Compounds for the treatment of PD-L1 disease

Abstract

Compounds useful as immunomodulators are provided. These compounds have the following formula (I), including stereoisomers and pharmaceutically acceptable salts thereof, wherein R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 3 , R 3a , R 4 , R 5 , R 6 , R 7 , R 8 and subscript n are defined herein. Also disclosed are methods related to the preparation and use of such compounds, as well as pharmaceutical compositions containing such compounds.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 62 / 864,002, filed June 20, 2019, which is incorporated herein by reference in its entirety.

[0002] STATEMENT OF RIGHTS TO INVENTIONS CREATED UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT Not applicable

[0003] Reference to a "Sequence Listing," a table, or a computer program listing attachment submitted on a compact disc Not applicable [Background technology]

[0004] Background to the disclosure Programmed cell death protein-1 (PD-1) is a member of the CD28 superfamily that delivers negative signals upon interaction with its two ligands, PD-L1 and PD-L2. PD-1 and its ligands are widely expressed and play a variety of immunoregulatory roles in T cell activation and tolerance. PD-1 and its ligands have been implicated in attenuating infection and tumor immunity and promoting the progression of chronic infections and tumors.

[0005] Modulation of the PD-1 pathway has therapeutic potential in various human diseases (Hyun-Tak Jin et al., Curr Top Microbiol Immunol. (2011); 350:17-37). Blockade of the PD-1 pathway has become an attractive target for cancer therapy. Therapeutic antibodies that block the programmed cell death protein-1 (PD-1) immune checkpoint pathway prevent T cell downregulation and promote immune responses against cancer. Several PD-1 pathway inhibitors have shown robust activity in various phases of clinical trials (RD Harvey, Clinical Pharmacology and Therapeutics (2014); 96(2), 214-223).

[0006] Substances that block the interaction of PD-L1 with either PD-1 or CD80 are desirable. Several antibodies have been developed and marketed. A few patent applications disclosing non-peptide small molecules have been published (WO 2015 / 160641, WO 2015 / 034820, and WO 2017 / 066227 and WO2018 / 009505 from Bristol-Myers Squibb; WO 2015 / 033299 and WO 2018 / 009505 from Aurigene). 2015 / 033301; WO2017 / 070089, US2017 / 0145025, WO2017 / 106634, US2017 / 0174679, WO2017 / 192961, WO2017 / 222976, WO2017 / 205464, WO2017 / 112730, WO2017 / 041899 and WO2018 / 013789 from Incyte; WO2018 / 006795 from Maxinovel; and WO2018 / 005374 from ChemoCentryx, the present inventors. However, there remains a need for alternative compounds, such as small molecules, as inhibitors of PD-L1 and which have advantageous characteristics with regard to oral administration, stability, bioavailability, therapeutic index, and toxicity. Summary of the Invention

[0007] A brief summary of the disclosure In one embodiment, a compound having the following formula (I):

[0008] [ka] or a pharmaceutically acceptable salt thereof, or a prodrug or bioequivalent thereof, is provided herein: 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 3 , R 3a , R 4 , R 5 , R 6 , R 7 , R 8 , and subscript n are defined herein.

[0009] In addition to the compounds provided herein, the disclosure further provides pharmaceutical compositions containing one or more of these compounds, as well as methods related to the preparation and use of such compounds. In some embodiments, the compounds are used in therapeutic methods for treating diseases associated with the PD-1 / PD-L1 pathway. DETAILED DESCRIPTION OF THE INVENTION

[0010] Detailed Description of Disclosure Abbreviations and Definitions As used herein, the terms "a," "an," or "the" include not only embodiments with one member, but also embodiments with two or more members. For example, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a cell" includes a plurality of such cells, and reference to "the agent" includes reference to one or more agents known to those skilled in the art, and so forth.

[0011] The terms "about" and "approximately" are intended to generally refer to an acceptable degree of error for a quantity measured with a given quality or precision of measurement. Typically, illustrative degrees of error are within 20 percent (%), preferably within 10%, and more preferably within 5% of a given value or range of values. Alternatively, and particularly in biological systems, the terms "about" and "approximately" can refer to values ​​within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold of a given value. Numerical quantities given herein are approximate unless otherwise specified, meaning that the terms "about" and "approximately" can be inferred even if not explicitly stated.

[0012] The term "alkyl," by itself or as part of another substituent, unless otherwise specified, has the specified number of carbon atoms (i.e., C 1-8 means 1 to 8 carbons), straight-chain or branched-chain hydrocarbon groups. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. The term "alkenyl" refers to unsaturated alkyl groups having one or more double bonds. Similarly, the term "alkynyl" refers to unsaturated alkyl groups having one or more triple bonds. Examples of alkenyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, and 3-(1,4-pentadienyl). Examples of alkynyl groups include ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.

[0013] The term "cycloalkyl" refers to a hydrocarbon ring or rings having a specified number of ring atoms (e.g., C 3-6"Cycloalkyl" refers to rings that are fully saturated or have only one double bond between the ring vertices. "Cycloalkyl" is also meant to refer to bicyclic and polycyclic hydrocarbon rings, such as, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. The bicyclic or polycyclic rings may be fused, bridged, spiro, or combinations thereof.

[0014] The term "heterocycloalkyl" or "heterocyclyl" refers to a cycloalkyl group containing 1 to 5 heteroatoms selected from N, O, and S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom(s) are optionally quaternized. A heterocycloalkyl can be a monocyclic, bicyclic, or polycyclic ring system. The bicyclic or polycyclic rings can be fused, bridged, spiro, or combinations thereof. "C 4-12 References to "heterocyclyl" are understood to refer, for example, to groups having 4 to 12 ring members, at least one of which is a heteroatom. Non-limiting examples of heterocycloalkyl groups include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, tetrazolone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, and the like. A heterocycloalkyl group can be attached to the remainder of the molecule through a ring carbon or a heteroatom.

[0015] The term "alkylene" by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified by -CHCHCHCH-. An alkylene group can be straight or branched. Examples of the latter are -CHC(CH)CH-, -CHC(CH)-, or -CH(CH)CHCH-. Typically, an alkyl (or alkylene) group will have from 1 to 12 carbon atoms, with those groups having 8 or fewer carbon atoms being preferred in this disclosure. Similarly, "alkenylene" and "alkynylene" refer to unsaturated forms of "alkylene" having a double or triple bond, respectively.

[0016] The terms "alkoxy," "alkylamino," and "alkylthio" (or thioalkoxy) are used in their ordinary sense and refer to those alkyl groups attached to the remainder of the molecule through an oxygen atom, an amino group, or a sulfur atom, respectively. In addition, for dialkylamino groups, the alkyl portions can be the same or different and can also, together with the nitrogen atom to which each is attached, form a 3- to 7-membered ring. Thus, -NR a R b A group depicted as: is meant to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl and the like.

[0017] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "C 1-4 "Haloalkyl" is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0018] The term "hydroxyalkyl" or "alkyl-OH" refers to an alkyl group as defined above in which at least one (and up to three) hydrogen atoms have been replaced by a hydroxy group. For alkyl groups, a hydroxyalkyl group is one having a C 1-6Exemplary hydroxyalkyl groups include hydroxymethyl, hydroxyethyl (wherein the hydroxy is in the 1- or 2-position), hydroxymethyl, hydroxyethyl ... Examples of hydroxypropyl include, but are not limited to, 2,3-dihydroxypropyl (wherein the hydroxy is in the 1-, 2-, or 3-position), and 2,3-dihydroxypropyl.

[0019] The term "aryl," unless otherwise specified, means a polyunsaturated, typically aromatic, hydrocarbon group which can be monocyclic or polycyclic (up to three cyclic) which are fused together or covalently linked.

[0020] The term "heteroaryl" refers to a 5- to 10-membered aromatic ring(s) having 1 to 5 heteroatom ring vertices, each selected from N, O, and S, where the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen atom(s) may be optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. 5-10References to heteroaryl are understood to refer to heteroaryl moieties having 5 to 10 ring members, wherein at least one ring member is a heteroatom. Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl, while non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindol ... Examples of heteroaryl groups include indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl, and the like. Substituents for each of the above-noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

[0021] When any of the above terms (e.g., "alkyl," "aryl," and "heteroaryl") are referred to as "substituted" without further notation as to the substituents, the substituted form of the specified group will be as provided below.

[0022] Substituents for alkyl groups (including such groups sometimes referred to as alkylene, alkenyl, alkynyl, and cycloalkyl) can be a variety of groups selected from: -halogen, -OR', -NR'R", -SR', -SiR'R"R"', -OC(O)R', -C(O)R', -COR', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR "R"', -NR"C(O)2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R", -NR'S(O)2R", -CN and -NO2; numbers ranging from 0 to (2m'+1), where m' is the total number of carbon atoms in such group. R', R" and R'' each independently represent hydrogen, unsubstituted C 1-8 Alkyl, unsubstituted heteroalkyl, unsubstituted aryl, aryl substituted with 1 to 3 halogens, unsubstituted C 1-8 Alkyl, C 1-8 Alkoxy or C 1-8 Thioalkoxy group, or unsubstituted aryl-C 1-4 refers to an alkyl group. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" is meant to include 1-pyrrolidinyl and 4-morpholinyl. The term "acyl," when used by itself or as part of another group, refers to an alkyl group in which two substituents on the carbon nearest to the point of attachment of the group have been replaced with the substituent =0 (e.g., -C(O)CH3, -C(O)CH2CH2OR', etc.).

[0023] Similarly, substituents on the aryl and heteroaryl groups are variable and generally selected from: halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO 2 , —C0 2 R′, —CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O) 2 R′, —NR′—C(O)NR″R″′, —NH—C(NH 2 )═NH, —NR′C(NH 2 )═NH, —NH—C(NH 2 )═NR′, —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R″, —NR′S(O) 2 R″, —N 3 , perfluoro(C 1 -C 4 )alkoxy, and perfluoro(C 1 -C 4 )alkyl; the number ranges from 0 to the maximum of the available valences on the aromatic ring system (open and wherein R', R" and R"' are hydrogen, C 1-8 Alkyl, C 3-6 Cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-C 1-4 Alkyl and unsubstituted aryloxy-C 1-4 Other suitable substituents include each of the above aryl substituents attached to a ring atom by an alkylene tether of 1 to 4 carbon atoms.

[0024] Two substituents on adjacent atoms of an aryl or heteroaryl ring are of the formula -TC(O)-(CH) q -U-, where T and U are independently -NH-, -O-, -CH2-, or a single bond, and q is an integer from 0 to 2. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally replaced by a substituent of the formula -A-(CH2) rwherein A and B are independently -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'- or a single bond, and r is an integer from 1 to 3. One of the single bonds of the new ring so formed may optionally be replaced by a double bond. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally replaced by a double bond. s -X-(CH2) t wherein s and t are independently integers from 0 to 3, and X is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituent R' in -NR'- and -S(O)2NR'- is hydrogen or an unsubstituted C 1-6 alkyl.

[0025] As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si). Within a ring system, heteroatoms at the ring vertices include N, O, and S.

[0026] The present disclosure further relates to prodrugs and bioisosteres thereof. Suitable bioisosteres would include, for example, carboxylate substitutions (phosphonic acid, phosphinic acid, sulfonic acid, sulfinic acid, and acidic heterocyclyl groups such as tetrazole). Suitable prodrugs would include those conventional groups known to hydrolyze and / or oxidize under physiological conditions to provide compounds of Formula I.

[0027] The terms "patient" and "subject" include primates (especially humans), domesticated companion animals (dogs, cats, horses, etc.), and livestock (cows, pigs, sheep, etc.).

[0028] As used herein, the term "treating" or "treatment" encompasses both disease-modifying and symptomatic treatment, either of which may be prophylactic (i.e., prior to the onset of symptoms, so as to prevent, delay or reduce the severity of symptoms) or therapeutic (i.e., after the onset of symptoms, so as to reduce the severity and / or duration of symptoms).

[0029] The term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the specific substituents found on the compounds described herein. When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese, manganous, potassium, sodium, zinc, and the like. Examples of salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, etc., such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperadine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like.Also included are salts of amino acids such as arginate, and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge, SM, et al, "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0030] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but while these salts are equivalent to the parent form of the compound for purposes of this disclosure.

[0031] Some compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present disclosure. Some compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0032] Some compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, positional isomers, and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present invention. When a stereochemical depiction is shown, this is intended to refer to a compound in which one of the isomers is present and substantially free of the other isomer. "Substantially free" of another isomer refers to at least an 80 / 20 ratio of the two isomers, more preferably 90 / 10, or 95 / 5 or greater. In some embodiments, one of these isomers will be present in an amount of at least 99%.

[0033] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, these compounds may contain, for example, tritium ( 3 H), iodine-125( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure. For example, these compounds may be radiolabeled with a radioactive isotope such as deuterium ( 2 H) isotopes can be prepared. Compounds of the present disclosure can also contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. Unnatural proportions of isotopes can be defined as a range from the naturally occurring amount of the atom in question to 100% of the amount. For example, these compounds can be prepared with, for example, tritium ( 3 H), iodine-125( 125 I) or carbon-14 ( 14 Radioactive isotopes such as C, or deuterium ( 2 H) or carbon-13 ( 13 Non-radioactive isotopes, such as C), may be incorporated. Such isotopic variations can provide utilities in addition to those described elsewhere in this application. For example, isotopic variants of the disclosed compounds can find additional utility, including, but not limited to, as diagnostic and / or imaging reagents or as cytotoxic / radiotoxic treatments. In addition, isotopic variants of the disclosed compounds can have modified pharmacokinetic and pharmacodynamic characteristics that can contribute to enhanced safety, tolerability, or efficacy during treatment. All isotopic variations of the disclosed compounds, whether radioactive or not, are intended to be encompassed within the scope of this disclosure.

[0034] compound In one aspect, the present disclosure provides a compound having the following formula (I):

[0035] [ka] or a pharmaceutically acceptable salt thereof, or a prodrug or bioequivalent thereof; {In formula: R 1a , R 1b , R 1c , and R 1d are H, F, Cl, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 are each independently selected from the group consisting of alkoxy and CN; X 1 is one or two C 1-2 C optionally substituted with alkyl or COH 1-3 is alkylene; R 2a and R 2b is H, C 1-8 Alkyl, C 1-8 Haloalkyl, -Y, -X 2 -C(O)2R a , -X 2 -OR a , -X 2 -NR a R b , -X 2 -CONR a R b , -X 2 -SO2R a , -X 2 -SO2NR a R b , -X 2 -SO3R a and -X 2 -Y, wherein each X 2 is C 1-6 Alkylene and any C 1-8 Alkyl or C 1-6 Alkylene is OH, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 and each Y is optionally further substituted with one or two members independently selected from alkyl or COH, and 3-6 Cycloalkyl, C 4-8 heterocyclyl and 5- to 6-membered heteroaryl, each of which is selected from the group consisting of oxo, OH, C1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkoxy, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 optionally further substituted with 1 to 4 substituents independently selected from the group consisting of alkyl, and COH; or R 2a and R 2b are combined to form a 4- to 8-membered ring or a spiro ring, optionally with 1 or 2 additional ring vertices selected from O, N, or S; or R 1a and R 2a or X 1 combine to form a 5- to 7-membered ring; or R 1b and R 2b or X 1 are combined to form a 5- to 7-membered ring; where R 2a and R 2b , R 1a and R 2a or X 1 , or R 1b and R 2b or X 1 The ring formed by the combination of 1-8 Alkyl, C 1-8 Haloalkyl, -X 3 -C(O)2R a , -X 3 -OR a , -X 3 -NR a R b , -X 3 -CONR a R b , -X 3 -SO2R a , -X 3 -SO2NR a R b , and -X 3 -SO3R aand wherein X is substituted with 0 to 4 substituents independently selected from the group consisting of 3 is a bond or C 1-6 is alkylene; R 3 are H, F, Cl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 2-3 selected from the group consisting of alkenyl and CN; The subscript n is 0, 1 or 2; Each R 3a are F, Cl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 2-3 independently selected from the group consisting of alkenyl and CN; R 4 , R 6 , R 7 and R 8 Each of these is H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -Y 1 , -X 4 -C(O)2R a , -X 4 -OR a , -X 4 -NR a R b , -X 4 -CONR a R b , -X 4 -SO2R a , -X 4 -SO2NR a R b , -X 4 -SO3R a , -OX 4 -Y 1 and -X 4 -Y 1 wherein each X is independently selected from the group consisting of4 is a bond or C 1-6 Alkylene, and OH, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 optionally further substituted with alkyl or COH, and each Y 1 is C 3-6 Cycloalkyl, C 4-8 heterocyclyl and 5- to 6-membered heteroaryl, each of which is selected from the group consisting of oxo, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkoxy, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 optionally further substituted with 1 to 4 substituents independently selected from the group consisting of alkyl, and COH; R 5 H, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -Y 2 , -X 5 -C(O)2R a , -X 5 -OR a , -X 5 -NR a R b , -X 5 -CONR a R b , -X 5 -SO2R a , -X 5 -SO2NR a R b , -X 5 -SO3R a , -X 5 -Y 2 , -OX 5 -Y 2 and -AZ; wherein each X 5 is a bond or C 1-6Alkylene, and OH, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 optionally further substituted with alkyl or COH, and each Y 2 is C 3-6 Cycloalkyl, C 4-8 Heterocyclyl, C 7-9 and 5- to 6-membered heteroaryl, each of which is selected from the group consisting of oxo, halogen, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkoxy, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 optionally further substituted with 1 to 4 substituents independently selected from the group consisting of alkyl, and COH; where A is a bond, -O- and -N(R a )- is a member selected from the group consisting of; Z is: i) 1 to 3 R c to a further optionally substituted monocyclic 5- or 6-membered heteroaryl ring, ii) 1 to 3 R c to more optionally substituted phenyl, and iii) 1 to 3 R c to an optionally substituted 5- or 6-membered non-aromatic heterocycle, is selected from the group consisting of and A is -O- or -N(R a )-, Z is other than phenyl; and R on the adjacent carbon atom 4 , R 5 , R 6 , R 7 and R 8 Any two of these can be combined to form O, -N(R b)- and ═N-, forming a 5- to 6-membered non-aromatic heterocyclic ring having one or two ring vertices selected from the group consisting of ═N- and ═N-; wherein the non-aromatic heterocyclic ring is optionally substituted by oxo and optionally 1 to 4 R c to More arbitrarily substituted; And R 4 , R 5 , R 6 , R 7 and R 8 at least one of is other than H; Each R a is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkylene-COH, C 1-6 Alkylene-COO-C 1-8 Alkyl, C 1-6 independently selected from the group consisting of alkylene-SO3H; Each R b is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkylene-COH, C 1-6 Alkylene-SO3H and C 1-6 Alkylene-Y 3 wherein Y is independently selected from the group consisting of 3 is C 3-6 Cycloalkyl or C 4-8 heterocyclyl, and each R b are oxo, OH, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 optionally further substituted with 1 or 2 members independently selected from alkyl and COH; And R a and R bare optionally combined when attached to the same nitrogen atom to form a 4- to 8-membered ring or spiro ring, said ring or spiro ring being free of halogen, OH, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 optionally substituted with alkyl or COH; Each R c H, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -Y 4 , -X 6 -C(O)2R a , -X 6 -OR a , -X 6 -NR a R b , -X 6 -CONR a R b , -X 6 -SO2R a , -X 6 -SO2NR a R b , -X 6 -SO3R a , and -N(R a )-X 6 -C(O)2R a wherein each X is independently selected from the group consisting of 6 is a bond or C 1-6 alkylene, and each Y 4 is C 3-6 Cycloalkyl and C 4-8 heterocyclyl; and optionally, two R on adjacent ring vertices c are combined to form a fused 5- to 6-membered heterocycle}.

[0036] In some embodiments, the present disclosure provides a compound of formula (Ia):

[0037] [ka] wherein R 2a , R 2b , R3 , R 4 , and R c is as defined for formula (I).

[0038] In some embodiments, the present disclosure provides a compound of formula (Ib):

[0039] [ka] wherein R 2a , R 2b , R 3 , R 4 , X 5 and Y 2 is as defined for formula (I). In some selected embodiments, compounds of formula (Ib) are provided, wherein Y 2 is as follows:

[0040] [ka] is selected from the group consisting of:

[0041] In some embodiments, the present disclosure provides a compound of formula (Ic):

[0042] [ka] wherein R 2a , R 2b , R 3 , R 4 , R a , R b and X 5 is as defined for formula (I).

[0043] In some selected embodiments, the compound of formula (I) is 5 is a compound in which -AZ.

[0044] In some selected embodiments, the compound of formula (I) is5 Ga-OX 5 -Y 2 It is a compound in which

[0045] In some selected embodiments, the compound of formula (I) is 5 is -AZ, A is a bond, and Z is 1 to 3 R c and n is 0 or 1. The compound is phenyl optionally substituted by

[0046] In some selected embodiments, the compound of formula (I) is 1 is a compound in which -CH2-.

[0047] In some selected embodiments, the compound of formula (I) is 1c , R 7 and R 8 is H, and R 3 is a compound selected from the group consisting of F, Cl, CH3, CF3 and OCH3.

[0048] In some selected embodiments, the compound of formula (I) is a compound of formula (I) wherein the ring is a pair of R 4 and R 5 , R 5 and R 6 , R 1b and R 2b , or R 1a and R 2a It is a compound formed between

[0049] In some selected embodiments, the compound of formula (I) is 5 is -AZ, and Z is a compound selected from the group consisting of piperidinyl, imidazolyl, and pyridinyl.

[0050] In some selected embodiments, the compound of formula (I) is one in which n is 0.

[0051] In some selected embodiments, the compound of formula (I) is 4is a compound selected from the group consisting of F, Cl, CH3, CF3 and OCH3.

[0052] In some selected embodiments, the compound of formula (I) is 1a is OCH3, and R 1b is a compound where F.

[0053] In some selected embodiments, the compound of formula (I) is 2a and R 2b are compounds in which each is H.

[0054] In some selected embodiments, the compound of formula (I) is 2a and R 2b are combined to form a 4- to 8-membered ring or spiro ring, optionally having one or two additional ring vertices selected from O, N, or S; wherein the ring or spiro ring is selected from oxo, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, -X 2 -C(O)2R a , -X 2 -OR a , -X 2 -NR a R b , -X 2 -CONR a R b , -X 2 -SO2R a , -X 2 -SO2NR a R b , and -X 2 -SO3R a- wherein X is independently substituted with 0 to 4 substituents selected from the group consisting of 2 is a bond or C 1-6 It is alkylene.

[0055] In some selected embodiments, the compound of formula (I) is 2a But H or C 1-8alkyl; and R 2b But -Y or -X 1 In further selected embodiments, Y is selected from the group consisting of oxo, OH, C, and the like. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkoxy, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 C optionally further substituted with 1 to 4 substituents independently selected from the group consisting of alkyl, and COH; 3-6 Cycloalkyl and C 4-8 heterocyclyl.

[0056] In some embodiments, for each of Formulas (I), (Ia), (Ib), and (Ic), and further selected embodiments above, the compound or pharmaceutically acceptable salt thereof is one selected from Table 1 that has ++ or +++ activity.

[0057] In addition to the compounds provided above, pharmaceutically acceptable salts of these compounds are also provided. In some embodiments, the pharmaceutically acceptable salts include ammonium, calcium, magnesium, potassium, sodium, zinc, arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, methylglucamine ... The acid may be selected from phosphorus, piperazine, piperadine, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, hydrochloric acid, carbonic acid, monohydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, alginic acid, glucuronic acid and galacturonic acid. In some embodiments, the pharmaceutically acceptable salt is selected from ammonium, calcium, magnesium, potassium, sodium, hydrochloric acid, carbonate, monohydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, alginic acid, glucuronic acid, and galacturonic acid. In some embodiments, the pharmaceutically acceptable salt is sodium or hydrochloric acid.

[0058] In addition to salt forms, the present disclosure provides compounds in prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0059] The esters can be used as prodrugs of the corresponding carboxylic acids. 1-10 Alkyl ester or C 1-10 Haloalkyl esters can be used as prodrugs of the corresponding carboxylic acids. The following esters can be used: ter-butyl ester, methyl ester, ethyl ester, isopropyl ester.

[0060] Pharmaceutical Composition In addition to the compounds provided herein, compositions of those compounds will typically include a pharmaceutical carrier or diluent.

[0061] As used herein, the term "composition" is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product that results directly or indirectly from combining the specified ingredients in the specified amounts. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0062] In another embodiment, a pharmaceutical composition is provided that contains a compound of the present disclosure, including a compound of Formula (I), (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0063] In some embodiments, the pharmaceutical composition further comprises one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of antimicrobial agents, antiviral agents, cytotoxic agents, gene expression modulators, chemotherapeutic agents, anticancer agents, angiogenesis inhibitors, immunotherapeutic agents, antihormonal agents, antifibrotic agents, radiation therapy, radiotherapeutic agents, antineoplastic agents, and antiproliferative agents. In some embodiments, the one or more additional therapeutic agents are antagonists of chemokine and / or chemoattractant receptors, including, but not limited to, CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CCR11, CCR12, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, C3aR, and / or C5aR.Antagonists of chemokine and / or chemoattractant receptors are known in the art and are described, for example, in WO2007 / 002667, WO2007 / 002293, WO / 2003 / 105853, WO / 2007 / 022257, WO / 2007 / 059108, WO / 2007 / 044804, WO2007 / 115232, WO2007 / 115 231, WO2008 / 147815, WO2010 / 030815, WO2010 / 075257, WO2011 / 163640, WO2010 / 054006, WO201 0 / 051561, WO2011 / 035332, WO2013 / 082490, WO2013 / 082429, WO2014 / 085490, WO2014 / 100735, WO2014 / 089495, WO2015 / 084842, WO2016 / 187393, WO2017 / 127409, WO2017 / 087607, WO2017 / 08 7610, WO2017 / 176620, WO2018 / 222598, WO2018 / 222601, WO2013 / 130811, WO2006 / 076644, WO20 08 / 008431, WO2009 / 038847, WO2008 / 008375, WO2008 / 008374, WO2008 / 010934, WO2009 / 009740, WO2005 / 112925, WO2005 / 112916, WO2005 / 113513, WO2004 / 085384, WO2004 / 046092. Chemokine and / or chemoattractant receptor antagonists also include CCX354, CCX9588, CCX140, CCX872, CCX598, CCX6239, CCX9664, CCX2553, CCX3587, CCX3624, CCX2991, CCX282, CCX025, CCX507, CCX430, CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, CCX168-M1, CCX3022 and / or CCX3384.

[0064] Pharmaceutical compositions for administering the compounds of the present disclosure may conveniently be provided in unit dosage form and may be prepared by any method well known in the art of pharmacy and drug delivery. All methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition, the active object compound is included in an amount sufficient to produce the desired effect on the process or condition of a disease.

[0065] Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions and self-emulsifying formulations such as those described in U.S. Patent Application No. 2002-0012680, hard or soft capsules, syrups, elixirs, liquids, buccal patches, oral gels, chewing gums, chewable tablets, effervescent powders, and effervescent tablets. Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more substances selected from the group consisting of sweeteners, flavoring agents, coloring agents, antioxidants, and preservatives to provide a pharmaceutically elegant and palatable preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as PVP, cellulose, PEG, starch, gelatin, or acacia gum; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or enteric-coated or otherwise coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time-delay material, such as glyceryl monostearate or glyceryl disterate, may be employed. They may also be coated by the techniques described in the US Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.

[0066] Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, polyethylene glycols (PEGs) of various average sizes (e.g., PEG400, PEG4000), and several surfactants, such as Cremophor or Solutol, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil. Additionally, emulsions can be prepared with water-immiscible ingredients, such as oils, and stabilized with surfactants, such as mono- or diglycerides, PEG esters, etc.

[0067] Aqueous suspensions contain the active substance mixed with excipients suitable for the manufacture of aqueous suspensions.Such excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and acacia gum; dispersing agents or wetting agents can be natural phosphatides, such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, such as heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with fatty acids and partial esters derived from hexitol, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with fatty acids and partial esters derived from hexitol anhydrides, such as polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example, ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0068] Oily suspensions can be formulated by suspending the active ingredient in vegetable oils such as peanut oil, olive oil, sesame oil, or coconut oil, or mineral oils such as liquid paraffin.Oily suspensions can contain thickening agents such as beeswax, hard paraffin, or cetyl alcohol.Sweeteners and flavoring agents such as those described above can be added to provide a palatable oral preparation.These compositions can be preserved by adding antioxidants such as ascorbic acid.

[0069] Dispersible powders and granules suitable for preparation of an aqueous suspension by adding water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, such as sweeteners, flavorings, and coloring agents, may also be present.

[0070] The pharmaceutical composition of the present disclosure may also be in the form of an oil-in-water emulsion.The oil phase may be, for example, a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin, or a mixture thereof.Suitable emulsifiers may be, for example, natural gums such as gum acacia or gum tragacanth, natural phosphatides such as soybeans, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and the condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.These emulsions may also contain sweeteners and flavoring agents.

[0071] Syrups and elixirs may be formulated with sweeteners, such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain demulcents, preservatives, and flavoring and coloring agents. Oral liquid preparations may be prepared in combination with, for example, cyclodextrin, PEG, and surfactants.

[0072] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. Such suspensions can be formulated as known in the art using suitable dispersing or wetting agents and suspending agents, as previously mentioned. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland, fixed oil, including synthetic mono- or diglycerides, may be employed. Additionally, fatty acids, such as oleic acid, are permitted for use in injectable preparations.

[0073] The compounds of the present disclosure may also be administered in the form of suppositories for rectal drug administration. These compositions can be prepared by mixing with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, thereby melting in the rectum and releasing the drug. Such materials include cocoa butter and polyethylene glycol. In addition, the compounds of the present disclosure can be administered by ocular delivery using a solution or ointment. Furthermore, transdermal delivery of the target compounds can be achieved using iontophoretic patches, etc. For topical use, creams, ointments, jellies, solutions, or suspensions containing the compounds of the present disclosure are used. As used herein, topical application also includes the use of mouthwashes and gargles.

[0074] The compounds of the present disclosure may also be coupled to carriers that are polymers suitable for targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present disclosure may be coupled to carriers that represent a class of biodegradable polymers useful in achieving controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels. Polymer and semipermeable polymer matrices may be formed into shaped articles, such as valves, stents, tubes, and prostheses. In one embodiment of the present disclosure, the compounds of the present disclosure are coupled to a polymer or semipermeable polymer matrix formed as a stent or stent-graft device.

[0075] Methods for treating diseases and disorders Compounds of the present disclosure can be used as immunomodulators. Compounds of the present disclosure can be used as agonists, antagonists, partial agonists, inverse agonists, or inhibitors of PD-1 and / or PD-L1 in a variety of contexts, both in vitro and in vivo. In some embodiments, compounds of the present disclosure can be used as inhibitors of PD-1 / PD-L1 protein-protein interaction. In some embodiments, compounds of the present disclosure can be used as inhibitors of PD-L1. In some embodiments, compounds of the present disclosure can be used as inhibitors of CD80 / PD-L1 protein-protein interaction. In some embodiments, compounds of the present disclosure can be used to inhibit the interaction between PD-1 and PD-L1 and / or PD-1 and CD80 and / or PD-1 and PD-L2 in vitro or in vivo. In some embodiments, compounds of the present disclosure can be used to inhibit VISTA and / or TIM-3. In some embodiments, compounds of the disclosure may be inhibitors of PD-1 / PD-L1 protein-protein interaction and inhibitors of VISTA and / or TIM-3. In some embodiments, compounds of the disclosure, in addition to being inhibitors of PD-1 / PD-L1 protein-protein interaction, may also be inhibitors of CTLA-4 and / or BTLA and / or LAG-3 and / or KLRG-1 and / or 2B4 and / or CD160 and / or HVEM and / or CD48 and / or E-cadherin and / or MHC-II and / or Galectin-9 and / or CD86 and / or PD-L2 and / or VISTA and / or TIM-3 and / or CD80.

[0076] The compounds of the present disclosure may be contacted with the interacting receptor in aqueous solution and under other conditions suitable for binding of the ligand to the receptor, which may be in suspension (e.g., in an isolated membrane or cell preparation), in cultured or isolated cells, or in a tissue or organ.

[0077] Preferably, the amount of a compound of the present disclosure contacted with the receptor should be sufficient to inhibit PD-1 / PD-L1 binding in vitro, as measured, for example, using ELISA. The receptor can be in solution or suspension, in a cultured or isolated cell preparation, or in a patient.

[0078] In some embodiments, the compounds of the present disclosure are useful for restoring and enhancing T cell activation. In some embodiments, the compounds of the present disclosure are useful for enhancing immune responses in patients. In some embodiments, the compounds of the present disclosure are useful for treating, preventing, or delaying the progression of diseases or disorders in various therapeutic areas, such as cancer and infectious diseases.

[0079] In some embodiments, compounds of the present disclosure can be used to treat patients suffering from conditions that respond to modulation of PD-1 / PD-L1 protein-protein interactions.

[0080] In some embodiments, methods are provided for modulating an immune response mediated by the PD-1 signaling pathway in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the disclosure, including a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt thereof, or a composition containing a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt thereof.

[0081] In some embodiments, provided are methods of enhancing, stimulating, modulating, and / or augmenting an immune response in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the disclosure, including a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt thereof, or a composition containing a compound of the disclosure, including a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt thereof.

[0082] In some embodiments, provided are methods of inhibiting the growth, proliferation, or metastasis of cancer cells in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, including a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt thereof, or a composition containing a compound of the present disclosure, including a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt thereof.

[0083] In some embodiments, methods are provided for treating a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, including a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt thereof, or a composition containing a compound of the present disclosure, including a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt thereof.

[0084] In some embodiments, the subject is suffering from a disease or disorder selected from the group consisting of an infectious disease, a bacterial infection, a viral infection, a fungal infection, a solid tumor, a hematological malignancy, an immune disorder, an inflammatory disease, and cancer. In some embodiments, the disease or disorder is selected from the group consisting of melanoma, glioblastoma, esophageal tumor, nasopharyngeal carcinoma, uveal melanoma, lymphoma, lymphocytic lymphoma, primary CNS lymphoma, T-cell lymphoma, diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, prostate cancer, castration-resistant prostate cancer, chronic myeloid leukemia, Kaposi's sarcoma, fibrosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, angiosarcoma, lymphangiosarcoma, synovoma, meningioma, leiomyosarcoma, transverse myeloid leukemia, thyroid cancer ... Rhabdomyosarcoma, soft tissue sarcoma, sarcoma, sepsis, bile duct tumor, basal cell carcinoma, thymus tumor, thyroid cancer, parathyroid cancer, uterine cancer, adrenal cancer, liver infection, Merkel cell carcinoma, nerve tumor, follicle center lymphoma, colon cancer, Hodgkin's disease, non-Hodgkin's lymphoma, leukemia, chronic or acute leukemia including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiple myeloma, ovarian tumor, myelodysplastic syndrome, cutaneous or intraocular malignant melanoma, renal cell carcinoma, small cell lung Cancer, lung cancer, mesothelioma, breast cancer, squamous non-small cell lung cancer (SCLC), non-squamous NSCLC, colorectal cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, pancreatic carcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma, head and neck squamous cell carcinoma, head and neck cancer, gastrointestinal cancer, stomach cancer, HIV, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus, papillomavirus, influenza, bone cancer, skin cancer, rectal cancer, anal cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulva cancer, esophageal cancer, small intestine cancer, endocrine system cancer, urethral cancer, The cancer is selected from the group consisting of penile cancer, bladder cancer, kidney cancer, ureter cancer, renal pelvis cancer, central nervous system (CNS) tumors, angiogenic tumors, spinal cord tumors, brain stem glioma, pituitary adenoma, epidermoid carcinoma, asbestosis, carcinoma, adenocarcinoma, papillary carcinoma, cystadenocarcinoma, bronchogenic carcinoma, renal cell carcinoma, transitional cell carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, pleomorphic adenoma, hepatocellular papilloma, renal tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma, and fibroma.

[0085] In some embodiments, a therapeutically effective amount of one or more additional therapeutic agents is further administered to the subject. In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of antimicrobial agents, antiviral agents, cytotoxic agents, gene expression modulators, chemotherapeutic agents, anticancer agents, angiogenesis inhibitors, immunotherapeutic agents, antihormonal agents, antifibrotic agents, radiation therapy, radiotherapeutic agents, antineoplastic agents, and antiproliferative agents. In some embodiments, the one or more additional therapeutic agents are antagonists of chemokine and / or chemoattractant receptors, including, but not limited to, CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CCR11, CCR12, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, C3aR, and / or C5aR.Antagonists of chemokine and / or chemoattractant receptors are known in the art and are described, for example, in WO2007 / 002667, WO2007 / 002293, WO / 2003 / 105853, WO / 2007 / 022257, WO / 2007 / 059108, WO / 2007 / 044804, WO2007 / 115232, WO2007 / 115 231, WO2008 / 147815, WO2010 / 030815, WO2010 / 075257, WO2011 / 163640, WO2010 / 054006, WO201 0 / 051561, WO2011 / 035332, WO2013 / 082490, WO2013 / 082429, WO2014 / 085490, WO2014 / 100735, WO2014 / 089495, WO2015 / 084842, WO2016 / 187393, WO2017 / 127409, WO2017 / 087607, WO2017 / 08 7610, WO2017 / 176620, WO2018 / 222598, WO2018 / 222601, WO2013 / 130811, WO2006 / 076644, WO20 08 / 008431, WO2009 / 038847, WO2008 / 008375, WO2008 / 008374, WO2008 / 010934, WO2009 / 009740, WO2005 / 112925, WO2005 / 112916, WO2005 / 113513, WO2004 / 085384, WO2004 / 046092. Chemokine and / or chemoattractant receptor antagonists also include CCX354, CCX9588, CCX140, CCX872, CCX598, CCX6239, CCX9664, CCX2553, CCX3587, CCX3624, CCX2991, CCX282, CCX025, CCX507, CCX430, CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, CCX168-M1, CCX3022 and / or CCX3384.

[0086] In some embodiments, compounds of the present disclosure can be used to inhibit infectious diseases, including pathogenic infections caused by HIV, influenza, herpes, giardia, malaria, leishmaniasis, hepatitis viruses (types A, B, and C), herpes viruses (e.g., VZV, HSV-I, HAV-6, HSV-II, and CMV, Epstein-Barr virus), adenovirus, influenza virus, flavivirus, echovirus, rhinovirus, coxsackievirus, corona virus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum contagiosum virus, poliovirus, rabies virus, JC virus, and arboviral encephalitis viruses, chlamydia, rickettsia, mycobacteria, staphylococci, streptococci, pneumoniae, and the like. Pathogenic infections caused by bacteria such as Neisseria meningitidis and Neisseria gonorrhoeae, Klebsiella, Proteus, Serratia, Pseudomonas, Escherichia coli, Legionella, Diphtheria, Salmonella, Bacillus, Cholera, Tetanus, Botulism, Anthrax, Plague, Leptospirosis, and Lyme disease; fungi such as Candida (albicans, krusei, glabrata, tropicalis), Cryptococcus neoformans, Aspergillus fumigatus, niger pathogenic infections caused by the genera Mucor (Mucorrhoea, Absidia, Rhizopus), Sporothrix schenckii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis, and Histoplasma capsulatum; and pathogenic infections caused by the parasites Entamoeba histolytica, Balantidium coli, Naegleria fowleri, Acanthamoeba spp., Giardia lambia, Cryptosporidium spp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondii, and Nippostrongylus brasiliensis.

[0087] In some embodiments, compounds of the present disclosure may be used to inhibit HIV infection, slow AIDS progression, deplete HIV viral reservoirs, or alleviate the severe symptoms of HIV infection and AIDS.

[0088] The compounds of the present disclosure may be used to treat cancer and pre-cancerous conditions in a subject.

[0089] The therapeutic methods provided herein generally involve administering to a patient an effective amount of one or more compounds provided herein. Suitable patients include those suffering from or susceptible to a disorder or disease identified herein (i.e., prophylactic treatment). Typical patients for treatment as described herein include mammals, particularly primates, and especially humans. Other suitable patients include domesticated companion animals such as dogs, cats, and horses, or livestock animals such as cows, pigs, and sheep.

[0090] Generally, the therapeutic methods provided herein involve administering to a patient an effective amount of one or more compounds provided herein. In preferred embodiments, the compound(s) of the present disclosure are preferably administered intravenously, orally, or topically to a patient (e.g., a human). An effective amount may be an amount sufficient to modulate PD-1 / PD-L1 interaction and / or an amount sufficient to reduce or alleviate symptoms exhibited by the patient. Preferably, the amount administered is sufficient to produce a plasma concentration of the compound (or, if the compound is a prodrug, its active metabolite) high enough to modulate PD-1 / PD-L1 interaction. Treatment regimens can vary depending on the compound used and the particular condition being treated; for treatment of most disorders, a dosing frequency of four times per day or less is preferred. Generally, a twice-daily dosing regimen is more preferred, with once-daily dosing being particularly preferred. It will be understood, however, that specific dosage levels and treatment regimens for any particular patient will vary depending on a variety of factors, including the activity of the specific compound employed, the patient's age, body weight, general health, sex, diet, time of administration, route of administration, excretion rate, concomitant medications (i.e., other drugs administered to the patient), and the severity of the particular condition being treated, as well as the judgment of the prescribing medical practitioner. Generally, use of the minimum amount sufficient to provide effective therapy is preferred. Patients are generally monitored for therapeutic effectiveness using medical or veterinary criteria appropriate for the condition being treated or prevented.

[0091] combination A combination drug containing a compound of the present disclosure and another drug may be administered as a combined preparation, in which both components are contained in a single preparation or administered as separate preparations. Administration in separate preparations includes simultaneous administration and administration with an interval. In the case of administration with an interval, the compound of the present disclosure may be administered first, followed by the other drug, or the other drug may be administered first, followed by the compound of the present disclosure. The administration method for each drug may be the same or different.

[0092] The dose of the other drug can be appropriately selected based on the dose used in clinical trials. The compounding ratio of the compound of the present disclosure to the other drug can be appropriately selected according to the age and weight of the subject to be administered, the administration method, the administration time, the disorder to be treated, symptoms, and combinations thereof. For example, the other drug may be used in an amount of 0.01 to 100 parts by mass based on 1 part by mass of the compound of the present disclosure. The other drug may be a combination of two or more drugs in an appropriate ratio.

[0093] The compounds described herein can be used or combined with one or more therapeutic agents such as antimicrobial agents, antiviral agents, cytotoxic agents, gene expression modulators, chemotherapeutic agents, anticancer agents, angiogenesis inhibitors, immunotherapeutic agents, antihormonal agents, antifibrotic agents, radiation therapy, radiotherapeutic agents, antineoplastic agents, and antiproliferative agents. These therapeutic agents can be in the form of chemical compounds, antibodies, polypeptides, or polynucleotides.

[0094] The compounds described herein can be used or combined with one or more of therapeutic antibodies, bispecific antibodies and "antibody-like" therapeutic proteins (DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives, etc.), antibody-drug conjugates (ADCs), viruses, oncolytic viruses, gene modifiers or editors such as CRISPR (including CRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALENs), CARs (chimeric antigen receptors), T-cell immunotherapeutics, or any combination thereof.

[0095] Examples of chemotherapeutic agents include alkylating agents, nitrosoureas, antimetabolites, anticancer antibiotics, alkaloids of plant origin, topoisomerase inhibitors, hormonal agents, hormone antagonists, aromatase inhibitors, P-glycoprotein inhibitors, platinum complex derivatives, other immunotherapeutic agents, and other anticancer agents.

[0096] The compounds described herein can be used or combined, either simultaneously or in the form of mixtures, with adjunct cancer therapeutic agents, such as leukopenia (neutropenia) therapeutic agents, thrombocytopenia therapeutic agents, antiemetic agents, and cancer pain mediating agents.

[0097] The compounds described herein can be used or combined with kinase inhibitors.

[0098] In one embodiment, the compounds of the present disclosure can be used together with other immunomodulators and / or enhancers, either simultaneously or in the form of a mixture. Examples of immunomodulators include various cytokines, vaccines, and adjuvants. Examples of these cytokines, vaccines, and adjuvants that stimulate the immune response include, but are not limited to, GM-CSF, M-CSF, G-CSF, interferon-alpha, beta, or gamma, IL-1, IL-2, IL-3, IL-12, poly(I:C), and CPG. Enhancers include cyclophosphamide and cyclophosphamide analogs, anti-TGF and imatinib (Gleevac), anti-mitotic agents such as paclitaxel, sunitinib (Sutent), or other angiogenesis inhibitors, aromatase inhibitors such as letrozole, A2a adenosine receptor (A2AR) antagonists, angiogenesis inhibitors, anthracyclines, oxaliplatin, doxorubicin, TLR4 antagonists, and IL-18 antagonists.

[0099] In some embodiments, the compounds described herein can be used or combined with one or more modulators of CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CCR11, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, ChemR23, C5aR, C5a, and C5. In some embodiments, the modulator is an antagonist.

[0100] In some embodiments, the compounds described herein are useful in the manufacture of pharmaceutical compositions and methods for treating various conditions, e.g., WO2007 / 002667, WO2007 / 002293, WO / 2003 / 105853, WO / 2007 / 022257, WO / 2007 / 059108, WO / 2007 / 044804, WO2007 / 115232, WO2007 / 115231, WO2008 / 147815, WO2010 / 030815, WO2010 / 075257, WO2011 / 163640, WO2010 / 054006, WO2010 / 051561, WO2011 / 035332, WO2013 / 082490, WO2013 / 082429, WO2014 / 085490, WO2014 / 100735, WO2014 / 089495, WO2015 / 084842, WO2016 / 1 87393, WO2017 / 127409, WO2017 / 087607, WO2017 / 087610, WO2017 / 176620, WO2018 / 222598, WO2018 / 2 22601, WO2013 / 130811, WO2006 / 076644, WO2008 / 008431, WO2009 / 038847, WO2008 / 008375, WO2008 / 00 8374, WO2008 / 010934, WO2009 / 009740, WO2005 / 112925, WO2005 / 112916, WO2005 / 113513, WO2004 / 085384, WO2004 / 046092. Chemokine and / or chemoattractant receptor antagonists useful in the present disclosure also include CCX354, CCX9588, CCX140, CCX872, CCX598, CCX6239, CCX9664, CCX2553, CCX3587, CCX3624, CCX2991, CCX282, CCX025, CCX507, CCX430, CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, CCX168-M1, CCX3022 and / or CCX3384.

[0101] dose Dosage levels of about 0.1 mg to about 140 mg / kg body weight / day are useful in treating or preventing conditions involving PD-1 / PD-L1 interaction. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host treated and the particular mode of administration. Unit dosage forms will generally contain about 1 mg to about 500 mg of active ingredient. For compounds administered orally, transdermally, intravenously, or subcutaneously, it is preferred that a sufficient amount of compound be administered to achieve a serum concentration of 5 ng (nanogram) / mL to 10 μg (microgram) / mL serum, more preferably, sufficient compound should be administered to achieve a serum concentration of 20 ng to 1 μg / mL serum, and most preferably, sufficient compound should be administered to achieve a serum concentration of 50 ng / mL to 200 ng / mL serum. For direct injection into the synovium (for the treatment of arthritis), sufficient compound should be administered to achieve a local concentration of approximately 1 micromolar.

[0102] Dosage frequency may also vary depending on the compound used and the particular disease being treated. However, for the treatment of most disorders, a four-times-daily, three-times-daily or less dosing regimen is preferred, with a once-daily or twice-daily dosing regimen being particularly preferred. It will be understood, however, that the specific dosage level for any particular patient will vary depending on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, route of administration and excretion rate, concomitant medications (i.e., other drugs administered to the patient), the severity of the particular disease being treated, and other factors, including the judgment of the prescribing medical practitioner.

[0103] In another aspect of the present disclosure, the compounds of the present disclosure can be used in a variety of non-pharmaceutical in vitro and in vivo applications. The compounds of the present disclosure can also be used as positive controls in assays for PD-1 / PD-L1 interaction activity, i.e., as standards for determining the ability of candidate substances to bind to PD-1 and / or PD-L1, or as radiotracers for positron emission tomography (PET) imaging or single photon emission computed tomography (SPECT).

[0104] Also within the scope of this disclosure is a kit comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and instructions for use. The kit may further comprise at least one additional reagent. The kit typically includes a label indicating the intended use of the contents of the kit. The term label includes any written or recorded material provided on or with the kit, or otherwise associated with the kit. [Example]

[0105] The following examples illustrate various methods of making compounds of the present disclosure, including compounds of formula (I), (Ia), (Ib), (Ic), or (Id). The following examples are provided for illustrative purposes and do not limit the claimed disclosure.

[0106] Reagents and solvents used below can be obtained from commercial suppliers, such as Aldrich Chemical Co. (Milwaukee, Wis., USA). 1H-NMR spectra were recorded on a Varian Mercury 400 MHz NMR analyzer. Prominent peaks were referenced relative to TMS and tabulated in the following order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), and proton number. Mass spectrometry results were reported as mass-to-charge ratios. In the examples, a single m / z value is reported for the M+H (or, as noted, MH) ion, which contains the most common atomic isotopes. The isotope pattern corresponds to the expected formula in all cases. Electrospray ionization (ESI) mass spectrometry was performed on a Hewlett-Packard MSD electrospray mass analyzer using an HP1100 HPLC for sample delivery. Typically, analytes were dissolved at 0.1 mg / mL in methanol or CH3CN, and 1 microliter, along with the mobile phase solvent, was injected into the mass analyzer, which scanned from 100 to 1000 daltons. All compounds can be analyzed in either positive or negative ESI mode using acetonitrile / water containing 1% formic acid as the mobile phase solvent.

[0107] The following abbreviations are used in the examples and throughout the description of this disclosure: TLC means thin layer chromatography; THF means tetrahydrofuran; DCE means 1,2-dichloroethane; DMF means N,N-dimethylformamide; TFA means trifluoroacetic acid; Bpin and pinB together mean 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl.

[0108] Compounds within the scope of the present disclosure can be synthesized as described below using a variety of reactions known to those of skill in the art. Those skilled in the art will also recognize that alternative methods are available to synthesize target compounds of the present disclosure, and that the approaches described within the body of this document, while not exhaustive, provide broadly applicable and practical routes to compounds of interest.

[0109] Some molecules claimed in this patent can exist in different enantiomeric and diastereomeric forms, and all such variations of these compounds are claimed unless a specific enantiomer is specified.

[0110] A detailed description of the experimental procedures used to synthesize key compounds in this document leads to molecules that are described by the physical data that identifies them as well as by their associated structural depictions.

[0111] Those skilled in the art will also recognize that acids and bases are frequently used during standard work-up procedures in organic chemistry. During the experimental procedures described within this patent, salts of the parent compounds are sometimes produced if they possess the necessary inherent acidity or basicity.

[0112] Example 1: 6-(2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-1,2,3,4-tetrahydroisoquinoline

[0113] [ka]

[0114] Step a: A solution of 6-bromo-1,2,3,4-tetrahydroisoquinoline (3.18 g, 15.0 mmol), di-tert-butyl dicarbonate (6.55 g, 30.0 mmol), and EtN (8.4 mL, 60.0 mmol) in MeOH (40 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and purified by silica gel flash chromatography (0-40% EtOAc / hexanes) to give tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate.

[0115] Step b: A mixture of tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (3.12 g, 10.0 mmol), bis(pinacolato)diboron (3.05 g, 12.0 mmol), and KOAc (2.94 g, 30.0 mmol) in dioxane (50 mL) was degassed (N) for 20 minutes. [1,1-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane adduct (817 mg, 1.0 mmol) was added, and the reaction mixture was degassed (N) for an additional 5 minutes and stirred overnight at 80 °C under N. The reaction mixture was cooled to room temperature, diluted with saturated NaHCO (100 mL), and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO, filtered, and concentrated. Purification by silica gel flash chromatography (0-30% EtOAc / hexanes) gave tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.

[0116] Step c: tert-Butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (750 mg, 2.1 mmol), 1-bromo-3-iodo-2-methylbenzene (802 mg, 2.7 mmol), dichloro[1,1'-bis(dicyclohexylphosphino)ferrocene]palladium(II) (159 mg, 0.21 mmol) in 3:1 t-BuOH:HO (12 mL) A mixture of 1,2-dimethyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (3-bromo-2-methylphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (3×10 mL) was degassed (N) for 10 minutes and stirred at 90° C. overnight. The reaction mixture was cooled to room temperature, diluted with HO (20 mL), and extracted with CHCl (3×10 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO, filtered, and concentrated. Purification by silica gel flash chromatography (0-30% EtOAc / hexanes) gave tert-butyl 6-(3-bromo-2-methylphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.

[0117] Step d: A mixture of tert-butyl 6-(3-bromo-2-methylphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg, 0.25 mmol), o-tolylboronic acid (52 mg, 0.38 mmol), dichloro[1,1′-bis(dicyclohexylphosphino)ferrocene]palladium(II) (19 mg, 0.025 mmol), and NaCO (67 mg, 0.63 mmol) in 3:1 t-BuOH:HO (2 mL) was degassed (N) for 5 min and stirred at 80 °C overnight. The reaction mixture was cooled to room temperature, diluted with HO (10 mL), and extracted with CHCl (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO, filtered, and concentrated. Purification by silica gel flash chromatography (0-100% CH 2 Cl 2 / hexanes) gave tert-butyl 6-(2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.

[0118] Step e: tert-Butyl 6-(2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (65 mg, 0.16 mmol) was dissolved in MeOH (0.5 mL), 4 M HCl / dioxane (0.5 mL) was added, and the reaction mixture was stirred for 1 h at 50° C. Purification by reverse-phase preparative HPLC (HO / MeCN with 0.1% TFA) gave 6-(2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-1,2,3,4-tetrahydroisoquinoline as the TFA salt. 1 H-NMR (400 MHz, (CD3)2SO) δ 9.09 (br s, 2H), 7.34-7.22 (m, 7H), 7.18 (dd, J = 1.4, 7.7 Hz, 1H), 7.10 (td, J = 1.6, 7.4 Hz, 2H), 4.33 (t, J MS: (ES) C 23 H 24 N [M+H] + Calculated m / z 314.2, observed 314.1.

[0119] Example 2: 6-(3'-methoxy-2-methyl-[1,1'-biphenyl]-3-yl)-1,2,3,4-tetrahydroisoquinoline

[0120] [ka]

[0121] Step a: A mixture of tert-butyl 6-(3-bromo-2-methylphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg, 0.25 mmol), 3-methoxyphenylboronic acid (58 mg, 0.38 mmol), dichloro[1,1′-bis(dicyclohexylphosphino)ferrocene]palladium(II) (19 mg, 0.025 mmol), and NaCO (67 mg, 0.63 mmol) in 3:1 t-BuOH:HO (2 mL) was degassed (N) for 5 min and stirred at 80 °C overnight. The reaction mixture was cooled to room temperature, diluted with HO (10 mL), and extracted with CHCl (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO, filtered, and concentrated. Purification by silica gel flash chromatography (0-30% EtOAc / hexanes) afforded tert-butyl 6-(3'-methoxy-2-methyl-[1,1'-biphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.

[0122] Step b: tert-Butyl 6-(3'-methoxy-2-methyl-[1,1'-biphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (75 mg, 0.17 mmol) was dissolved in MeOH (0.5 mL), 4 M HCl / dioxane (0.5 mL) was added, and the reaction mixture was stirred for 1 h at 50° C. Purification by reverse-phase preparative HPLC (HO / MeCN with 0.1% TFA) gave 6-(3'-methoxy-2-methyl-[1,1'-biphenyl]-3-yl)-1,2,3,4-tetrahydroisoquinoline as the TFA salt. 1 H-NMR (400 MHz, (CD3)2SO) δ 9.06 (br s, 2H), 7.39-7.16 (m, 7H), 6.95-6.89 (m, 3H), 4.36-4.30 (m, 2H), 3.79 (s, 3H), 3.47-3.40 (m, 2H), 3.05 (t, J = 6.3 Hz, 2H), 2.06 (s, 3H). MS: (ES) C 23 H 24NO [M+H] + Calculated m / z 330.2, observed 330.1.

[0123] Example 3: 6-(3'-methoxy-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-1,2,3,4-tetrahydroisoquinoline

[0124] [ka]

[0125] Step a: A mixture of tert-butyl 6-(3-bromo-2-methylphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg, 0.25 mmol), 3-methoxy-2-methylphenylboronic acid (63 mg, 0.38 mmol), dichloro[1,1′-bis(dicyclohexylphosphino)ferrocene]palladium(II) (19 mg, 0.025 mmol), and NaCO (67 mg, 0.63 mmol) in 3:1 t-BuOH:HO (2 mL) was degassed (N) for 5 min and stirred at 80 °C overnight. The reaction mixture was cooled to room temperature, diluted with HO (10 mL), and extracted with CHCl (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO, filtered, and concentrated. Purification by silica gel flash chromatography (0-30% EtOAc / hexanes) afforded tert-butyl 6-(3'-methoxy-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.

[0126] Step b: tert-Butyl 6-(3'-methoxy-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (70 mg, 0.16 mmol) was dissolved in MeOH (0.5 mL), 4 M HCl / dioxane (0.5 mL) was added, and the reaction mixture was stirred for 1 h at 50° C. Purification by reverse-phase preparative HPLC (HO / MeCN with 0.1% TFA) gave 6-(3'-methoxy-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-1,2,3,4-tetrahydroisoquinoline as the TFA salt. 1 H-NMR (400 MHz, (CD3)2SO) δ 9.05 (br s, 2H), 7.33-7.20 (m, 5H), 7.18 (dd, J = 1.4, 7.8 Hz, 1H), 7.07 (dd, J = 1.4, 7.6 Hz, 1H), 6.97 (dd, J = 1.1, 8.4 Hz, 1H), 6.72 (dd, J = 1.1, 7.5 Hz, 1H), 4.35-4.30 (m, 2H), 3.83 (s, 3H), 3.47-3.39 (m, 2H), 3.05 (t, J = 6.3 Hz, 2H), 1.88 (s, 3H), 1.85 (s, 3H). MS: (ES) C 24 H 26 NO [M+H] + Calculated m / z 344.2, observed 344.2.

[0127] Example 4: 6-(3'-(3-(2,2-dimethylazetidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-1,2,3,4-tetrahydroisoquinoline

[0128] [ka]

[0129] Step a: To a solution of 2-(3'-(3-bromopropoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (130 mg, 0.29 mmol) and 2,2-dimethylazetidine (33 mg, 0.38 mmol) in MeCN (2 mL) was slowly added iPrNEt (0.15 mL, 0.87 mmol). The mixture was heated to 50°C and stirred for 3 h. The reaction mixture was concentrated and the crude was purified by silica gel flash chromatography (0-15% MeOH / CH2Cl2) to give 1-(3-((2,2'-dimethyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-yl)oxy)propyl)-2,2-dimethylazetidine.

[0130] Step b: To a biphasic mixture of 1-(3-((2,2'-dimethyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-yl)oxy)propyl)-2,2-dimethylazetidine (45 mg, 0.10 mmol), 6-bromo-1,2,3,4-tetrahydroisoquinoline (42 mg, 0.20 mmol) in 0.5 M KPO (0.60 mL, 0.30 mmol) and THF (1.5 mL) was added XPhos Pd G (16 mg, 0.020 mmol). The reaction mixture was stirred at room temperature for 1 h and then heated at 40 °C for 12 h. The reaction mixture was cooled to room temperature and the organic layer was separated, filtered, and purified by reverse-phase preparative HPLC (HO / MeCN with 0.1% TFA) to give 6-(3'-(3-(2,2-dimethylazetidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-1,2,3,4-tetrahydroisoquinoline. MS: (ES) C 31 H 39 NO [M+H] + Calculated m / z value for 445.3, observed value 455.3. 1H-NMR (400 MHz, CDCl3) δ 7.29-7.26 (m, 1H), 7.25-7.22 (m, 1H), 7.22-7.18 (m, 1H), 7.18-7.16 (m, 2H), 7.15 (d, J = 8.0 Hz, 1H), 7.10 (dt, J = 7.5, 1.6 Hz, 1H), 6.82 (d, J = 1.8 Hz, 1H), 6.80 (d, J = 2.5 Hz, 1H), 4.43-4.34 (m, 3H), 4.12-4.02 (m, 2H), 3.62-3.47 (m, 3H), 3.36-3.25 (m, 1H), 3.21-3.08 (m, 3H), 2.67 (q, J = 9.9 Hz, 1H), 2.23-2.14 (m, 2H), 2.14-2.06 (m, 1H), 1.95 (s, 3H), 1.89 (s, 3H), 1.69 (s, 3H), 1.61 (s, 3H).

[0131] Example 5: 6-(3'-(3-(2,2-dimethylazetidin-1-yl)propoxy)-2'-methyl-[1,1'-biphenyl]-3-yl)-1,2,3,4-tetrahydroisoquinoline

[0132] [ka]

[0133] Step a: A mixture of 1-bromo-3-iodobenzene (283 mg, 1.0 mmol), tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (359 mg, 1.0 mmol), THF (10 mL), and 0.5 M KPO (10 mL) was degassed (N) for 5 min. XPhos Pd G (79 mg, 0.10 mmol) was added, and the reaction mixture was degassed (N) for an additional 5 min and stirred at room temperature overnight. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO, filtered, and concentrated. Purification by silica gel flash chromatography (0-30% EtOAc / hexanes) afforded tert-butyl 6-(3-bromophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.

[0134] Step b: A mixture of tert-butyl 6-(3-bromophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg, 0.26 mmol), 2-(3-(3-bromopropoxy)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (173 mg, 0.39 mmol), THF (3 mL), and 0.5 M KPO (3 mL) was degassed (N) for 5 min. XPhos Pd G (20 mg, 0.026 mmol) was added, and the reaction mixture was degassed (N) for an additional 5 min and stirred at room temperature overnight. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO, filtered, and concentrated. Purification by silica gel flash chromatography (0-30% EtOAc / hexanes) afforded tert-butyl 6-(3'-(3-bromopropoxy)-2'-methyl-[1,1'-biphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.

[0135] Step c: A solution of tert-butyl 6-(3'-(3-bromopropoxy)-2'-methyl-[1,1'-biphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (80 mg, 0.15 mmol), 2,2-dimethylazetidine (26 mg, 0.30 mmol), and iPrNEt (79 μL, 0.45 mmol) in MeCN (2 mL) was stirred at 50° C. for 5 h. The reaction mixture was cooled to room temperature and concentrated. Purification by silica gel flash chromatography (0-10% MeOH / CH2Cl2) gave tert-butyl 6-(3'-(3-(2,2-dimethylazetidin-1-yl)propoxy)-2'-methyl-[1,1'-biphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.

[0136] Step d: tert-Butyl 6-(3'-(3-(2,2-dimethylazetidin-1-yl)propoxy)-2'-methyl-[1,1'-biphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (55 mg, 0.10 mmol) was dissolved in MeOH (0.5 mL), 4 M HCl / dioxane (0.5 mL) was added, and the reaction mixture was stirred at 50° C. for 1 h. Purification by reverse-phase preparative HPLC (HO / MeCN with 0.1% TFA) gave 6-(3'-(3-(2,2-dimethylazetidin-1-yl)propoxy)-2'-methyl-[1,1'-biphenyl]-3-yl)-1,2,3,4-tetrahydroisoquinoline as the bis-TFA salt. 1H-NMR (400 MHz, (CD3)2SO) δ 9.64 (br s, 1H) 9.09 (br s, 2H), 7.67 (d, J = 8.0 Hz, 1H), 7.62-7.58 (m, 2H), 7.56-7.51 (m, 2H), 7.33-7.28 (m, 2H), 7.25 (t, J = 7.9 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H), 4.35-4.29 (m, 2H), 4.13-4.01 (m, 2H), 3.99-3.87 (m, 2H), 3.46-3.38 (m, 2H), 3.33-3.20 (m, 1H), 3.19-3.10 (m, 1H), 3.06 (t, J = 6.3 Hz, 2H), 2.39-2.29 (m, 1H), 2.15-2.06 (m, 4H), 2.03-1.94 (m, 2H), 1.57 (s, 3H), 1.55 (s, 3H). MS: (ES) C 30 H 37 NO [M+H] + Calculated m / z value for 441.3, observed value 441.3.

[0137] Example 6: 3'-(3-(2,2-dimethylazetidin-1-yl)propoxy)-2'-methyl-3-(1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,1'-biphenyl]-2-carbonitrile

[0138] [ka]

[0139] Step a: A mixture of 2-bromo-6-iodobenzonitrile (308 mg, 1.0 mmol), tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (359 mg, 1.0 mmol), THF (10 mL), and 0.5 M KPO (10 mL) was degassed (N) for 5 min. XPhos Pd G (79 mg, 0.10 mmol) was added, and the reaction mixture was degassed (N) for an additional 5 min and stirred at room temperature overnight. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO, filtered, and concentrated. Purification by silica gel flash chromatography (0-50% EtOAc / hexanes) afforded tert-butyl 6-(3-bromo-2-cyanophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.

[0140] Step b: A mixture of tert-butyl 6-(3-bromo-2-cyanophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (170 mg, 0.41 mmol), 2-(3-(3-bromopropoxy)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (275 mg, 0.62 mmol), THF (4 mL), and 0.5 M KPO (4 mL) was degassed (N) for 5 min. XPhos Pd G (32 mg, 0.041 mmol) was added, and the reaction mixture was degassed (N) for an additional 5 min and stirred at room temperature overnight. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO, filtered, and concentrated. Purification by silica gel flash chromatography (0-30% EtOAc / hexanes) afforded tert-butyl 6-(3'-(3-bromopropoxy)-2-cyano-2'-methyl-[1,1'-biphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.

[0141] Step c: A solution of tert-butyl 6-(3'-(3-bromopropoxy)-2-cyano-2'-methyl-[1,1'-biphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (140 mg, 0.25 mmol), 2,2-dimethylazetidine (43 mg, 0.50 mmol), and iPrNEt (0.13 mL, 0.75 mmol) in MeCN (3 mL) was stirred at 50° C. for 5 h. The reaction mixture was cooled to room temperature and concentrated. Purification by silica gel flash chromatography (0-10% MeOH / CH2Cl2) gave tert-butyl 6-(2-cyano-3'-(3-(2,2-dimethylazetidin-1-yl)propoxy)-2'-methyl-[1,1'-biphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.

[0142] Step d: tert-Butyl 6-(2-cyano-3'-(3-(2,2-dimethylazetidin-1-yl)propoxy)-2'-methyl-[1,1'-biphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (120 mg, 0.21 mmol) was dissolved in MeOH (0.5 mL), 4 M HCl / dioxane (0.5 mL) was added, and the reaction mixture was stirred at 50° C. for 1 h. Purification by reverse-phase preparative HPLC (HO / MeCN with 0.1% TFA) gave 3'-(3-(2,2-dimethylazetidin-1-yl)propoxy)-2'-methyl-3-(1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,1'-biphenyl]-2-carbonitrile as the bis-TFA salt. 1H-NMR (400 MHz, (CD3)2SO) δ 9.28 (br s, 1H) 9.16 (br s, 2H), 7.84 (d, J = 7.8 Hz, 1H), 7.61 (dd, J = 1.1, 7.9 Hz, 1H), 7.53-7.47 (m, 2H), 7.45 (dd, J = 1.1, 7.8 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 7.9 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 4.37 (t, J = 4.2 Hz, 2H), 4.17-4.02 (m, 2H), 4.00-3.87 (m, 2H), 3.49-3.41 (m, 2H), 3.34-3.22 (m, 1H), 3.19-3.11 (m, 1H), 3.08 (t, J = 6.2 Hz, 2H), 2.39-2.29 (m, 1H), 2.14-2.05 (m, 1H), 2.05-1.95 (m, 5H), 1.57 (s, 3H), 1.55 (s, 3H). MS: (ES) C 31 H 36 NO [M+H] + Calculated m / z 466.3, observed 466.4.

[0143] Example 7: 6-(3'-(3-(2,2-dimethylazetidin-1-yl)propoxy)-2-fluoro-2'-methyl-[1,1'-biphenyl]-3-yl)-1,2,3,4-tetrahydroisoquinoline

[0144] [ka]

[0145] Step a: A mixture of 1-bromo-2-fluoro-3-iodobenzene (250 mg, 0.83 mmol), tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (298 mg, 0.83 mmol), Na2CO3 (180 mg, 1.7 mmol), DME (8 mL), and HO (2 mL) was degassed (N2) for 5 min. Pd(PPh3)4 (197 mg, 0.17 mmol) was added, and the reaction mixture was degassed (N2) for an additional 5 min and stirred at 80 °C overnight. The reaction mixture was cooled to room temperature, diluted with HO (10 mL), and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO, filtered, and concentrated. Purification by silica gel flash chromatography (0-100% CHCl / hexanes) gave tert-butyl 6-(3-bromo-2-fluorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.

[0146] Step b: A mixture of tert-butyl 6-(3-bromo-2-fluorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (90 mg, 0.22 mmol), 2-(3-(3-bromopropoxy)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (146 mg, 0.33 mmol), THF (2 mL), and 0.5 M KPO (2 mL) was degassed (N) for 5 min. XPhos Pd G (17 mg, 0.022 mmol) was added, and the reaction mixture was degassed (N) for an additional 5 min and stirred at room temperature overnight. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO, filtered, and concentrated. Purification by silica gel flash chromatography (0-30% EtOAc / hexanes) afforded tert-butyl 6-(3'-(3-bromopropoxy)-2-fluoro-2'-methyl-[1,1'-biphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.

[0147] Step c: A solution of tert-butyl 6-(3′-(3-bromopropoxy)-2-fluoro-2′-methyl-[1,1′-biphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (60 mg, 0.11 mmol), 2,2-dimethylazetidine (19 mg, 0.22 mmol), and iPrNEt (58 μL, 0.33 mmol) in MeCN (1 mL) was stirred at 50° C. for 3 h. The reaction mixture was cooled to room temperature and concentrated. Purification by silica gel flash chromatography (0-10% MeOH / CH2Cl2) gave tert-butyl 6-(2-fluoro-3'-(3-(2,2-dimethylazetidin-1-yl)propoxy)-2'-methyl-[1,1'-biphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.

[0148] Step d: tert-Butyl 6-(2-fluoro-3'-(3-(2,2-dimethylazetidin-1-yl)propoxy)-2'-methyl-[1,1'-biphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (35 mg, 0.063 mmol) was dissolved in MeOH (0.5 mL), 4 M HCl / dioxane (0.5 mL) was added, and the reaction mixture was stirred at 50° C. for 1 h. Purification by reverse-phase preparative HPLC (HO / MeCN with 0.1% TFA) gave 6-(3'-(3-(2,2-dimethylazetidin-1-yl)propoxy)-2-fluoro-2'-methyl-[1,1'-biphenyl]-3-yl)-1,2,3,4-tetrahydroisoquinoline as the bis-TFA salt. 1 H-NMR (400 MHz, (CD3)2SO) δ 9.64 (br s, 1H) 9.10 (br s, 2H), 7.53 (td, J = 1.8, 7.6 Hz, 1H), 7.47-7.42 (m, 2H), 7.38 (t, J = 7.6 Hz, 1H), 7.35-7.23 (m, 3H), 7.02 (d, J = 8.0 Hz, 1H), 6.88 (d, J = 7.6 Hz, 1H), 4.36-4.30 (m, 2H), 4.14-4.02 (m, 2H), 3.98-3.86 (m, 2H), 3.47-3.38 (m, 2H), 3.32-3.21 (m, 1H), 3.18-3.09 (m, 1H), 3.05 (t, J = 6.3 Hz, 2H), 2.39-2.29 (m, 1H), 2.14-2.06 (m, 1H), 2.04-1.94 (m, 5H), 1.57 (s, 3H), 1.54 (s, 3H). MS: (ES) C 30 H 36 FN2O [M+H] + Calculated m / z value for 459.3, observed value 459.4.

[0149] Example 8: 6-(3'-(3-(2,2-dimethylazetidin-1-yl)propoxy)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-1,2,3,4-tetrahydroisoquinoline

[0150] [ka]

[0151] Step a: A mixture of 1-bromo-2-chloro-3-iodobenzene (250 mg, 0.79 mmol), tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (284 mg, 0.79 mmol), THF (8 mL), and 0.5 M KPO (8 mL) was degassed (N) for 5 min. XPhos Pd G (62 mg, 0.079 mmol) was added, and the reaction mixture was degassed (N) for an additional 5 min and stirred at room temperature overnight. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO, filtered, and concentrated. Purification by silica gel flash chromatography (0-100% CH2Cl2 / hexanes) gave tert-butyl 6-(3-bromo-2-chlorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.

[0152] Step b: A mixture of tert-butyl 6-(3-bromo-2-chlorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg, 0.23 mmol), 2-(3-(3-bromopropoxy)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (155 mg, 0.35 mmol), THF (3 mL), and 0.5 M KPO (3 mL) was degassed (N) for 5 min. XPhos Pd G (18 mg, 0.023 mmol) was added, and the reaction mixture was degassed (N) for an additional 5 min and stirred at room temperature overnight. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO, filtered, and concentrated. Purification by silica gel flash chromatography (0-100% CH2Cl2 / hexanes) gave tert-butyl 6-(3'-(3-bromopropoxy)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.

[0153] Step c: A solution of tert-butyl 6-(3′-(3-bromopropoxy)-2-chloro-2′-methyl-[1,1′-biphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg, 0.18 mmol), 2,2-dimethylazetidine (31 mg, 0.36 mmol), and iPrNEt (94 μL, 0.54 mmol) in MeCN (2 mL) was stirred at 50° C. for 4 h. The reaction mixture was cooled to room temperature and concentrated. Purification by silica gel flash chromatography (0-10% MeOH / CH2Cl2) gave tert-butyl 6-(2-chloro-3'-(3-(2,2-dimethylazetidin-1-yl)propoxy)-2'-methyl-[1,1'-biphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.

[0154] Step d: tert-Butyl 6-(2-chloro-3'-(3-(2,2-dimethylazetidin-1-yl)propoxy)-2'-methyl-[1,1'-biphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (70 mg, 0.12 mmol) was dissolved in MeOH (0.5 mL), 4 M HCl / dioxane (0.5 mL) was added, and the reaction mixture was stirred at 50° C. for 1 h. Purification by reverse-phase preparative HPLC (HO / MeCN with 0.1% TFA) gave 6-(3'-(3-(2,2-dimethylazetidin-1-yl)propoxy)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-1,2,3,4-tetrahydroisoquinoline as the bis-TFA salt. 1 H-NMR (400 MHz, (CD3)2SO) δ 9.66 (br s, 1H), 9.10 (br s, 2H), 7.48 (t, J = 7.6 Hz, 1H), 7.39 (dd, J = 1.8, 7.6 Hz, 1H), 7.36-7.29 (m, 3H), 7.29-7.21 (m, 2H), 6.99 (d, J = 8.2 Hz, 1H), 6.78 (d, J = 7.5 Hz, 1H), 4.37-4.31 (m, 2H), 4.13-4.00 (m, 2H), 3.99-3.86 (m, 2H), 3.47-3.39 (m, 2H), 3.33-3.21 (m, 1H), 3.19-3.09 (m, 1H), 3.05 (t, J = 6.3 Hz, 2H), 2.39-2.29 (m, 1H), 2.14-2.06 (m, 1H), 2.03-1.92 (m, 5H), 1.57 (s, 3H), 1.55 (s, 3H). MS: (ES) C 30 H 36 ClNO [M+H] + Calculated m / z value for 475.3, observed value 475.3.

[0155] Example 9: 6-(3'-(3-(2,2-dimethylazetidin-1-yl)propoxy)-2-methoxy-2'-methyl-[1,1'-biphenyl]-3-yl)-1,2,3,4-tetrahydroisoquinoline

[0156] [ka]

[0157] Step a: A mixture of 2-bromo-6-iodoanisole (250 mg, 0.80 mmol), tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (287 mg, 0.80 mmol), THF (8 mL), and 0.5 M KPO (8 mL) was degassed (N) for 5 min. XPhos Pd G (63 mg, 0.080 mmol) was added, and the reaction mixture was degassed (N) for an additional 5 min and stirred at room temperature overnight. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO, filtered, and concentrated. Purification by silica gel flash chromatography (0-100% CH2Cl2 / hexanes) gave tert-butyl 6-(3-bromo-2-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.

[0158] Step b: A mixture of tert-butyl 6-(3-bromo-2-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (80 mg, 0.19 mmol), 2-(3-(3-bromopropoxy)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (128 mg, 0.29 mmol), THF (2 mL), and 0.5 M KPO (2 mL) was degassed (N) for 5 min. XPhos Pd G (15 mg, 0.019 mmol) was added, and the reaction mixture was degassed (N) for an additional 5 min and stirred at room temperature overnight. The reaction mixture was diluted with H0 (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO, filtered, and concentrated. Purification by silica gel flash chromatography (0-100% CH2Cl2 / hexanes, then 0-20% EtOAc / CH2Cl2) gave tert-butyl 6-(3'-(3-bromopropoxy)-2-methoxy-2'-methyl-[1,1'-biphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.

[0159] Step c: A solution of tert-butyl 6-(3'-(3-bromopropoxy)-2-methoxy-2'-methyl-[1,1'-biphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (60 mg, 0.11 mmol), 2,2-dimethylazetidine (19 mg, 0.22 mmol), and iPrNEt (58 μL, 0.33 mmol) in MeCN (1 mL) was stirred at 50° C. for 4 h. The reaction mixture was cooled to room temperature and concentrated. Purification by silica gel flash chromatography (0-10% MeOH / CH2Cl2) gave tert-butyl 6-(2-methoxy-3'-(3-(2,2-dimethylazetidin-1-yl)propoxy)-2'-methyl-[1,1'-biphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.

[0160] Step d: tert-Butyl 6-(2-methoxy-3'-(3-(2,2-dimethylazetidin-1-yl)propoxy)-2'-methyl-[1,1'-biphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (40 mg, 0.070 mmol) was dissolved in MeOH (0.5 mL), 4 M HCl / dioxane (0.5 mL) was added, and the reaction mixture was stirred at 50° C. for 1 h. Purification by reverse-phase preparative HPLC (HO / MeCN with 0.1% TFA) gave 6-(3'-(3-(2,2-dimethylazetidin-1-yl)propoxy)-2-methoxy-2'-methyl-[1,1'-biphenyl]-3-yl)-1,2,3,4-tetrahydroisoquinoline as the bis-TFA salt. 1 H-NMR (400 MHz, (CD3)2SO) δ 9.67 (br s, 1H), 9.09 (br s, 2H), 7.47-7.39 (m, 2H), 7.36 (dd, J = 1.8, 7.6 Hz, 1H), 7.32-7.20 (m, 3H), 7.14 (dd, J = 1.8, 7.5 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 7.6 Hz, 1H), 4.37-4.30 (m, 2H), 4.14-4.01 (m, 2H), 3.99-3.88 (m, 2H), 3.47-3.41 (m, 2H), 3.34-3.22 (m, 1H), 3.19-3.09 (m, 1H), 3.09-3.01 (m, 5H), 2.39-2.29 (m, 1H), 2.15-2.06 (m, 1H), 2.04-1.94 (m, 5H), 1.58 (s, 3H), 1.55 (s, 3H). MS: (ES) C 31 H 39 N2O2[M+H] + Calculated m / z value for 471.3, observed value 471.4.

[0161] Example 10: 6-(3'-(3-(2,2-dimethylazetidin-1-yl)propoxy)-2'-methyl-2-vinyl-[1,1'-biphenyl]-3-yl)-1,2,3,4-tetrahydroisoquinoline

[0162] [ka]

[0163] Step a: Methyltriphenylphosphonium bromide (4.47 g, 12.5 mmol) was dissolved in THF (20 mL) and KOtBu (1.0 M solution in THF, 12.5 mL, 12.5 mmol) was added. The mixture was stirred at room temperature for 1 h. A solution of 2-bromo-6-hydroxy-benzaldehyde (1.01 g, 5.0 mmol) in THF (5 mL) was added dropwise, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with 1 M HCl (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO, filtered, and concentrated. Purification by silica gel flash chromatography (0-50% EtOAc / hexanes) gave 3-bromo-2-vinylphenol.

[0164] Step b: A mixture of 3-bromo-2-vinylphenol (299 mg, 1.5 mmol), tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (647 mg, 1.8 mmol), THF (15 mL), and 0.5 M KPO (15 mL) was degassed (N) for 10 min. XPhos Pd G (118 mg, 0.15 mmol) was added, and the reaction mixture was degassed (N) for an additional 10 min and stirred at room temperature overnight. The reaction mixture was diluted with HO (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO, filtered, and concentrated. Purification by silica gel flash chromatography (0-60% EtOAc / hexanes) afforded tert-butyl 6-(3-hydroxy-2-vinylphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.

[0165] Step c: tert-Butyl 6-(3-hydroxy-2-vinylphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (175 mg, 0.50 mmol) was dissolved in CHCl (5 mL). The solution was stirred at 78 °C, and pyridine (0.5 mL) was added, followed by the dropwise addition of trifluoromethanesulfonic anhydride (0.17 mL, 1.0 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated NaHCO (10 mL). The layers were separated, and the aqueous layer was extracted with CHCl (2 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO, filtered, and concentrated. Purification by silica gel flash chromatography (0-30% EtOAc / hexanes) afforded tert-butyl 6-(3-(((trifluoromethyl)sulfonyl)oxy)-2-vinylphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.

[0166] Step d: A mixture of tert-butyl 6-(3-(((trifluoromethyl)sulfonyl)oxy)-2-vinylphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (90 mg, 0.19 mmol), 2-(3-(3-bromopropoxy)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (102 mg, 0.23 mmol), THF (2 mL), and 0.5 M KPO (2 mL) was degassed (N) for 5 min. XPhos Pd G (15 mg, 0.019 mmol) was added, and the reaction mixture was degassed (N) for an additional 5 min and stirred at room temperature overnight. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO, filtered, and concentrated. Purification by silica gel flash chromatography (0-30% EtOAc / hexanes) gave tert-butyl 6-(3'-(3-bromopropoxy)-2'-methyl-2-vinyl-[1,1'-biphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.

[0167] Step e: A solution of tert-butyl 6-(3'-(3-bromopropoxy)-2'-methyl-2-vinyl-[1,1'-biphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (80 mg, 0.14 mmol), 2,2-dimethylazetidine (24 mg, 0.28 mmol), and iPrNEt (73 μL, 0.42 mmol) in MeCN (2 mL) was stirred at 50° C. for 3 h. The reaction mixture was cooled to room temperature and concentrated. Purification by silica gel flash chromatography (0-10% MeOH / CH2Cl2) gave tert-butyl 6-(3'-(3-(2,2-dimethylazetidin-1-yl)propoxy)-2'-methyl-2-vinyl-[1,1'-biphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.

[0168] Step f: tert-Butyl 6-(3'-(3-(2,2-dimethylazetidin-1-yl)propoxy)-2'-methyl-2-vinyl-[1,1'-biphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (55 mg, 0.097 mmol) was dissolved in MeOH (0.5 mL), 4 M HCl / dioxane (0.5 mL) was added, and the reaction mixture was stirred at 50 °C for 1 h. Purification by reverse-phase preparative HPLC (HO / MeCN with 0.1% TFA) gave 6-(3'-(3-(2,2-dimethylazetidin-1-yl)propoxy)-2'-methyl-2-vinyl-[1,1'-biphenyl]-3-yl)-1,2,3,4-tetrahydroisoquinoline as the bis-TFA salt. 1H-NMR (400 MHz, (CD3)2SO) δ 9.51 (br s, 1H), 9.01 (br s, 2H), 7.39 (t, J = 7.6 Hz, 1H), 7.28-7.17 (m, 5H), 7.10 (d, J = 7.9 Hz, 2H), 6.94 (d, J = 8.3 Hz, 1H), 6.77 (d, J = 7.7 Hz, 1H), 6.30 (dd, J = 11.6, 17.8 Hz, 1H), 4.93 (dd, J = 1.6, 11.6 Hz, 1H), 4.59 (dd, J = 1.6, 17.8 Hz, 1H), 4.35-4.29 (m, 2H), 4.12-3.98 (m, 2H), 3.97-3.87 (m, 2H), 3.32-3.18 (m, 2H), 3.18-3.07 (m, 2H), 3.03 (t, J = 6.4 Hz, 2H), 2.38-2.28 (m, 1H), 2.15-2.05 (m, 1H), 2.02-1.92 (m, 2H), 1.87 (s, 3H), 1.56 (s, 3H), 1.54 (s, 3H). MS: (ES) C 32 H 39 NO [M+H] + Calculated m / z 467.3, observed m / z 467.3.

[0169] Example 11: 2,2'-(((3,3'''-difluoro-5,5'''-dimethoxy-2',2''-dimethyl-[1,1':3',1'':3'',1'''-quaterphenyl]-4,4''''-diyl)bis(methylene))bis(azanediyl)bis(ethan-1-ol)

[0170] [ka]

[0171] Step a: In a 2 L round-bottom flask, a mixture containing 4-bromo-2-fluoro-6-methoxybenzaldehyde (22 g, 94 mmol), bis(pinacolato)diboron (27 g, 106 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (7.4 g, 9.1 mmol), potassium acetate (32 g, 330 mmol), and dioxane (460 mL) was prepared. The mixture was thoroughly degassed (N) for 1 hour and then stirred at 90 °C under N for 19 hours. The dioxane was then removed under reduced pressure, and the residue was dissolved in ethyl acetate and water and filtered through Celite®. The aqueous phase was separated and discarded. The organic phase was washed with brine, adsorbed onto silica gel, and purified by flash chromatography on silica gel (6-15% EtOAc / hexanes) to give 2-fluoro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde.

[0172] Step b: In a 200 mL round-bottom flask, 2,6-dibromotoluene (6.2 g, 25 mmol), 2-fluoro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (4.0 g, 14 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (1.1 g, 1.3 mmol), 2 M K2CO3 (20 mL, 40 mmol), and dioxane (50 mL) were combined. The mixture was thoroughly degassed (N2) for 45 min and then stirred at 90 °C under N2 for 2.5 h. After the reaction mixture was cooled to room temperature, it was diluted with diethyl ether and ethyl acetate, and the aqueous phase was separated. The resulting organic phase was purified by silica gel flash chromatography (4-16% EtOAc / hexanes) to give 3'-bromo-3-fluoro-5-methoxy-2'-methyl-[1,1'-biphenyl]-4-carbaldehyde.

[0173] Step c: In a 100 mL round-bottom flask, 3'-bromo-3-fluoro-5-methoxy-2'-methyl-[1,1'-biphenyl]-4-carbaldehyde (1.5 g, 4.6 mmol), bis(pinacolato)diboron (1.9 g, 7.3 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (510 mg, 0.62 mmol), potassium acetate (1.5 g, 15 mmol), and dioxane (55 mL) were combined. The mixture was degassed (N) and stirred at 90 °C under N for 16 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, ether, and water and filtered through Celite®. The aqueous phase was separated and discarded, and the remaining organic phase was purified by silica gel flash chromatography (8-14% EtOAc / hexanes) to give 3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde.

[0174] Step d: To a mixture of 3'-bromo-3-fluoro-5-methoxy-2'-methyl-[1,1'-biphenyl]-4-carbaldehyde (500 mg, 1.5 mmol), 3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (930 mg, 2.5 mmol), 2 M KCO (2.0 mL, 4.0 mmol), and dioxane (12 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane adduct (120 mg, 0.15 mmol). The mixture was degassed (N) and stirred at 90 °C for 5 h. After cooling to room temperature, the mixture was diluted with ethyl acetate, and the aqueous phase was separated and discarded. The organic phase was purified by silica gel flash chromatography (4-100% EtOAc / hexanes) to give 3,3'''-difluoro-5,5'''-dimethoxy-2',2''-dimethyl-[1,1':3',1'':3'',1'''-quaterphenyl]-4,4'''-dicarboxaldehyde.

[0175] Step e: To a solution of 3,3'''-difluoro-5,5'''-dimethoxy-2',2''-dimethyl-[1,1':3',1'':3'',1'''-quaterphenyl]-4,4'''-dicarboxaldehyde (70 mg, 0.14 mmol) and acetic acid (0.050 mL, 0.87 mmol) in DMF (2 mL) was added 2-aminoethanol (0.087 mL, 1.4 mmol). After stirring for 10 min at room temperature, Na(AcO)3BH (180 mg, 0.85 mmol) was added, and the mixture was stirred for an additional 1.5 h at room temperature. The reaction mixture was diluted with 2:1 chloroform:isopropanol and water, and the aqueous layer was separated and discarded. The resulting organic phase was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase preparative HPLC (HO / MeCN with 0.1% TFA) to give 2,2'-(((3,3'''-difluoro-5,5'''-dimethoxy-2',2''-dimethyl-[1,1':3',1'':3'',1'''-quaterphenyl]-4,4'''-diyl)bis(methylene))bis(azanediyl)bis(ethan-1-ol). 1 H-NMR (400 MHz, CD3OD) δ 7.34 (t, J = 7.6 Hz, 2H), 7.25 (d, J = 7.5 Hz, 2H), 7.18 (d, J = 7.5 Hz, 2H), 6.95-6.83 (m, 4H), 4.36 (s, 4H), 3.98 (s, 6H), 3.88-3.81 (m, 4H), 3.19 (t, J = 5.2 Hz, 4H), 1.97 (s, 6H). MS: (ES) C 34 H 39 F2N2O4[M+H] + Calculated m / z value for 577.3, observed value 577.2.

[0176] Example 12: 2-(((4'''-((dimethylamino)methyl)-3,3'''-difluoro-5,5'''-dimethoxy-2',2''-dimethyl-[1,1':3',1'':3'',1'''-quaterphenyl]-4-yl)methyl)amino)ethan-1-ol

[0177] [ka]

[0178] This compound was isolated as a by-product during the preparation of Example 11. 1 H-NMR (400 MHz, CD3OD) δ 7.37-7.15 (m, 6H), 6.98-6.83 (m, 4H), 4.43 (s, 2H), 4.36 (s, 2H), 3.99 (s, 3H), 3.98 (s, 3H), 3.88-3.81 (m, 2H), 3.19 (t, J = 5.3 Hz, 2H), 2.93 (s, 6H), 1.98 (s, 3H), 1.97 (s, 3H). MS: (ES) C 34 H 39 F2N2O3[M+H] + Calculated m / z value for 561.3, observed value 561.2.

[0179] Example 13: N-(4″-(aminomethyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)piperidin-4-amine

[0180] [ka]

[0181] Step a: To a stirred solution of 3'-bromo-3-fluoro-5-methoxy-2'-methyl-[1,1'-biphenyl]-4-carbaldehyde (5.0 g, 15 mmol) in acetonitrile (100 mL) was added hydroxylamine hydrochloride (1.6 g, 24 mmol) and triethylamine (3.3 mL, 24 mmol). The mixture was stirred at room temperature for 12 hours and then poured into saturated sodium bicarbonate (300 mL). The precipitated 3'-bromo-3-fluoro-5-methoxy-2'-methyl-[1,1'-biphenyl]-4-carbaldehyde oxime was collected by filtration, partially dried, and used in the next step without purification.

[0182] Step b: 3'-Bromo-3-fluoro-5-methoxy-2'-methyl-[1,1'-biphenyl]-4-carbaldehyde oxime was stirred in acetic acid to form a slurry. To this was added zinc powder (8.0 g, 120 mmol), and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was filtered through Celite® to remove the zinc, and the acetic acid was removed under reduced pressure. The residue was dissolved in a combination of 2:1 chloroform:isopropanol and saturated sodium bicarbonate, 6 M NaOH, and water. The aqueous phase was separated, and the organic phase was washed with brine and concentrated to give (3'-bromo-3-fluoro-5-methoxy-2'-methyl-[1,1'-biphenyl]-4-yl)methanamine (5.3 g) as a crude viscous oil.

[0183] Step c: To a solution of the oily residue from the previous step in dichloromethane (80 mL) was added di-tert-butyl dicarbonate (6.4 g, 29 mmol). After stirring at room temperature for 2 days, the dichloromethane was removed under reduced pressure, and the residue was purified by silica gel flash chromatography (4-80% EtOAc / hexanes) to give tert-butyl ((3'-bromo-3-fluoro-5-methoxy-2'-methyl-[1,1'-biphenyl]-4-yl)methyl)carbamate.

[0184] Step d: In a 500 mL round-bottom flask, tert-butyl ((3'-bromo-3-fluoro-5-methoxy-2'-methyl-[1,1'-biphenyl]-4-yl)methyl)carbamate (5.3 g, 13 mmol), bis(pinacolato)-diboron (4.0 g, 16 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (1.3 g, 1.6 mmol), potassium acetate (3.2 g, 33 mmol), and dioxane (100 mL) were combined. The mixture was degassed (N) and stirred at 90 °C under N for 3 h. After cooling to room temperature, approximately half of the dioxane was removed in vacuo, and the resulting mixture was diluted with ethyl acetate and water and filtered through Celite®. The organic phase was separated, washed with brine, and purified by silica gel flash chromatography (10-40% EtOAc / hexanes) to give tert-butyl ((3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)carbamate.

[0185] Step e: In a 40 mL vial, tert-butyl ((3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)carbamate (700 mg, 1.5 mmol), 3-bromo-2-methylaniline (340 mg, 1.8 mmol), [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) dichloromethane adduct (140 mg, 0.17 mmol), 2 M K2CO3 (2.0 mL, 4.0 mmol), and dioxane (12 mL) were combined. The mixture was thoroughly degassed (N2) and then stirred at 90 °C for 5 h. After cooling, the reaction mixture was diluted with brine and ether. The aqueous phase was separated and the organic phase was purified by silica gel flash chromatography (10-34% EtOAc / hexanes) to give tert-butyl ((3″-amino-3-fluoro-5-methoxy-2′,2″-dimethyl-[1,1′:3′,1″-terphenyl]-4-yl)methyl)carbamate.

[0186] Step f: To a solution of tert-butyl ((3″-amino-3-fluoro-5-methoxy-2′,2″-dimethyl-[1,1′:3′,1″-terphenyl]-4-yl)methyl)carbamate (40 mg, 0.089 mmol) in DCE (1 mL) was added 1-Boc-4-piperidone (24 mg, 0.12 mmol), and the reaction mixture was stirred at 70° C. for 1 h. After cooling to room temperature, Na(AcO)BH (87 mg, 0.41 mmol) was added, followed by acetic acid (0.010 mL, 0.17 mmol). After stirring at room temperature for 2.5 days, the reaction mixture was dissolved in chloroform and water. The aqueous phase was separated and the organic phase was purified by silica gel flash chromatography (4-30% EtOAc / hexanes) to give tert-butyl 4-((4″-(((tert-butoxycarbonyl)amino)methyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)amino)piperidine-1-carboxylate.

[0187] Step g: To a solution of tert-butyl 4-((4″-(((tert-butoxycarbonyl)amino)methyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)amino)piperidine-1-carboxylate (45 mg, 0.071 mmol) in dichloromethane (1 mL) was added 4 M HCl in dioxane (0.40 mL, 1.6 mmol). The reaction mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo, and the resulting residue was purified by reverse-phase preparative HPLC (HO / MeCN with 0.1% TFA as eluent) to give N-(4″-(aminomethyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)piperidin-4-amine. 1 H-NMR (400 MHz, CD3OD) δ 7.29 (t, J = 8.0 Hz, 1H), 7.20 (dd, J = 1.5, 8.0 Hz, 1H), 7.15-7.06 (m, 3H), 6.82 (dd, J = 1.4, 10.0 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.52 (d, J = 7.2 Hz, 1H), 4.22 (s, 2H), 3.97 (s, 3H), 3.80-3.69 (m, 1H), 3.48 (d, J = 13.4 Hz, 2H), 3.18 (t, J = 12.1 Hz, 2H), 2.31 (d, J = 14.2 Hz, 2H), 1.91 (s, 3H), 1.88 (s, 3H), 1.83-1.68 (m, 2H). MS: (ES) C 27 H 33 FN3O [M+H] + Calculated m / z 434.3, observed 434.2.

[0188] Example 14: 1,1'-((3,3'''-difluoro-5,5'''-dimethoxy-2',2''-dimethyl-[1,1':3',1'':3'',1'''-quaterphenyl]-4,4''''-diyl)bis(methylene))bis(piperidin-4-ol)

[0189] [ka]

[0190] Step a: 3,3'''-Difluoro-5,5'''-dimethoxy-2',2''-dimethyl-[1,1':3',1'':3'',1'''-quaterphenyl]-4,4'''-dicarboxaldehyde (97 mg, 0.20 mmol) was dissolved in MeOH (2 mL). The solution was stirred at 0 °C, and sodium borohydride (30 mg, 0.80 mmol) was slowly added. The reaction mixture was stirred for 2.5 h while gradually warming to room temperature. The reaction mixture was quenched with saturated NaHCO3 (10 mL) and extracted with CHCl2 (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered, and concentrated. Purification by silica gel flash chromatography gave (3,3'''-difluoro-5,5'''-dimethoxy-2',2''-dimethyl-[1,1':3'1'':3'',1'''-quaterphenyl]-4,4'''-diyl)dimethanol.

[0191] Step b: 3,3'''-Difluoro-5,5'''-dimethoxy-2',2''-dimethyl-[1,1':3',1'':3'',1'''-quaterphenyl]-4,4'''-diyl)dimethanol (38 mg, 0.077 mmol) was dissolved in CHCl (2 mL). The solution was stirred at 0 °C, and thionyl chloride (34 μL, 0.46 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated to give 4,4'''-bis(chloromethyl)-3,3'''-difluoro-5,5'''-dimethoxy-2',2''-dimethyl-1,1':3',1'':3'',1'''-quaterphenyl, which was used without further purification.

[0192] Step c: A mixture of 4,4'''-bis(chloromethyl)-3,3'''-difluoro-5,5'''-dimethoxy-2',2''-dimethyl-1,1':3',1'':3'',1''''-quaterphenyl (40 mg, 0.076 mmol), 4-hydroxypiperidine (47 mg, 0.46 mmol), iPrNEt (0.13 mL, 0.76 mmol), and MeCN (1 mL) was stirred overnight at 50 °C. Purification by reverse-phase preparative HPLC (HO / MeCN with 0.1% TFA) gave 1,1'-((3,3'''-difluoro-5,5'''-dimethoxy-2',2''-dimethyl-[1,1':3',1'':3'',1'''-quaterphenyl]-4,4'''-diyl)bis(methylene))bis(piperidin-4-ol). 1H-NMR (400 MHz, CD3OD) δ 7.32 (t, J = 7.6 Hz, 2H), 7.24 (d, J = 6.6 Hz, 2H), 7.15 (d, J = 7.3 Hz, 2H), 6.80 (s, 2H), 6.73 (d, J = 9.7 Hz, 2H), 3.88 (s, 6H), 3.74 (br s, 4H), 3.61 (br s, 2H), 2.96-2.87 (m, 4H), 2.43-2.32 (m, 4H), 1.98 (s, 6H), 1.90-1.80 (m, 4H), 1.66-1.54 (m, 4H). MS: (ES) C 40 H 47 F2N2O4[M+H] + Calculated m / z 657.3, observed 657.2.

[0193] Example 15: 4,4'-(((3,3'''-difluoro-5,5'''-dimethoxy-2',2''-dimethyl-[1,1':3',1'':3'',1'''-quaterphenyl]-4,4''''-diyl)bis(methylene))bis(azanediyl)dibutyric acid

[0194] [ka]

[0195] A solution of 3,3'''-difluoro-5,5'''-dimethoxy-2',2''-dimethyl-[1,1':3',1'':3'',1'''-quaterphenyl]-4,4'''-dicarboxaldehyde (36 mg, 0.074 mmol) and γ-aminobutyric acid (46 mg, 0.44 mmol) in DMF (3 mL) was stirred at room temperature for 2 h, after which Na(AcO)3BH (50 mg, 0.22 mmol) was added portionwise over 5 min. The reaction mixture was allowed to stir at room temperature overnight. Most of the DMF was removed in vacuo, and the crude was rediluted with MeOH and filtered. The filtrate was purified by reverse-phase preparative HPLC (HO / MeCN with 0.1% TFA) to give 4,4'-((3,3'''-difluoro-5,5'''-dimethoxy-2',2''-dimethyl-[1,1':3',1'':3'',1'''-quaterphenyl]-4,4'''-diyl)bis(methylene))bis(azanediyl)dibutyric acid. MS: (ES) C 38 H 43 F2N2O6[M+H] + Calculated m / z 661.3, observed 661.2. 1 H-NMR (400 MHz, CD3OD) δ 7.34 (t, J = 7.6 Hz, 2H), 7.25 (d, J = 7.6 Hz, 2H), 7.22-7.13 (m, 2H), 6.92 (s, 2H), 6.90-6.82 (m, 2H), 4.33 (d, J = 1.2 Hz, 4H), 3.98 (s, 6H), 3.23-3.09 (m, 4H), 2.49 (t, J = 6.9 Hz, 4H), 2.05-1.98 (m, 4H), 1.98 (s, 6H).

[0196] Example 16: (3″-(3-((2R,5R)-2,5-dimethylpyrrolidin-1-yl-)propoxy)-2′,2″-dimethyl-[1,1′:3′,1″-terphenyl]-4-yl)methanamine

[0197] [ka]

[0198] Step a: To a solution of 3-bromo-3'-(3-bromopropoxy)-2,2'-dimethyl-1,1'-biphenyl (170 mg, 0.42 mmol) and (2R,5R)-2,5-dimethylpyrrolidine hydrochloride (74 mg, 0.55 mmol) in MeCN (2 mL) was slowly added iPrNEt (0.30 mL, 1.7 mmol). The mixture was sonicated for several minutes, heated at 50 °C, and stirred for 18 h. After an incomplete reaction, a catalytic amount of sodium iodide (3 mg) was added, and the solution was stirred at 50 °C for an additional 8 h. The reaction mixture was concentrated. The crude material was purified by silica gel flash chromatography (0-5% MeOH / CH2Cl2) to give (2R,5R)-1-(3-((3'-bromo-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-2,5-dimethylpyrrolidine.

[0199] Step b: To a biphasic mixture of (2R,5R)-1-(3-((3'-bromo-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-2,5-dimethylpyrrolidine (38 mg, 0.091 mmol) and 4-(aminomethyl)phenylboronic acid hydrochloride (34 mg, 0.18 mmol) in 0.5 M KPO (0.90 mL, 0.46 mmol) and THF (2 mL) was added XPhos Pd G (14 mg, 0.018 mmol). The reaction mixture was heated at 50 °C for 12 h. The reaction mixture was cooled to room temperature, and the organic layer was separated, filtered, and purified by reverse-phase preparative HPLC (HO / MeCN with 0.1% TFA) to give (3″-(3-((2R,5R)-2,5-dimethylpyrrolidin-1-yl)propoxy)-2′,2″-dimethyl-[1,1′:3′,1″-terphenyl]-4-yl)methanamine. MS: (ES) C 30 H 39 NO [M+H] + Calculated m / z value for 443.3, observed value 443.2. 1H-NMR (400 MHz, CDCl3) δ 8.70-8.10 (br s, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.36-7.29 (m, 2H), 7.21-7.04 (m, 4H), 6.83-6.66 (m, 2H), 4.15-3.66 (m, 4H), 3.47-3.22 (m, 2H), 3.22-2.91 (m, 2H), 2.34-2.20 (m, 2H), 2.19 (s, 2H), 1.90 (s, 3H), 1.82 (d, J = 3.0 Hz, 3H), 1.53 (d, J = 6.6 Hz, 2H), 1.30 (d, J = 6.9 Hz, 3H), 1.27 (dd, J = 6.9, 8.6 Hz, 3H).

[0200] Example 17: (3-fluoro-5-methoxy-2',2''-dimethyl-[1,1':3',1'':3'',1'''-quaterphenyl]-4,4''''-diyl)dimethanamine

[0201] [ka]

[0202] Step a: To a mixture of 1,3-dibromo-2-methylbenzene (1.6 g, 6.5 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (1.0 g, 4.3 mmol), and 2 M K2CO3 (6.4 mL, 12.9 mmol) in dioxane (30 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane adduct (528 mg, 0.7 mmol). The reaction mixture was degassed (N2) for 2 minutes and stirred at 95 °C under N2 for 5 hours. The reaction mixture was diluted with EtOAc and filtered through Celite®. The filtrate was washed with brine, dried over MgSO4, filtered, and concentrated. Purification by silica gel flash chromatography (5-40% EtOAc / hexanes) afforded 3'-bromo-2'-methyl-[1,1'-biphenyl]-4-carbaldehyde. 1 H-NMR (400 MHz, CDCl3) δ 10.07 (s, 1H), 7.95 (dd, J = 6.3, 8.1 Hz, 2H), 7.90-7.68 (m, 1H), 7.67-7.37 (m, 2H), 7.22-7.07 (m, 2H), 2.30 (s, 3H).

[0203] Step b: To a mixture of 3'-bromo-2'-methyl-[1,1'-biphenyl]-4-carbaldehyde (223 mg, 0.81 mmol), 3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (200 mg, 0.54 mmol), and 2 M K2CO3 (0.81 mL, 1.62 mmol) in dioxane (4 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (66 mg, 0.08 mmol). The reaction mixture was degassed (N2) for 2 minutes and stirred at 95 °C under N2 for 5 hours. The reaction mixture was diluted with EtOAc and filtered through Celite®. The filtrate was washed with brine, dried over MgSO, filtered, and concentrated. Purification by silica gel flash chromatography (5-40% EtOAc / hexanes) gave 3-fluoro-5-methoxy-2',2''-dimethyl-[1,1':3',1'':3'',1''-quaterphenyl]-4,4''''-dicarboxaldehyde. 1 H-NMR (400 MHz, CDCl3) δ 10.46 (s, 1H), 10.08 (s, 1H), 7.99-7.92 (m, 2H), 7.54 (d, J = 8.0 Hz, 2H), 7.37-7.16 (m, 6H), 6.79-6.66 (m, 2H), 3.96 (s, 3H), 2.00 (s, 3H), 1.97 (s, 3H).

[0204] Step c: 3-Fluoro-5-methoxy-2',2''-dimethyl-[1,1':3',1'':3'',1'''-quaterphenyl]-4,4'''-dicarboxaldehyde (129 mg, 0.29 mmol) was dissolved in a 1:1 mixture of methanol and tetrahydrofuran (12 mL). The reaction mixture was cooled to 0 °C, and sodium borohydride (45 mg, 1.18 mmol) was slowly added. The reaction mixture was stirred while gradually warming to room temperature over 2 h. The reaction was cooled to 0 °C, diluted with saturated NaHCO3 (50 mL), and extracted with CHCl3 (3 x 50 mL). The combined organic fractions were dried over MgSO, filtered, and concentrated to give (3-fluoro-5-methoxy-2',2''-dimethyl-[1,1':3'1'':3'',1''''-quaterphenyl]-4,4''''-diyl)dimethanol. The crude material was then dissolved in CHCl (7 mL), cooled to 0 °C, and iPrNEt (0.57 mL, 3.3 mmol) and methanesulfonyl chloride (0.13 mL, 1.6 mmol) were added. The reaction mixture was stirred while gradually warming to room temperature over 2 h. The reaction mixture was cooled to 0 °C, diluted with water (25 mL), and extracted with CHCl (3 × 25 mL). The combined organic fractions were dried over MgSO4, filtered, and concentrated to give (3-fluoro-5-methoxy-2',2''-dimethyl-[1,1':3'1'':3'',1''''-quaterphenyl]-4,4''''diyl)bis(methylene)dimethanesulfonate.

[0205] Step d: (3-Fluoro-5-methoxy-2',2''-dimethyl-[1,1':3',1'':3'',1'''-quaterphenyl]-4,4'''-diyl)bis(methylene)dimethanesulfonate (163 mg, 0.27 mmol) was dissolved in dimethyl sulfoxide (3 mL) at room temperature. Sodium azide (88 mg, 1.4 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was cooled to 0 °C, diluted with water (25 mL), and extracted with CHCl (3 × 25 mL). The combined organic fractions were dried over MgSO, filtered, and concentrated to give 4,4'''-bis(azidomethyl)-3-fluoro-5-methoxy-2',2''-dimethyl-1,1':3',1'':3'',1'''-quaterphenyl.

[0206] Step e: 4,4'''-Bis(azidomethyl)-3-fluoro-5-methoxy-2',2''-dimethyl-1,1':3',1:3'',1''-quaterphenyl (98 mg, 0.20 mmol) was dissolved in a 4:1 mixture of tetrahydrofuran and methanol (7.5 mL). Triphenylphosphine (261 mg, 0.99 mmol) was slowly added, and the resulting solution was stirred at 50 °C for 2.5 h. The reaction was cooled to room temperature, diluted with water (25 mL), and extracted with EtOAc (3 x 25 mL). The combined organic fractions were dried over MgSO4, filtered, and concentrated. The residue was purified by preparative HPLC (H 2 O / MeCN with 0.1% TFA) to give (3-fluoro-5-methoxy-2′,2″-dimethyl-[1,1′:3′1'':3″,1′″-quaterphenyl]-4,4′″-diyl)dimethanamine. 1H-NMR (400 MHz, CD3OD) δ 7.56-7.49 (m, 2H), 7.43 (d, J = 8.1 Hz, 2H), 7.36-7.28 (m, 2H), 7.25-7.12 (m, 4H), 6.89 (s, 1H), 6.82 (dd, J = MS: (ES) C 29 H 27 FNO [M-NH2] + Calculated m / z 424.2, observed m / z 424.2.

[0207] Example 18: (2'',3-difluoro-3'',5-dimethoxy-2'-methyl-[1,1':3',1''-terphenyl]-4-yl)methanamine

[0208] [ka]

[0209] Step a: To a mixture of 1-bromo-2-fluoro-3-methoxybenzene (50 mg, 0.22 mmol), tert-butyl ((3-fluoro-5-methoxy-2′-methyl-3′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)carbamate (70 mg, 0.15 mmol), 2 M KCO (0.22 mL, 0.45 mmol), and dioxane (3 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (18 mg, 0.02 mmol). The reaction mixture was degassed (N) for 2 minutes and stirred at 95° C. under N for 5 hours. The reaction mixture was diluted with EtOAc and filtered through Celite®. The filtrate was washed with brine and dried over MgSO. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography (5-20% to 40% EtOAc / hexanes) to give tert-butyl ((2'',3-difluoro-3'',5-dimethoxy-2'-methyl-[1,1':3',1''-terphenyl]-4-yl)methyl)carbamate. 1 H-NMR (400 MHz, CDCl3) δ 7.33-7.17 (m, 3H), 7.15-7.10 (m, 1H), 7.03-6.96 (m, 1H), 6.87-6.82 (m, 1H), 6.74-6.63 (m, 2H), 3.93 (s, 3H), 3.86 (s, 3H), 3.70 (s, 2H), 2.04 (s, 3H), 1.45 (s, 9H).

[0210] Step b: To a solution of tert-butyl ((2'',3-difluoro-3'',5-dimethoxy-2'-methyl-[1,1':3',1''-terphenyl]-4-yl)methyl)carbamate (41 mg, 0.09 mmol) in CHCl (4 mL) was added trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated, and the residue was purified by preparative HPLC (HO / MeCN with 0.1% TFA) to give (2'',3-difluoro-3'',5-dimethoxy-2'-methyl-[1,1':3',1''-terphenyl]-4-yl)methanamine. 1 H-NMR (400 MHz, CD3OD) δ 7.35-7.30 (m, 1H), 7.28-7.10 (m, 4H), 6.90 (s, 1H), 6.85-6.77 (m, 2H), 4.23 (s, 2H), 3.97 (s, 3H), 3.91 (s, 3H), 2.03 (s, 3H). MS: (ES) C 22 H 19 F2O2[M-NH2] + Calculated m / z 353.1, observed 353.2.

[0211] Example 19: (3-fluoro-5-methoxy-2'-methyl-3'-(5-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-[1,1'-biphenyl]-4-yl)methanamine

[0212] [ka]

[0213] Step a: A mixture of 5-methyl-2,3-dihydrobenzo[b][1,4]dioxine (0.100 g, 0.67 mmol), NBS (0.118 g, 0.67 mmol) in acetonitrile (2.5 mL) was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography (0-30% EtOAc / hexanes) to give 6-bromo-5-methyl-2,3-dihydrobenzo[b][1,4]dioxine. MS: (ES) C9H8BrO2[MH] - Calculated m / z 227.0, observed m / z 227.0.

[0214] Step b: 6-bromo-5-methyl-2,3-dihydrobenzo[b][1,4]dioxine (0.044 g, 0.19 mmol), tert-butyl ((3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenanthroline]-2-yl)-2 ... A mixture of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.035 g, 0.043 mmol) was degassed (N) for 2 min and stirred at 95 °C under N for 1.5 h. The mixture was diluted with EtOAc and filtered through Celite® / NaSO. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography (0-70% EtOAc / hexanes) to give tert-butyl ((3-fluoro-5-methoxy-2'-methyl-3'-(5-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-[1,1'-biphenyl]-4-yl)methyl)carbamate. MS: (ES) C 29 H 32 FNNaO5[M+Na] + Calculated m / z 516.2, observed m / z 516.2.

[0215] Step c: A mixture of tert-butyl ((3-fluoro-5-methoxy-2'-methyl-3'-(5-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-[1,1'-biphenyl]-4-yl)methyl)carbamate (0.040 g, 0.080 mmol) was stirred in HCl (0.70 mL, 4 M in dioxane) for 30 minutes. The reaction mixture was then concentrated under reduced pressure. The resulting residue was purified by reverse-phase preparative HPLC (HO / MeCN with 0.1% TFA) to give (3-fluoro-5-methoxy-2'-methyl-3'-(5-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-[1,1'-biphenyl]-4-yl)methanamine). 1 H-NMR (400 MHz, CD3OD) δ 7.27 (t, J = 7.6 Hz, 1H), 7.18 (dd, J = 1.6, 7.2 Hz, 1H), 7.08 (dd, J = 1.6, 7.6, Hz 1H), 6.88 (s, 1H), 6.81 (dd, J = 1.2, 10 Hz, 1H), 6.71 (dd, J = 0.8, 8.4 Hz, 1H), 6.55 (d, J = 8.0 Hz, 1H), 4.32-4.29 (m, 2H), 4.26-4.23 (m, 2H), 4.22 (s, 2H), 3.96 (s, 3H), 1.91 (s, 3H), 1.89 (s, 3H). MS: (ES) C 24 H 22 FO3[M-NH2] + Calculated m / z 377.2, observed m / z 377.2.

[0216] Example 20: (3-fluoro-5-methoxy-2',2''-dimethyl-3''-(pyridin-2-yloxy)-[1,1':3',1''-terphenyl]-4-yl)methanamine

[0217] [ka]

[0218] Step A: To a stirred solution of 3-bromo-2-methylphenol (1.0 g, 5.34 mmol) in anhydrous DMF (10 mL) at room temperature was added 2-chloropyridine (0.78 g, 5.88 mmol) and cesium carbonate (2.6 g, 8.01 mmol). The reaction mixture was stirred at 150° C. for 24 hours. The reaction mixture was then poured into water (25 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were concentrated, and the crude residue was purified by silica gel flash chromatography (10–40% EtOAc / hexanes) to give 2-(3-bromo-2-methylphenoxy)pyridine.

[0219] Step b: To a mixture of 2-(3-bromo-2-methylphenoxy)pyridine (75 mg, 0.24 mmol), tert-butyl ((3-fluoro-5-methoxy-2′-methyl-3′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)carbamate (133 mg, 0.28 mmol), 2 M KCO (0.35 mL, 0.71 mmol), and dioxane (10 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (23 mg, 0.028 mmol). The reaction mixture was degassed (N) for 2 minutes and stirred at 95° C. under N for 5 hours. The reaction mixture was diluted with EtOAc and filtered through Celite®. The filtrate was washed with brine and dried over MgSO. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography (5-100% EtOAc / hexanes) to give tert-butyl ((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(pyridin-2-yloxy)-[1,1':3',1''-terphenyl]-4-yl)methyl)carbamate. MS: (ES) C 32 H 33 FN2O4[M+H] + Calculated m / z value for 529.2, observed value 529.0.

[0220] Step c: To a stirred solution of tert-butyl ((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(pyridin-2-yloxy)-[1,1':3',1''-terphenyl]-4-yl)methyl)carbamate (50 mg, 0.09 mmol) in anhydrous dichloromethane (2.5 mL) at room temperature, trifluoroacetic acid (107 mg, 0.94 mmol) was added dropwise over 5 minutes. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was removed in vacuo, and the crude residue was purified by reverse-phase preparative HPLC (HO / MeCN with 0.1% TFA) to give (3-fluoro-5-methoxy-2',2''-dimethyl-3''-(pyridin-2-yloxy)-[1,1':3',1''-terphenyl]-4-yl)methanamine. 1 H-NMR (400 MHz, CD3OD) δ 8.12 (dd, J = 2.2, 4.9 Hz, 1H), 7.83 (ddd, J = 1.9, 2.2, 6.6 Hz, 1H), 7.45-7.30 (m, 2H), 7.27-7.16 (m, 2H), 7.14-7.02 (m, 3H), 6.95-6.79 (m, 3H), 4.22 (s, 2H), 3.96 (s, 3H), 1.96 (s, 3H), 1.89 (s, 3H). MS: (ES) C 27 H 23 FNO2[M-NH2] + Calculated m / z 412.2, observed 412.0.

[0221] Example 21: (3'-(3-(aminomethyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-fluoro-5-methoxy-2'-methyl-[1,1'-biphenyl]-4-yl)methanamine

[0222] [ka]

[0223] Step a: To a stirred solution of 4-bromobenzene-1,2-diol (5.0 g, 26.4 mmol) in anhydrous acetone (100 mL) was added 2-chloroacrylonitrile (3.0 mL, 26.4 mmol) and potassium carbonate (7.3 g, 52.9 mmol) at room temperature. The mixture was heated at 75° C. for 24 hours. After completion of the reaction, the solvent was removed. The residue was poured into water (150 mL) and extracted with EtOAc (150 mL). The organic layer was concentrated, and the crude product was purified by silica gel flash chromatography (10-40% EtOAc / hexanes) to give 7-bromo-2,3-dihydrobenzo[b][1,4]dioxine-2-carbonitrile.

[0224] Step b: To a mixture of 7-bromo-2,3-dihydrobenzo[b][1,4]dioxine-2-carbonitrile (125 mg, 0.52 mmol), tert-butyl ((3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)carbamate (245 mg, 0.52 mmol), 2 M KCO (0.65 mL, 1.30 mmol), and dioxane (4 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane adduct (42 mg, 0.052 mmol). The reaction mixture was degassed (N) for 2 min and stirred at 95 °C under N for 4 h. The reaction mixture was diluted with EtOAc and filtered through Celite®. The filtrate was washed with brine and dried over MgSO4. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography (5-40% EtOAc / hexanes) to give tert-butyl ((3'-(3-cyano-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-fluoro-5-methoxy-2'-methyl-[1,1'-biphenyl]-4-yl)methyl)carbamate. MS: (ES) C 29 H 29 FN2O5[M+H] +Calculated m / z 505.21, observed 505.2.

[0225] Step c: To a solution of tert-butyl ((3'-(3-cyano-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-fluoro-5-methoxy-2'-methyl-[1,1'-biphenyl]-4-yl)methyl)carbamate (100 mg, 0.19 mmol) in MeOH (10 mL) was added Raney Ni (ca. 200 mg). The reaction mixture was hydrogenated under 50 psi for 5 hours. After completion of the reaction, the mixture was filtered through Celite®, rinsed with 1:1 EtOAc / MeOH (50 mL), and concentrated to dryness. The residue was dissolved in anhydrous dichloromethane (4 mL) at room temperature, and trifluoroacetic acid (141 mg, 1.23 mmol) was added dropwise over 5 minutes. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was removed in vacuo, and the crude residue was purified by reverse-phase preparative HPLC (HO / MeCN with 0.1% TFA) to give (3'-(3-(aminomethyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-fluoro-5-methoxy-2'-methyl-[1,1'-biphenyl]-4-yl)methanamine. 1 H-NMR (400 MHz, CD3OD) δ 7.33-7.14 (m, 3H), 7.07-6.92 (m, 2H), 6.91-6.78 (m, 3H), 4.55-4.45 (m, 1H), 4.39 (dd, J = 2.3, 11.9 Hz, 1H), 4.22 (s, 2H), 4.07 (dd, J = 6.9, 11.9 Hz, 1H), 3.96 (s, 3H), 3.37 (dd, J = 3.2, 13.5 Hz, 1H), 3.32 (dd, J = 3.2, 13.5 Hz, 1H), 2.12 (s, 3H).MS: (ES)C 24 H 23 FNO3[M-NH2] + Calculated m / z 392.2, observed 392.1.

[0226] Example 22: 7-(4'-(aminomethyl)-3'-fluoro-5'-methoxy-2-methyl-[1,1'-biphenyl]-3-yl)-3,4-dihydroquinolin-2(1H)-one

[0227] [ka]

[0228] The compound was prepared from 7-bromo-3,4-dihydroquinolin-2(1H)-one and tert-butyl ((3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)carbamate using the procedure in Example 21 (steps b and c). Purification by reverse-phase preparative HPLC (HO / MeCN with 0.1% TFA) gave 7-(4'-(aminomethyl)-3'-fluoro-5'-methoxy-2-methyl-[1,1'-biphenyl]-3-yl)-3,4-dihydroquinolin-2(1H)-one as a white solid. 1 H-NMR (400 MHz, CD3OD) δ 7.93-7.87 (m, 1H), 7.52-7.45 (m, 1H), 7.43-7.19 (m, 4H), 6.92 (d, J = 1.4 Hz, 1H), 6.85 (d, J = 9.9 Hz, 1H), 4.22 (s, 2H), 3.97 (s, 3H), 3.55 (t, J = 6.7 Hz, 2H), 3.05 (t, J = 6.7 Hz, 2H), 2.10 (s, 3H). MS: (ES) C 24 H 24 FN2O2[M+H] + Calculated m / z 391.2, observed 391.2.

[0229] Example 23: Methyl 6-(4'-(aminomethyl)-3'-fluoro-5'-methoxy-2-methyl-[1,1'-biphenyl]-3-yl)-2H-chromene-3-carboxylate

[0230] [ka]

[0231] The compound was prepared from methyl 6-bromo-2H-chromene-3-carboxylate and tert-butyl ((3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)carbamate using the procedure in Example 21 (steps b and c). The product was purified by reverse-phase HPLC (C18 column, acetonitrile-HO with 0.1% TFA as eluent) to give the desired product, methyl 6-(4'-(aminomethyl)-3'-fluoro-5'-methoxy-2-methyl-[1,1'-biphenyl]-3-yl)-2H-chromene-3-carboxylate, as a white solid. 1 H-NMR (400 MHz, CD3OD) δ 7.55 (s, 1H). 7.34-7.15 (m, 5H), 6.94-6.80 (m, 3H), 5.00 (s, 2H), 4.22 (s, 2H), 3.97 (s, 3H), 3.81 (s, 3H), 2.10 (s, 3H). MS: (ES) C 26 H 25 FNO4[M+H] + Calculated m / z 434.2, observed 434.1.

[0232] Example 24: 2,2'-(((3,3'''-difluoro-5,5'''-dimethoxy-2',2''-dimethyl-[1,1':3',1'':3'',1'''-quaterphenyl]-4,4'''-diyl)bis(methylene))bis(azanediyl))bis(ethane-1-sulfonic acid)

[0233] [ka]

[0234] To a stirred solution of 3,3'''-difluoro-5,5-'''dimethoxy-2',2''-dimethyl-[1,1':3',1'':3'',1'''-quaterphenyl]-4,4'''-dicarboxaldehyde (65 mg, 0.133 mmol) and 2-aminoethane-1-sulfonic acid (10 mg, 0.16 mmol) in DMF (2 mL) was added Na(AcO)3BH (52 mg, 0.24 mmol) and AcOH (5 drops). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative HPLC (HO / MeCN with 0.1% TFA) to give 2,2'-(((3,3'''-difluoro-5,5'''-dimethoxy-2',2''-dimethyl-[1,1':3',1'':3'',1'''-quaterphenyl]-4,4'''-diyl)bis(methylene))bis(azanediyl))-bis(ethane-1-sulfonic acid). 1 H-NMR (400 MHz, CD3OD) δ 7.33 (t, J = 7.6 Hz, 2H), 7.25 (dd, J = 1.5, 7.6 Hz, 2H), 7.21-7.14 (m, 2H), 6.96-6.81 (m, 4H), 4.39 (s, 4H), 3.98 (s, 6H) 3.49 (d, J = 6.3 Hz, 4H) 3.15 (t, J = 6.3 Hz, 4H) 1.97 (s, 6H). MS: (ES) C 34 H 39 F2N2O8S2[M+H] + Calculated m / z 705.2, observed 705.2.

[0235] Example 25: 2-(((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,1':3',1''-terphenyl]-4-yl)methyl)amino)ethan-1-ol

[0236] [ka]

[0237] Step a: To a mixture of tert-butyl 6-(3-bromo-2-methylphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg, 0.249 mmol) and 3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (101 mg, 0.27 mmol), 2 M K2CO3 (0.35 mL, 0.024 mmol), and dioxane (4 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (1 mg, 0.148 mmol). The reaction mixture was degassed (N2) for 2 min and stirred at 95 °C under N2 for 5 h. The reaction mixture was diluted with EtOAc and filtered through Celite®. The filtrate was washed with brine and dried over MgSO4. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography (5-100% EtOAc / hexanes) to give tert-butyl 6-(3''-fluoro-4''-formyl-5''-methoxy-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg). MS: (ES) C 36 H 36 FNO4[M+H] + Calculated m / z value for 566.3, observed value 566.2.

[0238] Step b: To a stirred solution of tert-butyl 6-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (70 mg, 0.082 mmol) and 2-aminoethanol (30 mg, 0.16 mmol) in MeOH / DCE (2 mL) was added Na(AcO)BH (65 mg, 0.24 mmol) and AcOH (5 drops). The reaction mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure to give crude tert-butyl 6-(3″-fluoro-4″-(((2-hydroxyethyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate, which was used without further purification.

[0239] Step c: To a stirred solution of tert-butyl 6-(3″-fluoro-4″-(((2-hydroxyethyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (70 mg, 0.114 mmol) in anhydrous dichloromethane (2.5 mL) at room temperature, trifluoroacetic acid (130 mg, 1.14 mmol) was added dropwise over 5 minutes. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was removed in vacuo. Purification by reverse-phase preparative HPLC (HO / MeCN with 0.1% TFA) gave 2-(((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,1':3',1''-terphenyl]-4-yl)methyl)amino)ethan-1-ol. 1H-NMR (400 MHz, CD3OD) δ 7.38-7.09 (m, 9H), 6.94-6.82 (m, 2H), 4.41 (s, 2H), 4.36 (s, 2H), 3.98 (s, 3H), 3.84 (dd, J = 1.4, 6.1 Hz, MS: (ES) C 33 H 36 FN2O2[M+H] + Calculated m / z value: 511.3, observed value: 511.2. Feature determination conditions Reversed-phase HPLC conditions used to determine retention times in Table 1: Column: ZORBAX (SB-C18 2.1 x 50 mm, 5 μm) Mobile phase A: 95% HO, 5% MeCN (containing 0.1% formic acid) Mobile phase B: 5%H2O, 95%MeCN (containing 0.1% formic acid) Flow rate: 1.0mL / min Gradient: (for Method A) 20% to 100% B in 3.5 minutes or (for Method B) 0 to 100% B in 4.5 minutes

[0240] Biological Example: Enzyme-Linked Immunosorbent Assay - ELISA Plates were coated with 1 μg / mL of human PD-L1 (obtained from R&D) in PBS overnight at 4°C. The wells were then blocked with 2% BSA (W / V) in PBS containing 0.05% TWEEN-20 for 1 hour at 37°C. The plates were washed three times with PBS / 0.05% TWEEN-20, and compounds were serially diluted (1:5) in dilution medium and added to the ELISA plate. Human PD-1 and biotin at 0.3 μg / mL (ACRO Biosystems) were added and incubated for 1 hour at 37°C, followed by washing three times with PBS / 0.05% TWEEN-20. Secondary blocking was performed with 2% BSA (W / V) in PBS / 0.05% TWEEN-20 for 10 minutes at 37°C, and the plates were washed three times with PBS / 0.05% TWEEN-20. Streptavidin-HRP was added for 1 hour at 37°C, after which the plate was washed three times with PBS / 0.05% TWEEN-20. TMB substrate was added and allowed to react for 20 minutes at 37°C. Stop solution (2N aqueous H2SO4) was added. Absorbance was measured at 450 nm using a microplate spectrophotometer. The results are shown in Table 1: IC 50 Values ​​were defined as follows: 1000-10,000 nm (+); less than 1000 nm (++).

[0241] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17]

[0242] Certain embodiments of the present invention are described herein, including the best mode known to the inventors for carrying out the invention. It is expected that variations of the disclosed embodiments may become apparent to those skilled in the art upon reading the foregoing description, and that such variations can be employed by those skilled in the art as appropriate. It is therefore intended that the invention be practiced otherwise than as specifically described herein, and that the invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, the invention encompasses any combination of the above-described elements in all possible variations thereof unless otherwise indicated herein or clearly contradicted by context.

[0243] All publications, patent applications, accession numbers, and other references cited herein are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

Claims

1. Formula (I): 【Chemistry 1】 {In the formula: R 1a , R 1b , R 1c , and R 1d are H, F, Cl, C 1-3 Alkyl, C 1-3 Haloalkyl, and C 1-3 are each independently selected from the group consisting of alkoxy; X 1 is one or two C 1 -CH2 optionally substituted with alkyl; R 2a and R 2b are each independently selected from the group consisting of H, and C1-4 alkyl, wherein any C1-4 alkyl is selected from the group consisting of OH, COO-C 1-8 Alkyl or CO 2 optionally further substituted with 1 or 2 members independently selected from H; or R 2a and R 2b are combined to form a six-membered ring; or R 1a and R 2a are combined to form a 5- to 7-membered ring; or R 1b and R 2b are combined to form a 5- to 7-membered ring; where R 2a and R 2b , R 1a and R 2a , or R 1b and R 2b The ring formed by the combination of -X 3 -C(O) 2 R a , and -X 3 -OR a and substituted with 0 to 1 substituents independently selected from the group consisting of: 3 is a bond or C 1-6 alkylene; R 3 are H, F, Cl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 selected from the group consisting of alkenyl and CN; The subscript n is 0; R 4 , R 6 , R 7 and R 8 Each of these is H, halogen, C 1-6 Alkyl, and C 1-6 independently selected from the group consisting of hydroxyalkyl; R 5 -OX 5 -Y 2 where each X 5 is C 1-3 alkylene, and each Y 2 is C 4-8 Heterocyclyl, and C 7-9 spiroheterocyclyl, each of which is selected from the group consisting of halogen, OH, and C 1-4 optionally further substituted with 1 to 2 substituents independently selected from the group consisting of alkyl; And R 5 and R 6 are optionally combined to form a 6-membered non-aromatic heterocycle having one or two ring vertices selected from the group consisting of O; wherein said non-aromatic heterocycle is c optionally substituted by; Each R a H, and C 1-6 independently selected from the group consisting of alkyl; Each R c H, and -Y 4 wherein each Y 4 is C 4-8 heterocyclyl} or a pharmaceutically acceptable salt thereof.

2. R 1c , R 7 and R 8 is H; and R 3 However, F, Cl, CH 3 , C.F. 3 and OCH 3 10. The compound of claim 1, selected from the group consisting of:

3. The ring is a pair of R 4 and R 5 , R 5 and R 6 , R 1b and R 2b , or R 1a and R 2a 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, formed between:

4. R 4 However, F, Cl, CH 3 and OCH 3 10. The compound of claim 1, selected from the group consisting of:

5. R 1a OCH 3 and R 1b or a pharmaceutically acceptable salt thereof.

6. R 2a and R 2b and R are each H, or a pharmaceutically acceptable salt thereof.

7. The following formula (Ib): 【Chemistry 2】 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the formula:

8. The Y 2 But the following: 【Transformation 3】 8. The compound of claim 7, selected from the group consisting of:

9. below: Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 2. The compound of claim 1, selected from:

10. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

11. 11. The pharmaceutical composition of claim 10, further comprising one or more additional therapeutic agents.

12. 12. The pharmaceutical composition of claim 11, wherein the one or more additional therapeutic agents are selected from the group consisting of antimicrobial agents, antiviral agents, cytotoxic agents, gene expression modulators, chemotherapeutic agents, anticancer agents, angiogenesis inhibitors, immunotherapeutic agents, antihormonal agents, antifibrotic agents, radiation therapy, radiotherapeutic agents, antineoplastic agents, and antiproliferative agents.

13. The pharmaceutical composition of any one of claims 10 to 12 for modulating an immune response mediated by the PD-1 signaling pathway in a subject in need thereof.

14. The pharmaceutical composition according to any one of claims 10 to 12 for enhancing, stimulating, modulating and / or increasing the immune response in a subject in need thereof.

15. The pharmaceutical composition of any one of claims 10 to 12 for inhibiting the growth, proliferation or metastasis of cancer cells in a subject in need thereof.

16. 13. The pharmaceutical composition of any one of claims 10 to 12, for treating a subject suffering from or susceptible to a disease or disorder mediated by the PD-1 signaling pathway.

17. 14. The pharmaceutical composition of claim 13, wherein the subject is suffering from a disease or disorder selected from the group consisting of an infectious disease, a bacterial infection, a viral infection, a fungal infection, a solid tumor, a malignant hematological disease, an immune disorder, an inflammatory disease, and cancer.

18. The disease or disorder is selected from the group consisting of melanoma, glioblastoma, esophageal tumor, nasopharyngeal carcinoma, uveal melanoma, lymphoma, lymphocytic lymphoma, primary CNS lymphoma, T-cell lymphoma, diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, prostate cancer, castration-resistant prostate cancer, chronic myeloid leukemia, Kaposi's sarcoma, fibrosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, angiosarcoma, lymphangiosarcoma, synovoma, meningioma, leiomyosarcoma, rhabdomyosarcoma, soft tissue sarcoma, and sarcoma. , sepsis, bile duct tumor, basal cell carcinoma, thymus tumor, thyroid cancer, parathyroid cancer, uterine cancer, adrenal cancer, liver infection, Merkel cell carcinoma, nerve tumor, follicle center lymphoma, colon cancer, Hodgkin's disease, non-Hodgkin's lymphoma, leukemia, chronic or acute leukemia, acute myeloid leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiple myeloma, ovarian tumor, myelodysplastic syndrome, cutaneous or intraocular malignant melanoma, renal cell carcinoma, small cell lung cancer, lung cancer, mesothelioma, breast cancer, squamous non-small cell lung cancer Small cell lung cancer (SCLC), non-squamous NSCLC, colorectal cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, pancreatic carcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma, head and neck squamous cell carcinoma, head and neck cancer, gastrointestinal cancer, stomach cancer, HIV, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus, papillomavirus, influenza, bone cancer, skin cancer, rectal cancer, anal cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulva cancer, esophageal cancer, small intestine cancer, endocrine system cancer, urethral cancer, penile cancer, bladder cancer, kidney cancer, ureter cancer 17. The pharmaceutical composition of claim 16, wherein the tumor is selected from the group consisting of renal pelvic carcinoma, central nervous system (CNS) tumor, angiogenic tumor, spinal cord tumor, brain stem glioma, pituitary adenoma, epidermoid carcinoma, asbestosis, carcinoma, adenocarcinoma, papillary carcinoma, cystadenocarcinoma, bronchial carcinoma, renal cell carcinoma, transitional cell carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, pleomorphic adenoma, hepatocellular papilloma, renal tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma, and fibroma.

19. 19. The pharmaceutical composition of claim 18, further to be administered to a subject in conjunction with a therapeutically effective amount of one or more additional therapeutic agents.

20. 20. The pharmaceutical composition of claim 19, wherein the one or more additional therapeutic agents are selected from the group consisting of antimicrobial agents, antiviral agents, cytotoxic agents, gene expression modulators, chemotherapeutic agents, anticancer agents, angiogenesis inhibitors, immunotherapeutic agents, antihormonal agents, antifibrotic agents, radiation therapy, radiotherapeutic agents, antineoplastic agents, and antiproliferative agents.

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