethanol (900 L), acetic acid (12 L, 0.210 mmol) and activated 4 A mol. sieves. The reaction was stirred at room temperature for 45 min, then treated dropwise with sodium cyanoborohydride, 1.0M in THF (230 L, 0.230 mmol) over 2-4 h. After the addition is complete, the reaction was stirred at room temperature overnight. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-80% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (11.5 mg, 20%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.01 (dd, J=5.8, 2.1 Hz, 4H), 8.46 (s, 2H), 7.52 (d, J=7.0 Hz, 2H), 7.43 (s, 2H), 7.31 (t, J=7.5 Hz, 2H), 7.17-7.08 (m, 4H), 5.38-5.32 (m, 4H), 5.31-5.24 (m, 4H), 3.78 (br d, J=13.7 Hz, 2H), 3.61 (br d, J=13.7 Hz, 2H), 3.13 (br dd, J=7.6, 4.3 Hz, 2H), 2.91-2.86 (m, 2H), 2.37-2.21 (m, 2H), 2.03 (s, 6H), 1.79 (br s, 2H), 1.72 (br d, J=9.2 Hz, 2H), 1.48 (br s, 6H), 1.36 (br s, 2H). LC/MS Condition E: ret time 1.76 min; m/e=1009 (M+H).sup.+.

(346) LC/MS Condition F: ret time 1.77 min; m/e=1009 (M+H).sup.+.

Example 2120: (S)-1-(5-chloro-4-((3-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-(hydroxymethyl)phenoxy)methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methoxy)-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid

(347) ##STR00141##

(348) From the reaction mixture for Example 2119, Example 2120 was also isolated: (11.8 mg, 22%). LC/MS Condition E: ret time 2.01 min; m/e=898 (M+H).sup.+. LC/MS Condition F: ret time 2.03 min; m/e=898 (M+H).sup.+.

Example 2121: (2R,2R)-2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4,1-phenylene))bis(methylene))bis(azanediyl))bis(3-hydroxy-2-methylpropanoic acid)

(349) ##STR00142##

(350) To a reaction vial containing 5,5-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(4-chloro-2-formyl-5,1-phenylene))bis(oxy))bis(methylene))dinicotinonitrile (45 mg, 0.057 mmol), and 2-methyl-d-serine (66.9 mg, 0.562 mmol), was added 1,2-dichloroethane (2.5 mL), ethanol (2.0 mL), acetic acid (22 L, 0.384 mmol) and activated 4 A mol. sieves. The reaction was stirred at room temp. for 2 h, then treated dropwise with sodium cyanoborohydride, 1.0M in THF (400 L, 0.400 mmol) over 3.5 h. After the addition was complete, the reaction was stirred at room temp. for 7 days. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 30-70% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (4.2 mg, 4%). LC/MS Condition E: ret time 1.67 min; m/e=989 (M+H).sup.+. LC/MS Condition F: ret time 1.76 min; m/e=989 (M+H).sup.+.

Example 2122: 2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-methoxy-4,1-phenylene))bis(methylene))bis(azanediyl))bis(propane-1,3-diol)

(351) ##STR00143##

(352) To a solution of 4,4-(((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-methoxybenzaldehyde) (35 mg, 0.060 mmol) in a mixture of 1,2-dichloroethane (1.25 mL) and ethanol (1.00 mL) was added 2-amino-1,3-propanediol (55 mg, 0.604 mmol), acetic acid (11.8 L, 0.206 mmol) and activated 4 A mol sieves. The reaction was stirred at room temp, for 45 min, then treated dropwise with sodium cyanoborohydride, 1.0 M in THF (242 L, 0.242 mmol) over 90 min. After the addition was complete, the reaction was allowed to stir at room temp overnight. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-60% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (36.2 mg, 82%). LC/MS Condition E: ret time 1.58 min; m/e=729 (M+H).sup.+.

(353) LC/MS Condition F: ret time 1.64 min; m/e=729 (M+H).sup.+.

Example 2123: (2S,2S)-2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4,1-phenylene))bis(methylene))bis(azanediyl))bis(3-hydroxy-2-methylpropanoic acid)

(354) ##STR00144##

(355) To a reaction vial containing 5,5-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(4-chloro-2-formyl-5,1-phenylene))bis(oxy))bis(methylene))dinicotinonitrile (78 mg, 0.100 mmol), and 2-methyl-L-serine (66.9 mg, 0.562 mmol), was added 1,2-dichloroethane (2.5 mL), ethanol (2.0 mL), acetic acid (22 L, 0.384 mmol) and activated 4 A mol. sieves. The reaction was stirred at room temp for 105 min, then treated dropwise with sodium cyanoborohydride, 1.0 M in THF (400 L, 0.400 mmol) over 2.5 h. After the addition was complete, anhydrous DMF (1.2 mL) was added and the reaction was stirred overnight at room temp. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-80% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (8.3 mg, 8%). LC/MS Condition E: ret time 1.67 min; m/e=989 (M+H).sup.+. LC/MS Condition F: ret time 1.73 min; m/e=989 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.03 (d, J=1.8 Hz, 2H), 9.01 (d, J=1.8 Hz, 2H), 8.51 (s, 2H), 7.55 (s, 2H), 7.49 (d, J=7.3 Hz, 2H), 7.30 (t, J=7.5 Hz, 2H), 7.14 (s, 2H), 7.12 (d, J=7.3 Hz, 2H), 5.36 (s, 4H), 5.31 (s, 4H), 3.98 (s, 4H), 2.55 (s, 4H), 2.03 (s, 6H), 1.25 (s, 6H).

Example 2124: (S)-2-((5-chloro-4-((3-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-(hydroxymethyl)phenoxy)methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methoxy)-2-((5-cyanopyridin-3-yl)methoxy)benzyl)amino)-3-hydroxy-2-methylpropanoic acid

(356) ##STR00145##

(357) From the reaction mixture for Example 2123, Example 2124 was also isolated (5.9 mg, 6%). LC/MS Condition E: ret time 2.01 min; m/e=888 (M+H).sup.+. LC/MS Condition F: ret time 2.16 min; m/e=888 (M+H).sup.+.

Example 2125: 5,5-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(4-chloro-6-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-3,1-phenylene))bis(oxy))bis(methylene))dinicotinonitrile

(358) ##STR00146##

(359) To a reaction vial containing 5,5-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(4-chloro-2-formyl-5,1-phenylene))bis(oxy))bis(methylene))dinicotinonitrile (78 mg, 0.100 mmol), and (R)-pyrrolidin-3-ol, HCl (111 mg, 0.898 mmol), was added 1,2-dichloroethane (2.5 mL), ethanol (2.0 mL), acetic acid (22 L, 0.384 mmol), N,N-diisopropylethylamine (20 L, 0.115 mmol) and activated 4 A mol. sieves. The reaction was stirred at room temp. for 70 min, then treated dropwise with sodium cyanoborohydride, 1.0M in THF (400 L, 0.400 mmol) over 2.5 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 40-85% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (38.4 mg, 38%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.01 (s, 2H), 8.99 (s, 2H), 8.43 (s, 2H), 7.52 (d, J=7.3 Hz, 2H), 7.37-7.27 (m, 4H), 7.16-7.10 (m, 4H), 5.33 (s, 4H), 5.27 (s, 4H), 4.22-4.16 (m, 2H), 3.59-3.49 (m, 4H), 2.67 (dd, J=9.5, 6.2 Hz, 2H), 2.61-2.55 (m, 2H), 2.46-2.39 (m, 2H), 2.31 (dd, J=9.5, 3.7 Hz, 2H), 2.04 (s, 6H), 1.99 (dd, J=13.4, 7.5 Hz, 2H), 1.57-1.51 (m, 2H). LC/MS Condition E: ret time 1.65 min; m/e=925 (M+H).sup.+.

(360) LC/MS Condition F: ret time 1.94 min; m/e=925 (M+H).sup.+.

Example 2126: (R)-5-((4-chloro-5-((3-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-((3-hydroxypyrrolidin-1-yl)methyl)phenoxy)methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methoxy)-2-(hydroxymethyl)phenoxy)methyl)nicotinonitrile

(361) ##STR00147##

(362) From the reaction mixture for Example 2125, Example 2126 was also isolated (7.8 mg, 9%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.02 (s, 2H), 8.98 (d, J=6.2 Hz, 2H), 8.43 (s, 2H), 7.51 (t, J=7.7 Hz, 2H), 7.36 (s, 1H), 7.33 (s, 1H), 7.32-7.26 (m, 2H), 7.15-7.08 (m, 4H), 5.33 (br.s., 4H), 5.27 (br. s., 4H), 4.48 (d, J=3.7 Hz, 2H), 4.21-4.16 (m, 1H), 3.91 (s, 1H), 3.59-3.54 (m, 1H), 3.53-3.48 (m, 1H), 3.39-3.37 (m, 1H), 2.67 (dd, J=9.5, 6.2 Hz, 1H), 2.60-2.56 (m, 1H), 2.44-2.38 (m, 1H), 2.31 (dd, J=9.7, 3.9 Hz, 1H), 2.05 (s, 6H), 1.99 (dd, J=13.0, 6.8 Hz, 1H), 1.58-1.51 (m, 1H). LC/MS Condition E: ret time 2.10 min; m/e=856 (M+H).sup.+. LC/MS Condition F: ret time 1.96 min; m/e=856 (M+H).sup.+.

Example 2127: 5,5-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(4-chloro-6-((((S)-2,3-dihydroxypropyl)amino)methyl)-3,1-phenylene))bis(oxy))bis(methylene))dinicotinonitrile

(363) ##STR00148##

(364) To a reaction vial containing 5,5-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(4-chloro-2-formyl-5,1-phenylene))bis(oxy))bis(methylene))dinicotinonitrile (78 mg, 0.100 mmol), and (S)-3-aminopropane-1,2-diol, HCl (121 mg, 0.948 mmol), was added 1,2-dichloroethane (2.5 mL), ethanol (2.0 mL), acetic acid (20 L, 0.349 mmol), N,N-diisopropylethylamine (20 L, 0.115 mmol) and activated 4 A mol. sieves. The reaction was stirred at room temp. for 70 min, then treated dropwise with sodium cyanoborohydride, 1.0M in THF (400 L, 0.400 mmol) over 3.5 h. After the addition was complete, the reaction was stirred overnight at room temperature. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-90% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (32.1 mg, 32%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.02 (d, J=1.8 Hz, 2H), 8.99 (d, J=1.5 Hz, 2H), 8.43 (s, 2H), 7.51 (d, J=7.7 Hz, 2H), 7.38 (s, 2H), 7.30 (t, J=7.7 Hz, 2H), 7.14-7.09 (m, 4H), 5.33 (s, 4H), 5.27 (s, 4H), 3.67 (d, J=4.0 Hz, 4H), 3.58-3.52 (m, 2H), 3.37-3.26 (m, 4H), 2.58 (dd, J=11.7, 4.4 Hz, 2H), 2.43 (dd, J=11.7, 7.3 Hz, 2H), 2.05 (s, 6H). LC/MS Condition E: ret time 1.81 min; m/e=933 (M+H).sup.+.

(365) LC/MS Condition F: ret time 1.66 min; m/e=933 (M+H).sup.+.

Example 2128: 5,5-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(4-chloro-6-(((1,3-dihydroxypropan-2-yl)amino)methyl)-3,1-phenylene))bis(oxy))bis(methylene))dinicotinonitrile

(366) ##STR00149##

(367) To a reaction vial containing 5,5-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(4-chloro-2-formyl-5,1-phenylene))bis(oxy))bis(methylene))dinicotinonitrile (63.6 mg, 0.081 mmol), and 2-aminopropane-1,3-diol (110 mg, 1.207 mmol), was added 1,2-dichloroethane (2.1 mL), ethanol (1.75 mL), acetic acid (15 L, 0.262 mmol), and activated 4 A mol. sieves. The reaction was stirred at room temp for 90 min, then treated dropwise with sodium cyanoborohydride, 1.0M in THF (0.35 mL, 0.350 mmol) over 4 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (49.4 mg, 64%). LC/MS Condition E: ret time 1.84 min; m/e=933 (M+H).sup.+. LC/MS Condition F: ret time 1.82 min; m/e=933 (M+H).sup.+.

Example 2129: 5-((4-chloro-5-((3-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-(((1,3-dihydroxypropan-2-yl)amino)methyl)phenoxy)methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methoxy)-2-(hydroxymethyl)phenoxy)methyl)nicotinonitrile

(368) ##STR00150##

(369) From the reaction mixture for Example 2128, the pure title compound above (Example 2129) (3.5 mg, 5%) was also isolated. LC/MS Condition E: ret time 2.39 min; m/e=860 (M+H).sup.+. LC/MS Condition F: ret time 2.27 min; m/e=860 (M+H).sup.+.

Example 2131: 5,5-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(4-chloro-6-(((1,3-dihydroxypropan-2-yl)((S)-2,3-dihydroxypropyl)amino)methyl)-3,1-phenylene))bis(oxy))bis(methylene))dinicotinonitrile

(370) ##STR00151##

(371) To a solution of 5,5-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(4-chloro-2-(((1,3-dihydroxypropan-2-yl)amino)methyl)-5,1-phenylene))bis(oxy))bis(methylene))dinicotinonitrile (10 mg, 10.7 mol) in methanol (500 L) was added (R)-glycidol (4 mg, 0.054 mmol), and the reaction was allowed to stir overnight at room temp. Additional (R)-glycidol (20 mg, 0.27 mmol) was added and the reaction was heated to 65 C. overnight. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 50-95% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (1.6 mg, 12%). LC/MS Condition E: ret time 1.73 min; m/e=1081 (M+H).sup.+. LC/MS Condition F: ret time 1.53 min; m/e=1081 (M+H).sup.+.

(372) Examples 2132 to 2136 were prepared as described below, and the HPLC LC/MS conditions employed for these examples were listed above for the 2001 compound series:

Example 2132: (1R,2S,5R)-3-((3-((3-(3-(((1R,2S,3R,4R)-2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl)amino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)amino)-5-(hydroxymethyl)cyclopentane-1,2-diol

(373) ##STR00152##

(374) To a solution of 3,3-bis(3-bromopropoxy)-2,2-dimethyl-1,1-biphenyl (20 mg, 0.044 mmol) and (1R,2S,3R,4R)-2,3-dihydroxy-4-(hydroxymethyl)-1-aminocyclopentane hydrochloride (84 mg, 0.457 mmol) in MeOH (1 mL) was added Hunig's Base (135 l, 0.773 mmol) and the reaction was heated at 65 C. for 18 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 5-50% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (16.2 mg, 63%). LC/MS Condition E: ret time 1.07 min; m/e=589 (M+H).sup.+. LC/MS Condition F: ret time 1.06 min; m/e=589 (M+H).sup.+.

Example 2133: 5,5-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(4-chloro-6-((4-(hydroxymethyl)-2-oxooxazolidin-3-yl)methyl)-3,1-phenylene))bis(oxy))bis(methylene))dinicotinonitrile

(375) ##STR00153##

(376) To a solution of 5,5-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(4-chloro-2-(((1,3-dihydroxypropan-2-yl)amino)methyl)-5,1-phenylene))bis(oxy))bis(methylene))dinicotinonitrile (20 mg, 0.021 mmol) and 1,1-carbonyldiimidazole (18.9 mg, 0.117 mmol) in anhydrous DMF (0.7 mL) was added Hunig's Base (8 l, 0.046 mmol) and the reaction was stirred at room temp for 18 h, followed by heating at 65 C. for 6 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 42-82% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound (1.3 mg, 6%). LC/MS Condition E: ret time 2.14 min; m/e=985 (M+H).sup.+. LC/MS Condition F: ret time 2.12 min; m/e=985 (M+H).sup.+.

Intermediate: tert-butyl (3-(3-bromo-2-chlorophenoxy)propyl)carbamate

(377) ##STR00154##

(378) To a mixture of tert-butyl (3-bromopropyl)carbamate (4.29 g, 18.02 mmol) and 3-bromo-2-chlorophenol (3.74 g, 18.02 mmol) in anhydrous DMF (25 mL) was added solid potassium carbonate (5 g, 36.2 mmol). The reaction was flushed with argon, stirred at room temp for 5 min, then heated at 50 C. for 19 h. The reaction was cooled to room temp, diluted with EtOAc (600 mL) and the organic layer was washed with water (4150 mL), sat. aq NaCl (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The crude product (6.5 g, 94%) was used as is without further purification in subsequent reactions. .sup.1H NMR (500 MHz, CHLOROFORM-d) 7.26 (dd, J=8.1, 1.2 Hz, 1H), 7.10 (t, J=8.2 Hz, 1H), 6.88 (dd, J=8.3, 1.1 Hz, 1H), 5.17 (br s, 1H), 4.13 (t, J=5.8 Hz, 2H), 3.40 (q, J=5.8 Hz, 2H), 2.14-2.01 (m, 2H), 1.46 (s, 9H).

Intermediate: tert-butyl (3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)carbamate

(379) ##STR00155##

(380) To a dry 150 mL pressure bottle under N.sub.2 was added tert-butyl (3-(3-bromo-2-chlorophenoxy)propyl)carbamate (2.5 g, 6.86 mmol), 4,4,4,4,5,5,5,5-octamethyl-2,2-bi(1,3,2-dioxaborolane) (2.96 g, 11.66 mmol), potassium acetate (2.1 g, 21.40 mmol), and anhydrous dioxane (60 mL). The reaction mixture was purged well with argon for 15 min, treated with [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (250 mg, 0.342 mmol), purged again with Ar for 15 min. The tube was securely capped and placed into an 80 C. oil bath for 24 h, followed by room temp for 5 days. The reaction mixture was diluted with EtOAc (400 mL) and water (300 mL), and filtered through a pad of celite. The organic layer was washed with brine (1200 mL), dried over Na.sub.2SO.sub.4 and concentrated. The crude residue was dissolved in dichloromethane, applied to the head of a 120 g Teledyne Isco Silica Flash Column and purified on Biotage using a gradient from 100% hexanes to 100% dichloromethane over 8 column volumes. The fractions containing the product were evaporated in vacuo and then dried on high vacuum to give the pure title compound (2.25 g, 80%). .sup.1H NMR (500 MHz, CHLOROFORM-d) 7.28-7.26 (m, 1H), 7.23-7.19 (m, 1H), 7.00 (dd, J=8.0, 1.4 Hz, 1H), 4.11 (t, J=5.7 Hz, 2H), 3.40 (q, J=5.6 Hz, 2H), 2.07-1.99 (m, 2H), 1.46 (s, 9H), 1.39 (s, 12H).

Intermediate: di-tert-butyl (((2,2-dichloro-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))dicarbamate

(381) ##STR00156##

(382) To a solution of tert-butyl (3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)carbamate (1.68 g, 4.08 mmol) and tert-butyl (3-(3-bromo-2-chlorophenoxy)propyl)carbamate (1.488 g, 4.08 mmol) in THF (150 mL) was added potassium phosphate tribasic 0.5 M in water (20.5 ml, 10.25 mmol). The reaction mixture was flushed with argon, treated with 2.sup.nd generation xphos precatalyst (320 mg, 0.407 mmol), flushed with argon again and stirred at room temp for 66 h. The reaction was diluted with EtOAc (350 mL) and water (150 mL). The water layer was back extracted with additional EtOAc (200 mL). The organic layers were combined, washed with brine (175 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude residue was applied to the head of a 120 g Teledyne Isco Silica Flash Column and purified on Biotage using a gradient from 100% hexanes to 100% CH.sub.2Cl.sub.2 over 5 column volumes, followed by 10-20% EtOAc in CH.sub.2Cl.sub.2. The fractions containing the product were evaporated in vacuo and then dried on high vacuum to give the pure title compound (2.08 g, 85%). .sup.1H NMR (500 MHz, CHLOROFORM-d) 7.31-7.26 (m, 1H), 6.98 (dd, J=8.3, 1.1 Hz, 1H), 6.89 (dd, J=7.6, 1.2 Hz, 1H), 4.25-4.09 (m, 2H), 3.52-3.31 (m, 2H), 2.17-2.07 (m, 2H), 1.45 (s, 9H). LC/MS Condition A: ret time 1.45 min; m/e=591, 593 (M+Na).

Example 2134: 3,3-((2,2-dichloro-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propan-1-amine)

(383) ##STR00157##

(384) To a solution of di-tert-butyl (((2,2-dichloro-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))dicarbamate (1.28 g, 2.248 mmol) in dichloromethane (50 mL) was added TFA (6 mL, 78 mmol), and the mixture stirred at room temp for 2 h. The solvent was removed in vacuo and the residue was diluted with EtOAc (250 mL), washed with sat'd aq NaHCO.sub.3 (150 mL), brine (150 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give the title compound (388 mg, 47%). LC/MS Condition A: ret time 0.67 min; m/e=369, 371 (M+H).sup.+.

Example 2135: N,N-(((2,2-dichloro-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(2,3-dihydroxypropanamide)

(385) ##STR00158##

(386) To a mixture of 3,3-((2,2-dichloro-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propan-1-amine) (18 mg, 0.049 mmol) and 1-hydroxy-7-azabenzotriazole (6.63 mg, 0.049 mmol) in DMF (0.9 mL) was added 2,3-dihydroxypropanoic acid, 2 M in water (190 L, 0.380 mmol), N-methylmorpholine (15 L, 0.136 mmol) and EDC (40 mg, 0.209 mmol). The reaction mixture was capped and allowed to stir at room temp for 18 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-55% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound (13.6 mg, 50%), as a bis TFA salt.

(387) LC/MS Condition E: ret time 1.22 min; m/e=545, 547 (M+H).sup.+. LC/MS Condition F: ret time 1.31 min; m/e=545, 547 (M+H).sup.+.

Example 2136: (3R,3R)-4,4-((((2,2-dichloro-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(azanediyl))bis(3-hydroxy-4-oxobutanoic acid)

(388) ##STR00159##

(389) To a mixture of 3,3-((2,2-dichloro-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propan-1-amine) (15.4 mg, 0.042 mmol), 1-hydroxy-7-azabenzotriazole (5 mg, 0.037 mmol), and D-(+)-malic acid (80 mg, 0.597 mmol) in DMF (0.9 mL) and water (0.2 mL) was added N-methylmorpholine (20 L, 0.182 mmol), followed by EDC (30 mg, 0.156 mmol). The reaction mixture was capped and allowed to stir at 35 C. for 5 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 0-45% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. The material was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 10-40% B over 18 minutes, then a 3-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound (2.6 mg, 9%) as a bis TFA salt. LC/MS Condition E: ret time 0.96 min; m/e=601, 603 (M+H).sup.+.

(390) LC/MS Condition F: ret time 1.34 min; m/e=601, 603 (M+H).sup.+.

Intermediate: 2,2-dimethyl-[1,1-biphenyl]-3,3-dicarbaldehyde

(391) ##STR00160##

(392) To a dry 150 mL pressure bottle was added (2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)dimethanol (856 mg, 3.53 mmol) and anhydrous CH.sub.2Cl.sub.2 (100 mL), followed by solid black activated manganese dioxide (4.1 g, 47.2 mmol). The reaction mixture was capped and placed in a 55 C. oil bath for 18 h. The mixture was filtered warm through a pad of Celite and the pad was washed with CH.sub.2Cl.sub.2 (430 mL). The organic layers were combined and the solvent removed in vacuo to give the pure title compound (781 mg, 88%) that was used as is without further purification. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 10.35 (s, 2H), 7.91 (dd, J=7.7, 1.4 Hz, 2H), 7.53 (t, J=7.6 Hz, 2H), 7.42 (dd, J=7.5, 1.4 Hz, 2H), 2.30 (s, 6H).

(393) Examples 3001 to 3032 were prepared as described below:

Intermediate: (R)-1-(3-(3-bromo-2-methylphenoxy)propyl)pyrrolidin-3-ol

(394) ##STR00161##

(395) To a solution of 3-bromo-2-methylphenol (2 g, 10.69 mmol, 1 eq) in DMF (30 mL), was added 1-bromo-3-chloropropane (1.052 mL, 10.69 mmol, 1 eq) and K.sub.2CO.sub.3 (1.773 g, 12.83 mmol, 1.2 eq.). The reaction mixture was stirred at 50 C. for 16 h. The reaction mixture was cooled to room temperature, diluted with EtOAc. The mixture was washed with sat. NaHCO.sub.3, water, brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The crude product was purified on silica gel (220 g Isco cartridge) employing 20 column volumes of 0-20% EtOAc/hexane to give 2.16 g (40%) of the mixture 1-bromo-3-(3-chloropropoxy)-2-methylbenzene and 1-bromo-3-(3-bromopropoxy)-2-methylbenzene as a colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.20-7.15 (m, 1H), 7.01 (m, 1H), 6.80 (m, 1H), 4.12 (m, 2H), 3.77 (t, J=6.2 Hz, 1.70H), 3.63 (t, J=6.2 Hz, 0.30H), 2.36-2.23 (m, 5H).

(396) To a sealed tube was added (R)-3-hydroxypyrrolidine HCl (1.153 g, 9.33 mmol, 1.5 eq), DMF (20 mL), the mixture of 1-bromo-3-(3-chloropropoxy)-2-methylbenzene and 1-bromo-3-(3-bromopropoxy)-2-methylbenzene (2.05 g, 6.22 mmol), sodium iodide (1.399 g, 9.33 mmol, 1.5 eq) and K.sub.2CO.sub.3 (2.150 g, 15.56 mmol, 2.5 eq). The vessel was sealed and the mixture stirred overnight at 50 C. The mixture was cooled to room temperature and evaporated to a paste. The mixture was taken up in 30 mL of DCM, washed with 10 mL water3, brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The resulting residue was diluted with 10 mL of methanol and then pushed through a Waters 5 g MCX cartridge. The cartridge was flushed with 20 mL of methanol and the product eluted with 20 mL of 2M ammonia in methanol. Evaporation of the 2M ammonia solution gave 1.15 g (59%) of (R)-1-(3-(3-bromo-2-methylphenoxy)propyl)pyrrolidin-3-ol as a light yellow powder.

(397) The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 m C18, 230 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a rate of 1 mL/minute. LCMS Rt (Retention time)=1.328 min., m/z 316.2 (M+H). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.22-7.17 (m, 1H), 7.12 (t, J=8.1 Hz, 1H), 6.99 (d, J=8.1 Hz, 1H), 5.51 (d, J=3.8 Hz, 1H), 4.46-4.37 (m, 1H), 4.08 (t, J=6.0 Hz, 2H), 3.32-3.24 (m, 5H), 3.17 (d, J=4.4 Hz, 1H), 2.26 (s, 3H), 2.22-2.13 (m, 3H), 1.90 (m, 1H).
The following intermediates were synthesized in an analogous fashion as described above.

Intermediate: (R)-1-(4-(3-bromo-2-methylphenoxy)butyl)pyrrolidin-3-ol

(398) ##STR00162##

(399) The intermediate was obtained in 59% yield as a light tan oil with a purity of 98%. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 m C18, 230 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a rate of 1 mL/minute. LCMS Rt=1.342 min., m/z 328.15 & 330.05 (M+H). .sup.1H NMR (500 MHz, CDCl.sub.3) 7.14 (dd, J=8.0, 0.6 Hz, 1H), 7.03-6.96 (m, 1H), 6.76 (d, J=8.2 Hz, 1H), 4.35 (m, 1H), 3.98 (t, J=6.2 Hz, 2H), 2.89 (m, 1H), 2.73-2.66 (m, 1H), 2.57-2.49 (m, 3H), 2.38-2.26 (m, 4H), 2.19 (m, 1H), 1.91-1.82 (m, 2H), 1.79-1.61 (m, 3H).

Intermediate: (R)-1-(5-(3-bromo-2-methylphenoxy)pentyl)pyrrolidin-3-ol

(400) ##STR00163##

(401) The intermediate was obtained in 66% yield as a light tan oil with a purity of 99%. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 m C18, 230 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a rate of 1 mL/minute. LCMS Rt=1.392 min., m/z 342.05 & 344.15 (M+H). .sup.1H NMR (500 MHz, CDCl.sub.3) 7.14 (d, J=7.9 Hz, 1H), 6.99 (t, J=8.1 Hz, 1H), 6.76 (d, J=8.2 Hz, 1H), 4.34 (m, 1H), 3.96 (t, J=6.4 Hz, 2H), 2.87 (m, 1H), 2.68 (d, J=9.9 Hz, 1H), 2.52 (dd, J=9.9, 5.2 Hz, 1H), 2.50-2.43 (m, 2H), 2.36-2.25 (m, 4H), 2.25-2.13 (m, 1H), 1.83 (quin, J=6.9 Hz, 2H), 1.79-1.70 (m, 1H), 1.65-1.46 (m, 4H).

Intermediate: (R)-1-(3-(4-bromo-3-methylphenoxy)propyl)pyrrolidin-3-ol

(402) ##STR00164##

(403) (R)-1-(3-(4-Bromo-3-methylphenoxy)propyl)pyrrolidin-3-ol was synthesized in a similar fashion. First to obtain 1.01 g (57% yield, 80% purity) of a 4:1 mixture of 1-bromo-4-(3-chloropropoxy)-2-methylbenzene and 1-bromo-4-(3-bromopropoxy)-2-methylbenzene as a colorless oil. .sup.1H NMR (500 MHz, CDCl.sub.3) 7.41 (m, 1H), 6.81 (m, 1H), 6.67-6.60 (m, 1H), 4.15-4.01 (m, 2H), 3.74 (t, J=6.3 Hz, 1.6H), 3.60 (t, J=6.3 Hz, 0.4H), 2.37 (s, 3H), 2.36-2.18 (m, 2H).

(404) (R)-1-(3-(4-Bromo-3-methylphenoxy) propyl)pyrrolidin-3-ol was then obtained (685 mg, 90% yield, 95% purity) as a tan oil. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 m C18, 230 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a rate of 1 mL/minute. LCMS Rt=1.192 min., m/z 316.1 (M+H). .sup.1H NMR (500 MHz, CDCl.sub.3) 7.39 (d, J=8.7 Hz, 1H), 6.80 (d, J=2.8 Hz, 1H), 6.61 (dd, J=8.7, 2.8 Hz, 1H), 4.39-4.29 (m, 1H), 4.04-3.91 (m, 2H), 2.91 (m, 1H), 2.71 (d, J=10.2 Hz, 1H), 2.62 (t, J=7.3 Hz, 2H), 2.53 (m, 1H), 2.44 (t, J=7.3 Hz, 1H), 2.36 (s, 3H), 2.30 (m, 1H), 2.24-2.15 (m, 1H), 2.02-1.90 (m, 1H), 1.75 (m, 1H).

Intermediate: 3-(3-bromo-2-methylphenoxy)-N,N-dimethylpropan-1-amine

(405) ##STR00165##

(406) To a small sealed tube was added DMF (5 mL), 3-bromo-2-methylphenol (100 mg, 0.535 mmol), 3-chloro-N,N-dimethylpropan-1-amine (65.0 mg, 0.535 mmol), and potassium carbonate (89 mg, 0.642 mmol). The vessel was sealed and the mixture stirred over night at 65 C. The mixture was cooled, diluted with DCM (15 mL), washed with water, brine, dried over sodium sulfate, filtered and evaporated to give 126 mg (78% yield, 90% purity) of 3-(3-bromo-2-methylphenoxy)-N,N-dimethylpropan-1-amine as a tan oil. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 m C18, 230 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a rate of 1 mL/minute. LCMS Rt=1.320 min., m/z 272.20 & 274.15 (M+H). .sup.1H NMR (500 MHz, CDCl.sub.3) 7.14 (dd, J=8.0, 0.6 Hz, 1H), 7.02-6.96 (m, 1H), 6.78 (d, J=8.0 Hz, 1H), 4.01 (t, J=6.3 Hz, 2H), 2.50-2.44 (m, 2H), 2.32 (s, 3H), 2.27 (s, 6H), 1.98 (m, 2H).

(407) Intermediates (R)-3-bromo-N-(4-(3-hydroxypyrrolidin-1-yl)butyl)-2-methylbenzamide, (R)-3-bromo-N-(3-(3-hydroxypyrrolidin-1-yl)propyl)-2-methylbenzamide, and (R)-3-bromo-N-(2-(3-hydroxypyrrolidin-1-yl)ethyl)-2-methylbenzamide were synthesized in the following manner:

(408) ##STR00166##

Intermediate: (R)-3-bromo-N-(3-(3-hydroxypyrrolidin-1-yl)propyl)-2-methylbenzamide

(409) To a scintillation vial was added 3-bromo-2-methylbenzoic acid (250 mg, 1.163 mmol) in DMF (10 mL) along with Hunig's base (0.508 mL, 2.91 mmol), 3-chloropropan-1-amine, HCl (151 mg, 1.163 mmol), and HATU (1.326 g, 3.49 mmol). The vial was capped and the mixture shaken at room temperature for 2 hours. The resulting crude mixture in DMF was diluted with 10 mL of water and pulled through two 1 g of Waters HLB resin extraction cartridges. The resin was flushed with 20 mL of water, and the product eluted with 20 mL of methanol which was then evaporated to give 468 mg of 3-bromo-N-(3-chloropropyl)-2-methylbenzamide (99% yield, 85% purity) as an orange solid. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 m C18, 230 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a rate of 1 mL/minute. LCMS Rt=1.633 min., m/z 292.0 & 294.2 (M+H). .sup.1H NMR (500 MHz, CDCl.sub.3) 7.60 (dd, J=8.0, 1.0 Hz, 1H), 7.25 (dd, J=8.0, 1.0 Hz, 1H), 7.10-7.04 (m, 1H), 3.69-3.58 (m, 4H), 2.46 (s, 3H), 2.17-2.09 (m, 2H).

(410) To 3-bromo-N-(3-chloropropyl)-2-methylbenzamide (460 mg, 1.346 mmol) in DMF (20 mL) was added (R)-pyrrolidin-3-ol hydrochloride (3 eq, 499 mg, 4.04 mmol), sodium iodide (504 mg, 3.36 mmol) and potassium carbonate (465 mg, 3.36 mmol). The mixture was heated overnight at 50 C. The mixture was cooled, diluted with 50 mL of DCM, washed with 4 mL of water, dried over sodium sulfate, filtered and evaporated. The crude oil was taken up in 10 mL of methanol and pushed through a Waters 6 g MCX resin cartridge. The resin was flushed with 30 mL of methanol and the product eluted with 50 mL of 2M ammonia in methanol. Upon evaporation, 266.1 mg of (R)-3-bromo-N-(3-(3-hydroxypyrrolidin-1-yl)propyl)-2-methylbenzamide was obtained as a tan oil (43% yield, 98% purity). The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 m C18, 230 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a rate of 1 mL/minute. LCMS Rt=1.373 min., m/z 341.0 & 343.1 (M+H). .sup.1H NMR (500 MHz, CDCl.sub.3) 7.58 (d, J=8.0, 1H), 7.29-7.25 (m, 1H), 7.08-7.03 (m, 1H), 4.27 (m, 1H), 3.58-3.50 (m, 2H), 2.88 (m, 1H), 2.70-2.61 (m, 3H), 2.55-2.47 (m, 5H), 2.15-2.05 (m, 1H), 1.87-1.72 (m, 2H), 1.66-1.57 (m, 1H).

Intermediate: (R)-3-bromo-N-(4-(3-hydroxypyrrolidin-1-yl)butyl)-2-methylbenzamide

(411) 387 mg of 3-bromo-N-(4-chlorobutyl)-2-methylbenzamide was obtained (82% yield, 85% purity) in a similar fashion employing 1 eq of 4-chlorobutan-1-amine hydrochloride. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 m C18, 230 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a rate of 1 mL/minute. LCMS Rt=1.707 min., m/z 306.0 & 308.0 (M+H). .sup.1H NMR (500 MHz, CDCl.sub.3) 7.59 (dd, J=8.0, 1.0 Hz, 1H), 7.25 (dd, J=7.6, 0.9 Hz, 1H), 7.08-7.02 (m, 1H), 3.60 (t, J=6.4 Hz, 2H), 3.48 (q, J=6.9 Hz, 2H), 2.46 (s, 3H), 1.93-1.84 (m, 2H), 1.82-1.73 (m, 2H).

(412) 227.4 mg of (R)-3-bromo-N-(4-(3-hydroxypyrrolidin-1-yl)butyl)-2-methylbenzamide was obtained (46% yield, 90% purity) as a tan oil. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 m C18, 230 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a rate of 1 mL/minute. LCMS Rt=1.147 min., m/z 355.15 & 357.15 (M+H). .sup.1H NMR (500 MHz, CDCl.sub.3) 7.61-7.55 (m, 1H), 7.26-7.23 (m, 1H), 7.08-7.02 (m, 1H), 4.20 (m, 1H), 3.47-3.38 (m, 2H), 2.75 (m, 1H), 2.63-2.55 (m, 1H), 2.53-2.43 (m, 7H), 2.32-2.22 (m, 1H), 2.04-1.93 (m, 1H), 1.78-1.50 (m, 4H).

Intermediate: (R)-3-bromo-N-(2-(3-hydroxypyrrolidin-1-yl)ethyl)-2-methylbenzamide

(413) 425.8 mg of 3-bromo-N-(2-chloroethyl)-2-methylbenzamide was obtained (99% yield, 90% purity) in a similar fashion employing 1 eq of 2-chloroethanamine hydrochloride. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 m C18, 230 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a rate of 1 mL/minute. LCMS Rt=1.537 min., m/z 276.05 & 278.05 (M+H). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.63 (d, J=8.0 Hz, 1H), 7.32 (d, J=7.5 Hz, 1H), 7.17-7.03 (m, 1H), 6.17 (br. s., 1H), 3.92-3.67 (m, 4H), 2.49 (s, 3H).

(414) 120 mg of (R)-3-bromo-N-(2-(3-hydroxypyrrolidin-1-yl)ethyl)-2-methylbenzamide was obtained (26% yield, 99% purity) as a tan oil. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 Dm C18, 230 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a rate of 1 mL/minute. LCMS Rt=0.935 min., m/z 326.90 & 328.95 (M+H). .sup.1H NMR (500 MHz, CDCl.sub.3) 7.64 (d, J=8.0 Hz, 1H), 7.33-7.28 (m, 1H), 7.11-7.01 (m, 1H), 4.76-4.61 (m, 1H), 4.09-3.78 (m, 3H), 3.66-3.50 (m, 1H), 3.50-3.27 (m, 2H), 3.20 (d, J=12.5 Hz, 1H), 3.13-2.99 (m, 1H), 2.51-2.38 (m, 4H), 2.29-2.11 (m, 1H).

(415) Intermediate (R)-1-(3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)pyrrolidin-3-ol was synthesized in the following manner:

(416) ##STR00167##

(417) To a sealed tube was added 3-bromo-2-methylphenol (501 mg, 2.68 mmol) in dioxane (15.0 ml) along with potassium acetate (789 mg, 8.04 mmol), bis(pinacolato)diboron (1089 mg, 4.29 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (255 mg, 0.348 mmol). The vessel was sealed, the contents evacuated/flushed three times with nitrogen and then heated for 24 hours at 90 C. The volatiles were removed under a stream of nitrogen. The reaction mixture was then diluted with 50 mL of ethyl acetate and pushed through diatomaceous earth (Celite), and the bed then washed with 210 mL of ethyl acetate. The combined filtrates were washed with water, saturated sodium bicarbonate and brine, dried over sodium sulfate, and then evaporated to a dark oily solid. The compound was purified using a 40 g silica gel cartridge emplying 20 column volumes of 0-9% MeOH/DCM to give 707 mg (96% yield) of 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 m C18, 230 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a rate of 1 mL/minute. LCMS Rt=1.650 min., m/z 235.2 (M+H). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.19 (s, 1H), 7.06 (d, J=7.3 Hz, 1H), 6.97 (t, J=7.3 Hz, 1H), 6.87 (d, J=7.3 Hz, 1H), 2.29 (s, 3H), 1.33-1.25 (m, 12H).

(418) To 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (707 mg, 2.57 mmol) in DMF (8 mL) was added potassium carbonate (426 mg, 3.08 mmol) and 1-bromo-3-chloropropane (0.253 mL, 2.57 mmol). The mixture was stirred for 18 hours at room temperature. To the mixture was added 1 eq of 1-bromo-3-chloropropane (0.253 mL, 2.57 mmol) and 0.5 eq (178 mgs, 1.29 mmol) of potassium carbonate. The mixture was stirred an additional 18 hours at room temperature. The resulting product was diluted with 50 mL of DCM, washed with 5 mL of water, brine, dried over sodium sulfate, filtered and evaporated under a stream of nitrogen. The crude product was purified with a 40 g silica gel cartridge employing 0 to 20% EtOAc/Hexane to give 574.7 mg of a 2:1 mixture of 2-(3-(3-chloropropoxy)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 2-(3-(3-bromopropoxy)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (54% yield) as a colorless oil. .sup.1H NMR (500 MHz, CDCl.sub.3) 7.37 (dd, J=7.5, 1.0 Hz, 1H), 7.18-7.06 (m, 1H), 6.96-6.85 (m, 1H), 4.14-4.08 (m, 2H), 3.82-3.60 (m, 2H), 2.43 (s, 3H), 2.27 (m, 2H), 1.36 (s, 12H).

(419) To a sealed flask was added (R)-3-hydroxypyrrolidine hydrochloride (223 mg, 1.804 mmol), 2-(3-(3-chloropropoxy)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (574.7 mg, 1.388 mmol, the 2:1 mixture prepared above was used), DMF (8 mL), sodium iodide (312 mg, 2.081 mmol), and potassium carbonate (479 mg, 3.47 mmol). The flask was sealed and the mixture stirred for 40 hours at 50 C. The crude mixture was diluted with 75 mL of DCM, washed with water, brine, dried over sodium sulfate, filtered and evaporated. The resulting crude oil was taken up in 20 mL of methanol and pushed through SCX Bondesil resin. The resin was washed with 60 mL of additional methanol. The desired product was then eluted with 60 mL of 2M NH.sub.3 in methanol. The volatiles were evaporated to give 319.5 mg (60% yield) of (R)-1-(3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)pyrrolidin-3-ol as a waxy solid. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 m C18, 230 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a rate of 1 mL/minute. LCMS Rt=1.338 min., m/z 362.3 (M+H). .sup.1H NMR (500 MHz, CDCl.sub.3) 7.34 (dd, J=7.5, 1.0 Hz, 1H), 7.17-7.11 (t, J=7.5 Hz, 1H), 6.91 (dd, J=7.5, 1.0 Hz, 1H), 4.38-4.29 (m, 1H), 4.05-3.97 (m, 2H), 2.91 (m, 1H), 2.75-2.63 (m, 2H), 2.58-2.45 (m, 2H), 2.43 (s, 3H), 2.35-2.28 (m, 1H), 2.24-2.15 (m, 1H), 2.08-1.95 (m, 2H), 1.81-1.69 (m, 1H), 1.35 (s, 12H).

(420) Intermediate (R)-1-(3-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)pyrrolidin-3-ol was synthesized in the following manner:

(421) ##STR00168##

(422) 3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol was obtained (99% yield, 90% purity) as a tan foam. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 m C18, 230 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a rate of 1 mL/minute. LCMS Rt=1.727 min., m/z 235.3 (M+H). .sup.1H NMR (500 MHz, CDCl.sub.3) 7.68 (d, J=7.9 Hz, 1H), 6.64 (m, 2H), 5.14 (br. s., 1H), 2.50 (s, 3H), 1.33 (m, 12H).

(423) 2-(4-(3-Chloropropoxy)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 2-(4-(3-bromopropoxy)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (mixture) was obtained (61% yield, 85% purity) as a light tan oil. .sup.1H NMR (500 MHz, CDCl.sub.3) 7.72 (d, J=7.9 Hz, 1H), 6.81-6.63 (m, 2H), 4.19-4.01 (m, 2H), 3.75 (t, J=6.3 Hz, 1.5H), 3.60 (t, J=6.3 Hz, 0.5H), 2.53 (m, 3H), 2.32 (quin, J=6.1 Hz, 0.5H), 2.24 (quin, J=6.1 Hz, 1.5H), 1.34 (s, 12H).

(424) (R)-1-(3-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)pyrrolidin-3-ol was obtained (40% yield, 90% purity) as a light tan oil. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 m C18, 230 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a rate of 1 mL/minute. LCMS Rt=1.437 min., m/z 362.25 (M+H). .sup.1H NMR (500 MHz, CDCl.sub.3) 7.71 (d, J=7.9 Hz, 1H), 6.74-6.66 (m, 2H), 4.41-4.27 (m, 1H), 4.04 (t, J=6.4 Hz, 2H), 2.98-2.82 (m, 1H), 2.74-2.69 (m, 1H), 2.63 (t, J=7.3 Hz, 2H), 2.56-2.50 (s, 3H), 2.35-2.27 (m, 1H), 2.24-2.15 (m, 1H), 2.03-1.91 (m, 3H), 1.80-1.71 (m, 1H), 1.33 (s, 12H).

Intermediate: 3-bromo-N-(3-(dimethylamino)propyl)-2-methylbenzenesulfonamide

(425) ##STR00169##

(426) To a screw capped vial was added DCM (5 mL), N,N-dimethyl-1,3-propanediamine (37.9 mg, 0.371 mmol), Hunig's base (0.065 mL, 0.371 mmol), and finally 3-bromo-2-methylbenzene-1-sulfonyl chloride (100 mg, 0.371 mmol). The vial was capped and the mixture shaken for 2 hours. The reaction mixture was further diluted with 5 mL of DCM, washed with water, brine, dried over sodium sulfate, filtered, and evaporated to give 115.9 mg (89% yield, 95% purity) of 3-bromo-N-(3-(dimethylamino)propyl)-2-methylbenzenesulfonamide as a clear colorless oil. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 m C18, 230 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a rate of 1 mL/minute. LCMS Rt=1.100 min., m/z 337.1 (M+H). .sup.1H NMR (500 MHz, CDCl.sub.3) 7.97 (dd, J=7.9, 1.1 Hz, 1H), 7.76 (dd, J=8.0, 1.1 Hz, 1H), 7.22-7.10 (m, 1H), 3.08-2.97 (m, 2H), 2.74 (s, 3H), 2.46-2.37 (m, 2H), 2.25 (s, 6H), 1.71-1.59 (m, 2H).

Intermediate: tert-Butyl 3-(3-bromo-2-methylphenylsulfonamido)propanoate

(427) ##STR00170##

(428) To a small RBF (round-bottomed flask) was added THF (5 mL), tert-butyl 3-aminopropanoate, HCl (162 mg, 0.890 mmol), Hunig's base (0.272 mL, 1.558 mmol), and finally 3-bromo-2-methylbenzene-1-sulfonyl chloride (120 mg, 0.445 mmol). The flask was sealed and the mixture stirred for 6 hours under nitrogen. The solvent was removed, and the crude oil diluted with 30 mL of DCM, washed with water, brine, dried over sodium sulfate, filtered, and evaporated to give 160 mg of tert-butyl 3-(3-bromo-2-methylphenyl sulfonamido)propanoate (100% yield, 80% purity) as a yellow oil. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+/) at 220 nm using the following set of conditions: Phenomenex Luna 3 m C18, 230 mm column, with a gradient of 0-100% B (B=95% HPLC grade acetonitrile/10 Mm ammonium acetate/5% HPLC grade water), (A=95% HPLC grade water/10 Mm ammonium acetate/5% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a rate of 1 mL/minute. LCMS Rt=1.737 min., m/z 376.18 & 378.18 (MH).

(429) .sup.1H NMR (500 MHz, CDCl.sub.3) 7.96 (d, J=7.9 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H), 3.68-3.63 (m, 2H), 2.74 (s, 3H), 2.41 (t, J=6.0 Hz, 2H), 1.41 (s, 9H).

Intermediate: (R)-3-bromo-N-(2-(3-hydroxypyrrolidin-1-yl)ethyl)-2-methylbenzenesulfonamide

(430) ##STR00171##

(431) To a small RBF was added THF (5 mL), N-ethyl-N-isopropylpropan-2-amine (0.233 mL, 1.336 mmol), 2-chloroethanamine hydrochloride (51.6 mg, 0.445 mmol), and finally 3-bromo-2-methylbenzene-1-sulfonyl chloride (120 mg, 0.445 mmol). The flask was sealed and the mixture stirred for 6 hours under nitrogen. The solvent was removed, and the crude oil diluted with 30 mL of DCM, washed with water, brine, dried over sodium sulfate, filtered, and evaporated to give 140 mg of 3-bromo-N-(2-chloroethyl)-2-methylbenzenesulfonamide (100% yield, 80% purity) as a white foam. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 m C18, 230 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a rate of 1 mL/minute. LCMS Rt=1.573 min., m/z 314.1 (M+H). .sup.1H NMR (500 MHz, CDCl.sub.3) 7.96 (dd, J=8.0, 1.0 Hz, 1H), 7.76 (dd, J=8.0, 1.0 Hz, 1H), 7.22-7.13 (m, 1H), 3.56 (t, J=6.1 Hz, 2H), 3.30 (t, J=6.1 Hz, 2H), 2.76 (s, 3H).

(432) To a sealed tube was added (R)-pyrrolidin-3-ol hydrochloride (308 mg, 2.50 mmol), DMF (17 mL), potassium carbonate (287 mg, 2.079 mmol), sodium iodide (312 mg, 2.079 mmol), and 3-bromo-N-(2-chloroethyl)-2-methylbenzenesulfonamide (260 mg, 0.832 mmol). The vessel was sealed and the mixture stirred overnight at 65 C. The mixture was cooled, diluted with 40 mL DCM, washed with water, brine, dried over sodium sulfate, filtered, and evaporated to give a crude oil. The crude oil was taken up in 10 mL of methanol and pushed through a 5 g Biotage SCX-2 resin cartridge. The resin was flushed with additional 50 mL of methanol, and the product then eluted with 50 mL of 2M ammonia in methanol. Evaporation of the volatiles gave 138.9 mg of (R)-3-bromo-N-(2-(3-hydroxypyrrolidin-1-yl)ethyl)-2-methylbenzenesulfonamide (39% yield, 85% purity) as a tan oil. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 m C18, 230 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a rate of 1 mL/minute. LCMS Rt=1.009 min., m/z 363.00 & 365.00 (M+H). .sup.1H NMR (500 MHz, CDCl.sub.3) 8.00 (dd, J=8.0, 1.0 Hz, 1H), 7.78 (dd, J=8.0, 1.0 Hz, 1H), 7.24-7.13 (t, J=8.0 Hz, 1H), 4.36 (m, 1H), 3.01 (t, J=5.8 Hz, 2H), 2.77 (s, 3H), 2.76-2.69 (m, 1H), 2.56-2.47 (m, 4H), 2.24 (m, 1H), 2.20-2.13 (m, 1H), 1.79-1.69 (m, 1H).

Intermediate: 5-((3-bromo-2-methylphenoxy)methyl)nicotinonitrile

(433) ##STR00172##

(434) To a sealed tube was added DMF (5 mL), potassium carbonate (247 mg, 1.785 mmol), 3-bromo-2-methylphenol (278 mg, 1.488 mmol), and 5-(chloromethyl)nicotinonitrile (227 mg, 1.488 mmol). The vessel was sealed and the mixture stirred overnight at 65 C. The reaction mixture was cooled, taken up in 50 mL DCM, washed with water, brine, dried over sodium sulfate, filtered, and evaporated to give 463.1 mg of 5-((3-bromo-2-methylphenoxy)methyl)nicotinonitrile as a light tan solid (92% yield, 90% purity). The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 m C18, 230 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a rate of 1 mL/minute. LCMS Rt=1.772 min., m/z 303.0 (M+H). .sup.1H NMR (500 MHz, CDCl.sub.3) 8.91 (m, 2H), 8.09 (m, 1H), 7.27 (dd, J=8.0, 0.6 Hz, 1H), 7.09-7.03 (m, 1H), 6.84 (d, J=8.0 Hz, 1H), 5.16 (s, 2H), 2.40 (s, 3H).

Intermediate: 3-((3-bromo-2-methylphenoxy)methyl)benzonitrile was synthesized in a similar fashion

(435) ##STR00173##

(436) 441.4 mgs of 3-((3-bromo-2-methylphenoxy)methyl)benzonitrile (97% yield, 100% purity) was obtained as a white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.90 (s, 1H), 7.80 (m, 2H), 7.65-7.59 (m, 1H), 7.19 (dd, J=8.0, 0.8 Hz, 1H), 7.10 (t, J=8.0 Hz, 1H), 7.07-7.01 (m, 1H), 5.19 (s, 2H), 2.28 (s, 3H).

Intermediate: (R)N-(3-bromo-2-methylphenyl)-3-(3-hydroxypyrrolidin-1-yl)propanamide

(437) ##STR00174##

(438) To a RBF at room temperature under nitrogen, was added 3-bromo-2-methylaniline (1.00 g, 5.37 mmol) in DCM (15 mL) along with Hunig's base (0.939 mL, 5.37 mmol). To this solution was then added 3-chloropropionyl chloride (0.516 mL, 5.37 mmol) dropwise. Stirring was continued overnight at room temperature. The product was further diluted with DCM (30 mL), washed with water, brine, dried over magnesium sulfate, filtered and evaporated to give 1.54 g (62% yield, 70% purity) of N-(3-bromo-2-methylphenyl)-3-chloropropanamide as a yellow solid. .sup.1H NMR (500 MHz, CDCl.sub.3) 7.63 (d, J=8.0 Hz, 1H), 7.43 (d, J=7.9 Hz, 1H), 7.17-7.02 (m, 1H), 3.91 (t, J=6.2 Hz, 2H), 2.95-2.79 (m, 2H), 2.38 (s, 3H).

(439) To a RBF was added (R)-pyrrolidin-3-ol hydrochloride (670 mg, 5.42 mmol), DMF (40 mL), N-(3-bromo-2-methylphenyl)-3-chloropropanamide (500 mg, 1.81 mmol), sodium iodide (678 mg, 4.52 mmol), and potassium carbonate (625 mg, 4.52 mmol). The mixture was stirred overnight at 65 C. The mixture was cooled, diluted with 30 mL of DCM, washed with 5 mL water, brine, dried over sodium sulfate, filtered and evaporated to a crude oil. The crude oily mixture was taken up in 10 mL of methanol and pushed through a 5 g Biotage SCX resin cartridge. The resin was flushed with 20 mL of additional methanol and then the product was eluted with 30 mL of 2M ammonia in methanol. Evaporation of the volatiles gave 554 mg of (R)N-(3-bromo-2-methylphenyl)-3-(3-hydroxypyrrolidin-1-yl)propanamide (84% yield, 90% purity) as a tan oil. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 m C18, 230 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a rate of 1 mL/minute. LCMS Rt=1.022 min., m/z 327.2 & 330.1 (M+H). .sup.1H NMR (500 MHz, CDCl.sub.3) 10.57 (br. s., 1H), 7.95 (d, J=8.0 Hz, 1H), 7.38-7.30 (m, 1H), 7.05 (t, J=8.0 Hz, 1H), 4.57-4.47 (m, 1H), 3.03-2.95 (m, 1H), 2.95-2.81 (m, 3H), 2.77 (dd, J=10.5, 2.6 Hz, 1H), 2.64-2.55 (m, 3H), 2.38 (s, 3H), 2.30-2.17 (m, 1H), 1.90-1.79 (m, 1H).

Intermediate: (R)-1-(3-((3-bromo-2-methylphenyl)amino)propyl)pyrrolidin-3-ol

(440) ##STR00175##

(441) To (R)N-(3-bromo-2-methylphenyl)-3-(3-hydroxypyrrolidin-1-yl)propanamide (50 mg, 0.153 mmol) in THF (2 mL) under nitrogen at room temperature was added 1M borane-tetrahydrofuran complex (0.458 mL, 0.458 mmol). The mixture was stirred overnight under nitrogen. The reaction mixture was cooled to 0 C. and 5 mL of methanol was added dropwise. The mixture was stirred for 8 hours slowly reaching room temperature and then evaporated to dryness. An additional 5 mL of methanol was added and the product solution was again evaporated to give 45 mg (98% yield, 70% purity) of (R)-1-(3-((3-bromo-2-methylphenyl)amino)propyl)pyrrolidin-3-ol as a glass. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 m C18, 230 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a rate of 1 mL/minute. LCMS Rt=1.032 min., m/z 313.05 & 315.05 (M+H).

(442) .sup.1H NMR (500 MHz, CDCl.sub.3) 6.95 (m, 2H), 6.52 (t, J=4.7 Hz, 1H), 4.65 (m, 1H), 3.42 (m, 1H), 3.26 (m, 1H), 3.17 (m, 1H), 3.06 (m, 1H), 2.83 (m, 2H), 2.55 (m, 2H), 2.26 (s, 3H), 2.22 (m, 2H), 1.88 (m, 2H).

Intermediate: (R)-1-(3-bromo-2-methylphenyl)-3-(2-(3-hydroxypyrrolidin-1-yl)ethyl)urea

(443) ##STR00176##

(444) To a solution of 3-bromo-2-methylaniline (500 mg, 2.69 mmol) in THF (17 mL), under nitrogen, was added 2-chloroethyl isocyanate (0.229 mL, 2.69 mmol). The mixture was stirred at room temperature overnight. To the reaction mixture was added an additional 1 eq of 2-chloroethyl isocyanate (0.229 mL, 2.69 mmol). The solution was stirred for 24 hours at room temperature.

(445) The white heterogeneous reaction mixture was cooled to 0 C. and the resulting white solid was filtered to give 683 mg (87% yield, 100% purity) of 1-(3-bromo-2-methylphenyl)-3-(2-chloroethyl)urea as a fluffy white solid. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 m C18, 230 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a rate of 1 mL/minute. LCMS Rt=1.415 min., m/z 293.1 & 295.0 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.05 (br.s., 1H), 7.72 (d, J=7.8 Hz, 1H), 7.26 (d, J=7.8 Hz, 1H), 7.11-7.00 (t, J=7.8 Hz, 1H), 6.84 (t, J=5.5 Hz, 1H), 3.66 (t, J=5.9 Hz, 2H), 3.42 (q, J=5.9 Hz, 3H), 2.27 (s, 3H).

(446) To a sealed tube was added 1-(3-bromo-2-methylphenyl)-3-(2-chloroethyl)urea (200 mg, 0.686 mmol), DMF (10 mL), (R)-pyrrolidin-3-ol hydrochloride (848 mg, 6.86 mmol), potassium carbonate (379 mg, 2.74 mmol) and sodium iodide (206 mg, 1.372 mmol). The vessel was sealed and the mixture stirred overnight at 50 C. The mixture was cooled, diluted with water (10 mL) and pushed through two 1 g Waters HLB extraction cartridges. The resin was flushed with additional water (20 mL), and the product eluted with 20 mL of methanol. The product contained in the methanol solution was then pushed through a Biotage 5 g SCX-2 resin cartridge. The resin cartridge was flushed with additional methanol, and the product eluted with 50 mL of 2M ammonia in methanol. The volatiles were removed to give (R)-1-(3-bromo-2-methylphenyl)-3-(2-(3-hydroxypyrrolidin-1-yl)ethyl)urea (115 mg, 49% yield, 95% purity) as a tan glass. The LC/MS data was obtained on a Shimadzu analytical UPLC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Waters Aquity 1.7 m C18, 2.150 mm column, with a gradient of 0-100% B (B=100% HPLC grade acetonitrile/0.05% trifluoroacetic acid), (A=100% HPLC grade water/0.1% trifluoroacetic acid), in 1.5 minutes with a 0.5 minute hold at a rate of 0.8 mL/minute. LCMS Rt=1.009 min., m/z 341.80 & 343.80 (M+H). .sup.1H NMR (500 MHz, CDCl.sub.3) 7.43 (d, J=8.0 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.03 (t, J=8.0 Hz, 1H), 5.60 (m, 1H), 4.35-4.27 (m, 1H), 3.40-3.30 (m, 2H), 2.98-2.91 (m, 1H), 2.75 (m, 1H), 2.63 (m, 2H), 2.49 (m, 1H), 2.35 (s, 3H), 2.30-2.25 (m, 1H), 2.20-2.10 (m, 1H), 1.77-1.66 (m, 1H).

(447) Intermediate (3R,3R)-1,1-(((4-bromo-1,2-phenylene)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol) was synthesized in the following manner.

(448) ##STR00177##

(449) To a sealed tube was added DMF (10 mL), potassium carbonate (877 mg, 6.35 mmol), 1-bromo-3-chloropropane (0.458 mL, 4.66 mmol), and 4-bromocatechol (400 mg, 2.116 mmol). The vessel was sealed and the mixture stirred overnight at 65 C. The reaction mixture was cooled, diluted with 20 mL of water and pushed through two 1 g Waters HLB resin extraction cartridges. The resin was flushed with 220 mL of water. The product was eluted with 320 mL of methanol. Evaporation of the volatiles gave 556 mg of a mixture of 4-bromo-1,2-bis(3-chloropropoxy)benzene, 4-bromo-1-(3-bromopropoxy)-2-(3-chloropropoxy)benzene, 4-bromo-2-(3-bromopropoxy)-1-(3-chloropropoxy)benzene, and 4-bromo-1,2-bis(3-bromopropoxy)benzene as a crude red oil.

(450) To a sealed tube was added the above isolated red oil (556 mg, 1.625 mmol) in DMF (30 mL) along with (R)-pyrrolidin-3-ol hydrochloride (442 mg, 3.58 mmol), sodium iodide (609 mg, 4.06 mmol), and potassium carbonate (674 mg, 4.88 mmol). The vessel was sealed and the mixture stirred overnight at 65 C. The reaction mixture was cooled, diluted with 20 mL of water and pushed through a 5 g Waters HLB resin extraction cartridge. The cartridge flushed with an additional 30 mL of water. The product was eluted with 50 mL of methanol. The methanol solution was pushed through a Biotage SCX-2 ion exchange cartridge (5 g), and the cartridge flushed with 50 mL of additional methanol. The desired basic product was eluted with 75 mL of 2M ammonia in methanol. Evaporation of the volatiles gave 385 mg of a dark oil. The crude product mixture was taken up in methanol and purified using a Shimadzu preparative HPLC employing methanol/water/TFA where solvent A was 10% MeOH/90% H.sub.2O/0.1% trifluoroacetic acid and solvent B was 10% H.sub.2O/90% MeOH/0.1% trifluoroacetic acid with a Waters Sunfire 5 m C18 19100 mm column at a gradient of 20-100% B and a flow rate of 30 mL/min. over 15 minutes with a 3 minute hold. Evaporation of solvent gave 201.8 mg of (3R,3R)-1,1-(((4-bromo-1,2-phenylene)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol), 2 TFA (20% yield, 100% purity) as a light tan oil. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 m C18, 230 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a rate of 1 mL/minute. LCMS Rt=1.397 min., m/z 443.15 & 445.10 (M+H). .sup.1H NMR (500 MHz, CDCl.sub.3) 7.12-7.01 (m, 1H), 6.96 (s, 1H), 6.79-6.66 (m, 1H), 4.24 (m, 2H), 4.05 (d, J=5.4 Hz, 4H), 3.33 (m, 2H), 3.22 (m, 1H), 3.06 (m, 1H), 2.92 (m, 4H), 2.42 (m, 2H), 2.28 (m, 6H), 2.18 (m, 4H).

Example 3001: (3R,3R)-1,1-(((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol)

(451) ##STR00178##

(452) To a sealed tube was added (R)-1-(3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)pyrrolidin-3-ol (20 mg, 0.055 mmol), (R)-1-(3-(3-bromo-2-methyl phenoxy)propyl)pyrrolidin-3-ol (17.39 mg, 0.055 mmol), THF (2.0 mL), water (0.67 mL), potassium phosphate, tribasic (23.50 mg, 0.111 mmol), and second generation X-Phos precatalyst (2.178 mg, 2.77 mol). The flask was sealed, the mixture de-gassed/flushed with nitrogen and then heated overnight at 80 C. The reaction mixture was cooled, diluted with DCM (20 mL), extracted, washed with water, brine, dried over sodium sulfate, filtered, and evaporated to give a yellow oil. The crude oil was taken up in methanol and was purified via preparative LC/MS using the following conditions: Waters XBridge 5 m C18, 19200 mm where mobile phase A was 5:95 acetonitrile: water with 0.1% TFA and mobile phase B was 95:5 acetonitrile:water with 0.1% TFA at a gradient of 10-50% B over 20 minutes with a 5-minute hold at a flow rate of 20 mL/minute. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 26.3 mg (100%) as the bis-TFA salt, and its estimated purity by LCMS analysis was 100%.

(453) Two analytical LC/MS injections were used to determine the final purity.

(454) Injection 1 Conditions:

(455) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B was 95:5 acetonitrile:water with 10 mM ammonium acetate at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm.

(456) Injection 2 Conditions:

(457) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B was 95:5 acetonitrile:water with 0.1% trifluoroacetic acid at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm. Analysis condition 1: Retention time=1.218 min; ESI-MS(+) m/z=469.1 (M+H). Analysis condition 2: Retention time=1.158 min; ESI-MS(+) m/z=469.1 (M+H). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.20 (t, J=7.7 Hz, 2H), 6.95 (d, J=7.7 Hz, 2H), 6.66 (d, J=7.7 Hz, 2H), 5.43 (br. s., 2H), 4.42 (br. s., 2H), 4.20-3.94 (m, 4H), 3.51-3.02 (m, 6H), 2.74 (m, 2H), 2.55 (m, 4H), 2.27-2.02 (m, 6H), 1.85 (m, 8H).

(458) The following Examples were synthesized in an analogous fashion.

Example 3002: (R)-1-(3-((3-(4-((R)-3-hydroxypyrrolidin-1-yl)butoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl) pyrrolidin-3-ol

(459) ##STR00179##

(460) The crude material was purified via preparative LC/MS using the following conditions: Waters XBridge 5 m C18, 19200 mm where mobile phase A was 5:95 methanol:water with 10 mM ammonium acetate and mobile phase B was 95:5 methanol:water 10 mM ammonium acetate at a gradient of 20-60% B over 20 minutes with a 5-minute hold at a flow rate of 20 mL/minute. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 8.6 mg (30%), and its estimated purity by LCMS analysis was 94%.

(461) Two analytical LC/MS injections were used to determine the final purity.

(462) Injection 1 Conditions:

(463) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B was 95:5 acetonitrile:water with 10 mM ammonium acetate at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm.

(464) Injection 2 Conditions:

(465) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B was 95:5 acetonitrile:water with 0.1% trifluoroacetic acid at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm. Analysis condition 1: Retention time=1.131 min; ESI-MS(+) m/z=483.2 (M+H); Analysis condition 2: Retention time=1.209 min; ESI-MS(+) m/z=483.2 (M+H); .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.16 (t, J=7.9 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 6.62 (d, J=7.7 Hz, 2H), 4.18 (m, 2H), 4.07-3.94 (m, 4H), 2.76-2.70 (m, 2H), 2.65-2.55 (m, 4H), 2.49-2.43 (m, 3H), 2.39-2.33 (m, 2H), 2.02-1.91 (m, 3H), 1.90 (m, 2H), 1.81 (s, 6H), 1.79-1.73 (m, 2H), 1.66-1.59 (m, 2H), 1.54 (m, 2H).

Example 3003: (R)-1-(3-((3-((5-((R)-3-hydroxypyrrolidin-1-yl)pentyl)oxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(466) ##STR00180##

(467) The crude material was purified via preparative LC/MS using the following conditions: Waters XBridge 5 m C18, 19200 mm where mobile phase A was 5:95 methanol:water with 10 mM ammonium acetate and mobile phase B was 95:5 methanol:water 10 mM ammonium acetate at a gradient of 20-60% B over 25 minutes with a 5-minute hold at a flow rate of 20 mL/minute. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 10.3 mg (37%), and its estimated purity by LCMS analysis was 97%.

(468) Two analytical LC/MS injections were used to determine the final purity.

(469) Injection 1 Conditions:

(470) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B was 95:5 acetonitrile:water with 10 mM ammonium acetate at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm.

(471) Injection 2 Conditions:

(472) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B was 95:5 acetonitrile:water with 0.1% trifluoroacetic acid at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm. Analysis condition 1: Retention time=1.368 min; ESI-MS(+) m/z=497.2 (M+H); Analysis condition 2: Retention time=1.302 min; ESI-MS(+) m/z=497.2 (M+H); .sup.1H NMR (500 MHz, CDCl.sub.3) 7.16 (t, J=7.8 Hz, 2H), 6.82 (d, J=8.2 Hz, 2H), 6.73 (t, J=7.4 Hz, 2H), 4.49-4.39 (m, 2H), 4.15-3.97 (m, 4H), 3.42-3.34 (m, 1H), 3.29-3.19 (m, 2H), 3.13-3.05 (m, 1H), 2.88-2.84 (m, 2H), 2.83-2.67 (m, 4H), 2.65-2.49 (m, 2H), 2.32-2.20 (m, 2H), 2.14 (m, 2H), 1.92 (m, 8H), 1.90-1.83 (m, 2H), 1.80-1.70 (m, 2H), 1.64-1.52 (m, 2H).

Example 3004: (R)-1-(3-((3-(4-((R)-3-hydroxypyrrolidin-1-yl)butoxy)-2,2-dimethyl-[1,1-biphenyl]-4-yl)oxy)propyl) pyrrolidin-3-ol

(473) ##STR00181##

(474) The crude material was purified via preparative LC/MS using the following conditions: Waters XBridge 5 m C18, 19200 mm where mobile phase A was 5:95 methanol:water with 10 mM ammonium acetate and mobile phase B was 95:5 methanol:water 10 mM ammonium acetate at a gradient of 5-45% B over 20 minutes with a 5-minute hold at a flow rate of 20 mL/minute. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 19.6 mg (70%), and its estimated purity by LCMS analysis was 96%.

(475) Two analytical LC/MS injections were used to determine the final purity.

(476) Injection 1 Conditions:

(477) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B was 95:5 acetonitrile:water with 10 mM ammonium acetate at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm.

(478) Injection 2 Conditions:

(479) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B was 95:5 acetonitrile:water with 0.1% trifluoroacetic acid at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm. Analysis condition 1: Retention time=1.212 min; ESI-MS(+) m/z=483.1 (M+H); Analysis condition 2: Retention time=1.252 min; ESI-MS(+) m/z=483.2 (M+H); .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.15 (t, J=7.9 Hz, 1H), 6.92 (t, J=7.5 Hz, 2H), 6.84 (s, 1H), 6.78-6.75 (m, 1H), 6.62 (d, J=7.3 Hz, 1H), 4.19 (m, 2H), 4.04-3.96 (m, 4H), 3.33 (m, 2H), 2.73 (m, 2H), 2.63 (m, 2H), 2.61-2.53 (m, 4H), 2.38 (m, 2H), 2.02-1.93 (m, 5H), 1.89-1.85 (m, 2H), 1.83 (s, 3H), 1.81-1.73 (m, 2H), 1.65-1.58 (m, 2H), 1.55 (m, 2H).

Example 3005: (R)-1-(3-((3-((5-((R)-3-hydroxypyrrolidin-1-yl)pentyl)oxy)-2,2-dimethyl-[1,1-biphenyl]-4-yl)oxy)propyl)pyrrolidin-3-ol

(480) ##STR00182##

(481) The crude material was purified via preparative LC/MS using the following conditions: Waters XBridge 5 m C18, 19200 mm where mobile phase A was 5:95 methanol:water with 10 mM ammonium acetate and mobile phase B was 95:5 methanol:water 10 mM ammonium acetate at a gradient of 5-45% B over 20 minutes with a 5-minute hold at a flow rate of 20 mL/minute. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 9.3 mg (33%), and its estimated purity by LCMS analysis was 98%.

(482) Two analytical LC/MS injections were used to determine the final purity.

(483) Injection 1 Conditions:

(484) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B was 95:5 acetonitrile:water with 10 mM ammonium acetate at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm.

(485) Injection 2 Conditions:

(486) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B was 95:5 acetonitrile:water with 0.1% trifluoroacetic acid at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm. Analysis condition 1: Retention time=1.297 min; ESI-MS(+) m/z=497.2 (M+H); Analysis condition 2: Retention time=1.327 min; ESI-MS(+) m/z=497.2 (M+H); .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.19-7.13 (m, 1H), 6.92 (t, J=7.9 Hz, 2H), 6.85 (m, 1H), 6.78 (dd, J=8.4, 1.0 Hz, 1H), 6.63 (d, J=7.3 Hz, 1H), 4.21 (m, 2H), 4.06-3.96 (m, 4H), 3.39 (m, 2H), 2.85-2.68 (m, 3H), 2.68-2.54 (m, 5H), 2.41 (m, 2H), 2.05-1.97 (m, 2H), 1.95 (s, 3H), 1.92-1.86 (m, 2H), 1.83 (s, 3H), 1.80-1.72 (m, 2H), 1.63-1.43 (m, 6H).

Example 3006: (3R,3R)-1,1-(((2,2-dimethyl-[1,1-biphenyl]-3,4-diyl)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol)

(487) ##STR00183##

(488) The crude material was purified via preparative LC/MS using the following conditions: Waters XBridge 5 m C18, 19200 mm where mobile phase A was 5:95 methanol:water with 10 mM ammonium acetate and mobile phase B was 95:5 methanol:water 10 mM ammonium acetate at a gradient of 5-45% B over 20 minutes with a 5-minute hold at a flow rate of 20 mL/minute. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 16.7 mg (64%), and its estimated purity by LCMS analysis was 100%.

(489) Two analytical LC/MS injections were used to determine the final purity.

(490) Injection 1 Conditions:

(491) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B was 95:5 acetonitrile:water with 10 mM ammonium acetate at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm.

(492) Injection 2 Conditions:

(493) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B was 95:5 acetonitrile:water with 0.1% trifluoroacetic acid at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm. Analysis condition 1: Retention time=1.148 min; ESI-MS(+) m/z=469.1 (M+H); Analysis condition 2: Retention time=1.190 min; ESI-MS(+) m/z=469.1 (M+H); .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.16 (t, J=7.9 Hz, 1H), 6.92 (m, 2H), 6.85 (m, 1H), 6.82-6.73 (m, 1H), 6.63 (d, J=7.3 Hz, 1H), 4.19 (m, 2H), 4.08-3.98 (m, 4H), 2.78-2.70 (m, 2H), 2.68-2.56 (m, 5H), 2.48 (m, 2H), 2.37 (m, 2H), 2.05-1.97 (m, 2H), 1.95 (s, 3H), 1.94-1.85 (m, 5H), 1.83 (s, 3H), 1.61-1.49 (m, 2H).

Example 3007: (R)-1-(3-((3-(3-(dimethylamino)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(494) ##STR00184##

(495) The crude material was purified via preparative LC/MS using the following conditions: Waters XBridge 5 m C18, 19200 mm where mobile phase A was 5:95 acetonitrile:water with 0.1% TFA and mobile phase B was 95:5 acetonitrile:water with 0.1% TFA at a gradient of 10-50% B over 20 minutes with a 5-minute hold at a flow rate of 20 mL/minute. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 55.6 mg (56%), and its estimated purity by LCMS analysis was 97%.

(496) Two analytical LC/MS injections were used to determine the final purity.

(497) Injection 1 Conditions:

(498) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B was 95:5 acetonitrile:water with 10 mM ammonium acetate at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm.

(499) Injection 2 Conditions:

(500) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B was 95:5 acetonitrile:water with 0.1% trifluoroacetic acid at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm. Analysis condition 1: Retention time=1.131 min; ESI-MS(+) m/z=427.1 (M+H); Analysis condition 2: Retention time=1.127 min; ESI-MS(+) m/z=427.3 (M+H); .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.19 (t, J=7.9 Hz, 2H), 6.94 (d, J=8.1 Hz, 2H), 6.65 (d, J=7.3 Hz, 2H), 4.43 (br. s., 1H), 4.11-4.01 (m, 4H), 3.43 (m, 4H), 3.32 (m, 2H), 3.28-3.09 (m, 2H), 2.81 (s, 6H), 2.21-2.07 (m, 5H), 1.84 (m, 7H).

Example 3008: N-(4-((R)-3-hydroxypyrrolidin-1-yl)butyl)-3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-carboxamide

(501) ##STR00185##

(502) The crude material was purified via preparative LC/MS using the following conditions: Waters XBridge 5 m C18, 19200 mm where mobile phase A was 5:95 acetonitrile:water with 0.1% TFA and mobile phase B was 95:5 acetonitrile:water with 0.1% TFA at a gradient of 10-50% B over 20 minutes with a 5-minute hold at a flow rate of 20 mL/minute. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 63.2 mg (58.4%), and its estimated purity by LCMS analysis was 100%.

(503) Two analytical LC/MS injections were used to determine the final purity.

(504) Injection 1 Conditions:

(505) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B was 95:5 acetonitrile:water with 10 mM ammonium acetate at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm.

(506) Injection 2 Conditions:

(507) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B was 95:5 acetonitrile:water with 0.1% trifluoroacetic acid at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm. Analysis condition 1: Retention time=1.023 min; ESI-MS(+) m/z=510.2 (M+H); Analysis condition 2: Retention time=1.032 min; ESI-MS(+) m/z=510.2 (M+H); .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.38 (br. s., 1H), 7.28 (m, 2H), 7.22 (t, J=7.9 Hz, 1H), 7.14-7.06 (m, 1H), 6.96 (d, J=8.4 Hz, 1H), 6.65 (d, J=7.7 Hz, 1H), 4.43 (br. s., 2H), 4.08 (m, 2H), 3.59 (m, 1H), 3.44 (m, 4H), 3.33 (m, 2H), 3.24 (m, 3H), 3.16 (m, 2H), 3.07 (m, 1H), 2.15 (m, 4H), 1.96 (m, 4H), 1.85 (m, 5H), 1.68 (m, 2H), 1.53 (m, 2H).

Example 3009: 3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-N-(3-((R)-3-hydroxypyrrolidin-1-yl)propyl)-2,2-dimethyl-[1,1-biphenyl]-3-carboxamide

(508) ##STR00186##

(509) The crude material was purified via preparative LC/MS using the following conditions: Waters XBridge 5 m C18, 19200 mm where mobile phase A was 5:95 acetonitrile:water with 0.1% TFA and mobile phase B was 95:5 acetonitrile:water with 0.1% TFA at a gradient of 5-45% B over 20 minutes with a 5-minute hold at a flow rate of 20 mL/minute. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 62.1 mg (58%), and its estimated purity by LCMS analysis was 99%.

(510) Two analytical LC/MS injections were used to determine the final purity.

(511) Injection 1 Conditions:

(512) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B was 95:5 acetonitrile:water with 10 mM ammonium acetate at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm.

(513) Injection 2 Conditions:

(514) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B was 95:5 acetonitrile:water with 0.1% trifluoroacetic acid at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm. Analysis condition 1: Retention time=0.903 min; ESI-MS(+) m/z=496.2 (M+H); Analysis condition 2: Retention time=0.953 min; ESI-MS(+) m/z=496.2 (M+H); .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.51-8.41 (m, 1H), 7.37-7.27 (m, 2H), 7.23 (t, J=7.9 Hz, 1H), 7.11 (d, J=7.3 Hz, 1H), 6.97 (d, J=8.1 Hz, 1H), 6.66 (d, J=7.7 Hz, 1H), 4.44 (br. s., 2H), 4.15-4.02 (m, 2H), 3.65 (m, 1H), 3.42 (m, 5H), 3.29 (m, 4H), 3.25 (m, 4H), 2.26 (m, 1H), 2.16 (m, 2H), 1.98 (m, 4H), 1.95-1.79 (m, 7H).

Example 3010: (R)N-(3-(dimethylamino)propyl)-3-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-sulfonamide

(515) ##STR00187##

(516) The crude material was purified via preparative LC/MS using the following conditions: Waters XBridge 5 m C18, 19200 mm where mobile phase A was 5:95 acetonitrile:water with 0.1% TFA and mobile phase B was 95:5 acetonitrile:water with 0.1% TFA at a gradient of 10-50% B over 20 minutes with a 5-minute hold at a flow rate of 20 mL/minute. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 68.9 mg (65%), and its estimated purity by LCMS analysis was 99%.

(517) Two analytical LC/MS injections were used to determine the final purity.

(518) Injection 1 Conditions:

(519) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B was 95:5 acetonitrile:water with 10 mM ammonium acetate at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm.

(520) Injection 2 Conditions:

(521) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B was 95:5 acetonitrile:water with 0.1% trifluoroacetic acid at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm. Analysis condition 1: Retention time=0.991 min; ESI-MS(+) m/z=490.1 (M+H); Analysis condition 2: Retention time=1.036 min; ESI-MS(+) m/z=490.1 (M+H); .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.86 (d, J=7.7 Hz, 1H), 7.46 (t, J=7.7 Hz, 1H), 7.33 (d, J=7.3 Hz, 1H), 7.26 (t, J=7.7 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.70 (d, J=7.7 Hz, 1H), 4.44 (br. s., 1H), 4.16-4.04 (m, 2H), 3.41-3.30 (m, 4H), 3.34 (m, 1H), 3.25 (m, 1H), 3.06 (m, 2H), 2.91 (m, 2H), 2.75 (s, 6H), 2.25 (s, 3H), 2.16 (m, 3H), 1.91 (m, 1H), 1.83 (s, 3H), 1.78 (m, 2H).

Example 3011: (R)-5-(((3-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)methylnicotinonitrile

(522) ##STR00188##

(523) The crude material was purified via preparative LC/MS using the following conditions: Waters XBridge 5 m C18, 19200 mm where mobile phase A was 5:95 acetonitrile:water with 10-mM ammonium acetate and mobile phase B was 95:5 acetonitrile:water with 10-mM ammonium acetate at a gradient of 20-60% B over 20 minutes with a 5-minute hold at a flow rate of 20 mL/minute. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 22.8 mg (37%), and its estimated purity by LCMS analysis was 98%.

(524) Two analytical LC/MS injections were used to determine the final purity.

(525) Injection 1 Conditions:

(526) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B was 95:5 acetonitrile:water with 10 mM ammonium acetate at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm.

(527) Injection 2 Conditions:

(528) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B was 95:5 acetonitrile:water with 0.1% trifluoroacetic acid at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm. Analysis condition 1: Retention time=2.051 min; ESI-MS(+) m/z=458.1 (M+H); Analysis condition 2: Retention time=1.986 min; ESI-MS(+) m/z=458.1 (M+H); .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.00 (m, 2H), 8.43 (t, J=2.0 Hz, 1H), 7.26-7.14 (m, 2H), 7.07 (d, J=8.2 Hz, 1H), 6.93 (d, J=7.9 Hz, 1H), 6.71 (d, J=7.3 Hz, 1H), 6.64 (d, J=7.3 Hz, 1H), 5.31-5.19 (m, 2H), 4.23-4.13 (m, 1H), 4.10-3.97 (m, 2H), 2.73-2.66 (m, 1H), 2.62-2.52 (m, 3H), 2.43 (m, 1H), 2.32 (m, 1H), 1.97 (m, 1H), 1.90 (m, 2H), 1.86 (s, 3H), 1.82 (s, 3H), 1.53 (m, 1H).

Example 3012: (3R,3R)-1,1-(((2,2-dimethyl-[1,1-biphenyl]-4,4-diyl)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol)

(529) ##STR00189##

(530) The crude material was purified via preparative LC/MS using the following conditions: Waters XBridge 5 m C18, 19200 mm where mobile phase A was 5:95 acetonitrile:water with 10 mM ammonium acetate and mobile phase B was 95:5 methanol:water with 10 mM ammonium acetate at a gradient of 3-38% B over 30 minutes with a 5-minute hold at a flow rate of 20 mL/minute. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 18.1 mg (35%), and its estimated purity by LCMS analysis was 100%.

(531) Two analytical LC/MS injections were used to determine the final purity.

(532) Injection 1 Conditions:

(533) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B was 95:5 acetonitrile:water with 10 mM ammonium acetate at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm.

(534) Injection 2 Conditions:

(535) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B was 95:5 acetonitrile:water with 0.1% trifluoroacetic acid at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm. Analysis condition 1: Retention time=1.479 min; ESI-MS(+) m/z=469.2 (M+H); Analysis condition 2: Retention time=1.816 min; ESI-MS(+) m/z=469.1 (M+H); .sup.1H NMR (500 MHz, DMSO-d.sub.6) 6.93 (d, J=8.2 Hz, 2H), 6.85 (d, J=2.4 Hz, 2H), 6.78 (dd, J=8.2, 2.4 Hz, 2H), 5.02 (br. s., 2H), 4.29 (m, 2H), 4.04 (t, J=6.3 Hz, 4H), 2.96 (m, 4H), 2.85 (m, 6H), 2.71 (m, 2H), 2.06 (m, 2H), 2.01-1.97 (m, 2H), 1.96 (m, 10H), 1.68 (m, 2H).

Example 3013: 3-((R)-3-hydroxypyrrolidin-1-yl)-N-(3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)propanamide

(536) ##STR00190##

(537) The crude material was purified via preparative LC/MS using the following conditions: Waters XBridge 5 m C18, 19200 mm where mobile phase A was 5:95 acetonitrile:water with 10 mM ammonium acetate and mobile phase B was 95:5 methanol:water with 10 mM ammonium acetate at a gradient of 3-43% B over 30 minutes with a 5-minute hold at a flow rate of 20 mL/minute. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 29.8 mg (53.6%), and its estimated purity by LCMS analysis was 96%.

(538) Two analytical LC/MS injections were used to determine the final purity.

(539) Injection 1 Conditions:

(540) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B was 95:5 acetonitrile:water with 10 mM ammonium acetate at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm.

(541) Injection 2 Conditions:

(542) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B was 95:5 acetonitrile:water with 0.1% trifluoroacetic acid at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm. Analysis condition 1: Retention time=1.422 min; ESI-MS(+) m/z=482.1 (M+H); Analysis condition 2: Retention time=1.446 min; ESI-MS(+) m/z=482.1 (M+H); .sup.1H NMR (500 MHz, DMSO-d.sub.6) 10.02 (s, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.18 (t, J=7.9 Hz, 2H), 6.93 (d, J=8.1 Hz, 1H), 6.83 (d, J=7.7 Hz, 1H), 6.63 (d, J=7.7 Hz, 1H), 4.19 (m, 2H), 4.09-3.99 (m, 2H), 2.79-2.66 (m, 5H), 2.66-2.55 (m, 3H), 2.49 (m, 4H), 2.43 (m, 1H), 2.37 (m, 1H), 1.98 (m, 2H), 1.93-1.91 (m, 2H), 1.87 (s, 3H), 1.81 (s, 3H), 1.60-1.48 (m, 2H).

Example 3014: (R)-3-(3-(3-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)ureido)propanoic acid

(543) ##STR00191##

(544) The crude material was purified via preparative LC/MS using the following conditions: Waters XBridge 5 m C18, 19200 mm where mobile phase A was 5:95 acetonitrile:water with 10 mM ammonium acetate and mobile phase B was 95:5 acetonitrile:water with 10 mM ammonium acetate at a gradient of 5-45% B over 15 minutes with a 5-minute hold at a flow rate of 20 mL/minute. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 12.7 mg (25%), and its estimated purity by LCMS analysis was 100%.

(545) Two analytical LC/MS injections were used to determine the final purity.

(546) Injection 1 Conditions:

(547) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B was 95:5 acetonitrile:water with 10 mM ammonium acetate at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm.

(548) Injection 2 Conditions:

(549) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B was 95:5 acetonitrile:water with 0.1% trifluoroacetic acid at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm. Analysis condition 1: Retention time=0.967 min; ESI-MS(+) m/z=456.2 (M+H); Analysis condition 2: Retention time=1.290 min; ESI-MS(+) m/z=456.4 (M+H); .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.81 (d, J=8.1 Hz, 1H), 7.78 (br. s., 1H), 7.18 (t, J=7.9 Hz, 1H), 7.12 (t, J=7.9 Hz, 1H), 6.93 (d, J=8.1 Hz, 1H), 6.72-6.61 (m, 3H), 4.21 (br. s., 1H), 4.10-3.99 (m, 2H), 2.77 (d, J=7.7 Hz, 1H), 2.70-2.59 (m, 3H), 2.55 (m, 3H), 2.43 (m, 3H), 1.94 (m, 3H), 1.83 (m, 6H), 1.57 (d, J=4.0 Hz, 1H).

Example 3015: N-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)-3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-carboxamide

(550) ##STR00192##

(551) The crude material was purified via preparative LC/MS using the following conditions: Waters XBridge 5 m C18, 19200 mm where mobile phase A was 5:95 methanol:water with 10-mM ammonium acetate and mobile phase B was 95:5 methanol:water with 10-mM ammonium acetate at a gradient of 30-70% B over 15 minutes with a 5-minute hold at a flow rate of 20 mL/minute. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 22.4 mg (42%), and its estimated purity by LCMS analysis was 100%.

(552) Two analytical LC/MS injections were used to determine the final purity.

(553) Injection 1 Conditions:

(554) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B was 95:5 acetonitrile:water with 10 mM ammonium acetate at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm.

(555) Injection 2 Conditions:

(556) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B was 95:5 acetonitrile:water with 0.1% trifluoroacetic acid at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm. Analysis condition 1: Retention time=1.335 min; ESI-MS(+) m/z=482.1 (M+H); Analysis condition 2: Retention time=1.136 min; ESI-MS(+) m/z=482.1 (M+H); .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.24 (t, J=5.5 Hz, 1H), 7.27 (m, 2H), 7.20 (t, J=8.1 Hz, 1H), 7.10 (t, J=7.7 Hz, 1H), 6.95 (d, J=8.1 Hz, 1H), 6.64 (d, J=7.7 Hz, 1H), 4.20 (m, 2H), 4.12-4.00 (m, 2H), 2.78 (m, 2H), 2.65 (m, 4H), 2.62-2.54 (m, 4H), 2.50 (m, 2H), 2.46 (m, 1H), 2.38 (m, 1H), 2.06-1.93 (m, 7H), 1.84 (s, 3H), 1.56 (m, 2H).

Example 3016: N-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)-3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-sulfonamide

(557) ##STR00193##

(558) The crude material was purified via preparative LC/MS using the following conditions: Waters XBridge 5 m C18, 19200 mm where mobile phase A was 5:95 acetonitrile:water with 10-mM ammonium acetate and mobile phase B was 95:5 acetonitrile:water with 10-mM ammonium acetate at a gradient of 5-45% B over 30 minutes with a 5-minute hold at a flow rate of 20 mL/minute. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS using the following conditions: Waters XBridge 5 m C18, 19200 mm where mobile phase A was 5:95 acetonitrile:water with 0.1% TFA and mobile phase B was 95:5 acetonitrile:water with 0.1% TFA at a gradient of 10-100% B over 15 minutes with a 5-minute hold at a flow rate of 20 mL/minute. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 18.7 mg (33%), and its estimated purity by LCMS analysis was 100%.

(559) Two analytical LC/MS injections were used to determine the final purity.

(560) Injection 1 Conditions:

(561) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B was 95:5 acetonitrile:water with 10 mM ammonium acetate at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm.

(562) Injection 2 Conditions:

(563) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B was 95:5 acetonitrile:water with 0.1% trifluoroacetic acid at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm. Analysis condition 1: Retention time=1.077 min; ESI-MS(+) m/z=518.2 (M+H); Analysis condition 2: Retention time=1.029 min; ESI-MS(+) m/z=518.2 (M+H); .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.87 (d, J=7.7 Hz, 1H), 7.47 (t, J=7.7 Hz, 1H), 7.34 (d, J=7.0 Hz, 1H), 7.25 (t, J=7.0 Hz, 1H), 7.00 (d, J=7.7 Hz, 1H), 6.70 (d, J=7.0 Hz, 1H), 4.48-4.37 (m, 2H), 4.09 (m, 2H), 3.37 (m, 5H), 3.16 (m, 1H), 2.69 (m, 2H), 2.54 (m, 2H), 2.49 (m, 3H), 2.24 (s, 3H), 2.16 (m, 5H), 1.88 (m, 2H), 1.82 (s, 3H).

Example 3017: 1-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)-3-(3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)urea

(564) ##STR00194##

(565) The crude material was purified via preparative LC/MS using the following conditions: Waters XBridge 5 m C18, 19200 mm where mobile phase A was 5:95 acetonitrile:water with 10 mM ammonium acetate and mobile phase B was 95:5 acetonitrile:water with 10 mM ammonium acetate at a gradient of 0-30% B over 25 minutes with a 5-minute hold at a flow rate of 20 mL/minute. Fractions containing the desired product were combined and dried via centrifugal evaporation.

(566) The compound was further purified via preparative LC/MS using the following conditions: Waters XBridge 5 m C18, 19200 mm where mobile phase A was 5:95 acetonitrile:water with 0.1% TFA and mobile phase B was 95:5 acetonitrile:water with 0.1% TFA at a gradient of 0-40% B over 20 minutes with a 5-minute hold at a flow rate of 20 mL/minute. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 12.5 mg (10%), and its estimated purity by LCMS analysis was 99%.

(567) Two analytical LC/MS injections were used to determine the final purity.

(568) Injection 1 Conditions:

(569) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B was 95:5 acetonitrile:water with 10 mM ammonium acetate at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm.

(570) Injection 2 Conditions:

(571) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B was 95:5 acetonitrile:water with 0.1% trifluoroacetic acid at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm. Analysis condition 1: Retention time=1.032 min; ESI-MS(+) m/z=497.2 (M+H); Analysis condition 2: Retention time=1.075 min; ESI-MS(+) m/z=497.2 (M+H); .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.99 (br. s., 1H), 7.74 (d, J=8.2 Hz, 1H), 7.24-7.11 (m, 2H), 6.94 (d, J=8.2 Hz, 1H), 6.88 (t, J=5.8 Hz, 1H), 6.72 (d, J=7.0 Hz, 1H), 6.66 (d, J=7.6 Hz, 1H), 4.43 (m, 2H), 4.17-4.02 (m, 2H), 3.74-3.54 (m, 2H), 3.48-3.41 (m, 4H), 3.3 (m, 4H), 3.26 (m, 2H), 3.16 (m, 2H), 2.15 (m, 4H), 1.94-1.76 (m, 8H).

Example 3018: (R)-1-(3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)amino)propyl)pyrrolidin-3-ol

(572) ##STR00195##

(573) The crude material was purified via preparative LC/MS using the following conditions: Waters XBridge 5 m C18, 19200 mm where mobile phase A was 5:95 acetonitrile:water with 10 mM ammonium acetate and mobile phase B was 95:5 acetonitrile:water with 10 mM ammonium acetate at a gradient of 5-50% B over 25 minutes with a 5-minute hold at a flow rate of 20 mL/minute. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3.5 mg (6%), and its estimated purity by LCMS analysis was 98%.

(574) Two analytical LC/MS injections were used to determine the final purity.

(575) Injection 1 Conditions:

(576) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B was 95:5 acetonitrile:water with 10 mM ammonium acetate at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm.

(577) Injection 2 Conditions:

(578) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B was 95:5 acetonitrile:water with 0.1% trifluoroacetic acid at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm. Analysis condition 1: Retention time=1.130 min; ESI-MS(+) m/z=468.2 (M+H); Analysis condition 2: Retention time=1.023 min; ESI-MS(+) m/z=468.2 (M+H); .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.15 (t, J=7.9 Hz, 1H), 7.04 (t, J=7.3 Hz, 1H), 6.90 (d, J=7.9 Hz, 1H), 6.62 (d, J=7.3 Hz, 1H), 6.52 (d, J=7.9 Hz, 1H), 6.30 (d, J=7.3 Hz, 1H), 4.21 (m, 2H), 4.09-3.98 (m, 2H), 3.15 (m, 2H), 2.83-2.73 (m, 2H), 2.73-2.56 (m, 6H), 2.50 (m, 2H), 2.41 (m, 2H), 2.05-1.93 (m, 2H), 1.93-1.86 (m, 2H), 1.85-1.75 (m, 5H), 1.72 (s, 3H), 1.63-1.51 (m, 2H).

Example 3019: (R)-3-(((3-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)methyl)benzonitrile

(579) ##STR00196##

(580) The crude material was purified via preparative LC/MS using the following conditions: Waters XBridge 5 m C18, 19200 mm where mobile phase A was 5:95 acetonitrile:water with 10 mM ammonium acetate and mobile phase B was 95:5 acetonitrile:water with 10 mM ammonium acetate at a gradient of 28-68% B over 22 minutes with a 5-minute hold at a flow rate of 20 mL/minute. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 37.4 mg (74%), and its estimated purity by LCMS analysis was 100%.

(581) Two analytical LC/MS injections were used to determine the final purity.

(582) Injection 1 Conditions:

(583) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B was 95:5 acetonitrile:water with 10 mM ammonium acetate at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm.

(584) Injection 2 Conditions:

(585) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B was 95:5 acetonitrile:water with 0.1% trifluoroacetic acid at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm. Analysis condition 1: Retention time=1.990 min; ESI-MS(+) m/z=457.1 (M+H); Analysis condition 2: Retention time=1.844 min; ESI-MS(+) m/z=457.1 (M+H); .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.92 (s, 1H), 7.83 (m, 2H), 7.68-7.61 (m, 1H), 7.19 (m, 2H), 7.04 (d, J=8.1 Hz, 1H), 6.93 (d, J=8.1 Hz, 1H), 6.69 (d, J=7.3 Hz, 1H), 6.64 (d, J=7.3 Hz, 1H), 5.21 (m, 2H), 4.18 (m, 1H), 4.10-3.98 (m, 2H), 2.77-2.68 (m, 1H), 2.66-2.53 (m, 3H), 2.49-2.42 (m, 1H), 2.34 (dd, J=9.9, 3.3 Hz, 1H), 2.05-1.92 (m, 1H), 1.92-1.86 (m, 5H), 1.82 (s, 3H), 1.60-1.47 (m, 1H).

Example 3020: (R)-3-(3-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-ylsulfonamido)propanoic acid

(586) ##STR00197##

(587) To a small sealed tube was added THF (6.0 mL), water (2.0 mL), (R)-1-(3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)pyrrolidin-3-ol (40 mg, 0.111 mmol), tert-butyl 3-(3-bromo-2-methylphenylsulfonamido)propanoate (52.4 mg, 0.111 mmol), tribasic potassium phosphate (47.0 mg, 0.221 mmol), and second generation X-Phos precatalyst (4.36 mg, 5.54 mol). The vessel was sealed, the mixture de-gassed/flushed with nitrogen and then heated overnight at 80 C. The reaction mixture was cooled and the product concentrated to an oil. The oil was diluted with 10 mL of DCM, washed with water, brine, dried over sodium sulfate, filtered, and evaporated. The crude intermediate was taken up in 4 mL of DCM. To this solution was then added 1 mL of TFA dropwise. The mixture was stirred for 30 minutes and then evaporated to an oil. The crude material was purified via preparative LC/MS using the following conditions: Waters XBridge 5 m C18, 19200 mm where mobile phase A was 5:95 methanol:water with 10-mM ammonium acetate and mobile phase B was 95:5 methanol:water with 10-mM ammonium acetate at a gradient of 30-70% B over 20 minutes with a 5-minute hold at a flow rate of 20 mL/minute. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3.0 mg (6%), and its estimated purity by LCMS analysis was 98%.

(588) Two analytical LC/MS injections were used to determine the final purity.

(589) Injection 1 Conditions:

(590) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B was 95:5 acetonitrile:water with 10 mM ammonium acetate at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm.

(591) Injection 2 Conditions:

(592) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B was 95:5 acetonitrile:water with 0.1% trifluoroacetic acid at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm. Analysis condition 1: Retention time=1.419 min; ESI-MS(+) m/z=477.0 (M+H); Analysis condition 2: Retention time=1.452 min; ESI-MS(+) m/z=477.0 (M+H); .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.89 (dd, J=7.7, 1.1 Hz, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.32 (d, J=7.7 Hz, 1H), 7.25 (t, J=8.1 Hz, 1H), 7.00 (d, J=8.1 Hz, 1H), 6.72 (d, J=7.7 Hz, 1H), 4.48-4.38 (m, 1H), 4.18-4.01 (m, 2H), 3.39-3.22 (m, 4H), 3.09-3.00 (m, 2H), 2.55 (m, 2H), 2.36 (td, J=7.1, 2.0 Hz, 2H), 2.24 (s, 3H), 2.15 (m, 3H), 1.83 (m, 4H).

Example 3021: (3S,3S)-1,1-(((2-methyl-[1,1-biphenyl]-3,4-diyl)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol)

(593) ##STR00198##

(594) The crude material was purified via preparative LC/MS using the following conditions: Waters XBridge 5 m C18, 19200 mm where mobile phase A was 5:95 acetonitrile:water with 10 mM ammonium acetate and mobile phase B was 95:5 acetonitrile:water with 10 mM ammonium acetate at a gradient of 15-55% B over 15 minutes with a 5-minute hold at a flow rate of 20 mL/minute. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 11.8 mg (33.5%), and its estimated purity by LCMS analysis was 96%.

(595) Two analytical LC/MS injections were used to determine the final purity.

(596) Injection 1 Conditions:

(597) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B was 95:5 acetonitrile:water with 10 mM ammonium acetate at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm.

(598) Injection 2 Conditions:

(599) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B was 95:5 acetonitrile:water with 0.1% trifluoroacetic acid at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm. Analysis condition 1: Retention time=1.228 min; ESI-MS(+) m/z=455.1 (M+H); Analysis condition 2: Retention time=1.232 min; ESI-MS(+) m/z=455.1 (M+H); .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.30-7.16 (m, 4H), 7.01 (d, J=8.2 Hz, 1H), 6.89 (d, J=1.8 Hz, 1H), 6.83 (dd, J=8.1, 2.0 Hz, 1H), 4.26-4.18 (m, 2H), 4.04 (q, J=6.3 Hz, 4H), 2.85-2.77 (m, 2H), 2.77-2.63 (m, 6H), 2.63-2.54 (m, 2H), 2.49-2.43 (m, 2H), 2.24 (s, 3H), 2.06-1.94 (m, 2H), 1.94-1.86 (m, 4H), 1.59 (m, 2H).

Example 3022: (3S,3S)-1,1-(((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2-methyl-[1,1-biphenyl]-3,4-diyl)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol)

(600) ##STR00199##

(601) The crude material was purified via preparative LC/MS using the following conditions: Waters XBridge 5 m C18, 19200 mm where mobile phase A was 5:95 acetonitrile:water with 10 mM ammonium acetate and mobile phase B was 95:5 acetonitrile:water with 10 mM ammonium acetate at a gradient of 5-40% B over 15 minutes with a 5-minute hold at a flow rate of 20 mL/minute. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 18.8 mg (42%), and its estimated purity by LCMS analysis was 99%.

(602) Two analytical LC/MS injections were used to determine the final purity.

(603) Injection 1 Conditions:

(604) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B was 95:5 acetonitrile:water with 10 mM ammonium acetate at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm.

(605) Injection 2 Conditions:

(606) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B was 95:5 acetonitrile:water with 0.1% trifluoroacetic acid at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm. Analysis condition 1: Retention time=0.994 min; ESI-MS(+) m/z=598.3 (M+H); Analysis condition 2: Retention time=0.954 min; ESI-MS(+) m/z=598.3 (M+H); .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.19-7.13 (m, 1H), 7.00 (d, J=8.2 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.85 (d, J=1.8 Hz, 1H), 6.81-6.75 (m, 2H), 4.25-4.16 (m, 3H), 4.08-3.98 (m, 6H), 2.79-2.73 (m, 3H), 2.70-2.57 (m, 9H), 2.50 (m, 3H), 2.44-2.35 (m, 3H), 2.05-1.93 (m, 3H), 1.93-1.83 (m, 9H), 1.57 (m, 3H).

Intermediate: 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

(607) ##STR00200##

(608) To a sealed tube was added 3-bromo-2-methylphenol (1000 mg, 5.35 mmol) in dioxane (15.0 ml) along with potassium acetate (1574 mg, 16.04 mmol), bis(pinacolato)diboron (2172 mg, 8.55 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (509 mg, 0.695 mmol). The vessel was sealed, the contents evacuated/flushed with nitrogen three times, and the mixture then heated for 24 hours at 90 C. The solvent was removed, The residue was purified by silica gel column chromatography (Biotage 25 m, MeOH/CH.sub.2Cl.sub.2=0 to 15%) to give 1350 mg (108%) of the product.

(609) .sup.1H NMR (400 MHz, CHLOROFORM-d) 7.37 (d, J=7.5 Hz, 1H), 7.10 (t, J=7.7 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 4.66 (s, 1H), 2.47 (s, 3H), 1.36 (s, 12H).

Intermediates: 2-(3-(3-chloropropoxy)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 2-(3-(3-bromopropoxy)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

(610) ##STR00201##

(611) To 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1300 mg, 5.55 mmol) in DMF (15 mL) was added potassium carbonate (921 mg, 6.66 mmol) and 1-bromo-3-chloropropane (0.546 mL, 5.55 mmol). The mixture was stirred for 23 hrs at 50 C. The solid was removed by filtration. The solvent was removed, and the residue was purified by silica gel column chromatography (Biotage 25m, EtOAc/Hexane=20%) to give 1.015 g (59%) of a mixture of 3-chloropropoxy and 3-bromopropoxy compounds as an oil. Based on .sup.1H NMR: 3-chloropropoxy was 77% and 3-bromopropoxy was 23%.

(612) .sup.1H NMR (500 MHz, CHLOROFORM-d) 7.40 (d, J=7.3 Hz, 1H), 7.21-7.16 (m, 1H), 6.96 (d, J=8.0 Hz, 1H), 4.16-4.10 (m, 2H), 3.81 (t, J=6.3 Hz, 1.55H), 3.67 (t, J=6.5 Hz, 0.45H), 2.47 (s, 3H), 2.37 (quin J=6.1 Hz, 0.45H), 2.29 (quin, J=6.0 Hz, 1.55H), 1.39 (s, 12H).

Intermediate: (R)-1-(3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)pyrrolidin-3-ol

(613) ##STR00202##

(614) The mixture of (R)-3-hydroxypyrrolidine hydrochloride (606 mg, 4.90 mmol), 2-(3-(3-chloropropoxy)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1015 mg, 3.27 mmol, the mixture of chloro- and bromopropoxy prepared above was used and mmol based on the chloro compound), sodium iodide (490 mg, 3.27 mmol), and potassium carbonate (1129 mg, 8.17 mmol) in DMF (50 mL) was stirred for 48 hrs at 50 C. The solid was removed by filtration. The solvent was removed. The residue was purified by silica gel column chromatography (Biotage 25s, NH.sub.3/Methanol/CH.sub.2Cl.sub.2=0:0:100 to 1:19:80) to give 650 mg (55%) of target compound as an oil. .sup.1H NMR (500 MHz, CHLOROFORM-d) 7.37-7.34 (m, 1H), 7.18-7.13 (m, 1H), 6.94-6.91 (m, 1H), 4.38 (ddt, J=7.1, 4.8, 2.3 Hz, 1H), 4.04 (t, J=6.1 Hz, 2H), 2.97 (td, J=8.7, 5.5 Hz, 1H), 2.79-2.70 (m, 3H), 2.63 (dd, J=10.0, 5.0 Hz, 1H), 2.45 (s, 3H), 2.48-2.36 (m, 1H), 2.22 (dddd, J=13.9, 8.6, 7.0, 5.5 Hz, 1H), 2.10-2.02 (m, 2H), 1.84-1.76 (m, 1H), 1.37 (m, 12H).

Intermediate: 1-bromo-3-(3-chloropropoxy)benzene and 1-bromo-3-(3-bromopropoxy)benzene

(615) ##STR00203##

(616) The mixture (410 mg, 57%) of 1-bromo-3-(3-chloropropoxy)benzene and 1-bromo-3-(3-bromopropoxy)benzene was obtained from 3-bromophenol and 1-bromo-3-chloropropane using the procedure described for 2-(3-(3-chloropropoxy)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 2-(3-(3-bromopropoxy)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Base on .sup.1H NMR and: 3-chloropropoxy was 80% and 3-bromopropoxy was 20%. .sup.1H NMR (400 MHz, CHLOROFORM-d) 7.21-7.08 (m, 3H), 6.87 (ddd, J=8.0, 2.4, 1.1 Hz, 1H), 4.16-4.09 (m, 2H), 3.76 (t, J=6.3 Hz, 1.6H), 3.62 (t, J=6.4 Hz, 0.4H), 2.34 (quin, J=6.1 Hz, 0.4H), 2.26 (quin, J=6.0 Hz, 1.6H).

Intermediate: 1-bromo-2-chloro-3-(3-chloropropoxy)benzene

(617) ##STR00204##

(618) 1-Bromo-2-chloro-3-(3-chloropropoxy)benzene (1.29 g, crude) was obtained from 3-bromo-2-chlorophenol and 1-bromo-3-chloropropane using the procedure described for 2-(3-(3-chloropropoxy)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

Intermediate: (R)-1-(3-(3-bromophenoxy)propyl)pyrrolidin-3-ol

(619) ##STR00205##

(620) (R)-1-(3-(3-Bromophenoxy)propyl)pyrrolidin-3-ol (210 mg, 50%) was obtained from (R)-3-hydroxypyrrolidine hydrochloride and 1-bromo-3-(3-chloropropoxy)benzene (the mixture of chloro- and bromopropoxy prepared above was used) using the procedure described for (R)-1-(3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)pyrrolidin-3-ol. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) 7.26-7.19 (m, 1H), 7.19-7.11 (m, 2H), 6.96 (dd, J=8.3, 2.3 Hz, 1H), 4.60 (br. s., 1H), 4.17-4.11 (m, 2H), 3.69 (d, J=6.0 Hz, 1H), 3.53-3.39 (m, 5H), 2.41-2.20 (m, 3H), 2.09 (d, J=5.8 Hz, 1H).

Intermediate: (R)-1-(3-(3-bromo-2-chlorophenoxy)propyl)pyrrolidin-3-ol

(621) ##STR00206##

(622) (R)-1-(3-(3-Bromo-2-chlorophenoxy)propyl)pyrrolidin-3-ol (1.78 g, 110%) was obtained from (R)-3-hydroxypyrrolidine hydrochloride and 1-bromo-2-chloro-3-(3-chloropropoxy)benzene using the procedure described for (R)-1-(3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)pyrrolidin-3-ol. .sup.1H NMR (500 MHz, CHLOROFORM-d) 7.25 (dd, J=8.0, 1.3 Hz, 1H), 7.09 (t, J=8.2 Hz, 1H), 6.90 (dd, J=8.4, 1.3 Hz, 1H), 4.42 (ddt, J=6.9, 4.7, 2.2 Hz, 1H), 4.14 (t, J=6.1 Hz, 2H), 3.04 (td, J=8.7, 5.9 Hz, 1H), 2.87-2.79 (m, 3H), 2.72 (dd, J=10.2, 4.9 Hz, 1H), 2.52 (br. s., 1H), 2.24 (dddd, J=14.0, 8.5, 6.8, 5.8 Hz, 1H), 2.17-2.09 (m, 2H), 1.84 (td, J=6.9, 0.9 Hz, 1H).

Intermediate: (R)-2-bromo-6-(3-(3-hydroxypyrrolidin-1-yl)propoxy)benzonitrile

(623) ##STR00207##

(624) (R)-2-Bromo-6-(3-(3-hydroxypyrrolidin-1-yl)propoxy)benzonitrile (1.01 g, 74%) was obtained from (R)-3-hydroxypyrrolidine hydrochloride and 2-bromo-6-(3-chloropropoxy)benzonitrile using the procedure described for (R)-1-(3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)pyrrolidin-3-ol. .sup.1H NMR (500 MHz, CHLOROFORM-d) 7.41-7.35 (m, 1H), 7.24 (d, J=8.0 Hz, 1H), 6.96 (d, J=8.5 Hz, 1H), 4.39 (ddt, J=6.9, 4.7, 2.2 Hz, 1H), 4.20 (t, J=6.1 Hz, 2H), 2.99 (td, J=8.7, 5.5 Hz, 1H), 2.83-2.73 (m, 3H), 2.63 (dd, J=10.2, 5.0 Hz, 1H), 2.46-2.39 (m, 1H), 2.26-2.18 (m, 1H), 2.11 (quin, J=6.6 Hz, 2H), 1.85-1.76 (m, 1H).

Example 3023: (3R,3R)-1,1-(((2-methyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol)

(625) ##STR00208##

(626) A mixture of (R)-1-(3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)pyrrolidin-3-ol (20 mg, 0.055 mmol), (R)-1-(3-(3-bromophenoxy)propyl)pyrrolidin-3-ol (16.62 mg, 0.055 mmol), THF (3 mL), and water (1.0 mL), potassium phosphate, tribasic (23.50 mg, 0.111 mmol), and second generation X-Phos precatalyst (2.178 mg, 2.77 mol) was de-gassed/flushed with nitrogen, and then heated overnight at 80 C. The solvent was removed. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 5-45% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 11.9 mg (31%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.33 (t, J=7.9 Hz, 1H), 7.19 (t, J=7.9 Hz, 1H), 6.93 (dd, J=15.4, 8.1 Hz, 2H), 6.84 (d, J=7.3 Hz, 1H), 6.82-6.76 (m, 2H), 4.19 (br. s., 2H), 4.08-3.99 (m, 4H), 2.78-2.68 (m, 2H), 2.68-2.53 (m, 6H), 2.48 (br. s., 2H), 2.37 (br. s., 2H), 2.05 (s, 3H), 2.02-1.82 (m, 6H), 1.60-1.49 (m, 2H).

(627) Two analytical LC/MS injections were used to determine the final purity.

(628) Injection 1 Conditions:

(629) Column: Waters Acquity UPLC BEH C18, 2.150 mm, 1.7-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm.

(630) Injection 2 Conditions:

(631) Column: Waters Acquity UPLC BEH C18, 2.150 mm, 1.7-m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm. LCMS (Injection 1 condition) Rt=1.194 min, ESI m/z 455 (M+1); LCMS (Injection 2 condition) Rt=1.122 min, ESI m/z 455 (M+1).

Example 3024: (3R,3R)-1,1-(((2-chloro-2-methyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol)

(632) ##STR00209##

(633) (3R,3R)-1,1-(((2-Chloro-2-methyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol) (18.3 mg, 44.3%)) was obtained from (R)-1-(3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)pyrrolidin-3-ol and (R)-1-(3-(3-bromo-2-chlorophenoxy)propyl)pyrrolidin-3-ol using the procedure described for (3R,3R)-1,1-(((2-methyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol). The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 5-45% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.33 (t, J=7.9 Hz, 1H), 7.20 (t, J=8.1 Hz, 1H), 7.15 (d, J=8.1 Hz, 1H), 6.96 (d, J=8.1 Hz, 1H), 6.81 (d, J=7.7 Hz, 1H), 6.67 (d, J=7.7 Hz, 1H), 4.21 (br. s., 2H), 4.14 (m, 2H), 4.05 (m, 2H), 2.76 (br. s., 2H), 2.64 (br. s., 6H), 2.57-2.48 (m, 2H), 2.43 (br. s., 2H), 2.05-1.89 (m, 6H), 1.86 (s, 3H), 1.57 (br. s., 2H).

(634) Two analytical LC/MS injections were used to determine the final purity.

(635) Injection 1 Conditions:

(636) Column: Waters Acquity UPLC BEH C18, 2.150 mm, 1.7-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm.

(637) Injection 2 Conditions:

(638) Column: Waters Acquity UPLC BEH C18, 2.150 mm, 1.7-m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm.

(639) LCMS (Injection 1 condition) Rt=1.068 min, ESI m/z 489 (M+1).

(640) LCMS (Injection 2 condition) Rt=1.098 min, ESI m/z 489 (M+1).

Example 3025: 3,3-bis(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2-methyl-[1,1-biphenyl]-2-carbonitrile

(641) ##STR00210##

(642) 3,3-Bis(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2-methyl-[1,1-biphenyl]-2-carbonitrile (18.7 mg, 46%) was obtained from (R)-1-(3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)pyrrolidin-3-ol and (R)-2-bromo-6-(3-(3-hydroxypyrrolidin-1-yl)propoxy)benzonitrile using the procedure described for (3R,3R)-1,1-(((2-methyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol). The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 0-40% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.67 (t, J=8.1 Hz, 1H), 7.28-7.21 (m, 2H), 7.03 (d, J=8.4 Hz, 1H), 6.94 (d, J=7.7 Hz, 1H), 6.77 (d, J=7.7 Hz, 1H), 4.26-4.16 (m, 4H), 4.12-4.01 (m, 2H), 2.77-2.69 (m, 2H), 2.67-2.55 (m, 6H), 2.49-2.42 (m, 2H), 2.40-2.32 (m, 2H), 2.05-1.89 (m, 9H), 1.55 (br. s., 2H).

(643) Two analytical LC/MS injections were used to determine the final purity.

(644) Injection 1 Conditions:

(645) Column: Waters Acquity UPLC BEH C18, 2.150 mm, 1.7-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm.

(646) Injection 2 Conditions:

(647) Column: Waters Acquity UPLC BEH C18, 2.150 mm, 1.7-m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm. LCMS (Injection 1 condition) Rt=1.128 min, ESI m/z 480 (M+1); LCMS (Injection 2 condition) Rt=1.080 min, ESI m/z 480 (M+1).

Example 3026: (3R,3R)-1,1-(((2-methyl-2-(trifluoromethyl)-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol), 2 TFA

(648) ##STR00211##

(649) (3R,3R)-1,1-(((2-Methyl-2-(trifluoromethyl)-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol), 2 TFA (8.2 mg, 19%) was obtained from (R)-1-(3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)pyrrolidin-3-ol and (R)-1-(3-(3-bromo-2-(trifluoromethyl)phenoxy)propyl)pyrrolidin-3-ol using the procedure described for (3R,3R)-1,1-(((2-methyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol). The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-50% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: waters xbridge c-18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-50% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.62 (t, J=8.1 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.18 (t, J=8.1 Hz, 1H), 6.95 (d, J=8.1 Hz, 1H), 6.75 (d, J=7.7 Hz, 1H), 6.66 (d, J=7.3 Hz, 1H), 4.44 (br. s., 2H), 4.22 (br. s., 2H), 4.15-4.02 (m, 2H), 3.80-3.90 (m, 12H), 2.36-2.10 (m, 5H), 2.03-1.78 (m, 3H), 1.85 (s, 3H).

(650) Two analytical LC/MS injections were used to determine the final purity.

(651) Injection 1 Conditions:

(652) Column: Waters Acquity UPLC BEH C18, 2.150 mm, 1.7-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm.

(653) Injection 2 Conditions:

(654) Column: Waters Acquity UPLC BEH C18, 2.150 mm, 1.7-m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm. LCMS (Injection 1 condition) Rt=1.134 min, ESI m/z 523 (M+1). LCMS (Injection 2 condition) Rt=1.261 min, ESI m/z 523 (M+1).

Intermediate: 1-bromo-3-(3-phenylpropoxy)benzene

(655) ##STR00212##

(656) 1-Bromo-3-(3-phenylpropoxy)benzene (481 mg, 66%) was obtained from 1-bromo-3-phenylpropane and 3-bromophenol using the procedure described for 2-(3-(3-chloropropoxy)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. .sup.1H NMR (500 MHz, CHLOROFORM-d) 7.36-7.30 (m, 2H), 7.27-7.21 (m, 3H), 7.18-7.13 (m, 1H), 7.12-7.06 (m, 2H), 6.85 (ddd, J=8.2, 2.4, 1.0 Hz, 1H), 3.97 (t, J=6.2 Hz, 2H), 2.83 (t, J=7.6 Hz, 2H), 2.17-2.09 (m, 2H).

Intermediate: 1-(3-(3-bromo-2-methylphenoxy)propyl)-3-phenylpyrrolidin-3-ol

(657) ##STR00213##

(658) 1-(3-(3-Bromo-2-methylphenoxy)propyl)-3-phenylpyrrolidin-3-ol (246 mg, 77%) was obtained from 1-bromo-3-(3-chloropropoxy)-2-methylbenzene (a mixture of chloro- and bromopropoxy was used) and 3-phenylpyrrolidin-3-ol using the procedure described for 2-(3-(3-chloropropoxy)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. .sup.1H NMR (500 MHz, CHLOROFORM-d) 7.54-7.50 (m, 1.48H), 7.49-7.44 (m, 0.52H), 7.41-7.33 (m, 2H), 7.29-7.24 (m, 1H), 7.18-7.14 (m, 1H), 7.00 (t, J=8.1 Hz, 1H), 6.78 (d, J=8.2 Hz, 1H), 4.03 (t, J=6.1 Hz, 2H), 3.87-3.78 (m, 1H), 3.75-3.67 (m, 1H), 3.67-3.56 (m, 1H), 3.24-3.18 (m, 1H), 3.08 (d, J=9.9 Hz, 1H), 2.42-2.32 (m, 4H), 2.30-2.18 (m, 2H), 2.05 (quin, J=6.7 Hz, 2H).

Example 3027: (R)-1-(3-((2-methyl-3-(3-phenylpropoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(659) ##STR00214##

(660) (R)-1-(3-((2-Methyl-3-(3-phenylpropoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (7.2 mg, 19%) was obtained from (R)-1-(3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)pyrrolidin-3-ol and 1-bromo-3-(3-phenylpropoxy)benzene using the procedure described for for (3R,3R)-1,1-(((2-methyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol). The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 45-85% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.33 (t, J=7.9 Hz, 1H), 7.31-7.26 (m, 2H), 7.25-7.22 (m, 2H), 7.22-7.16 (m, 2H), 6.97-6.90 (m, 2H), 6.84 (d, J=7.7 Hz, 1H), 6.82-6.77 (m, 2H), 4.25 (br. s., 1H), 4.05 (t, J=6.1 Hz, 2H), 4.00 (t, J=6.4 Hz, 2H), 3.35 (br. s., 1H), 2.90-2.70 (m, 6H), 2.68 (br. s., 1H), 2.56 (br. s., 1H), 2.08-1.93 (m, 7H), 1.63 (br. s., 1H).

(661) Two analytical LC/MS injections were used to determine the final purity.

(662) Injection 1 Conditions:

(663) Column: Waters Acquity UPLC BEH C18, 2.150 mm, 1.7-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm.

(664) Injection 2 Conditions:

(665) Column: Waters Acquity UPLC BEH C18, 2.150 mm, 1.7-m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm LCMS (Injection 1 condition) Rt=2.190 min, ESI m/z 446 (M+1). LCMS (Injection 2 condition) Rt=2.112 min, ESI m/z 446 (M+1).

Example 3028: 1-(3-((3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)-3-phenylpyrrolidin-3-ol, 2 TFA

(666) ##STR00215##

(667) 1-(3-((3-(3-((R)-3-Hydroxypyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)-3-phenylpyrrolidin-3-ol (16.9 mg, 56%) 2 TFA was obtained from (R)-1-(3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)pyrrolidin-3-ol and 1-(3-(3-bromo-2-methylphenoxy)propyl)-3-phenylpyrrolidin-3-ol using the procedure described for (3R,3R)-1,1-(((2-methyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol). The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-60% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-55% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.58 (d, J=8.1 Hz, 1.48H), 7.51 (br. s., 0.52H), 7.42 (t, J=7.5 Hz, 2H), 7.35 (d, J=7.3 Hz, 1H), 7.21 (t, J=7.9 Hz, 2H), 6.96 (t, J=7.9 Hz, 2H), 6.66 (d, J=7.7 Hz, 2H), 4.51-4.37 (m, 1H), 4.09 (br. s., 4H), 3.89-3.77 (m, 1H), 3.71 (d, J=10.6 Hz, 2H), 3.46 (br. s., 4H), 3.39-3.33 (m, 3H) 3.16 (d, J=12.1 Hz, 2H), 2.55-2.48 (m, 1H), 2.40-2.10 (m, 6H), 2.07-1.90 (m, 1H), 1.86 (d, J=6.2 Hz, 6H).

(668) Two analytical LC/MS injections were used to determine the final purity.

(669) Injection 1 Conditions:

(670) Column: Waters Acquity UPLC BEH C18, 2.150 mm, 1.7-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm.

(671) Injection 2 Conditions:

(672) Column: Waters Acquity UPLC BEH C18, 2.150 mm, 1.7-m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm

(673) LCMS (Injection 1 condition) Rt=1.506 min, ESI m/z 545 (M+1).

(674) LCMS (Injection 2 condition) Rt=1.302 min, ESI m/z 545 (M+1).

Intermediate: 3-((3-bromo-2-methylphenoxy)methyl)-1-methylpiperidine

(675) ##STR00216##

(676) To a solution of 3-bromo-2-methylphenol (500 mg, 2.67 mmol) in DMF (15 mL) was added 3-(chloromethyl)-1-methylpiperidine, HCl (492 mg, 2.67 mmol) and K.sub.2CO.sub.3 (813 mg, 5.88 mmol). The reaction mixture was stirred at 80 C. for for 19 h. The solvent was removed, and the residue was purified by silica gel column chromatography (Biotage 25s, MeOH/CH.sub.2Cl.sub.2=0 to 10%) to afford 284 mg of the target compound. .sup.1H NMR (500 MHz, CHLOROFORM-d) 7.15 (dd, J=8.0, 0.6 Hz, 1H), 7.02-6.97 (m, 1H), 6.76 (d, J=8.2 Hz, 1H), 3.88-3.83 (m, 1H), 3.83-3.78 (m, 1H), 3.00 (d, J=10.2 Hz, 1H), 2.81 (d, J=11.0 Hz, 1H), 2.33 (s, 3H), 2.32 (s, 3H), 2.25-2.14 (m, 1H), 1.99 (td, J=11.2, 2.7 Hz, 1H), 1.93-1.63 (m, 4H), 1.16 (qd, J=11.8, 4.2 Hz, 1H).

Example 3029: (3R)-1-(3-((2,2-dimethyl-3-((1-methylpiperidin-3-yl)methoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(677) ##STR00217##

(678) (3R)-1-(3-((2,2-Dimethyl-3-((1-methylpiperidin-3-yl)methoxy)-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (32.7 mg, 75%) was obtained from (R)-1-(3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)pyrrolidin-3-ol, and 3-((3-bromo-2-methylphenoxy)methyl)-1-methylpiperidine using the procedure described for (3R,3R)-1,1-(((2-methyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol). The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-55% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.17 (t, J=7.9 Hz, 2H), 6.95-6.89 (m, 2H), 6.64 (d, J=7.7 Hz, 2H), 4.19 (br. s., 1H), 4.09-3.99 (m, 2H), 3.94-3.81 (m, 2H), 3.46 (br. s., 2H), 2.83 (br. s., 1H), 2.75-2.67 (m, 1H), 2.65 (br. s., 1H), 2.62-2.54 (m, 3H), 2.45 (br. s., 1H), 2.33 (d, J=5.9 Hz, 1H), 2.16 (s, 3H), 2.09-1.94 (m, 2H), 1.94-1.84 (m, 2H) 1.83 (d, J=3.7 Hz, 6H), 1.75 (d, J=11.0 Hz, 1H), 1.64 (br. s., 1H), 1.53 (d, J=8.4 Hz, 2H), 1.11 (d, J=10.3 Hz, 1H).

(679) Two analytical LC/MS injections were used to determine the final purity.

(680) Injection 1 Conditions:

(681) Column: Waters Acquity UPLC BEH C18, 2.150 mm, 1.7-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm. Injection 2 conditions: Column: Waters Acquity UPLC BEH C18, 2.150 mm, 1.7-m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm. LCMS (Injection 1 condition) Rt=1.224 min, ESI m/z 453 (M+1). LCMS (Injection 2 condition) Rt=1.302 min, ESI m/z 453 (M+1).

Intermediates: (3R)-1-(2-(7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)ethyl)pyrrolidin-3-ol (Isomer-1), and (3R)-1-(2-(7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)ethyl)pyrrolidin-3-ol (Isomer-2)

(682) ##STR00218##

(683) A mixture of 2-(7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)acetaldehyde (1 g, 3.89 mmol), (R)-3-hydroxypyrrolidine hydrochloride (1.442 g, 11.67 mmol), and sodium triacetoxyborohydride (2.56 g, 12.06 mmol) in DMF (10 mL) was stirred at rt for 19 hrs. The Solvent was removed, and residue was purified by silica gel column chromatography (Biotage 25m, MeOH/CH.sub.2Cl.sub.2=0 to 50%) to obtain the two pure diastereomers and a mixture of both isomers. Isomer-1 was obtained in 78 mg: 1H NMR (500 MHz, CHLOROFORM-d) 7.02 (dd, J=2.2, 1.4 Hz, 1H), 6.97 (dd, J=8.6, 2.3 Hz, 1H), 6.77 (d, J=8.7 Hz, 1H), 4.66 (br. s., 1H), 4.34-4.25 (m, 2H), 3.91 (d, J=7.4 Hz, 1H), 3.74-3.62 (m, 1H), 3.54 (d, J=11.3 Hz, 1H), 3.48-3.25 (m, 3H), 2.34 (br. s., 2H), 2.13 (br. s., 1H), 2.18-2.07 (m, 2H). Isomer-2 was obtained in 130 mg: 1H NMR (500 MHz, CHLOROFORM-d) 6.97 (d, J=2.2 Hz, 1H), 6.90 (dd, J=8.7, 2.2 Hz, 1H), 6.71 (d, J=8.7 Hz, 1H), 4.42 (t, J=5.8 Hz, 1H), 4.25-4.14 (m, 2H), 3.86 (dd, J=11.2, 7.3 Hz, 1H), 3.28-3.19 (m, 1H), 3.05 (d, J=10.9 Hz, 1H), 3.02-2.83 (m, 3H), 2.78-2.68 (m, 1H), 2.21 (ddt, J=13.8, 8.5, 6.8 Hz, 1H), 2.01-1.86 (m, 3H).

(684) In addition, a mixture of Isomer-1 and Isomer-2 was also obtained in 570 mg.

Example 3030: (3R)-1-(3-(3-(3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenoxy)propyl)pyrrolidin-3-ol

(685) ##STR00219##

(686) (3R)-1-(3-(3-(3-(2-((R)-3-Hydroxypyrrolidin-1-yl)ethyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenoxy)propyl)pyrrolidin-3-ol (13.1 mg, 48%) was obtained from (R)-1-(3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)pyrrolidin-3-ol and (3R)-1-(2-(7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)ethyl)pyrrolidin-3-ol (Isomer-1) using the procedure described for (3R,3R)-1,1-(((2-methyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol). The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-50% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.16 (t, J=7.9 Hz, 1H), 6.93-6.88 (m, 2H), 6.78-6.71 (m, 3H), 4.37 (d, J=11.4 Hz, 1H), 4.29-4.23 (m, 1H), 4.22-4.15 (m, 2H), 4.03 (t, J=6.2 Hz, 2H), 3.95 (dd, J=11.0, 8.4 Hz, 1H), 2.76-2.66 (m, 2H), 2.66-2.54 (m, 6H), 2.47 (d, J=7.3 Hz, 2H), 2.36 (d, J=9.5 Hz, 2H), 2.05 (s, 3H), 1.98 (dd, J=12.8, 7.0 Hz, 2H), 1.94-1.87 (m, 2H), 1.78 (q, J=6.6 Hz, 2H), 1.55 (d, J=3.7 Hz, 2H).

(687) Two analytical LC/MS injections were used to determine the final purity.

(688) Injection 1 Conditions:

(689) Column: Waters Acquity UPLC BEH C18, 2.150 mm, 1.7-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm.

(690) Injection 2 Conditions:

(691) Column: Waters Acquity UPLC BEH C18, 2.150 mm, 1.7-m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm. LCMS (Injection 1 condition) Rt=1.080 min, ESI m/z 483 (M+1). LCMS (Injection 2 condition) Rt=1.074 min, ESI m/z 483 (M+1).

Example 3031: (3R)-1-(3-(3-(3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenoxy)propyl)pyrrolidin-3-ol

(692) ##STR00220##

(693) (3R)-1-(3-(3-(3-(2-((R)-3-Hydroxypyrrolidin-1-yl)ethyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenoxy)propyl)pyrrolidin-3-ol (27.8 mg, 92%) was obtained from (R)-1-(3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)pyrrolidin-3-ol and (3R)-1-(2-(7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)ethyl)pyrrolidin-3-ol (Isomer-2) using the procedure described for (3R,3R)-1,1-(((2-methyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol). The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-50% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.16 (t, J=7.7 Hz, 1H), 6.91 (d, J=8.1 Hz, 2H), 6.78-6.71 (m, 3H), 4.35 (dd, J=16.0, 11.6 Hz, 1H), 4.30-4.16 (m, 3H), 4.03 (t, J=6.1 Hz, 2H), 3.99-3.89 (m, 1H), 2.88-2.58 (m, 8H), 2.55-2.48 (m, 2H), 2.48-2.38 (m, 2H), 2.05 (s, 3H), 2.04-1.92 (m, 4H), 1.85-1.74 (m, 2H), 1.66-1.51 (m, 2H).

(694) Two analytical LC/MS injections were used to determine the final purity.

(695) Injection 1 Conditions:

(696) Column: Waters Acquity UPLC BEH C18, 2.150 mm, 1.7-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm.

(697) Injection 2 Conditions:

(698) Column: Waters Acquity UPLC BEH C18, 2.150 mm, 1.7-m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm. LCMS (Injection 1 condition) Rt=1.542 min, ESI m/z 483 (M+1). LCMS (Injection 2 condition) Rt=1.566 min, ESI m/z 483 (M+1).

Intermediate: (3R)-1-(2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)ethyl)pyrrolidin-3-ol

(699) ##STR00221##

(700) To a sealed tube was added (3R)-1-(2-(7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)ethyl)pyrrolidin-3-ol (200 mg, 0.609 mmol) (mixture of Isomer-1 and Isomer-2) in dioxane (7 mL) along with bis(pinacolato)diboron (542 mg, 2.133 mmol), triethylamine (0.255 mL, 1.828 mmol) and bis-(triphenylphosphino)-palladous chloride (20.31 mg, 0.030 mmol). The vessel was sealed, the mixture flushed with nitrogen three times and then stirred at 120 C. for 20 hours. The solvent was removed. The resulting residue was purified by silica gel column chromatography (Biotage 25S, MeOH/CH.sub.2CL.sub.2=0 to 50%) to give 151 mg of the target compound. .sup.1H NMR (500 MHz, CHLOROFORM-d) 7.34-7.23 (m, 2H), 6.85-6.79 (m, 1H), 4.62 (br. s., 1H), 4.29-4.20 (m, 2H), 3.95-3.87 (m, 1H), 3.64-3.31 (m, 6H), 2.36-2.17 (m, 3H), 2.17-2.06 (m, 1H), 1.29 (s, 12H).

Example 3032: (3R,3R)-1,1-((2,2,3,3-tetrahydro-[6,6-bibenzo[b][1,4]dioxine]-3,3-diyl)bis(ethane-2,1-diyl))bis(pyrrolidin-3-ol)

(701) ##STR00222##

(702) (3R,3R)-1,1-((2,2,3,3-Tetrahydro-[6,6-bibenzo[b][1,4]dioxine]-3,3-diyl)bis(ethane-2,1-diyl))bis(pyrrolidin-3-ol) (1.2 mg, 3%) was obtained from (3R)-1-(2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)ethyl)pyrrolidin-3-ol (prepared as described above) and (3R)-1-(2-(7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)ethyl)pyrrolidin-3-ol (Isomer-1) using the procedure described for (3R,3R)-1,1-(((2-methyl-[1,1-biphenyl]-3,3-diyl)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol). The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-50% B over 18 minutes, then a 3-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.09-7.01 (m, 4H), 6.88 (d, J=8.8 Hz, 2H), 4.35 (d, J=11.4 Hz, 2H), 4.24 (d, J=6.6 Hz, 2H), 4.18 (br. s., 2H), 3.97-3.89 (m, 2H), 2.75-2.66 (m, 2H), 2.65-2.54 (m, 6H), 2.49-2.39 (m, 2H), 2.39-2.30 (m, 2H), 2.04-1.93 (m, 2H), 1.82-1.73 (m, 4H), 1.55 (br. s., 2H).

(703) Two analytical LC/MS injections were used to determine the final purity.

(704) Injection 1 Conditions:

(705) Column: Waters Acquity UPLC BEH C18, 2.150 mm, 1.7-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm.

(706) Injection 2 Conditions:

(707) Column: Waters Acquity UPLC BEH C18, 2.150 mm, 1.7-m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm. LCMS (Injection 1 condition) Rt=1.194 min, ESI m/z 497 (M+1). LCMS (Injection 2 condition) Rt=1.080 min, ESI m/z 497 (M+1).

(708) Examples 3033 to 3035 were prepared in a similar manner as described for the 3001 compound series:

Example 3033: (R)-1-(3-((3-((3-aminobenzyl)oxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(709) ##STR00223##

(710) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 20-60% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 13.9 mg (36%), and its estimated purity by LCMS analysis was 97%.

(711) Two analytical LC/MS injections were used to determine the final purity.

(712) Injection 1 Conditions:

(713) Column: Waters Acquity UPLC BEH C18, 2.150 mm, 1.7-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm.

(714) Injection 2 Conditions:

(715) Column: Waters Acquity UPLC BEH C18, 2.150 mm, 1.7-m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm.

(716) Analysis condition 1: Retention time=1.735 min; ESI-MS(+) m/z=447.2 (M+H)

(717) Analysis condition 2: Retention time=1.339 min; ESI-MS(+) m/z=447.2 (M+H)

(718) .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.18 (t, J=7.9 Hz, 2H), 7.06-6.99 (m, 2H), 6.93 (d, J=8.2 Hz, 1H), 6.70-6.63 (m, 3H), 6.61 (d, J=7.6 Hz, 1H), 6.52 (d, J=7.9 Hz, 1H), 5.09 (br. s., 2H), 4.99 (d, J=4.3 Hz, 2H), 4.18 (m, 1H), 4.09-3.98 (m, 2H), 2.75-2.66 (m, 1H), 2.62-2.53 (m, 3H), 2.48-2.40 (m, 1H), 2.37-2.30 (m, 1H), 2.02-1.81 (m, 9H), 1.60-1.50 (m, 1H).

Example 3035: (R)-1-(3-((3-(3-((R)-3-fluoropyrrolidin-1-yl)propoxy)-2,2-dimethyl-[1,1-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol

(719) ##STR00224##

(720) The crude material was purified via preparative LC/MS using the following conditions: Waters XBridge 5 m C18, 19200 mm where mobile phase A was 5:95 acetonitrile:water with 10 mM ammonium acetate and mobile phase B was 95:5 acetonitrile: water 10 mM ammonium acetate at a gradient of 10-50% B over 22 minutes with a 5-minute hold at a flow rate of 20 mL/minute. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 20.1 mg (47%), and its estimated purity by LCMS analysis was 98%.

(721) Two analytical LC/MS injections were used to determine the final purity.

(722) Injection 1 Conditions:

(723) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B was 95:5 acetonitrile:water with 10 mM ammonium acetate at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm.

(724) Injection 2 Conditions:

(725) Waters Acquity UPLC BEH 1.7 m C18, 2.150 mm where mobile phase A was 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B was 95:5 acetonitrile:water with 0.1% trifluoroacetic acid at a temperature of 50 C. at a gradient of 0-100% B over 3 minutes with a 0.75-minute hold at 100% B at a flow rate of 1.0 mL/minute at a UV wavelength of 220 nm.

(726) Analysis condition 1: Retention time=1.380 min; ESI-MS(+) m/z=471.3 (M+H)

(727) Analysis condition 2: Retention time=1.169 min; ESI-MS(+) m/z=471.2 (M+H)

(728) .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.18 (t, J=7.9 Hz, 2H), 6.93 (d, J=7.9 Hz, 2H), 6.64 (d, J=7.9 Hz, 2H), 5.25-5.13 (m, 1H), 4.76 (br. s., 1H), 4.21 (br. s., 1H), 4.04 (m, 4H), 2.89-2.71 (m, 3H), 2.70-2.56 (m, 6H), 2.42 (m, 1H), 2.30 (m, 1H), 2.21-2.06 (m, 1H), 2.04-1.85 (m, 7H), 1.83 (s, 6H), 1.57 (m, 1H).

(729) Examples 5001-5039 were prepared in a manner analogous to those described above

Example 5001: 2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(2,5-dimethyl-4,1-phenylene))bis(methylene))bis(azanediyl))bis(2-methylpropane-1,3-diol)

(730) ##STR00225##

(731) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 35-75% B over 16 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation, and its estimated purity by LCMS analysis was 100%. Analytical LC/MS was used to determine the final purity.

(732) Injection 1 Conditions:

(733) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 100.0%; Observed Mass: 685.44; Retention Time: 1.6 min.

(734) Injection 2 Conditions:

(735) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 100.0%; Observed Mass: 685.33; Retention Time: 1.64 min.

Example 5002: (2S,2S)-1,1-(((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(2,5-dimethyl-4,1-phenylene))bis(methylene))bis(piperidine-2-carboxylic acid)

(736) ##STR00226##

(737) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 30-70% B over 19 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation, and its estimated purity by LCMS analysis was 100%. Analytical LC/MS was used to determine the final purity.

(738) Injection 1 Conditions:

(739) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 100.0%; Observed Mass: 733.34; Retention Time: 1.69 min.

(740) Injection 2 Conditions:

(741) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 100.0%; Observed Mass: 367.28; Retention Time: 1.74 min.

Example 5003: 2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-((3,5-difluorobenzyl)oxy)-4,1-phenylene))bis(methylene))bis(azanediyl))bis(propane-1,3-diol)

(742) ##STR00227##

(743) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 47-87% B over 19 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation, and its estimated purity by LCMS analysis was 99%. Analytical LC/MS was used to determine the final purity.

(744) Injection 1 Conditions:

(745) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 98.9%; Observed Mass: 952.97; Retention Time: 2.48 min.

(746) Injection 2 Conditions:

(747) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 98.7%; Observed Mass: 477.98; Retention Time: 2 min.

Example 5004: 2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(2,5-dimethyl-4,1-phenylene))bis(methylene))bis(azanediyl))bis(propane-1,3-diol)

(748) ##STR00228##

(749) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 28-68% B over 22 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation, and its estimated purity by LCMS analysis was 99%. Analytical LC/MS was used to determine the final purity.

(750) Injection 1 Conditions:

(751) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 99.0%; Observed Mass: 657.22; Retention Time: 1.92 min.

(752) Injection 2 Conditions:

(753) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 100.0%; Observed Mass: 657.2; Retention Time: 1.68 min.

Example 5005: 2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-((3,5-difluorobenzyl)oxy)-4,1-phenylene))bis(methylene))bis(methylazanediyl))bis(propane-1,3-diol)

(754) ##STR00229##

(755) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 50-100% B over 19 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation, and its estimated purity by LCMS analysis was 94%. Analytical LC/MS was used to determine the final purity.

(756) Injection 1 Conditions:

(757) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 94.0%; Observed Mass: 981.03; Retention Time: 2.79 min.

(758) Injection 2 Conditions:

(759) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 93.8%; Observed Mass: 981.04; Retention Time: 2.1 min.

Example 5006: (2S,2S)-1,1-(((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-((3,5-difluorobenzyl)oxy)-4,1-phenylene))bis(methylene))bis(piperidine-2-carboxylic acid)

(760) ##STR00230##

(761) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 38-78% B over 19 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation, and its estimated purity by LCMS analysis was 100%. Analytical LC/MS was used to determine the final purity.

(762) Injection 1 Conditions:

(763) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 100.0%; Observed Mass: 1029.26; Retention Time: 2.4 min.

(764) Injection 2 Conditions:

(765) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 100.0%; Observed Mass: 1029.26; Retention Time: 2.41 min.

Example 5007: 2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-((3,5-difluorobenzyl)oxy)-4,1-phenylene))bis(methylene))bis(azanediyl))bis(2-methylpropane-1,3-diol)

(766) ##STR00231##

(767) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 42-82% B over 19 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation, and its estimated purity by LCMS analysis was 100%. Analytical LC/MS was used to determine the final purity.

(768) Injection 1 Conditions:

(769) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 100.0%; Observed Mass: 981.2; Retention Time: 2.73 min.

(770) Injection 2 Conditions:

(771) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 100.0%; Observed Mass: 981.24; Retention Time: 2.28 min.

Example 5008: (2S,2S)-2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-((3,5-difluorobenzyl)oxy)-4,1-phenylene))bis(methylene))bis(azanediyl))bis(3-hydroxypropanoic acid)

(772) ##STR00232##

(773) The crude material was purified via preparative LC/MS with the following conditions: Column: waters xbridge c-18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 30-70% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation., and its estimated purity by LCMS analysis was 96%. Analytical LC/MS was used to determine the final purity.

(774) Injection 1 Conditions:

(775) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 95.7%; Observed Mass: 981.13; Retention Time: 2.23 min.

(776) Injection 2 Conditions:

(777) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 95.9%; Observed Mass: 981.19; Retention Time: 2.23 min.

Example 5009: (2S,2S)-2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-((3,5-difluorobenzyl)oxy)-4,1-phenylene))bis(methylene))bis(azanediyl))bis(3-hydroxy-2-methylpropanoic acid)

(778) ##STR00233##

(779) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 30-70% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation, and its estimated purity by LCMS analysis was 99%. Analytical LC/MS was used to determine the final purity.

(780) Injection 1 Conditions:

(781) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 98.8%; Observed Mass: 1009.13; Retention Time: 2.27 min.

(782) Injection 2 Conditions:

(783) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 100.0%; Observed Mass: 1009.19; Retention Time: 2.28 min.

Example 5012: 2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-((3,5-difluorobenzyl)oxy)-4,1-phenylene))bis(methylene))bis(methylazanediyl))bis(2-methylpropane-1,3-diol)

(784) ##STR00234##

(785) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 50-100% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation and its estimated purity by LCMS analysis was 99%. Analytical LC/MS was used to determine the final purity.

(786) Injection 1 Conditions:

(787) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 100.0%; Observed Mass: 1009.26; Retention Time: 2 min.

(788) Injection 2 Conditions:

(789) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 99.3%; Observed Mass: 1009.24; Retention Time: 2.27 min.

Example 5013: (2S,2S)-2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-((3,5-difluorobenzyl)oxy)-4,1-phenylene))bis(methylene))bis(methylazanediyl))bis(3-hydroxypropanoic acid)

(790) ##STR00235##

(791) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 35-75% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. and its estimated purity by LCMS analysis was 100%. Analytical LC/MS was used to determine the final purity.

(792) Injection 1 Conditions:

(793) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 100.0%; Observed Mass: 1009.22; Retention Time: 1.96 min.

(794) Injection 2 Conditions:

(795) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 100.0%; Observed Mass: 1009.2; Retention Time: 1. 96 min.

Example 5014: (2S,2S)-2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-((3,5-difluorobenzyl)oxy)-4,1-phenylene))bis(methylene))bis(methylazanediyl))bis(3-hydroxy-2-methylpropanoic acid)

(796) ##STR00236##

(797) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 38-78% B over 19 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation and its estimated purity by LCMS analysis was 100%. Analytical LC/MS was used to determine the final purity.

(798) Injection 1 Conditions:

(799) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 100.0%; Observed Mass: 1037.21; Retention Time: 2 min.

(800) Injection 2 Conditions:

(801) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 100.0%; Observed Mass: 1037.22; Retention Time: 2.01 min.

Example 5015: (2S,2S)-2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-((3,5-difluorobenzyl)oxy)-4,1-phenylene))bis(methylene))bis(methylazanediyl))bis(3-methylbutanoic acid)

(802) ##STR00237##

(803) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 40-90% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation and its estimated purity by LCMS analysis was 99%. Analytical LC/MS was used to determine the final purity.

(804) Injection 1 Conditions:

(805) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 100.0%; Observed Mass: 1033.25; Retention Time: 2.12 min.

(806) Injection 2 Conditions:

(807) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 98.9%; Observed Mass: 1033.28; Retention Time: 2.24 min.

Example 5016: (2S,2S)-2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-((3,5-difluorobenzyl)oxy)-4,1-phenylene))bis(methylene))bis(methylazanediyl))dipentanoic acid

(808) ##STR00238##

(809) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 42-82% B over 19 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation and its estimated purity by LCMS analysis was 100%. Analytical LC/MS was used to determine the final purity.

(810) Injection 1 Conditions:

(811) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 100.0%; Observed Mass: 1033.3; Retention Time: 2.2 min.

(812) Injection 2 Conditions:

(813) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 100.0%; Observed Mass: 1033.33; Retention Time: 2.16 min.

Example 5017: (2S,2S)-2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-((3,5-difluorobenzyl)oxy)-4,1-phenylene))bis(methylene))bis(methylazanediyl))bis(4-methylpentanoic acid)

(814) ##STR00239##

(815) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 40-90% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation and its estimated purity by LCMS analysis was 99%. Analytical LC/MS was used to determine the final purity. Injection 1 conditions: Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 99.1%; Observed Mass: 532.14; Retention Time: 2.45 min.

Example 5018: (2S,2S,3R,3R)-2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(2-((6-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-5-chloro-4,1-phenylene))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid)

(816) ##STR00240##

(817) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 20-100% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation and its estimated purity by LCMS analysis was 94%. Analytical LC/MS was used to determine the final purity.

(818) Injection 1 Conditions:

(819) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 94.4%; Observed Mass: 1071.22; Retention Time: 1.84 min. Injection 2 conditions: Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 98.4%; Observed Mass: 1071.27; Retention Time: 1.78 min.

Example 5019: 2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(2-((6-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-5-chloro-4,1-phenylene))bis(methylene))bis(azanediyl))bis(propane-1,3-diol)

(820) ##STR00241##

(821) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 40-80% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation and its estimated purity by LCMS analysis was 99%. Analytical LC/MS was used to determine the final purity.

(822) Injection 1 Conditions:

(823) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 100.0%; Observed Mass: 1015.28; Retention Time: 1.94 min.

(824) Injection 2 Conditions:

(825) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 98.6%; Observed Mass: 1015.28; Retention Time: 1.79 min.

Example 5020: 2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(2-((6-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-5-chloro-4,1-phenylene))bis(methylene))bis(azanediyl))bis(2-methylpropane-1,3-diol)

(826) ##STR00242##

(827) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 42-82% B over 20 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation and its estimated purity by LCMS analysis was 98%. Analytical LC/MS was used to determine the final purity.

(828) Injection 1 Conditions:

(829) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 100.0%; Observed Mass: 1043.31; Retention Time: 1.93 min.

(830) Injection 2 Conditions:

(831) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 97.6%; Observed Mass: 1043.32; Retention Time: 1.83 min.

Example 5021: (2S,2S)-1,1-(((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(2-((6-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-5-chloro-4,1-phenylene))bis(methylene))bis(piperidine-2-carboxylic acid)

(832) ##STR00243##

(833) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 35-85% B over 27 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation and its estimated purity by LCMS analysis was 100%. Analytical LC/MS was used to determine the final purity.

(834) Injection 1 Conditions:

(835) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 100.0%; Observed Mass: 1091.34; Retention Time: 1.97 min.

(836) Injection 2 Conditions:

(837) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 100.0%; Observed Mass: 1091.29; Retention Time: 1.99 min.

Example 5022: (2S,2S)-2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(2-((6-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-5-chloro-4,1-phenylene))bis(methylene))bis(azanediyl))bis(3-hydroxy-2-methylpropanoic acid)

(838) ##STR00244##

(839) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 35-75% B over 20 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation and its estimated purity by LCMS analysis was 98%. Analytical LC/MS was used to determine the final purity.

(840) Injection 1 Conditions:

(841) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 98.2%; Observed Mass: 1071.27; Retention Time: 1.86 min.

(842) Injection 2 Conditions:

(843) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 100.0%; Observed Mass: 1071.35; Retention Time: 1.91 min.

Example 5023: 2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(2-((6-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-5-chloro-4,1-phenylene))bis(methylene))bis(methylazanediyl))bis(2-methylpropane-1,3-diol)

(844) ##STR00245##

(845) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 45-85% B over 20 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation and its estimated purity by LCMS analysis was 99%. Analytical LC/MS was used to determine the final purity.

(846) Injection 1 Conditions:

(847) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 99.0%; Observed Mass: 1071.2; Retention Time: 1.93 min.

(848) Injection 2 Conditions:

(849) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 99.1%; Observed Mass: 537.08; Retention Time: 2.18 min.

Example 5024: 2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(2-((6-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-5-chloro-4,1-phenylene))bis(methylene))bis(methylazanediyl))bis(2-methylpropanoic acid)

(850) ##STR00246##

(851) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 35-90% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation and its estimated purity by LCMS analysis was 99%. Analytical LC/MS was used to determine the final purity.

(852) Injection 1 Conditions:

(853) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 98.6%; Observed Mass: 1067.19; Retention Time: 1.98 min.

(854) Injection 2 Conditions:

(855) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 100.0%; Observed Mass: 535; Retention Time: 1.99 min.

Example 5025: (2S,2S)-2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(2-((6-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-5-chloro-4,1-phenylene))bis(methylene))bis(methylazanediyl))bis(4-hydroxybutanoic acid)

(856) ##STR00247##

(857) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 32-72% B over 22 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation and its estimated purity by LCMS analysis was 98%. Analytical LC/MS was used to determine the final purity.

(858) Injection 1 Conditions:

(859) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 100.0%; Observed Mass: 1099.38; Retention Time: 1.86 min.

(860) Injection 2 Conditions:

(861) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 98.3%; Observed Mass: 551.07; Retention Time: 1.9 min.

Example 5026: (2S,2S)-2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(2-((6-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-5-chloro-4,1-phenylene))bis(methylene))bis(methylazanediyl))dipentanoic acid

(862) ##STR00248##

(863) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 42-82% B over 20 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation and its estimated purity by LCMS analysis was 100%. Analytical LC/MS was used to determine the final purity.

(864) Injection 1 Conditions:

(865) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 100.0%; Observed Mass: 1095.37; Retention Time: 2.1 min.

(866) Injection 2 Conditions:

(867) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 100.0%; Observed Mass: 1095.36; Retention Time: 2.11 min.

Example 5027: (2S,2S)-2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(2-((6-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-5-chloro-4,1-phenylene))bis(methylene))bis(methylazanediyl))bis(3-hydroxy-2-methylpropanoic acid)

(868) ##STR00249##

(869) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 38-78% B over 19 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation and its estimated purity by LCMS analysis was 99%. Analytical LC/MS was used to determine the final purity.

(870) Injection 1 Conditions:

(871) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 98.8%; Observed Mass: 1099.23; Retention Time: 1.93 min.

(872) Injection 2 Conditions:

(873) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 100.0%; Observed Mass: 1099.04; Retention Time: 1.96 min.

Example 5028: 2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(2-((6-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-5-chloro-4,1-phenylene))bis(methylene))bis(methylazanediyl))bis(propane-1,3-diol)

(874) ##STR00250##

(875) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 47-87% B over 19 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation and its estimated purity by LCMS analysis was 96%. Analytical LC/MS was used to determine the final purity.

(876) Injection 1 Conditions:

(877) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 96.3%; Observed Mass: 1043.34; Retention Time: 2.27 min.

(878) Injection 2 Conditions:

(879) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 95.6%; Observed Mass: 1043.35; Retention Time: 1.9 min.

Example 5029: (2S,2S,3R,3R)-2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(2-((6-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-5-chloro-4,1-phenylene))bis(methylene))bis(methylazanediyl))bis(3-hydroxybutanoic acid)

(880) ##STR00251##

(881) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 25-80% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation and its estimated purity by LCMS analysis was 99%. Analytical LC/MS was used to determine the final purity.

(882) Injection 1 Conditions:

(883) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 99.1%; Observed Mass: 1099.29; Retention Time: 1.88 min.

(884) Injection 2 Conditions:

(885) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 100.0%; Observed Mass: 1099.18; Retention Time: 1.95 min.

Example 5030: N-(4-((3-((4-((((S)-1-carboxy-3-hydroxypropyl)(methyl)amino)methyl)-2-chloro-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methoxy)-5-chloro-2-methoxybenzyl)-N-methyl-L-homoserine

(886) ##STR00252##

(887) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 16-56% B over 22 minutes, then a 6-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation and its estimated purity by LCMS analysis was 98%. Analytical LC/MS was used to determine the final purity.

(888) Injection 1 Conditions:

(889) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 98.6%; Observed Mass: 915.25; Retention Time: 1.59 min.

(890) Injection 2 Conditions:

(891) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 97.5%; Observed Mass: 915.26; Retention Time: 1.61 min.

Example 5031: 3-((4-((3-((4-(((2-carboxyethyl)(methyl)amino)methyl)-2-chloro-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methoxy)-5-chloro-2-methoxybenzyl)(methyl)amino)propanoic acid

(892) ##STR00253##

(893) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 19-59% B over 20 minutes, then a 6-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation and its estimated purity by LCMS analysis was 96%. Analytical LC/MS was used to determine the final purity.

(894) Injection 1 Conditions:

(895) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 98.5%; Observed Mass: 855.15; Retention Time: 1.65 min.

(896) Injection 2 Conditions:

(897) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 96.3%; Observed Mass: 855.22; Retention Time: 1.61 min.

Example 5032: 1,1-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-methoxy-4,1-phenylene))bis(N-((1H-pyrazol-3-yl)methyl)methanamine)

(898) ##STR00254##

(899) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 26-66% B over 22 minutes, then a 6-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation and its estimated purity by LCMS analysis was 93%. Analytical LC/MS was used to determine the final purity.

(900) Injection 1 Conditions:

(901) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 93.3%; Observed Mass: 741.14; Retention Time: 1.67 min.

(902) Injection 2 Conditions:

(903) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 100.0%; Observed Mass: 741.21; Retention Time: 1.93 min.

Example 5033: 1,1-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-methoxy-4,1-phenylene))bis(N-(pyrimidin-5-ylmethyl)methanamine)

(904) ##STR00255##

(905) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 40-80% B over 20 minutes, then a 6-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation and its estimated purity by LCMS analysis was 88%. Analytical LC/MS was used to determine the final purity.

(906) Injection 1 Conditions:

(907) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 88.2%; Observed Mass: 765.26; Retention Time: 1.61 min.

(908) Injection 2 Conditions:

(909) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 94.0%; Observed Mass: 765.22; Retention Time: 2.25 min.

Example 5034: 1,1-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-methoxy-4,1-phenylene))bis(N-(thiazol-5-ylmethyl)methanamine)

(910) ##STR00256##

(911) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 40-80% B over 23 minutes, then a 6-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation and its estimated purity by LCMS analysis was 96%. Analytical LC/MS was used to determine the final purity.

(912) Injection 1 Conditions:

(913) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 96.9%; Observed Mass: 775.05; Retention Time: 2.51 min.

(914) Injection 2 Conditions:

(915) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 95.5%; Observed Mass: 775.11; Retention Time: 1.68 min.

Example 5035: 3,3-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-methoxy-4,1-phenylene))bis(methylene))bis(azanediyl))dipropionic acid

(916) ##STR00257##

(917) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 15-55% B over 22 minutes, then a 6-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation and its estimated purity by LCMS analysis was 100%. Analytical LC/MS was used to determine the final purity.

(918) Injection 1 Conditions:

(919) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 100.0%; Observed Mass: 725.17; Retention Time: 1.55 min.

(920) Injection 2 Conditions:

(921) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 100.0%; Observed Mass: 725.16; Retention Time: 1.65 min.

Example 5036: (2S,2S)-2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-methoxy-4,1-phenylene))bis(methylene))bis(azanediyl))bis(4-hydroxybutanoic acid)

(922) ##STR00258##

(923) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 20-60% B over 20 minutes, then a 6-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation and its estimated purity by LCMS analysis was 96%. Analytical LC/MS was used to determine the final purity.

(924) Injection 1 Conditions:

(925) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 100.0%; Observed Mass: 785.24; Retention Time: 1.61 min.

(926) Injection 2 Conditions:

(927) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 96.1%; Observed Mass: 785.24; Retention Time: 1.52 min.

Example 5037: 1,1-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-methoxy-4,1-phenylene))bis(N-((1H-pyrazol-3-yl)methyl)-N-methylmethanamine)

(928) ##STR00259##

(929) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 34-74% B over 22 minutes, then a 6-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation and its estimated purity by LCMS analysis was 95%. Analytical LC/MS was used to determine the final purity.

(930) Injection 1 Conditions:

(931) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 95.2%; Observed Mass: 769.25; Retention Time: 1.71 min.

(932) Injection 2 Conditions:

(933) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 97.4%; Observed Mass: 769.19; Retention Time: 2.23 min.

Example 5038: 1,1-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-methoxy-4,1-phenylene))bis(N-methyl-N-(pyrimidin-5-ylmethyl)methanamine)

(934) ##STR00260##

(935) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 56-96% B over 20 minutes, then a 6-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation and its estimated purity by LCMS analysis was 99%. Analytical LC/MS was used to determine the final purity.

(936) Injection 1 Conditions:

(937) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 98.7%; Observed Mass: 793.21; Retention Time: 2.7 min.

(938) Injection 2 Conditions:

(939) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 98.8%; Observed Mass: 793.18; Retention Time: 1.63 min.

Example 5039: 1,1-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-methoxy-4,1-phenylene))bis(N-methyl-N-(thiazol-5-ylmethyl)methanamine)

(940) ##STR00261##

(941) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 63-100% B over 20 minutes, then a 8-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation and its estimated purity by LCMS analysis was 100%. Analytical LC/MS was used to determine the final purity.

(942) Injection 1 Conditions:

(943) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 100.0%; Observed Mass: 803.17; Retention Time: 2.93 min.

(944) Injection 2 Conditions:

(945) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 100.0%; Observed Mass: 803.15; Retention Time: 1.71 min.

Intermediate: 5-chloro-4-hydroxy-2-methylbenzaldehyde (A) and 3-chloro-4-hydroxy-2-methylbenzaldehyde (B)

(946) ##STR00262##

(947) NCS (1.177 g, 8.81 mmol) was added to a stirring solution of 4-hydroxy-2-methylbenzaldehyde (1 g, 7.34 mmol) in DCM (24.48 ml) and acetonitrile (12.24 mL) at rt for 16 h. The solvent was removed under vacuum and the crude residue was purified by flash silica gel chromatography using DCM. The product fractions were collected and the solvent removed under vacuum to give a mixture of regioisomers 5-chloro-4-hydroxy-2-methylbenzaldehyde (A) and 3-chloro-4-hydroxy-2-methylbenzaldehyde (B) (923 mg, 74% yield) which were not separated. LCMS (M+H)=171.03, 172.94.

Intermediate: 5-chloro-2-methyl-4-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)benzaldehyde (A) and 3-chloro-2-methyl-4-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)benzaldehyde (B)

(948) ##STR00263##

(949) A solution of diisopropyl azodicarboxylate (334 l, 1.612 mmol) in THF (3053 l) was added dropwise to the solution of (2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (364 mg, 1.465 mmol), a mixture of regio-isomers 5-chloro-4-hydroxy-2-methylbenzaldehyde and 3-chloro-4-hydroxy-2-methylbenzaldehyde (250 mg, 1.465 mmol), and triphenylphosphine (423 mg, 1.612 mmol) in THF (6106 L) at 0 C. The resulting yellow solution was allowed to warm to rt and stirred for 16 h. The solvent was removed under vacuum. The crude material was purified by silica gel chromatography using 5-50% EtOAc/Hex. The product fractions were collected and the solvent removed under vacuum to give: 5-chloro-2-methyl-4-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)benzaldehyde (A) and 3-chloro-2-methyl-4-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)benzaldehyde (B). The regio isomers were then separated by SFC chromatography.

(950) Experimental Details for SFC chromatography:

(951) Column: ChiralCel OD-H, 30250 mm, 5 m

(952) Mobile Phase: 15% MeOH/85% C02

(953) Pressure: 150 bar

(954) Temperature: 35 C.

(955) Flow Rate: 80 mL/min

(956) UV: 220 nm

(957) Injection: 0.5 mL (30 mg/mL in MeOH:CHCl.sub.3, 1:1)

(958) Peak 1 and Peak 2 were concentrated under vacuum. Peak 1 corresponds to the acetal of 5-chloro-2-methyl-4-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)benzaldehyde (A) by NMR formed under SFC conditions. The aldehyde was reformed by dissolving Peak 1 in 2 mL DCM and adding 1 mL water and 1 mL TFA. The mixture was stirred for 30 min. The organic layer was collected and washed with bicarbonate and brine, dried over sodium sulfate and concentrated to give 5-chloro-2-methyl-4-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)benzaldehyde (70 mg, 12% yield). LCMS (M+H)=400.97. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.07 (s, 1H), 8.31 (s, 1H), 7.86 (s, 1H), 7.64 (dd, J=7.5, 1.5 Hz, 1H), 7.60-7.55 (m, 1H), 7.32 (s, 1H), 7.23 (t, J=7.4 Hz, 1H), 5.30 (s, 2H), 2.63 (s, 3H), 1.31 (s, 11H). The same procedure was followed for Peak 2 3-chloro-2-methyl-4-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)benzaldehyde (B) (100 mg, 17% yield). LCMS (M+H)=400.97.

Intermediate: 4-((3-bromo-2-methylbenzyl)oxy)-5-chloro-2-methylbenzaldehyde (A) and 4-((3-bromo-2-methylbenzyl)oxy)-3-chloro-2-methylbenzaldehyde (B)

(959) ##STR00264##

(960) A solution of diisopropyl azodicarboxylate (2.67 ml, 12.90 mmol) in THF (24.42 ml) was added dropwise to the solution of (3-bromo-2-methylphenyl)methanol (2.357 g, 11.72 mmol), a mixture of regio-isomers 5-chloro-4-hydroxy-2-methylbenzaldehyde and 3-chloro-4-hydroxy-2-methylbenzaldehyde (2 g, 11.72 mmol), and triphenylphosphine (3.38 g, 12.90 mmol) in THF (48.8 ml) at 0 C. The resulting yellow solution was allowed to warm to rt and stirred overnight. The solvent was removed under vacuum. The crude material was purified by silica gel chromatography using 5-50% EtOAc/Hex. The product fractions were collected and the solvent removed under vacuum to give: 4-((3-bromo-2-methylbenzyl)oxy)-5-chloro-2-methylbenzaldehyde (A) and 4-((3-bromo-2-methylbenzyl)oxy)-3-chloro-2-methylbenzaldehyde (B) (1.1 g, 27% yield). The regio isomers were then separated by SFC chromatography.

(961) Experimental Details for SFC chromatography:

(962) Column: ChiralCel OD-H, 525 cm, 5 m

(963) Mobile Phase: 38% MeOH/62% C02

(964) Pressure: 100 bar

(965) Temperature: 35 C.

(966) Flow Rate: 300 mL/min

(967) UV: 220 nm

(968) Injection: 3.5 mL (13.6 mg/mL in MeOH:CHCl.sub.3, 1:1)

(969) Peak 1 and Peak 2 were concentrated under vacuum. Peak 1 corresponds to the acetal of 4-((3-bromo-2-methylbenzyl)oxy)-5-chloro-2-methylbenzaldehyde (A) by NMR formed under SFC conditions. The aldehyde was reformed by dissolving Peak 1 in 2 mL DCM and adding 1 mL water and 1 mL TFA. The mixture was stirred for 30 min. The organic layer was collected and washed with bicarbonate and brine, dried over sodium sulfate and concentrated to give 4-((3-bromo-2-methylbenzyl)oxy)-5-chloro-2-methylbenzaldehyde (140 mg). .sup.1H NMR (400 MHz, CHLOROFORM-d) 10.12 (s, 1H), 7.86 (s, 1H), 7.60 (d, J=7.3 Hz, 1H), 7.44 (d, J=7.5 Hz, 1H), 7.12 (t, J=7.8 Hz, 1H), 6.85 (s, 1H), 5.20 (s, 2H), 2.67 (s, 3H), 2.47 (s, 3H).
Example 5500 to Example 5507 were prepared in a manner analogous to those described above.

Example 5500: (2S,2S)-1,1-(((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(3-methyl-4,1-phenylene))bis(methylene))bis(piperidine-2-carboxylic acid)

(970) ##STR00265##

(971) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 20-60% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 13.9 mg, and its estimated purity by LCMS analysis was 98%. Analytical LC/MS was used to determine the final purity.

(972) Injection 1 Conditions:

(973) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 100%; Observed Mass: ESI-MS(+) m/z 705.1; Retention Time: 1.75 min.

(974) Injection 2 Conditions:

(975) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 97.6%; Observed Mass: ESI-MS(+) m/z 705.1; Retention Time: 1.70 min.

Example 5501: (2S,2S)-1,1-(((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-methyl-4,1-phenylene))bis(methylene))bis(piperidine-2-carboxylic acid)

(976) ##STR00266##

(977) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 18-63% B over 23 minutes, then a 6-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 2.8 mg, and its estimated purity by LCMS analysis was 100%. Analytical LC/MS was used to determine the final purity.

(978) Injection 1 Conditions:

(979) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 100.0%; Observed Mass: ESI-MS(+) m/z 773.2; Retention Time: 1.71 min.

(980) Injection 2 Conditions:

(981) Column: Waters Xbridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 100.0%; Observed Mass: ESI-MS(+) m/z 773.21; Retention Time: 1.66 min.

Example 5502: 3,3-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-methyl-4,1-phenylene))bis(methylene))bis(azanediyl))dipropionic acid

(982) ##STR00267##

(983) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 14-59% B over 22 minutes, then a 6-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 1.7 mg, and its estimated purity by LCMS analysis was 95%. Analytical LC/MS was used to determine the final purity.

(984) Injection 1 Conditions:

(985) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 98.0%; Observed Mass: ESI-MS(+) m/z 693.13; Retention Time: 1.54 min.

(986) Injection 2 Conditions:

(987) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 94.8%; Observed Mass: ESI-MS(+) m/z 693.14; Retention Time: 1.61 min.

Example 5503: (S)-1-(4-((3-((4-(((S)-2-carboxypiperidin-1-yl)methyl)-2-chloro-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methoxy)-5-chloro-2-methylbenzyl)piperidine-2-carboxylic acid

(988) ##STR00268##

(989) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 19-63% B over 23 minutes, then a 6-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 4.4 mg, and its estimated purity by LCMS analysis was 95%. Analytical LC/MS was used to determine the final purity.

(990) Injection 1 Conditions:

(991) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 94.7%; Observed Mass: ESI-MS(+) m/z 891.21; Retention Time: 1.72 min.

(992) Injection 2 Conditions:

(993) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 98.0%; Observed Mass: ESI-MS(+) m/z 891.22; Retention Time: 1.67 min.

Example 5504: 3-((4-((3-((4-(((2-carboxyethyl)amino)methyl)-2-chloro-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methoxy)-5-chloro-2-methylbenzyl)amino)propanoic acid

(994) ##STR00269##

(995) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 15-57% B over 23 minutes, then a 6-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 5.0 mg, and its estimated purity by LCMS analysis was 97%. Analytical LC/MS was used to determine the final purity.

(996) Injection 1 Conditions:

(997) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 96.2%; Observed Mass: ESI-MS(+) m/z 811.2; Retention Time: 1.63 min.

(998) Injection 2 Conditions:

(999) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 97.5%; Observed Mass: ESI-MS(+) m/z 811.2; Retention Time: 1.57 min.

Example 5505: N-(4-((3-((4-((((S)-1-carboxy-3-hydroxypropyl)(methyl)amino)methyl)-2-chloro-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methoxy)-5-chloro-2-methylbenzyl)-N-methyl-L-homoserine

(1000) ##STR00270##

(1001) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 20-60% B over 20 minutes, then a 6-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 7.0 mg, and its estimated purity by LCMS analysis was 97%. Analytical LC/MS was used to determine the final purity.

(1002) Injection 1 Conditions:

(1003) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 96.6%; Observed Mass: ESI-MS(+) m/z 899.19; Retention Time: 1.63 min.

(1004) Injection 2 Conditions:

(1005) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 98.2%; Observed Mass: ESI-MS(+) m/z 899.22; Retention Time: 1.67 min.

Example 5507: (S)-2-((4-((3-((4-((((S)-2-carboxy-1-hydroxypropan-2-yl)amino)methyl)-2-chloro-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methoxy)-5-chloro-2-methylbenzyl)amino)-3-hydroxy-2-methylpropanoic acid

(1006) ##STR00271##

(1007) The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 18-61% B over 28 minutes, then a 6-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3.2 mg, and its estimated purity by LCMS analysis was 97%. Analytical LC/MS was used to determine the final purity.

(1008) Injection 1 Conditions:

(1009) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 97.4%; Observed Mass: ESI-MS(+) m/z 871.16; Retention Time: 1.72 min.

(1010) Injection 2 Conditions:

(1011) Column: Waters XBridge C18, 2.1 mm50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 96.9%; Observed Mass: ESI-MS(+) m/z 871.18; Retention Time: 1.58 min.

(1012) Analytical LC-MS Methods USED to Identify the Structures in Table 40000 to Table 90000:

(1013) TABLE-US-00001 LC Condition A Solvent A 5% ACN:95% Water:10 mM Ammonium Actetate Solvent B 95% ACN:5% Water:10 mM Ammonium Actetate Start % B 0 Final % B 100 Gradient Time 2 min Flow Rate 1 mL/min Wavelength 220 Temperature 40 C. Column Phenomenex LUNA C18, 30 2, 3u LC Condition B Solvent A 90% Water-10% Methanol-0.1% TFA Solvent B 10% Water-90% Methanol-0.1% TFA Start % B 50 Final % B 100 Gradient Time 4 min Flow Rate 0.8 mL/min Wavelength 220 Temperature 40 C. Column PHENOMENEX-LUNA 2.0 50 mm 3 um LC Condition C Solvent A 5% ACN:95% Water:10 mM Ammonium Actetate Solvent B 95% ACN:5% Water:10 mM Ammonium Actetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Temperature 40 C. Column Acquity BEH C18 2.1 50 mm; 1.7 um LC Condition D Solvent A 95% Water-5% ACN-0.1% TFA Solvent B 5% Water-95% ACN-0.1% TFA Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 0.8 mL/min Wavelength 220 Temperature 40 C. Column Acquity BEH C18 2.1 50 mm; 1.7 um LC Condition E Solvent A 5% ACN:95% Water:10 mM Ammonium Actetate Solvent B 95% ACN:5% Water:10 mM Ammonium Actetate Start % B 30 Final % B 100 Gradient Time 2 min Flow Rate 1 mL/min Temperature 40 C. Solvent Pair ACN:Water:Ammonium Actetate Column Phenomenex LUNA C18, 30 2, 3u LC Condition F Solvent A 5% ACN:95% Water:10 mM Ammonium Actetate Solvent B 95% ACN:5% Water:10 mM Ammonium Actetate Start % B 50 Final % B 100 Gradient Time 2 min Flow Rate 1 mL/min Wavelength 220 Temperature 40 C. Column Phenomenex LUNA C18, 30 2, 3u LC Condition G Solvent A 90% Water-10% Methanol-0.1% TFA Solvent B 10% Water-90% Methanol-0.1% TFA Start % B 20 Final % B 100 Gradient Time 4 min Flow Rate 0.8 mL/min Wavelength 220 Temperature 40 C. Column PHENOMENEX-LUNA 2.0 50 mm 3 um LC Condition H Solvent A 90% Water-10% Methanol-0.1% TFA Solvent B 10% Water-90% Methanol-0.1% TFA Start % B 40 Final % B 100 Gradient Time 4 min Flow Rate 0.8 mL/min Wavelength 220 Temperature 40 C. Column PHENOMENEX-LUNA 2.0 50 mm 3 um LC Condition I Solvent A 90% Water-10% Methanol-0.1% TFA Solvent B 10% Water-90% Methanol-0.1% TFA Start % B 0 Final % B 100 Gradient Time 4 min Flow Rate 0.8 mL/min Wavelength 220 Temperature 40 C. Column PHENOMENEX-LUNA 2.0 50 mm 3 um LC Condition J Solvent A 5% ACN:95% Water:10 mM Ammonium Actetate Solvent B 95% ACN:5% Water:10 mM Ammonium Actetate Start % B 20 Final % B 100 Gradient Time 4 min Flow Rate 0.8 mL/min Wavelength 220 Temperature 40 C. Column Phenomenex LUNA C18, 50 2, 3u LC Condition K Solvent A 5% ACN:95% Water:10 mM Ammonium Actetate Solvent B 95% ACN:5% Water:10 mM Ammonium Actetate Start % B 0 Final % B 100 Gradient Time 4 min Flow Rate 0.8 mL/min Wavelength 220 Temperature 40 C. Column Phenomenex LUNA C18, 50 2, 3u LC Condition L Solvent A 5% ACN:95% Water:10 mM Ammonium Actetate Solvent B 95% ACN:5% Water:10 mM Ammonium Actetate Start % B 50 Final % B 100 Gradient Time 4 min Flow Rate 0.8 mL/min Temperature 40 C. Solvent Pair ACN:Water:Ammonium Actetate Column Phenomenex LUNA C18, 50 2, 3u LC Condition M Solvent A 5:95 acetonitrile:water with 0.1% trifluoroacetic acid Solvent B 95:5 acetonitrile:water with 0.1% trifluoroacetic acid Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Temperature 50 C. Column Waters XBridge C18, 2.1 mm 50 mm, 1.7 m particles LC Condition N Solvent A 5:95 acetonitrile:water with 10 mM ammonium acetate Solvent B 95:5 acetonitrile:water with 10 mM ammonium acetate Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Temperature 50 C. Column Waters XBridge C18, 2.1 mm 50 mm, 1.7 m particles LC Condition O Solvent A 5:95 acetonitrile:water with 0.1% trifluoroacetic acid Solvent B 95:5 acetonitrile:water with 0.1% trifluoroacetic acid Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 0.75 mL/min Wavelength 220 Temperature 70 C. Column Waters CSH C18, 2.1 mm 50 mm, 1.7 m particles LC Condition P Solvent A 5:95 acetonitrile:water with 0.1% trifluoroacetic acid Solvent B 95:5 acetonitrile:water with 0.1% trifluoroacetic acid Start % B 0 Final % B 100 Gradient Time 3 min Flow Rate 1 mL/min Wavelength 220 Temperature 70 C. Column Waters XBridge C18, 2.1 mm 50 mm, 1.7 m particles
General Procedure for the Preparation of the Structures in Tables 40000 to 70000:
A mixture of aldehyde intermediate (1 eq.), amine (1-20 eq.), Et.sub.3N (1-20 eq.) and acetic acid (2-40 eq.) in CH.sub.2Cl.sub.2/EtOH/DMF (1:1:2) was stirred at room for 2 hours. To the mixture was added NaCN(BH.sub.3) (1-20 eq.) slowly by small portion within 3 hours. Then the mixture was stirred at room temperature for 16 hours. After all the solvents were removed under vacuum, the residue was purified by the preparative HPLC to give the compounds in Table 40000 to Table 70000.

(1014) TABLE-US-00002 TABLE 40000 LC- MS MS MS (M + (M + Cmpd Meth- R.sub.f H).sup.+ H).sup.+ # Structure od (min) Calcd. Observ. 40010 C 1.73 933.3 933.2 40040 C 1.60 961.3 961.1 40050 D 1.72 981.3 981.1 40060 D 2.57 893.3 893.3 40070 D 1.47 983.5 983.3 40090 D 1.64 1017.3 1017.2 40100 D 1.62 989.3 989.2 40110 D 1.60 989.3 989.2 40130 0 D 1.39 873.3 873.1 40140 C 1.60 1029.2 1029.1 40150 C 2.41 1017.3 1017.2 40160 C 1.48 757.2 757.2 40170 C 1.60 1029.2 1029.2 40180 C 1.79 865.3 865.3 40190 C 1.64 1029.2 1029.1 40200 C 1.84 1141.4 1141.1 40210 G 3.52 989.3 989.3 40220 G 3.42 961.3 961.4 40230 0 G 3.23 989.3 989.4 40240 H 2.80 989.3 989.5 40250 G 3.24 961.3 961.4 40260 G 3.33 961.3 961.4 40270 G 3.30 989.3 989.4 40280 G 4.08 953.3 953.4 40300 I 3.60 1037.4 1037.6 40310 K 3.60 1069.4 1069.4 40340 H 3.33 989.3 989.4 40350 H 3.19 981.3 981.4 40360 00 J 2.46 1053.3 1053.5 40370 01 J 2.11 1013.3 1013.4 40380 02 G 3.51 1009.3 1009.5 40390 03 G 3.87 1117.3 1117.5 40400 04 G 3.53 957.3 957.5 40410 05 G 3.51 929.3 929.4 40420 06 J 2.10 953.3 953.4 40430 07 G 3.66 1009.3 1009.5 40440 08 G 3.68 985.3 985.5 40450 09 J 2.28 1049.3 1049.4 40460 0 G 3.91 1159.4 1159.6 40470 G 3.72 979.3 979.4 40480 G 3.86 1081.3 1081.5 40490 C 1.73 1009.3 1009.1 40500 G 3.52 957.3 957.5 40510 G 3.58 1009.3 1009.5 40520 J 2.76 1201.3 1201.5 40530 G 4.11 1361.2 1361.5 40550 G 3.95 1069.4 1069.6 40590 J 3.51 1079.4 1079.5 40620 0 G 3.12 1059.4 1059.5 40670 G 3.41 979.3 979.5 40680 G 3.35 979.3 979.5 40690 G 3.36 979.3 979.5 40700 C 1.85 1159.4 1159.1 40710 G 3.19 1017.3 1017.5 40720 G 3.52 985.3 985.5 40730 G 3.92 953.3 953.4 40740 J 1.98 989.3 989.4 40750 J 2.12 1073.4 1073.6 40760 0 G 3.21 1017.3 1017.4 40770 G 3.58 989.3 989.4 40780 C 1.77 1017.3 1017.2 40800 J 1.92 1045.4 1045.4 40810 J 1.83 1017.3 1017.3 40820 J 2.05 1073.4 1073.3 40830 K 2.66 1097.4 1097.2 40840 J 1.92 1043.3 1043.2 40850 J 2.49 1101.4 1101.3 40870 J 1.75 1025.3 1025.0 40880 0 J 2.07 989.3 989.3 40890 J 2.06 989.3 989.1 40900 J 3.50 1017.3 1017.1 40910 J 3.47 1017.3 1017.1 40930 G 3.73 1101.4 1101.4 40940 J 2.25 1017.3 1017.2 40950 G 3.72 1129.5 1129.5 40960 J 2.83 1169.4 1169.2 40990 G 4.20 1183.3 1183.3 41010 G 3.79 1129.5 1129.6 41020 0 K 2.41 1157.4 1157.5 41030 G 3.54 1073.4 1073.5 41050 J 2.64 1169.4 1169.6 41070 C 2.80 989.3 989.5 41090 C 1.70 989.3 989.2 41100 I 2.90 989.3 989.4 41110 C 1.68 989.3 989.2 41120 I 3.58 961.3 961.3 41130 I 3.61 989.3 989.4 41140 I 3.62 1009.3 1009.5 41170 0 C 1.53 913.2 913.1 41180 C 1.52 913.2 913.1 41190 K 2.64 1029.2 1029.2 41200 K 2.63 1029.2 1029.2 41210 L 0.59 989.3 989.4 41220 M 1.65 989.3 989.2 41230 N 2.41 1085.4 1085.3

(1015) TABLE-US-00003 TABLE 50000 LC- MS MS MS (M + (M + Cmpd Meth- R.sub.f H).sup.+ H).sup.+ # Structure od (min) Calcd. Observ. 50020 D 1.97 870.3 870.1 50040 D 2.23 886.2 886.1 50060 I 4.28 964.3 964.3 50070 0 G 3.75 888.3 888.3 50080 H 3.32 888.2 888.3 50100 G 4.06 900.2 900.3 50110 G 3.93 898.3 898.4 50120 G 3.91 898.3 898.4 50150 G 3.90 888.2 888.3 50170 J 2.92 944.3 944.3 50180 C 2.02 888.2 888.2 50190 J 2.59 888.2 888.1 50200 J 2.62 888.2 888.1 50210 0 C 2.03 888.2 888.2 50220 K 3.17 888.2 888.6 50230 C 2.00 888.2 888.2 50240 I 4.05 874.2 874.3 50250 I 4.07 888.2 888.3 50260 I 3.94 898.3 898.4 50270 C 2.03 888.2 888.1 50280 G 3.79 888.2 888.3 50300 G 3.76 874.2 874.3 50310 G 3.93 888.2 888.3 50330 0 C 1.95 888.2 888.2 50340 C 3.42 916.3 916.3 50360 G 3.78 888.2 888.3 50380 M 1.97 928.2 928.1 50390 M 1.98 888.3 888.2 50400 M 2.07 928.2 928.1

(1016) TABLE-US-00004 TABLE 60000 LC- MS MS MS (M + (M + Meth- R.sub.f H).sup.+ H).sup.+ Cmpd# Structure od (min) Calcd. Observ. 60010 K 3.25 900.3 900.3 60020 K 3.25 900.3 900.2 60030 L 1.39 900.3 900.3 60040 M 2.23 940.2 940.0 60050 00 M 2.15 928.3 928.2 60060 01 M 2.23 940.1 940.0 60070 02 M 2.15 900.3 900.2 60080 03 M 2.23 940.2 940.2 60090 04 M 2.13 900.3 900.1

(1017) TABLE-US-00005 TABLE 70000 LC- MS MS MS (M + (M + Meth- R.sub.f H).sup.+ H).sup.+ Cmpd# Structure od (min) Calcd. Observ. 70010 05 M 2.30 892.2 892.1 70020 06 M 2.32 892.2 892.1 70030 07 M 2.31 892.2 892.1 70040 08 M 2.31 892.2 892.1 70050 09 N 2.35 920.2 920.1 70060 0 M 2.32 892.2 892.1
Intermediates Used in Synthesizing the Structures in Table 80000 and Table 90000:
Diacid I

(1018) ##STR00411##

(1019) To a solution of 5,5-((((((2,2-dichloro-[1,1-biphenyl]-3,3-diyl)bis(methylene)) bis(oxy))bis(4-chloro-6-formyl-3,1-phenylene))bis(oxy))bis(methylene))dinicotinonitrile (800 mg, 0.970 mmol) in THF (20 mL)/water (5 mL) was added sodium chlorite (263 mg, 2.91 mmol) and sulfamic acid (283 mg, 2.91 mmol) at 5 C. The mixture was stirred at 5 C. for 5 minutes and then room temperature for 20 minutes. The reaction mixture was diluted with EtOAc and washed with water. The precipitate was collected by filtration to give 4,4-(((2,2-dichloro-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzoic acid) (700 mg, 0.817 mmol, 84% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.00 (br d, J=14.0 Hz, 4H), 8.49 (br s, 2H), 7.76 (s, 4H), 7.54 (t, J=7.5 Hz, 2H), 7.41 (br d, J=7.0 Hz, 2H), 7.13 (br s, 2H), 5.41 (br s, 4H), 5.37 (br s, 4H). LCMS (M+H)=855.4

(1020) Diacid II

(1021) ##STR00412##

(1022) To a solution of 5,5-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene)) bis(oxy))bis(4-chloro-6-formyl-3,1-phenylene))bis(oxy))bis(methylene))dinicotinonitrile (400 mg, 0.510 mmol) in THF (10 mL)/water (3 mL) was added sodium chlorite (138 mg, 1.531 mmol) and sulfamic acid (149 mg, 1.531 mmol) at 5 C. The mixture was stirred at 5 C. for 5 minutes and then room temperature for 20 minutes. The reaction mixture was diluted with EtOAc and washed with water. The precipitate was collected by filtration to give 4,4-(((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxy))bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzoic acid) (300 mg, 0.357 mmol, 70.0% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.01 (br d, J=8.2 Hz, 4H), 8.48 (s, 2H), 7.78 (s, 2H), 7.55 (br d, J=7.3 Hz, 2H), 7.32 (br t, J=7.6 Hz, 2H), 7.20 (s, 2H), 7.14 (br d, J=7.0 Hz, 2H), 5.48-5.34 (m, 8H), 2.11-2.00 (m, 6H). LCMS (M+H)=815.2

(1023) General Procedure for the Preparation of the Structures in Tables 80000 to 90000:

(1024) Et.sub.3N or iPr.sub.2NEt (1-200 eq.) was added into a solution of diacid I or II (1 eq.), amine (1-10 eq.), HCTU or HATU or HOBt (1-20 eq.) in DMF or THF or dioxane or DME. The mixture was stirred at room temperature to 100 C. for 0.5 to 72 hours, before the reaction was quenched with methanol or water. After all the solvents were removed under vacuum, the residue was purified by the preparative HPLC to give the compounds of in Table 80000 and Table 90000.

(1025) TABLE-US-00006 TABLE 80000 LC- MS MS MS (M + (M + Meth- R.sub.f H).sup.+ H).sup.+ Cmpd# Structure od (min) Calcd. Observ. 80010 M 2.15 1017.2 1017.3 80020 N 2.03 969.2 969.2 80030 M 1.61 1019.2 1019.2 80040 M 2.08 1021.2 1021.1 80050 M 2.27 993.2 993.3 80060 M 2.03 1021.2 1021.1 80090 M 2.11 997.3 997.2 80100 0 M 2.27 953.3 953.2 80120 M 2.8 1017.3 1017.2 80140 M 2.08 1089.1 1089.0 80160 M 2.18 1021.2 1021.3 80180 N 3.01 965.1 965.1 80200 N 2.86 941.1 941.1 80220 M 2.46 1025.1 1025.1 80230 M 2.17 977.3 977.2

(1026) TABLE-US-00007 TABLE 90000 LC- MS MS MS (M + (M + Meth- R.sub.f H).sup.+ H).sup.+ Cmpd# Structure od (min) Calcd. Observ. 90010 N 2.59 898.1 898.0 90020 M 3.19 894.1 893.9 90030 0 M 2.14 912.1 912.1 90040 M 2.22 938.1 938.2 90050 N 2.68 910.1 910.1 90060 M 2.51 938.1 938.1

Biological Assay

(1027) The ability of the compounds of formula (I) to bind to PD-L1 was investigated using a PD-1/PD-L1 Homogenous Time-Resolved Fluorescence (HTRF) binding assay.

(1028) Homogenous Time-Resolved Fluorescence (HTRF) Binding Assay.

(1029) The interaction of PD-1 and PD-L1 can be assessed using soluble, purified preparations of the extracellular domains of the two proteins. The PD-1 and PD-L1 protein extracellular domains were expressed as fusion proteins with detection tags, for PD-1, the tag was the Fc portion of Immunoglobulin (PD-1-Ig) and for PD-L1 it was the 6 histidine motif (PD-L1-His). All binding studies were performed in an HTRF assay buffer consisting of dPBS supplemented with 0.1% (with) bovine serum albumin and 0.05% (v/v) Tween-20. For the h/PD-L1-His binding assay, inhibitors were pre-incubated with PD-L1-His (10 nM final) for 15 m in 4 l of assay buffer, followed by addition of PD-1-Ig (20 nM final) in 1 l of assay buffer and further incubation for 15 m. HTRF detection was achieved using europium crypate-labeled anti-Ig (1 nM final) and allophycocyanin (APC) labeled anti-His (20 nM final). Antibodies were diluted in HTRF detection buffer and 5 l was dispensed on top of the binding reaction. The reaction mixture was allowed to equilibrate for 30 minutes and the resulting signal (665 nm/620 nm ratio) was obtained using an EnVision fluorometer. Additional binding assays were established between the human proteins PD-1-Ig/PD-L2-His (20 & 5 nM, respectively) and CD80-His/PD-L1-Ig (100 & 10 nM, respectively).

(1030) Recombinant Proteins: Human PD-1 (25-167) with a C-terminal human Fc domain of immunoglobulin G (Ig) epitope tag [hPD-1 (25-167)-3S-IG] and human PD-L1 (18-239) with a C-terminal His epitope tag [hPD-L1(18-239)-TVMV-His] were expressed in HEK293T cells and purified sequentially by ProteinA affinity chromatography and size exclusion chromatography. Human PD-L2-His and CD80-His was obtained through commercial sources.

Sequence of Recombinant Human PD-1-Ig

(1031) TABLE-US-00008 hPD1(25-167)-3S-IG (SEQIDNO:1) 1 LDSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTSESPVLNWYRMSPSN 51 QTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRNDSGTYLCG 101 AISLAPKAQIKESLRAELRVTERRAEVPTAHPSPSPRPAGQFQGSPGGGG 151 GREPKSSDKTHTGPPSPAPELLGGSSVFLFPPKPDKTLMISRTPEVTCVV 201 VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYPVVSVLTVLHQDW 251 LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQV 301 SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD 351 KSPMQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Sequence of Recombinant Human PD-L1-his

(1032) TABLE-US-00009 hPDL1(18-239)-TVMV-His (SEQIDNO:2) 1 AFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYWEMEDKNIIQF 51 VHGEEDLKVQHSSYRQRAPLLKDQLSLGNAALQITDVKLQDAGVYRCMIS 101 YGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIW 151 TSSDHQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPE 201 ENHTAELVIPELPLAHPPNERTGSSETVRFQGHHHHHH

(1033) The table below lists the IC.sub.50 values for representative examples of this disclosure measured in the PD-1/PD-L1 Homogenous Time-Resolved Fluorescence (HTRF) binding assay. Ranges are as follows: A=0.00004 M-0.0200 M; B=0.0201 M-0.0900 M; C=0.0901 M-1.000 M; D=1.001 M-10.00 M; E=>10 M.

(1034) TABLE-US-00010 Example Range or IC50 Number (M) 1001 B 1002 A 1003 E 1004 D 2001 B 2002 0.099 2003 B 2004 B 2005 B 2006 C 2007 C 2008 C 2009 B 2010 B 2011 B 2012 C 2013 C 2014 B 2015 B 2016 B 2017 B 2018 0.069 2019 A 2020 A 2021 B 2022 A 2023 B 2024 B 2025 B 2026 A 2027 B 2028 A 2029 A 2030 A 2031 A 2032 B 2033 A 2034 B 2035 A 2036 C 2037 C 2038 C 2039 D 2040 B 2041 C 2042 B 2043 C 2044 C 2045 C 2046 B 2047 C 2048 B 2049 C 2050 D 2051 D 2052 C 2053 C 2054 B 2055 C 2056 3.177 2057 C 2058 C 2059 A 2060 B 2061 B 2062 B 2063 B 2064 B 2065 B 2066 C 2067 B 2068 C 2069 C 2070 C 2071 C 2072 C 2073 B 2074 C 2075 B 2076 B 2077 B 2078 A 2079 A 2080 A 2081 B 2082 C 2083 A 2084 B 2085 C 2086 A 2087 C 2088 A 2089 0.0071 2090 B 2091 B 2092 B 2093 B 2094 A 2095 B 2096 B 2097 C 2098 A 2099 1.248 2100 B 2101 B 2102 B 2103 A 2104 A 2105 B 2106 B 2107 B 2108 C 2109 C 2110 C 2111 B 2112 0.081 2113 B 2114 C 2115 B 2116 C 2117 C 2118 B 2119 A 2120 A 2121 A 2122 A 2123 A 2124 A 2125 A 2126 B 2127 A 2128 A 2129 C 2131 A 3001 A 3002 A 3003 A 3004 D 3005 D 3006 D 3007 A 3008 D 3009 D 3010 10.00 3011 B 3012 E 3013 D 3014 E 3015 E 3016 E 3017 D 3018 C 3019 0.106 3020 D 3021 E 3022 E 3023 C 3024 0.012 3025 C 3026 C 3027 D 3028 B 3029 A 3030 A 3031 A 3032 B 2132 A 2133 C 2134 C 2135 D 2136 3.453 3033 D 3035 A 5001 A 5002 B 5003 C 5004 A 5005 C 5006 A 5007 A 5008 B 5009 A 5012 B 5013 B 5014 B 5015 B 5016 0.031 5017 A 5018 A 5019 B 5020 A 5021 A 5022 A 5023 B 5024 A 5025 A 5026 A 5027 A 5028 C 5029 B 5030 A 5031 A 5032 A 5033 A 5034 B 5035 A 5036 A 5037 B 5038 C 5039 C 5500 C 5501 A 5502 A 5503 A 5504 A 5505 A 5507 A 40010 A 40040 A 40050 A 40060 B 40070 A 40090 A 40100 A 40110 A 40130 A 40140 A 40150 B 40160 A 40170 A 40180 A 40190 A 40200 A 40210 0.0011 40220 A 40230 A 40240 A 40250 A 40260 A 40270 A 40280 A 40300 C 40310 B 40340 A 40350 A 40360 A 40370 A 40380 A 40390 B 40400 A 40410 A 40420 A 40430 A 40440 A 40450 A 40460 A 40470 A 40480 A 40490 A 40500 A 40510 A 40520 C 40530 C 40550 9.22 40590 C 40620 B 40670 B 40680 C 40690 C 40700 A 40710 A 40720 B 40730 0.022 40740 A 40750 A 40760 A 40770 0.00004 40780 A 40800 A 40810 B 40820 A 40830 A 40840 A 40850 A 40870 A 40880 A 40890 A 40900 D 40910 D 40930 A 40940 A 40950 0.168 40960 B 40990 A 41010 A 41020 A 41030 A 41050 B 41070 A 41090 A 41100 A 41110 A 41120 A 41130 A 41140 A 41170 A 41180 A 41190 A 41200 A 41210 A 41220 A 41230 B 50020 B 50040 0.115 50060 A 50070 A 50080 A 50100 A 50110 A 50120 A 50150 A 50170 A 50180 A 50190 A 50200 A 50210 A 50220 A 50230 A 50240 A 50250 A 50260 A 50270 0.023 50280 A 50300 A 50310 B 50330 A 50340 A 50360 A 50380 A 50390 A 50400 A 60010 A 60020 A 60030 0.006 60040 A 60050 A 60060 A 60070 A 60080 A 60090 B 70010 C 70020 A 70030 B 70040 1.05 70050 C 70060 B 80010 B 80020 C 80030 A 80040 B 80050 B 80060 A 80090 C 80100 A 80120 0.105 80140 A 80160 D 80180 D 80200 C 80220 D 80230 B 90010 A 90020 B 90030 B 90040 C 90050 C 90060 D

(1035) The compounds of formula (I) possess activity as inhibitors of the PD-1/PD-L1 interaction, and therefore, may be used in the treatment of diseases or deficiencies associated with the PD-1/PD-L1 interaction. Via inhibition of the PD-1/PD-L1 interaction, the compounds of the present disclosure may be employed to treat infectious diseases such as HIV, Hepatitis A, B, C, or D and cancer.