IP Library › Granted Patent US 10,144,706

Granted Patent B2

US 10,144,706 · App. 15/689,115 · Granted Dec 4, 2018

Compounds useful as immunomodulators

Inventors: Kap-Sun Yeung (Madison, CT); Katharine A. Grant-Young (Madison, CT); Juliang Zhu (North Haven, CT); Mark G. Saulnier (Higganum, CT); David B. Frennesson (Naugatuck, CT); David R. Langley (Meriden, CT); Piyasena Hewawasam (Middletown, CT); Tao Wang (Farmington, CT); Zhongxing Zhang (Madison, CT); Zhaoxing Meng (Middletown, CT); Li-Qiang Sun (Glastonbury, CT); Eric Mull (Guilford, CT); Paul Michael Scola (Glastonbury, CT)

Assignee: Bristol-Myers Squibb Company

C07D207/12 C07C217/18 C07C217/28 C07C217/58 C07C229/14 C07C235/08 C07C237/04 C07C237/06 C07C255/24 C07C255/25 C07D205/04 C07D207/14 C07D207/16 C07D211/22 C07D211/46 C07D211/58 C07D211/60 C07D211/66 C07D211/90 C07D213/38 C07D213/42 C07D213/55 C07D213/73 C07D213/79 C07D213/85 C07D231/12 C07D239/26 C07D277/28 C07D295/088 C07D401/04 C07D401/12 C07D401/14 C07D403/12 C07D405/06 C07D405/12 C07D405/14 C07D413/14 C07D417/12 C07C2601/02 C07C2601/04 C07C2601/08

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Quick Facts

Patent No.: US 10,144,706
App. No.: 15/689,115
Granted: Dec 4, 2018
Kind: B2

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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 (251)

1. A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

R 1 and R 5 are independently selected from hydrogen, —CH 3 , cyano, halo, halomethyl, dihalomethyl, and trihalomethyl;

R 2 and R 3 are independently selected from hydrogen, —O(CH 2 ) m Ph, —(CH 2 ) m OPh, —O(CH 2 ) n NR a R b , —(CH 2 ) m Ph, -(alkenylene)Ph, —S(O) 2 NH(CH 2 ) n NR a R b , —S(O) 2 NH(CH 2 ) n CO 2 H, —O(CH 2 )piperidinyl, —O(CH 2 ) m pyridinyl, —(CH 2 ) m NH(CH 2 ) n NR a R b , —NH(CH 2 ) n NR a R b , —C(O)NH(CH 2 ) n NR a R b , —NHC(O)(CH 2 ) n NR a R b , —NHC(O)NH(CH 2 ) n NR a R b , and —NHC(O)NH(CH 2 ) n CO 2 H; wherein each piperidinyl group is optionally substituted with a C 1 -C 3 alkyl 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 1 -C 3 alkoxy, C 1 -C 3 alkyl, C 1 -C 3 alkylcarbonyl, amino, carboxy, (C 3 -C 6 cycloalkyl)alkoxy, cyano, halo, hydroxy, hydroxymethyl, —CHO, —C(O)NR a R b , —(CH 2 ) m NR a R b ; —OCH 2 phenyl wherein the phenyl is optionally substituted with one or two halo groups, and —OCH 2 pyridinyl optionally substituted with a cyano group, aminocarbonyl group, or a pyrazole ring; or

R 2 and R 3 , together with the atoms to which they are attached, form a 1,4-dioxane ring optionally substituted with —O(CH 2 ) n NR a R b ;

R 4 is selected from hydrogen, —O(CH 2 ) m Ph, —(CH 2 ) m OPh, —O(CH 2 ) n NR a R b , —(CH 2 ) m Ph, -(alkenylene)Ph, —S(O) 2 NH(CH 2 ) n NR a R b , —S(O) 2 NH(CH 2 ) n CO 2 H, —O(CH 2 )piperidinyl, —O(CH 2 ) m pyridinyl, —NH(CH 2 ) n NR a R b , —C(O)NH(CH 2 ) n NR a R b , NHC(O)(CH 2 ) n NR a R b , —NHC(O)NH(CH 2 ) n NR a R b , and —NHC(O)NH(CH 2 ) n CO 2 H, wherein each piperidinyl group is optionally substituted with a C 1 -C 3 alkyl 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 1 -C 3 alkoxy, C 1 -C 3 alkyl, C 1 -C 3 alkylcarbonyl, amino, carboxy, cyano, (C 3 -C 6 cycloalkyl)alkoxy, halo, hydroxy, hydroxymethyl, —C(O)NR a R b , —(CH 2 ) m NR a R b ; —OCH 2 phenyl wherein the phenyl is optionally substituted with one or two halo groups, and —OCH 2 pyridinyl optionally substituted with a cyano group, aminocarbonyl group, or a pyrazole ring;

R 6 and R 7 are independently selected from hydrogen; —O(CH 2 ) m Ph, —(CH 2 ) m OPh, —O(CH 2 ) n NR a R b , —(CH 2 ) m Ph, -(alkenylene)Ph, —S(O) 2 NH(CH 2 ) n NR a R b , —S(O) 2 NH(CH 2 ) n CO 2 H, —O(CH 2 )piperidinyl, —O(CH 2 ) m pyridinyl, —(CH 2 ) m NH(CH 2 ) n NR a R b , —NH(CH 2 ) n NR a R b , —C(O)NH(CH 2 ) n NR a R b , NHC(O)(CH 2 ) n NR a R b , —NHC(O)NH(CH 2 ) n NR a R b , and —NHC(O)NH(CH 2 ) n CO 2 H, wherein the piperidinyl group is optionally substituted with a C 1 -C 3 alkyl 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 1 -C 3 alkoxy, C 1 -C 3 alkyl, C 1 -C 3 alkylcarbonyl, amino, carboxy, cyano, (C 3 -C 6 cycloalkyl)alkoxy, halo, hydroxy, hydroxymethyl, —C(O)NR a R b , —(CH 2 ) m NR a R b ; —OCH 2 phenyl wherein the phenyl is optionally substituted with one or two halo groups; and —OCH 2 pyridinyl optionally substituted with a cyano group, aminocarbonyl group, or a pyrazole ring; or

R 6 and R 7 , together with the atoms to which they are attached, form a 1,4-dioxane ring optionally substituted with —O(CH 2 ) n NR a R b ;

provided that at least two of R 2 , R 3 , R 4 , R 6 , and R 7 are other than hydrogen; and

provided that when R 2 is —(CH 2 ) m OPh, —(CH 2 ) m Ph, or -(alkenylene)Ph then R 6 is selected from —(CH 2 ) m OPh, —(CH 2 ) m Ph, and -(alkenylene)Ph;

m is 1, 2, or 3;

n is 2, 3, 4, 5;

R a and R b are independently selected from hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkylsulfonylC 1 -C 3 alkyl, aminocarbonylC 1 -C 6 alkyl, carboxyC 2 -C 6 alkenyl, carboxyC 1 -C 6 alkyl, (carboxyC 1 -C 3 alkyl)carbonyl, cyanoC 1 -C 3 alkyl, (C 3 -C 6 cycloalkyl)C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, haloC 1 -C 3 alkyl, hydroxyC 1 -C 6 alkyl, (hydroxyC 1 -C 6 alkyl)carbonyl, imidazolylC 1 -C 3 alkyl, morpholinylC 1 -C 3 alkyl, oxeranyl, phenyl, phenylC 1 -C 3 alkyl, piperidinyl, piperidinylC 1 -C 3 alkyl, pyridinylC 1 -C 3 alkyl, pyrimidinylC 1 -C 3 alkyl, pyrazolylC 1 -C 3 alkyl, tetrahydrofurylC 1 -C 3 alkyl, thiazolyl, thiazolylC 1 -C 3 alkyl, (NR c R d )C 1 -C 3 alkyl,

wherein the alkyl part of the carboxyC 1 -C 3 alkyl is further optionally substituted with one or two groups selected from C 1 -C 3 alkoxy, C 1 -C 3 alkylsulfanyl, cyano, hydroxy, indolyl, phenylC 1 -C 3 alkoxy, phenyl optionally substituted with one halo, and pyridinyl; and

wherein the alkyl part of the (C 3 -C 6 cycloalkyl)C 1 -C 3 alkyl, the haloC 1 -C 3 alkyl, the imidazolylC 1 -C 3 alkyl, and the phenylC 1 -C 3 alkyl 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 3 -C 6 cycloalkyl and the cycloalkyl part of the (C 3 -C 6 cycloalkyl)C 1 -C 3 alkyl is optionally substituted with one, two, or three groups independently selected from hydroxy and hydroxyC 1 -C 3 alkyl; and

wherein the alkyl part of the hydroxyC 1 -C 6 alkyl is further optionally substituted with one group selected from C 1 -C 3 alkoxy, C 1 -C 6 alkoxycarbonyl, C 3 -C 6 cycloalkyl, phenylC 1 -C 3 alkoxycarbonyl, tetrahydrofuryl, imidazolyl optionally substituted with one or two groups independently selected from C 1 -C 3 alkyl and halo, pyridinyl, phenyl optionally substituted with two halo groups, and thiazolyl; and

wherein the imidazolyl part of the imidazolylC 1 -C 3 alkyl, the piperidinyl, the piperidinyl part of the piperidinylC 1 -C 3 alkyl, the pyrazolyl part of the pyrazolylC 1 -C 3 alkyl, and the pyridinyl part of the pyridinylC 1 -C 3 alkyl are optionally substituted with one, two, or three groups independently selected from C 1 -C 3 alkyl, cyano, halo, and hydroxyC 1 -C 3 alkyl; and

wherein the phenyl and the phenyl part of the phenylC 1 -C 3 alkyl is optionally substituted with one or two groups independently selected from C 1 -C 3 alkoxy, amino and halo; or

R a and R 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 1 -C 3 alkoxy, C 1 -C 3 alkoxycarbonyl, C 1 -C 3 alkyl, C 1 -C 3 alkylcarbonyl, aminocarbonyl, carboxy, carboxyC 1 -C 3 alkyl, halo, hydroxy, hydroxyC 1 -C 3 alkyl, —NR c R d , (NR c R d )carbonyl, (NR c R d )carbonylC 1 -C 3 alkyl, oxo, pyridinyl, and phenyl optionally substituted with a halo or methoxy group; and

R c and R d are independently selected from hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkylcarbonyl; and

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

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

4. A compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein:

one of R 2 and R 3 is hydrogen and the other is selected from —O(CH 2 ) m Ph, —(CH 2 ) m OPh, —O(CH 2 ) n NR a R b , —S(O) 2 NH(CH 2 ) n NR a R b , —S(O) 2 NH(CH 2 ) n CO 2 H, —O(CH 2 ) m pyridinyl, —(CH 2 ) m NH(CH 2 ) n NR a R b , —C(O)NH(CH 2 ) n NR a R b , —NHC(O)(CH 2 ) n NR a R b , —NHC(O)NH(CH 2 ) n NR a R b ; and —NHC(O)NH(CH 2 ) n CO 2 H; wherein each piperidinyl group is optionally substituted with a C 1 -C 3 alkyl 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 1 -C 3 alkoxy, C 1 -C 3 alkyl, C 1 -C 3 alkylcarbonyl, amino, carboxy, (C 3 -C 6 cycloalkyl)alkoxy, cyano, halo, hydroxy, hydroxymethyl, —CHO, —C(O)NR a R b , —(CH 2 ) m NR a R b , —OCH 2 phenyl wherein the phenyl is optionally substituted with one or two halo groups, and —OCH 2 pyridinyl optionally substituted with a cyano group, aminocarbonyl group, or a pyrazole ring; and

one of R 6 and R 7 is hydrogen and the other is selected from —O(CH 2 ) m Ph, —(CH 2 ) m OPh, —O(CH 2 ) n NR a R b , —S(O) 2 NH(CH 2 ) n NR a R b , —S(O) 2 NH(CH 2 ) n CO 2 H, —O(CH 2 ) m pyridinyl, —(CH 2 ) m NH(CH 2 ) n NR a R b , —C(O)NH(CH 2 ) n NR a R b , —NHC(O)(CH 2 ) n NR a R b , —NHC(O)NH(CH 2 ) n NR a R b , and —NHC(O)NH(CH 2 ) n CO 2 H, 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 1 -C 3 alkoxy, C 1 -C 3 alkyl, C 1 -C 3 alkylcarbonyl, amino, carboxy, cyano, (C 3 -C 6 cycloalkyl)alkoxy, halo, hydroxy, hydroxymethyl, —C(O)NR a R b , —(CH 2 ) m NR a R b ; —OCH 2 phenyl wherein the phenyl is optionally substituted with one or two halo groups; and —OCH 2 pyridinyl 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,2′S,4R,4′R)-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,3′R)-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,2′S)-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-((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,2′S)-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,3′S)-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,3′S,4S,4′S)-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,1′S,2R,2′R,3R,3′R,5R,5′R)-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,3′R)-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,3′R)-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,1′R,2R,2′R)-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,2′S)-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,2′S)-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,2′S)-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,2′R)-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,2′S)-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,3′R)-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,3′R)-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,3′R)-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,3′S)-1,1′-(((2′-methyl-[1,1′-biphenyl]-3,4-diyl)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol);

(3S,3′S)-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,3′R)-1,1′-(((2-methyl-[1,1′-biphenyl]-3,3′-diyl)bis(oxy))bis(propane-3,1-diyl))bis(pyrrolidin-3-ol);

(3R,3′R)-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,3′R)-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,3′R)-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,3′R)-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,2′S)-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,2′S)-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,2′S)-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);

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,2′S,3R,3′R)-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);

(2S,2′S)-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,2′S)-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);

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,2′S)-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,2′S)-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,2′S)-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;

(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

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.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 2, 2017

From: YEUNG, KAP-SUN; GRANT-YOUNG, KATHARINE A.; ZHU, JULIANG; SAULNIER, MARK G.; FRENNESSON, DAVID B.; LANGLEY, DAVID R.; HEWAWASAM, PIYASENA; WANG, TAO; ZHANG, ZHONGXING; MENG, ZHAOXING; SUN, LI-QIANG; MULL, ERIC; SCOLA, PAUL MICHAEL

To: BRISTOL-MYERS SQUIBB COMPANY

Reel/Frame 043757/0058 →

Continuity (2)

Provisional Application 62382480 · Sep 1, 2016

Related Publication 20180057455A1 · Mar 1, 2018

Cited By (1)

US 12,715,856