Triaryl Compounds for the Treatment of PD-L1 Disease

Abstract

Compounds useful as immunomodulators are provided, including stereoisomers and pharmaceutically acceptable salts thereof, having the formula (I): JPEG2022531970000306.jpg42155 (In the formula, R 1a , R 1b , R 1C and R 1d , R 2a , R 2b , R 3 , R 3a , R 4 , R 6 , R 7 , R 8 , A, Z, X 1 , and n are as defined herein. Also disclosed are methods relating 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 priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 62 / 848,114, filed May 15, 2019, the entire contents of which are incorporated herein by reference.

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT N / A

[0003] Reference for sequence list etc. N / A [Background technology]

[0004] 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 or PD-L2. PD-1 and its ligands are widely expressed and play a broad immunoregulatory role in T cell activation and tolerance. PD-1 and its ligands are involved in attenuating infection and tumor immunity and promoting chronic infection and tumor progression.

[0005] Modulating the PD-1 pathway has the potential to treat a variety of human diseases (Hyun-Tak Jin et al., Curr-Top Microbiol-Immunol. (2011);350:17-37). Blocking 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 potent activity in various stages of clinical trials (RD Harvey, Clinical Pharmacology and Therapeutics (2014);96(2), 214-223).

[0006] Agents that block the interaction of PD-L1 with either PD-1 or CD80 are desirable. Several antibodies have been developed and commercialized. Several patent applications have been published that disclose non-peptide small molecules (BMS applications WO 2015 / 160641(A), WO 2015 / 034820(A), and WO 2017 / 066227(A) and WO 2018 / 009505(A); Aurigene applications WO 2015 / 033299(A) and WO 2015 / 033301(A); Incyte applications WO 2017 / 070089(A), U.S. Patent Application Publication No. 2017 / 0106299(A), and ... 45025, WO 2017 / 106634(A), U.S. Patent Application Publication No. 2017 / 0174679, WO 2017 / 192961(A), WO 2017 / 222976(A), WO 2017 / 205464(A), WO 2017 / 112730(A), WO 2017 / 041899(A) and WO 2018 / 013789(A), WO 2018 / 006795(A) to Maxinove, and WO 2018 / 005374(A) to US ChemoCentryx. However, there remains a need for alternative compounds, such as small molecule PD-L1 inhibitors, that may have advantageous properties in terms of oral administration, stability, bioavailability, therapeutic index, and toxicity. Summary of the Invention

[0007] Provided herein as one aspect of the present invention is a compound of formula (I): [ka] (In the formula, A, Z, X 1 , R 1a , R 1b , R 1c , R 1d , R2a , R 2b , R 3 , R 3a , R 4 , R 6 , R 7 , R 8 , and subscript n are as defined herein.) or a pharma- ceutically acceptable salt thereof.

[0008] In addition to the compounds provided herein, the disclosure further provides pharmaceutical compositions comprising one or more of these compounds, as well as methods relating 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. [Brief description of the drawings]

[0009] N / A DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

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

[0011] The terms "about" and "approximately" are generally intended to mean an acceptable degree of error for a measured quantity, taking into account the characteristics or precision of the measurement. A typical degree of error is exemplified by within 20 percent (%), preferably within 10%, and more preferably within 5% of a given value or range of values. Alternatively, particularly in biological systems, the terms "about" and "approximately" can mean values ​​within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold of a given value. Numerical values ​​described herein are approximate unless otherwise stated, and the term "about" or "approximately" means that they can be inferred when not explicitly stated.

[0012] The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical having the specified number of carbon atoms (i.e., C 1~8 means 1 to 8 carbons). 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 an unsaturated alkyl group having one or more double bonds. Similarly, the term "alkynyl" refers to an unsaturated alkyl group 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. The term "cycloalkyl" refers to an alkyl group having the indicated number of ring atoms (e.g., C 3-6"Cycloalkyl" refers to a hydrocarbon ring that is fully saturated or has only one double bond between the ring vertices. "Cycloalkyl" also refers 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. The term "heterocycloalkyl" or "heterocyclyl" refers to a cycloalkyl group containing 1 to 5 heteroatoms selected from N, O, and S, in which the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. The heterocycloalkyl group may be a monocyclic, bicyclic, or polycyclic ring system. The bicyclic or polycyclic rings may be fused or bridged, spiro, or combinations thereof. C 4-12 Heterocyclyl is understood to refer to groups having 4 to 12 ring members, at least one of the ring members being 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. Heterocycloalkyl groups can be attached to the remainder of the molecule via a ring carbon or heteroatom.

[0013] The term “alkylene” by itself or as part of another substituent means a —CH 2 CH 2 CH 2 CH 2 - means a divalent radical derived from an alkane, as exemplified by -. The alkylene group may be linear or branched. An example of the latter is -CH 2 C(CH 3 ) 2 CH 2 -, -CH 2 C(CH 3 ) 2- or -CH(CH 3 )CH 2 CH 2 Typically, an alkyl (or alkylene) group will have from 1 to 12 carbon atoms, with groups having 8 or fewer carbon atoms being preferred in this disclosure. Similarly, "alkenylene" and "alkynylene" refer to unsaturated forms of "alkylene" having double or triple bonds, respectively.

[0014] The term "heteroalkyl", by itself or in combination with another term, means, unless otherwise stated, a stable linear or branched chain, or cyclic hydrocarbon radical, or combination thereof, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, Si, and S, where the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatoms O, N, and S may be placed at any interior position of the heteroalkyl group. The heteroatom Si may be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule. Examples of such molecules include -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N(CH 3 )-CH 3 , -CH 2 -S-CH 2 -CH 3 , -CH 2 -CH 2 , -S(O)-CH 3 , -CH 2 -CH 2 -S(O) 2 -CH 3 , -CH=CH-O-CH 3 , -Si(CH 3 ) 3 , -CH 2 -CH=N-OCH 3 , and -CH=CH-N(CH 3 )-CH 3For example, -CH 2 -NH-OCH 3 and -CH 2 -O-Si(CH 3 ) 3 Similarly, the terms "heteroalkenyl" and "heteroalkynyl", by themselves or in combination with other terms, mean, respectively, an alkenyl or alkynyl group containing the stated number of carbons and one to three heteroatoms selected from the group consisting of O, N, Si and S, unless otherwise stated, wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatoms O, N and S may be placed at any interior position of the heteroalkyl group.

[0015] The term "heteroalkylene" by itself or as part of another substituent means a -CH 2 -CH 2 -S-CH 2 CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -, -O-CH 2 -CH=CH-, -CH 2 -CH=C(H)CH 2 -O-CH 2 -and-S-CH 2 -C≡C- refers to a saturated or unsaturated or polyunsaturated divalent group derived from heteroalkyl. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino groups, and the like).

[0016] The terms "alkoxy," "alkylamino," and "alkylthio" (or thioalkoxy) are used in their conventional sense to refer to those alkyl groups attached to the remainder of the molecule through an oxygen atom, an amino group, or a sulfur atom, respectively. Furthermore, in the case of dialkylamino groups, the alkyl portions may be the same or different and may combine to form a 3- to 7-membered ring with the nitrogen atom to which each is attached. Thus, -NR a R b A group represented 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, "C 1-4 The term "haloalkyl" is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl groups and the like.

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

[0019] "C 1-3 The term "alkyl-guanidinyl" refers to the C 1-3 It refers to an alkyl group in which at least one of the hydrogen atoms is a guanidinyl group (-NHC(NH)NH 2) has been replaced.

[0020] The term "aryl" refers to a polyunsaturated, typically aromatic, hydrocarbon group, which may be a single ring or multiple rings (up to three rings) that are fused or covalently linked together, unless otherwise specified. The term "heteroaryl" refers to an aryl group (or ring) 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 heteroaryl group can be attached to the remainder of the molecule through a heteroatom. C 5-10 Heteroaryl groups are understood to refer to heteroaryl moieties having 5 to 10 ring members, with at least one of the ring members being a heteroatom. Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl, and non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolyl, and aryl. Examples include dolidinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiazolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl groups 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] The terms "carbocyclic ring", "carbocyclic" and "carbocyclyl" refer to a ring moiety having only carbon atoms at the ring vertices. A carbocyclic moiety may be saturated or unsaturated and aromatic. Generally, a carbocyclic moiety has 3 to 10 ring members. A carbocyclic moiety having multiple ring structures (e.g., bicyclic) may contain a cycloalkyl ring fused to an aromatic ring (e.g., 1,2,3,4-tetrahydronaphthalene). Thus, carbocyclic rings include cyclopentyl, cyclohexenyl, naphthalene, and 1,2,3,4-tetrahydronaphthyl groups. The term "heterocycle" refers to both "heterocycloalkyl" and "heteroaryl" moieties. Thus, a heterocycle may be saturated or unsaturated and aromatic. Generally, a heterocycle has 4 to 10 ring members and includes piperidinyl, tetrazinyl, pyrazolyl, and indolyl.

[0022] When any of the above terms (e.g., "alkyl," "aryl" and "heteroaryl") are referred to as "substituted" without further indication of a substituent, the substitution form of the indicated group is as provided below.

[0023] Substituents for the alkyl group (including those often 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', -CO 2 R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O) 2 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) 2R'', -CN, -NO 2 and the total number of carbon atoms is zero to (2m'+1), where m' is the total number of carbon atoms in such a group. R', R'', and R''' are each independently hydrogen, unsubstituted C 1-8 Alkyl, unsubstituted heteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted C 1-8 Alkyl, C 1-8 Alkoxy or C 1-8 A thioalkoxy group or an unsubstituted aryl-C 1-4 It 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 groups. The term "acyl" used by itself or as part of another group refers to an alkyl group in which both substituents on the carbon closest to the point of attachment have been replaced with the substituent =O (e.g., -C(O)CH 3 , -C(O)CH 2 CH 2 OR', etc.

[0024] Similarly, substituents on the aryl and heteroaryl groups are varied and generally include -halogen, -OR', -OC(O)R', -NR'R'', -SR', -R', -CN, -NO 2 , -CO 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 groups, the number of open valences ranges from 0 to the total number of open valences on the aromatic ring system, and R', R'', and R''' are each independently 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.

[0025] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring are optionally represented by the formula -TC(O)-(CH 2 ) q -U-, where T and U are independently -NH-, -O, or -CH 2 - or a single bond, and q is an integer from 0 to 2. Alternatively, two substituents on adjacent atoms of an aryl or heteroaryl ring are optionally represented by the formula -A-(CH 2 ) r A and B can be independently substituted with -CH 2 -, -O-, -NH-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 NR'- or a single bond, where r is an integer from 1 to 3. One of the single bonds in the new ring so formed can optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring can optionally be replaced with a group of the formula -(CH 2 ) s -X-(CH 2 ) t In this case, s and t are independently integers of 0 to 3, and X is -O-, -NR'-, -S-, -S(O)-, -S(O) 2 - or -S(O) 2 -NR'- and -S(O) 2The substituent R' in NR'- is hydrogen or an unsubstituted C 1-6 is selected from alkyl.

[0026] As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).

[0027] Further disclosed herein are prodrugs and bioisosteres thereof.For example, suitable bioisosteres may include carboxylate substitutions (phosphonic acid, phosphinic acid, sulfonic acid, sulfinic acid, and acidic heterocyclic groups such as tetrazole).Suitable prodrugs include conventional groups known to hydrolyze and / or oxidize under physiological conditions to provide compounds of formula I.

[0028] The terms "patient" and "subject" include primates (especially humans), domesticated companion animals (eg, dogs, cats, horses), and farm animals (eg, cows, pigs, sheep).

[0029] As used herein, the term "treat" or "treatment" includes both disease-modifying and symptomatic treatments, either of which may be prophylactic (i.e., aimed at preventing, delaying, or reducing the severity of symptoms before the onset of symptoms) or therapeutic (i.e., to reduce the severity and / or duration of symptoms after onset of symptoms).

[0030] The term "pharmaceutical acceptable salts" is meant 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 the compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds, either neat or in a suitable inert solvent, with a sufficient amount of the desired base. Examples of salts derived from pharmaceutical acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganous, potassium, sodium, zinc, and the like. Salts derived from pharma- ceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, and the like, 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, piperazine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. 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, neat or in a suitable inert solvent, with a sufficient amount of the desired acid. Examples of pharma- ceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphate, dihydrogenphosphate, sulfuric, monohydrogensulfuric, hydroiodic, or phosphoric acid, as well as salts derived from relatively non-toxic organic acids such as acetic, propionic, isobutyric, malonic, benzoic, succinic, nitrous, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, or other acid.Also included are salts of amino acids such as arginates, and salts of organic acids such as glucuronic or galactunolic acids (see, e.g., Berge, SM et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19).Certain compounds of the present disclosure contain both basic and acidic functional groups that allow the compounds to be converted into either base or acid addition salts.

[0031] 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 forms of the compounds differ from the salt forms in certain physical properties, such as solubility in polar solvents, but are otherwise identical to the parent forms of the compounds for purposes of this disclosure.

[0032] Certain 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 within the scope of the present disclosure.Certain compounds of the present disclosure can exist in polycrystalline or amorphous forms.In general, all physical forms are equivalent for the applications contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0033] Certain compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds, and all of their racemates, diastereomers, geometric isomers, positional isomers, and individual isomers (e.g., individual enantiomers) are intended to be included within the scope of the present invention. When a stereochemical depiction of a compound is shown, it means that one of the isomers of the compound is present and is substantially free of the other isomer. "Substantially free" of another isomer refers to a ratio of the two isomers that is at least 80 / 20, more preferably 90 / 10, or 95 / 5 or greater. In some embodiments, one of the isomers will be present in an amount of at least 99%.

[0034] 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, the compounds may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. 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 included within the scope of the present disclosure. For example, the compounds may be radiolabeled with a radioisotope such as deuterium ( 2 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. Unnatural proportions of an isotope may be defined as a range from the amount found in nature to the amount that is 100% of the atom in question. For example, the compounds may be prepared with, for example, tritium ( 3 H), iodine-125( 125 I) or carbon-14( 14 Radioisotopes such as C, or deuterium ( 2 H) or carbon-13 ( 13 C). Such isotopic variants may provide additional utility to those described elsewhere in this application. For example, isotopic variants of the compounds of the present disclosure may find additional utility, including but not limited to, as diagnostic and / or imaging reagents or as cytotoxic / radiotoxic therapeutic agents. In addition, isotopic variants of the compounds of the present disclosure may alter pharmacokinetic and pharmacodynamic properties that may contribute to improved safety, tolerability, or efficacy during treatment. All isotopic variants of the compounds of the present disclosure, whether radioactive or not, are intended to be included within the scope of the present disclosure.

[0035] compound In one aspect of the disclosure, a compound of formula (I): [ka] or a pharma- ceutically acceptable salt, prodrug or bioequivalent thereof, wherein R 1a , R 1b , R 1C and R 1d are each independently H, halogen, or C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 selected from the group consisting of alkoxy and CN; X 1 Optionally, one or two C 1-2 Alkyl or CO 2 C substituted with H 1-3 is alkylene; R 2a and R 2b are independently H, C 1-8 Alkyl, C 1-8 Haloalkyl, -Y, -X 2 -C(O) 2 R a , -X 2 -OR a , -X 2 -NR a R b , -X 2 -CONR a R b , -X 2 -SO 2 R a , -X 2 -SO 2 NR a R b , -X 2 -SO 3 R 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, OH, SO 2 NH 2 ,CONH 2 , C(O)NHOH, PO 3 H 2 , COO-C 1-8 Alkyl or CO 2H, and each Y is optionally further substituted with one or two groups independently selected from C 3-6 Cycloalkyl, C 4-8 heterocyclyl and 5-6 membered heteroaryl groups, 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, SO 2 NH 2 ,CONH 2 , C(O)NHOH, PO 3 H 2 , COO-C 1-8 Alkyl, SO 3 H and CO 2 H; or R 2a and R 2b are combined to form a 4-10 membered ring or spiro ring, optionally with one or two additional ring vertices selected from O, N, or S, 2a and R 2b The ring formed by combining these is oxo, C 1-8 Alkyl, C 1―8 Haloalkyl, C 1-8 Hydroxyalkyl, -X 3 -C(O) 2 R a , -X 3 -OR a , -X 3 -NR a R b , -X 3 -CONR a R b , -X 3 -SO 2 R a , -X 3 -SO 2 NR a R b , and -X 3 -SO 3 R a (In the formula, X3 is a single bond or C 1-6 alkylene), R 3 and R 4 are F, Cl, CN, and CH 3 , O.C.H. 3 , C.H. 2 CH 3 and CF 3 independently selected from the group consisting of: The subscript n is 0, 1, 2, or 3; Each R 3a are H, F, Cl, and 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 6 , R 7 and R 8 are H, F, Cl, CN, and CH 3 , O.C.H. 3 , C.H. 2 CH 3 and CF 3 independently selected from the group consisting of: A is -N(R a )-, -C(=O)N(R a )-, -S(O)N(R a )- and -S(O) 2 N(R a )-, a member selected from the group consisting of; Z is selected from the group: i) optionally substituted with one or two oxo groups, and optionally up to four R a and / or R b monocyclic, bicyclic or spirocyclic non-aromatic heterocycles substituted with ii) Optionally, 1 to 3 R c a monocyclic 5- or 6-membered heteroaryl ring substituted with iii) Optionally, 1 to 3 R cA fused bicyclic heteroaryl ring substituted with -N(R a )-, Z is optionally 1 to 3 R c is a fused bicyclic heteroaryl ring substituted with; Each R a , H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkylene-CO 2 H, C 1-6 Alkylene-SO 3 H; Each R b , H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkylene-CO 2 H and C 1-6 Alkylene-SO 3 H, each of which is independently selected from the group consisting of OH, SO 2 NH 2 ,CONH 2 , C(O)NHOH, PO 3 H 2 , COO-C 1-8 Alkyl and CO 2 H; and R a and R b are optionally combined when attached to the same nitrogen atom and are optionally halogen, OH, SO 2 NH 2 ,CONH 2 , C(O)NHOH, PO 3 H 2 , COO-C 1-8 Alkyl or CO 2 forming a 4-8 membered ring or spiro ring substituted with H; Each R c H, halogen, CN, C 1-6 Alkyl, C 1-6Haloalkyl, -Y 1 , -X 4 -C(O) 2 R a , -OX 4 -C(O) 2 R a , -X 4 -OR a , -X 4 -NR a R b , -X 4 -CONR a R b , -OX 4 -CONR a R b , -X 4 -SO 2 R a , -X 4 -SO 2 NR a R b , -X 4 -SO 3 R a , and -N(R a )-X 4 -C(O) 2 R a wherein each X 4 is a single bond or C 1-6 alkylene, and each Y 1 is C 3-6 Cycloalkyl and C 4-8 heterocyclyl; and optionally, two R on adjacent ring vertices are selected from the group consisting of c combine to form a fused 5- or 6-membered heterocycle.

[0036] In one aspect of the disclosure, a compound of formula (I): [ka] or a pharma- ceutically acceptable salt, prodrug or bioequivalent thereof is provided: R 1a , R 1b , R 1C and R 1d are each independently H, halogen, or C 1-3 Alkyl, C1-3 Haloalkyl, C 1-3 selected from the group consisting of alkoxy and CN; X 1 Optionally, one or two C 1-2 Alkyl or CO 2 C substituted with H 1-3 is alkylene; R 2a and R 2b are independently H, C 1-8 Alkyl, C 1-8 Haloalkyl, -Y, -X 2 -C(O) 2 R a , -X 2 -OR a , -X 2 -NR a R b , -X 2 -CONR a R b , -X 2 -SO 2 R a , -X 2 -SO 2 NR a R b , -X 2 -SO 3 R 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, OH, SO 2 NH 2 ,CONH 2 , C(O)NHOH, PO 3 H 2 , COO-C 1-8 Alkyl or CO 2 H), and each Y is optionally further substituted with one or two groups independently selected from C 3-6 Cycloalkyl, C 4-8 heterocyclyl and 5-6 membered heteroaryl groups, each of which is selected from the group consisting of oxo, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkoxy, SO 2 NH 2 ,CONH 2 , C(O)NHOH, PO 3 H 2 , COO-C 1-8 Alkyl, SO 3 H and CO 2 H; or R 2a and R 2b are combined to form a 4-9 membered ring or spiro ring, optionally with one or two additional ring vertices selected from O, N, or S, 2a and R 2b The ring formed by combining these is oxo, C 1-8 Alkyl, C 1―8 Haloalkyl, C 1-8 Hydroxyalkyl, -X 3 -C(O) 2 R a , -X 3 -OR a , -X 3 -NR a R b , -X 3 -CONR a R b , -X 3 -SO 2 R a , -X 3 -SO 2 NR a R b , and -X 3 -SO 3 R a (In the formula, X 3 is a single bond or C 1-6 alkylene), R 3 and R 4 are F, Cl, CN, and CH 3 , O.C.H. 3 , C.H.2 CH 3 and CF 3 independently selected from the group consisting of: The subscript n is 0, 1, 2, or 3; Each R 3a are H, F, Cl, and 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 6 , R 7 and R 8 are H, F, Cl, CN, and CH 3 , O.C.H. 3 , C.H. 2 CH 3 and CF 3 independently selected from the group consisting of: A is -N(R a )-, -C(=O)N(R a )-, -S(O)N(R a )- and -S(O) 2 N(R a )-, a member selected from the group consisting of; Z is selected from the group: i) optionally substituted with one or two oxo groups, and optionally up to four R a and / or R b monocyclic, bicyclic or spirocyclic non-aromatic heterocycles substituted with ii) Optionally, 1 to 3 R c a monocyclic 5- or 6-membered heteroaryl ring substituted with iii) Optionally, 1 to 3 R c A fused bicyclic heteroaryl ring substituted with -N(R a )-, Z is optionally 1 to 3 R c is a fused bicyclic heteroaryl ring substituted with; Each R a , H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkylene-CO 2 H, C 1-6 Alkylene-SO 3 H; Each R b , H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkylene-CO 2 H and C 1-6 Alkylene-SO 3 H, each of which is independently selected from the group consisting of OH, SO 2 NH 2 ,CONH 2 , C(O)NHOH, PO 3 H 2 , COO-C 1-8 Alkyl and CO 2 H; and R a and R b are optionally combined when attached to the same nitrogen atom and are optionally halogen, OH, SO 2 NH 2 ,CONH 2 , C(O)NHOH, PO 3 H 2 , COO-C 1-8 Alkyl or CO 2 forming a 4-8 membered ring or spiro ring substituted with H; Each R c H, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -Y 1 , -X 4 -C(O) 2 R a , -OX 4 -C(O) 2 R a , -X 4 -OR a , -X 4 -NR a Rb , -X 4 -CONR a R b , -OX 4 -CONR a R b , -X 4 -SO 2 R a , -X 4 -SO 2 NR a R b , -X 4 -SO 3 R a , and -N(R a )-X 4 -C(O) 2 R a wherein each X 4 is a single bond or C 1-6 alkylene, and each Y 1 is C 3-6 Cycloalkyl and C 4-8 heterocyclyl; and optionally, two R on adjacent ring vertices are selected from the group consisting of c combine to form a fused 5- or 6-membered heterocycle.

[0037] In some embodiments of the present disclosure, the compound of formula (Ia): [ka] (Wherein, the following groups, R 1a , R 1b , R 1c , R 2a , R 2b , R 3 , R 4 , A, X 1 and Z has the meanings given for formula (I). The compound of formula (I) is provided:

[0038] In some embodiments of the present disclosure, the compound of formula (Ib): [ka] (Wherein, the following groups, R 1a , R 1b , R 1c , R 2a , R 2b , R 3 , R 4 , A, X 1 and Z has the meanings given for formula (I). The compound of formula (I) is provided:

[0039] In some embodiments of the present disclosure, the compound of formula (Ic): [ka] (Wherein, the following groups, R 1a , R 1b , R 2a , R 2b , R 3 , R 4 , A, X 1 and Z has the meanings given for formula (I). The compound of formula (I) is provided:

[0040] In some embodiments of the present disclosure, the compound of formula (Id): [ka] (Wherein, the following groups, R 1a , R 1b , R 2a , R 2b , R 3 , R 4 , A, and Z have the meanings provided for formula (I). The compound of formula (I) is provided:

[0041] In some selected embodiments, the compound of Formula (I), (Ia), (Ib), (Ic) or (Id) is a compound wherein Z is selected from the group consisting of: [ka] and wherein the compound is a non-aromatic heterocycle having a formula selected from:

[0042] In some selected embodiments, the compound of Formula (I), (Ia), (Ib), (Ic) or (Id) is a compound wherein Z is selected from piperidinyl, morpholinyl, tetrahydropyranyl, and tetrahydrofuranyl groups, each of which optionally has up to four R a and / or R b The compound is a non-aromatic heterocycle substituted with

[0043] In some selected embodiments, the compound of Formula (I), (Ia), (Ib), (Ic) or (Id) is a compound wherein Z is selected from the group consisting of: [ka] and wherein the compound is a fused bicyclic heteroaryl ring having a formula selected from:

[0044] In some selected embodiments, compounds of Formula (I), (Ia), (Ib), (Ic) or (Id) include compounds wherein Z is a monocyclic 5- or 6-membered heteroaryl ring and optionally 1 to 3 R c wherein said heterocycle is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, and pyrazolyl groups.

[0045] In selected embodiments, including any of those described above with respect to compounds of formula (I), (Ia), (Ib), (Ic) or (Id), further embodiments include those in which A is -C(=O)N(R a )

[0046] In selected embodiments, including any of those described above with respect to compounds of formula (I), (Ia), (Ib), (Ic) or (Id), further embodiments include those in which the group R 1a OCH 3 and R 1bis from F.

[0047] In selected embodiments, including any of those described above, for compounds of formula (I), (Ia), (Ib), (Ic) or (Id), further embodiments include 2a and R 2b Each of these is from H.

[0048] In selected embodiments, including any of those described above, for compounds of formula (I), (Ia), (Ib), (Ic) or (Id), further embodiments are as follows: R 2a and R 2b are combined to form a 4-9 membered ring or spiro ring, optionally having one or two additional ring vertices selected from O, N or S, said ring or spiro ring being selected from oxo, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, -X 2 -C(O) 2 R a , -X 2 -OR a , -X 2 -NR a R b , -X 2 -CONR a R b , -X 2 -SO 2 R a , -X 2 -SO 2 NR a R b , and -X 2 -SO 3 R a (In the formula, X 2 is a single bond or C 1-6 is substituted with 0 to 4 substituents independently selected from the group consisting of alkylene.

[0049] In selected embodiments, including any of those described above with respect to compounds of formula (I), (Ia), (Ib), (Ic) or (Id), further embodiments include -N(R 2a )(R2b ) is the following compound: [ka] is selected from the group consisting of:

[0050] In selected embodiments, including any of those described above with respect to compounds of formula (I), (Ia), (Ib), (Ic) or (Id), further embodiments include -N(R 2a )(R 2b ) is the following compound: [ka] is selected from the group consisting of:

[0051] In selected embodiments, including any of those described above with respect to compounds of formula (I), (Ia), (Ib), (Ic) or (Id), further embodiments include -N(R 2a )(R 2b ) is the following compound: [ka] is selected from the group consisting of:

[0052] In selected embodiments, including any of those described above, for compounds of formula (I), (Ia), (Ib), (Ic) or (Id), further embodiments include 2a is H or C 1-8 R is alkyl; 2b is -Y or -X 2 -Y.

[0053] In selected embodiments, including any of those described above, for compounds of formula (I), (Ia), (Ib), (Ic) or (Id), further embodiments include 2a is H or C 1-8 R is alkyl; 2b is -Y or -X2 -Y, where Y is C 3-6 Cycloalkyl and C 4-8 heterocyclyl groups, 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, SO 2 NH 2 ,CONH 2 , C(O)NHOH, PO 3 H 2 , COO-C 1-8 Alkyl, and CO 2 H.

[0054] In selected embodiments, including any of those described above with respect to compounds of formula (I), (Ia), (Ib), (Ic) or (Id), further embodiments include those in which A is -C(=O)N(R a )- and Z is a 5- or 6-membered non-aromatic heterocycle, which is optionally substituted with one or two oxo groups, and optionally R a and / or R b is replaced by

[0055] In selected embodiments, including any of those described above with respect to compounds of formula (I), (Ia), (Ib), (Ic) or (Id), further embodiments include those in which A is -C(=O)N(R a )- and Z is a monocyclic 5- or 6-membered heteroaryl ring, which ring is optionally joined to one or more R c is replaced by

[0056] In selected embodiments, including any of those described above with respect to compounds of formula (I), (Ia), (Ib), (Ic) or (Id), further embodiments include those in which A is -C(=O)N(R a)-; Z is a 5- or 6-membered non-aromatic heterocycle, which is optionally substituted with one or two oxo groups, and optionally R a and / or R b and R 1c , R 6 , R 7 , R 8 are H, respectively.

[0057] In selected embodiments, including any of those described above with respect to compounds of formula (I), (Ia), (Ib), (Ic) or (Id), further embodiments include those in which A is -C(=O)N(R a ); Z is a monocyclic 5- or 6-membered heteroaryl ring, which ring is optionally joined to one or more of R c and R 1c , R 6 , R 7 , R 8 are H, respectively.

[0058] In selected embodiments, including any of those described above with respect to compounds of formula (I), (Ia), (Ib), (Ic) or (Id), further embodiments include those in which A is -C(=O)N(R a )-; Z is a 5- or 6-membered non-aromatic heterocycle, which is optionally substituted with one or two oxo groups, and optionally R a and / or R b and said non-aromatic heterocycle is selected from the group consisting of piperidinyl, morpholinyl, tetrahydropyranyl, and tetrahydrofuranyl groups.

[0059] In selected embodiments, including any of those described above with respect to compounds of formula (I), (Ia), (Ib), (Ic) or (Id), further embodiments include those in which A is -C(=O)N(R a )-; Z is a monocyclic 5- or 6-membered heteroaryl ring, which ring is optionally joined to one or more of R cand said heterocycle is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, and pyrazolyl.

[0060] In select embodiments, including any of those described above with respect to compounds of formula (I), (Ia), (Ib), (Ic) or (Id), further embodiments are those in which the compound is selected from Table 1. In select embodiments, including any of those described above with respect to compounds of formula (I), (Ia), (Ib), (Ic) or (Id), further embodiments are those in which the compound is selected from Table 2.

[0061] In select embodiments, including any of those described above with respect to compounds of formula (I), (Ia), (Ib), (Ic) or (Id), further embodiments are those in which the compound is selected from Table 1. In select embodiments, including any of those described above with respect to compounds of formula (I), (Ia), (Ib), (Ic) or (Id), further embodiments are those in which the compound has an activity of ++ or +++ and is selected from Table 2.

[0062] In select embodiments, including any of those described above with respect to compounds of formula (I), (Ia), (Ib), (Ic) or (Id), further embodiments are those in which the compound has an activity of +++ and is selected from Table 1. In select embodiments, including any of those described above with respect to compounds of formula (I), (Ia), (Ib), (Ic) or (Id), further embodiments are those in which the compound has an activity of +++ and is selected from Table 2.

[0063] In addition to the compounds provided above, pharma- ceutically acceptable salts of those compounds are also provided. In some embodiments, the pharma- ceutically acceptable salts are selected from the group consisting of 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, methylglucose ... and salts selected from the group consisting of amine, morpholine, piperazine, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, hydrochloric acid, carbonic acid, monohydrogen carbonate, monohydrogen phosphate, dihydrogen phosphate, acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, uric 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 pharma- ceutically acceptable salt is a salt selected from ammonium, calcium, magnesium, potassium, sodium, hydrochloric acid, carbon, carbon monohydrogen, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, tartaric acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, alginate, glucuronic acid, and galacturonic acid. In some embodiments, the pharma-ceutically acceptable salt is a salt of sodium or hydrochloric acid.

[0064] In addition to salt forms, the present disclosure provides compounds in prodrug form. Prodrugs of the compounds described herein are compounds that undergo easy chemical changes under physiological conditions to provide the compounds of the present disclosure. Furthermore, 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 the appropriate enzyme or chemical reagent.

[0065] 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 acid. The following esters can be used: tert-butyl ester, methyl ester, ethyl ester, isopropyl ester.

[0066] Pharmaceutical Compositions In addition to the compounds provided herein, compositions of these compounds typically include a pharmaceutical carrier or diluent.

[0067] 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 the combination of the specified ingredients in the specified amounts. "Pharmaceutically acceptable" means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0068] In another embodiment, there is provided a pharmaceutical composition comprising a compound of the present disclosure, including a compound of Formula (I), (Ia), (Ib), (Ic) or (Id), or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0069] 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 antibacterial agents, antiviral agents, cytotoxic agents, gene expression modulators, chemotherapeutic agents, anticancer agents, antiangiogenic agents, immunotherapeutic agents, antihormonal agents, antifibrotic agents, radiation therapy, radiotherapy agents, antitumor agents, and antiproliferative agents. In some embodiments, the one or more additional therapeutic agents are antagonists of chemokines and / or chemotactic 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. Chemokine and / or chemotactic receptor antagonists are known in the art and are described, for example, in WO 2007 / 002667(A), WO 2007 / 002293(A), WO 2003 / 105853(A), WO 2007 / 022257(A), WO 2007 / 059108(A), WO 2007 / 044804(A), WO 2007 / 115232(A), WO 2007 / 115231(A), WO 2008 / 147815(A), WO 2010 / 03(A), WO 2011 / 04(A), WO 2012 / 03(A), WO 2013 / 04(A), WO 2014 / 05(A), WO 2015 / 06(A), WO 2016 / 01(A), WO 2015 / 02(A), WO 2016 / 03(A), WO 2017 / 02(A), WO 2015 / 03(A), WO 2016 / 01(A), WO 2015 ... 0815(A), WO 2010 / 075257(A), WO 2011 / 163640(A), WO 2010 / 054006(A), WO 2010 / 051561(A), WO 2011 / 035332(A), WO 2013 / 082490(A), WO 2013 / 082429(A), WO 2014 / 085490(A), WO 2014 / 100735(A), WO 2014 / 089495(A), WO 2015 / 084842(A),International Publication No. WO 2016 / 187393(A), International Publication No. WO 2017 / 127409(A), International Publication No. WO 2017 / 087607(A), International Publication No. WO 2017 / 087610(A), International Publication No. WO 2017 / 176620(A), International Publication No. WO 2018 / 222598(A), International Publication No. WO 2018 / 222601(A), International Publication No. WO 2013 / 130811(A), International Publication No. WO 2006 / 076644(A), International Publication No. WO 2008 / 008431(A), WO 2009 / 038847(A), WO 2008 / 008375(A), WO 2008 / 008374(A), WO 2008 / 010934(A), WO 2009 / 009740(A), WO 2005 / 112925(A), WO 2005 / 112916(A), WO 2005 / 113513(A), WO 2004 / 085384(A), WO 2004 / 046092(A). Chemokine and / or chemotactic 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.

[0070] The pharmaceutical composition for administering the compounds of the present disclosure can be conveniently presented in unit dosage form and can be prepared by any method well known in the art of pharmacy and drug delivery. All methods include the step of combining the active ingredient with a carrier which constitutes one or more accessory ingredients. In general, pharmaceutical compositions are prepared by combining the active ingredient in a uniform mixture with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition, the active subject compound is included in an amount sufficient to produce the desired effect on the disease process or disease state.

[0071] 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 as described in US Patent Application No. 2002-0012680, hard or soft capsules, syrups, elixirs, solutions, buccal patches, oral gels, chewing gums, chewable tablets, effervescent powders, and effervescent tablets. Compositions intended for oral use can be prepared according to methods known in the art for producing pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, antioxidants, and preservatives, which provide a pharma- ceutically smooth and palatable formulation. Tablets contain the active ingredient mixed with non-toxic pharma- ceutically acceptable excipients suitable for their manufacture. 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, and lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and provide a sustained enteral action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used. Osmotic therapeutic tablets for controlled release may also be used, coated by the techniques described in U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874.

[0072] The preparation for oral use may also be presented as a hard gelatin capsule, in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin, polyethylene glycols (PEG) having various average sizes (e.g., PEG400, PEG4000) and a specific surfactant such as Cremophor or Solutol, or as a soft gelatin capsule in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.Furthermore, emulsions may be prepared with non-water-miscible ingredients such as oils, and stabilized with surfactants such as mono- or diglycerides, PEG esters, etc.

[0073] Aqueous suspensions contain the active substance mixed with excipients suitable for the manufacture of aqueous suspensions.Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum taracantha and gum arabic;dispersing agents or wetting agents may be naturally occurring phosphatides, for example, lecithin, or condensation products of alkylene oxides with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters of fatty acids and hexitols, such as polyoxyethylene sorbitan monooleate, or condensation products of ethylene oxide with partial esters of fatty acids and hexitol anhydrides, for example, polyethylene sorbitan monooleate. The aqueous suspensions may 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.

[0074] Oily suspensions can be formulated by suspending the active ingredient in vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or mineral oil, such as liquid paraffin.Oily suspensions can contain thickening agents, for example, beeswax, hard paraffin or cetyl alcohol.Sweetening agents, such as those mentioned above, and flavoring agents can be added to provide a palatable oral preparation.These compositions can be preserved by the addition of antioxidants, such as ascorbic acid.

[0075] Dispersible powders and granules suitable for preparing an aqueous suspension by adding water provide the active ingredient mixed 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.

[0076] The pharmaceutical composition of the present disclosure may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers are naturally occurring gums, such as gum acacia or gum tragacanth, naturally occurring phosphatides, such as soybean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and the condensation products of said partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. Emulsions may also contain sweeteners and flavoring agents.

[0077] Syrups and elixirs can be formulated with sweeteners, such as glycerol, propylene glycol, sorbitol or sucrose. Such preparations may also contain mucilages, preservatives, flavorings and coloring agents. Oral liquid preparations can be prepared in combination with, for example, cyclodextrin, PEG and surfactants.

[0078] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable preparation may also be a non-toxic, orally acceptable solution or suspension in a sterile injectable diluent or solvent, for example, 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. In addition, sterile, fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0079] The compounds of the present disclosure may also be administered in the form of suppositories for administering the drug to the rectum. These compositions may be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and melts in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycol. Additionally, the compounds may be administered ophthalmically using solutions or ointments. Additionally, transdermal delivery of the subject compounds may be achieved by iontophoresis patches and the like. For topical use, creams, ointments, jellies, solutions or suspensions containing the compounds of the present disclosure may be used. As used herein, topical application is also meant to include the use of mouthwashes and mouthwashes.

[0080] The compounds of the present disclosure may also be coupled to carriers that are polymers suitable for targetable drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymers, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Additionally, the compounds of the present disclosure may be coupled to carriers of the biodegradable polymer class that is useful for achieving controlled release of drugs, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels. The polymers and semipermeable polymer matrices may be formed into shaped articles such as valves, stents, tubes, prostheses, etc. In one embodiment of the present disclosure, the compounds of the present disclosure are coupled to polymers or semipermeable polymer matrices that are formed as stents or stent graft devices.

[0081] How to treat illnesses and disorders The compounds of the present disclosure can be used as immunomodulators. The compounds of the present disclosure can be used as agonists, antagonists, partial agonists, inverse agonists, and inhibitors of PD-1 and / or PD-L1 in a variety of contexts, both in vitro and in vivo. In some embodiments, the compounds of the present disclosure can be used as inhibitors of PD-1 / PD-L1 protein-protein interaction. In some embodiments, the compounds of the present disclosure can be used as inhibitors of PD-L1. In some embodiments, the compounds of the present disclosure can be used as inhibitors of CD80 / PD-L1 protein-protein interaction. In some embodiments, the 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, the compounds of the present disclosure can be used to inhibit VISTA and / or TIM-3. In some embodiments, the compounds of the present disclosure can be inhibitors of PD-1 / PD-L1 protein-protein interaction, as well as inhibitors of VISTA and / or TIM-3. In some embodiments, the compounds of the disclosure, in addition to being inhibitors of PD-1 / PD-L1 protein-protein interaction, may 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.

[0082] The compounds of the present disclosure can be contacted with the receptor with which they interact in aqueous solution or under conditions otherwise suitable for the ligand to bind to the receptor. The receptor can be in suspension (e.g., in an isolated membrane or cell preparation), in cultured or isolated cells, or in a tissue or organ.

[0083] Preferably, the amount of compound of the disclosure that contacts the receptor should be sufficient to inhibit PD-1 / PD-L1 binding in vitro as measured, for example, using ELISA. The receptor may be present in solution or suspension, in a cultured or isolated cell preparation, or in a patient.

[0084] 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 response in patients.In some embodiments, the compounds of the present disclosure are useful for treating, preventing, or slowing the progression of diseases or disorders in various therapeutic areas, such as cancer and infectious diseases.

[0085] In some embodiments, compounds of the disclosure can be used to treat patients suffering from conditions responsive to PD-1 / PD-L1 protein-protein interaction.

[0086] In some embodiments, there is provided a method of modulating an immune response mediated by the PD-1 signaling pathway in a subject, the method 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 pharma- ceutically acceptable salt thereof, or a composition comprising a compound of Formula (I), (Ia), (Ib), (Ic) or (Id), or a pharma- ceutically acceptable salt thereof.

[0087] In some embodiments, there is provided a method of enhancing, stimulating, modulating and / or increasing an immune response 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 pharma- ceutically acceptable salt thereof, or a composition of a compound of the present disclosure comprising a compound of Formula (I), (Ia), (Ib), (II), (IIa), or (IIb), or a pharma- ceutically acceptable salt thereof.

[0088] In some embodiments, there is provided a method 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 comprising Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharma- ceutically acceptable salt thereof, or a composition of a compound of the present disclosure comprising a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharma- ceutically acceptable salt thereof.

[0089] In some embodiments, there is provided a method of 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 pharma- ceutically acceptable salt thereof, or a composition of a compound of the present disclosure comprising a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharma- ceutically acceptable salt thereof.

[0090] 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 malignant 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, synovium, meningioma, leiomyosarcoma, rhabdomyosarcoma, malignant soft tissue tumor, sarcoma, sepsis, bile duct tumor, basal cell carcinoma, thymus tumor, thyroid cancer, parathyroid cancer, uterine cancer, adrenal cancer, liver infection, Merkel cell carcinoma, neural tumor, follicular 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 cancer), hepatocellular carcinoma, pancreatic carcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma, head and neck squamous cell carcinoma, head and neck cancer, gastrointestinal tract, gastric cancer cancer), HIV, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus, papilloma virus, influenza, bone cancer, skin cancer, rectal cancer, anal cancer, testicular cancer, fallopian tube cancer , endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, small intestine cancer, endocrine cancer, urethral cancer, penile cancer, bladder cancer, kidney cancer, ureteral cancer, renal pelvic cancer, central nervous system (CNS) tumor, tumor angiogenesis, spinal cord Axial tumors, brain stem glioma, pituitary adenoma, epidermoid carcinoma, abestosis, carcinoma, adenocarcinoma, papillary carcinoma, cystadenocarcinoma, bronchogenic carcinoma, renal cell carcinoma, transitional cell carcinoma, choroidal carcinoma, seminoma, embryonal carcinoma, Wilms' tumor, pleomorphic adenoma, hepatocellular papilloma, renal tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma and fibroma.

[0091] In some embodiments, the subject is further administered a therapeutically effective amount of one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of antibacterial agents, antiviral agents, cytotoxic agents, gene expression modulating agents, chemotherapeutic agents, anticancer agents, antiangiogenic agents, immunotherapeutic agents, antihormonal agents, antifibrotic agents, radiation therapy, radiotherapy agents, antitumor agents, and antiproliferative agents. In some embodiments, the one or more additional therapeutic agents are antagonists of chemokines and / or chemotactic 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. Chemokine and / or chemotactic receptor antagonists are known in the art and are described, for example, in WO 2007 / 002667(A), WO 2007 / 002293(A), WO 2003 / 105853(A), WO 2007 / 022257(A), WO 2007 / 059108(A), WO 2007 / 044804(A), WO 2007 / 115232(A), WO 2007 / 115231(A), WO 2008 / 147815(A), WO 2010 / 0308 ... 15(A), International Publication No. 2010 / 075257(A), International Publication No. 2011 / 163640(A), International Publication No. 2010 / 054006(A), International Publication No. 2010 / 051561(A), International Publication No. 2011 / 035332(A), International Publication No. 2013 / 082490(A), International Publication No. 2013 / 082429(A), International Publication No. 2014 / 085490(A), International Publication No. 2014 / 100735(A), International Publication No. 2014 / 089495(A), International Publication No. 2015 / 084842(A),International Publication No. WO 2016 / 187393(A), International Publication No. WO 2017 / 127409(A), International Publication No. WO 2017 / 087607(A), International Publication No. WO 2017 / 087610(A), International Publication No. WO 2017 / 176620(A), International Publication No. WO 2018 / 222598(A), International Publication No. WO 2018 / 222601(A), International Publication No. WO 2013 / 130811(A), International Publication No. WO 2006 / 076644(A), International Publication No. WO 2008 / 008431(A), WO 2009 / 038847(A), WO 2008 / 008375(A), WO 2008 / 008374(A), WO 2008 / 010934(A), WO 2009 / 009740(A), WO 2005 / 112925(A), WO 2005 / 112916(A), WO 2005 / 113513(A), WO 2004 / 085384(A), WO 2004 / 046092(A). Chemokine and / or chemotactic 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.

[0092] In some embodiments, the compounds of the present disclosure may be used to inhibit infectious diseases, including, but not limited to, the following: Pathogenic infections caused by, for example, HIV, influenza, herpes, giardiasis, malaria, leishmaniasis, and hepatitis (A, B, and C) viruses, such as herpes viruses (e.g., VZV, HSV-I, HAV-6, HSV-II, and CMV, Epstein-Barr virus), adenoviruses, influenza viruses, flaviviruses, echoviruses, rhinoviruses, coxsackieviruses, cornoviruses, respiratory syncytial viruses, mumps viruses, rotaviruses, measles viruses, rubella viruses, parvoviruses, vaccinia viruses, HTLV viruses, dengue viruses, papilloma viruses, molluscum viruses, polio viruses, rabies viruses, JC viruses, and arboencephalitis viruses, and by bacteria such as chlamydia, rickettsia bacteria, mycobacteria, staphylococci, streptococci, pneumococci, meningococci and gonococci, klebsiella, plaques, and the like. Pathogenic infections caused by Bacillus subtilis, Serratia marcescens, Pseudomonas aeruginosa, Escherichia coli, Legionella pneumoniae, Corynebacterium diphtheriae, Salmonella enterica, Bacillus subtilis, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme borreliosis, as well as Candida albicans, B. krusei, B. glabrata, and B. tropicalis, Cryptococcus neoformans, Aspergillus moulds (B. fumigatus, B. niger, and others), Mucor mycosis (Mucorrhoea, Abscissionia, Rhizopus, sporotrichosis, blastomycosis, paracoccidioidomycosis, coccidioidomycosis and histoplasmosis, and pathogenic infections with the parasites Entamoeba histolytica, Balantidium coli, Naegleria fowleria, Acanthamoeba, giardiasis, cryptosporidiosis, pneumonia carinii, Plasmodium vivax, babesiosis, trypanosomiasis, Chagas disease, leishmaniasis, toxoplasmosis and Nippostrongylus brasiliensis.

[0093] In some embodiments, compounds of the disclosure may be used to inhibit HIV infection, slow AIDS progression, deplete HIV viral reservoirs, or reduce the symptoms or severity of HIV infection and AIDS.

[0094] The compounds of the present disclosure can be used to treat cancer and precancerous conditions in a subject.

[0095] The therapeutic methods provided herein generally include administering to a patient an effective amount of one or more compounds provided herein. Such patients include patients suffering from or at risk of suffering from a disorder or disease identified herein (i.e., prophylactic treatment). Typical patients receiving the treatment described herein include mammals, particularly primates, and especially humans. Other suitable patients include domesticated companion animals such as dogs, cats, horses, or livestock such as cows, pigs, sheep, etc.

[0096] In general, the methods of treatment provided herein include administering to a patient an effective amount of one or more compounds provided herein. In a preferred embodiment, the compounds 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. The amount administered preferably results in a plasma concentration of the compound (or an active metabolite thereof, if the compound is a prodrug) sufficient to sufficiently modulate PD-1 / PD-L1 interaction. Treatment regimens may vary depending on the compound used and the particular condition being treated. For the treatment of most disorders, a dosing frequency of four times a day or less is preferred. In general, a twice-daily dosing regimen is more preferred, with once-daily administration being particularly preferred. It will be understood, however, that any particular patient's specific dose level and treatment regimen will depend on a variety of factors, such as the activity of the particular compound used, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combinations (i.e., other drugs being administered to the patient) and the severity of the particular disease being treated, as well as the judgment of the prescribing practitioner. In general, it is preferable to use the minimum dose sufficient to provide effective treatment. Patients may generally be monitored for the effectiveness of their treatment in accordance with medical or veterinary standards appropriate to the condition being treated or prevented.

[0097] Use in combination The combination drug containing the 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 as separate preparations.The administration by separate preparations includes simultaneous administration and administration at a certain time interval.When administration at a certain time interval, the compound of the present disclosure can be administered first, and then the other drug, or the other drug can be administered first, and then the compound of the present disclosure.The administration method of each drug may be the same or different.

[0098] The dosage of the other drug can be appropriately selected based on the dosage used clinically. 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, the symptoms, and combinations thereof. For example, the other drug can 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 types of any drug in an appropriate ratio.

[0099] The compounds described herein may be used with or in combination with one or more therapeutic agents, such as antibacterial agents, antiviral agents, cytotoxic agents, gene expression modulating agents, chemotherapeutic agents, anticancer agents, antiangiogenic agents, immunotherapeutic agents, antihormonal agents, antifibrotic agents, radiation therapy, radiotherapy agents, antitumor agents, and antiproliferative agents, etc. These therapeutic agents may be in the form of a chemical compound, an antibody, a polypeptide, or a polynucleotide.

[0100] The compounds described herein may be used in conjunction with therapeutic antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins (such as 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), CAR (chimeric antigen receptor) T cell immunotherapeutics, or in any combination thereof.

[0101] Examples of chemotherapeutic agents include alkylating agents, nitrosoureas, antimetabolites, anticancer antibiotics, plant-derived alkaloids, topoisomerase inhibitors, hormonal agents, hormone antagonists, aromatase inhibitors, P-glycoprotein inhibitors, platinum complex derivatives, other immunotherapeutic agents and other anticancer agents.

[0102] The compounds described herein can be used in combination with or in adjunct forms to cancer treatment, such as leukopenia (neutropenia) treatments, thrombocytopenia treatments, emetics, and cancer pain intervention drugs.

[0103] The compounds described herein may be used together or in combination with kinase inhibitors.

[0104] In one embodiment, the compounds of the present disclosure can be used in combination with other immunomodulators and / or enhancers or in mixed form. Examples of immunomodulators include various cytokines, vaccines and adjuvants. These cytokines, vaccines and adjuvants that stimulate immune response include, but are not limited to, GM-CSF, M-CSF, G-CSF, interferon-α, β, γ, IL-1, IL-2, IL-3, IL-12, poly(I:C) and CPG. Enhancers include cyclophosphamide and cyclophosphamide analogues, anti-TGF and mitotic inhibitors such as imatinib (Gleevac), paclitaxel, sunitinib (Sutent) or other anti-angiogenic agents, aromatase inhibitors such as letrozole, A2a adenosine receptor (A2AR) antagonists, angiogenesis inhibitors, anthracyclines, oxaliplatin, doxorubicin, TLR4 antagonists, and IL-18 antagonists.

[0105] In some embodiments herein, the compounds may be used together or in combination with CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CCR11, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, ChemR23, C5aR, C5a, and C5.

[0106] In some embodiments, the compounds herein may be used or combined with one or more chemokine and / or chemotactic receptor antagonists, as described, for example, in WO 2007 / 002667(A), WO 2007 / 002293(A), WO 2003 / 105853(A), WO 2007 / 022257(A), WO 2007 / 059108(A), WO 2007 / 044804(A), WO 2007 / 115232(A), WO 2007 / 11523 ... 1(A), International Publication No. 2008 / 147815(A), International Publication No. 2010 / 030815(A), International Publication No. 2010 / 075257(A), International Publication No. 2011 / 163640(A), International Publication No. 2010 / 054006(A), International Publication No. 2010 / 051561(A), International Publication No. 2011 / 035332(A), International Publication No. 2013 / 082490(A), International Publication No. 2013 / 082429(A), International Publication No. 2014 / 085490(A), International Publication No. 2014 / 100735(A), International Publication No. 2014 / 089495(A), International Publication No. 2015 / 084842(A), International Publication No. 2016 / 187393(A), International Publication No. 2017 / 127409(A), International Publication No. 2017 / 087607(A), International Publication No. 2017 / 0876 10(A), International Publication No. 2017 / 176620(A), International Publication No. 2018 / 222598(A), International Publication No. 2018 / 222601(A), International Publication No. 2013 / 130811(A), International Publication No. 2006 / 076644(A), International Publication No. 2008 / 008431(A), International Publication No. 2009 / 038847(A), International Publication No. 2008 / 008375(A),WO 2008 / 008374(A), WO 2008 / 010934(A), WO 2009 / 009740(A), WO 2005 / 112925(A), WO 2005 / 112916(A), WO 2005 / 113513(A), WO 2004 / 085384(A), WO 2004 / 046092(A). Chemokine and / or chemotactic 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.

[0107] Dosage Dosage levels on the order of about 0.1 mg to about 140 mg per kilogram of body weight per day are useful for the treatment or prevention of conditions involving PD-1 / PD-L1 interaction (about 0.5 mg to about 7 g per human patient per day). The amount of active ingredient which can be combined with the carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. A unit dosage form will generally contain from 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 the compound is administered to achieve a serum concentration of 5 ng (nanogram) / mL to 10 μg (microgram) / mL, more preferably a sufficient amount of the compound is administered to achieve a serum concentration of 20 ng to 1 μg / ml, and most preferably a sufficient amount of the compound is administered to achieve a serum concentration of 50 ng / ml to 200 ng / ml. For direct injection into the synovium (for the treatment of arthritis), a sufficient amount of compound should be administered to achieve a local concentration of about 1 micromolar.

[0108] The frequency of administration may also vary depending on the compound used and the specific disease being treated.However, for the treatment of most disorders, a four times a day, three times a day or less administration schedule is preferred, with a once a day or twice a day administration schedule being particularly preferred.However, it will be understood that the specific dose level for a particular patient will depend on a variety of factors, including the activity of the particular compound used, age, body weight, general health, sex, diet, time of administration, route of administration, excretion rate, drug combination (i.e., other drugs being administered to the patient), the severity of the particular disease being treated, and other factors, including the judgment of the prescribing practitioner.

[0109] In another aspect of the present disclosure, the compounds of the present disclosure can be used with various non-pharmaceutical agents in vitro and in vivo. The compounds of the present disclosure can also be used as positive controls in assays of PD-1 / PD-L1 interaction activity. That is, candidate agents can be used as standards to determine their ability to bind to PD-1 and / or PD-L1. Or, they can be used as radiotracers for positron emission tomography (PET) imaging or single photon emission computed tomography (SPECT).

[0110] Also included within the scope of this disclosure is a kit comprising a compound of the present disclosure or a pharma- ceutically 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 on or accompanying the kit, or that accompanies the kit. EXAMPLES

[0111] The following examples illustrate various methods of making the compounds of the present disclosure, including compounds of formula (I), (Ia), (Ib), (Ic) or (Id). The following examples are presented for illustrative purposes and are not intended to limit the scope of the disclosure in the claims.

[0112] Reagents and solvents used below can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wis., USA). 1 H-NMR spectra were recorded on a Varian Mercury 400MHz NMR spectrometer. Important peaks are provided relative to TMS and are tabulated in order of multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet) and number of protons. Mass spectrometry results are reported as mass to charge ratio. In the examples, a single m / z value is reported for the M+H (or MH as mentioned above) ion containing the most common atomic isotopes. The isotopic pattern corresponds to the expected formula in all cases. Electrospray ionization (ESI) mass spectrometry was performed on a Hewlett-Packard MSD electrospray mass spectrometer using an HP1100 HPLC as the sample carrier. Analytes were typically dissolved in methanol or CH4. 3 Compounds were dissolved in CN at a concentration of 0.1 mg / mL and 1 μL was injected into the mass spectrometer with the carrier solvent. The mass spectrometer scanned from 100 to 1000 Daltons. All compounds could be analyzed in either positive or negative ESI mode using acetonitrile / water with 1% formic acid as the carrier solvent.

[0113] The following abbreviations are used throughout the examples and description of this disclosure: TLC means thin layer chromatography.

[0114] Compounds within the scope of the present disclosure can be synthesized as described below using a variety of reactions known to those skilled in the art. Those skilled in the art will also recognize that alternative methods can be used to synthesize the desired compounds of the present disclosure, and that the approaches described within this document, while not exhaustive, are broadly applicable and practical routes to the desired compounds.

[0115] Certain molecules within the scope of this patent may exist in different enantiomeric and diastereomeric forms, and unless specified, a particular enantiomer encompasses all such variations of these compounds.

[0116] Detailed descriptions in this text of the experimental procedures used to synthesize compounds of interest result in molecules that have physical data that allow their identification and whose molecular structures can be delineated.

[0117] Those skilled in the art will also recognize that acids and bases are frequently used when performing standard work-up procedures in organic chemistry. In cases where the parent compound possesses inherent acidity or basicity that is required, its salt may be generated during the experimental procedures described in this patent.

[0118] Example 1: (S)—N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((5-oxopyrrolidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide [ka] Step a: To a mixture of 1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid (0.75 g, 4.87 mmol), 3-bromo-2-methylaniline (0.91 g, 4.87 mmol) in DMF (30 mL) was added HATU (2.22 g, 5.84 mmol) and diisopropylethylamine (0.94 g, 7.30 mmol). The reaction was stirred at room temperature for 16 hours. After completion of the reaction, half of the solvent was removed. The resulting solution was diluted with water (100 mL) and the mixture was stirred for 20 minutes. The solid was filtered through a plastic funnel, washed with water (10 ml) and dried under vacuum to give the desired product N-(3-bromo-2-methylphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide as a white solid. 1 H NMR (400MHz, CD3 OD) δ 8.89(s,1H),8.68(s,1H),8.08-8.05(m,1H),7.44-7.42(m,1H),7.13(td,J=8.1,0.7Hz,1H),3.67(s,3H),2.49(s,3H). MS:(ES)C 13 H 13 BrN 3 O 2 [M+H] + The calculated m / z for is 322.0 and the measured value is 322.0.

[0119] Step b: N-(3-bromo-2-methylphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide (1.2 g, 3.72 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 (1.4 g, 3.72 mmol), and 2M K in p-dioxane (32 mL). 2 CO 3 To a mixture of (5.6 mL, 11.2 mmol) Pd(dppf)Cl with dichloromethane 2 The complex (456 mg, 0.559 mmol) was added. The reaction mixture was degassed (N 2 ) and N 2 The reaction mixture was stirred at 95 °C for 5 h under 5% CO. The reaction mixture was diluted with EtOAc, filtered through Celite, washed with brine, and washed with MgSO. 4 The solvent was removed under reduced pressure and the residue was purified by silica gel flash chromatography (5-20%-40% EtOAc / Hexanes) to give N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide as a brown solid. 1 H NMR (400MHz, CD 3OD) δ 10.40(s,1H),8.91(s,1H),8.67(s,1H),8.15(dd,J=8.3,1.3Hz,1H),7.37-7.25(m,3H),7.18(dd,J=7.3,1.5Hz,1H ),6.99(dd,J=7.3,1.5Hz,1H),6.95(s,1H),6.85-6.77(m,1H),3.98(s,3H),3.65(s,3H),2.12(s,3H),1.96(s,3H). MS:(ES)C 28 H 25 FN 3 O 4 [M+H] + The calculated m / z for this compound was 486.2, the measured value was 486.2.

[0120] Step c: To a stirred solution of N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide (100 mg, 0.206 mmol) and (S)-4-aminopyrrolidin-2-one (82 mg, 0.824 mmol) in ethanol (1 mL) was added acetic acid (5 drops). The reaction mixture was stirred at 70° C. for 1 h. The mixture was then cooled to 0° C. and diluted with NaCNBH 3 (13 mg, 0.206 mmol) was added slowly. The mixture was stirred at 0° C. for 10 min. The solvent was removed under reduced pressure and the residue was purified by HPLC (0-40%-100% MeCN / H 2 0) to give (S)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((5-oxopyrrolidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD 3OD) δ 11.41(s,1H),8.92(s,1H),8.68(s,1H),8.13-8.10(m,1H),7.38-7.21(m,3H),7.20-7.13 (m,1H),7.01-6.97(m,1H),6.96-6.94(m,1H),6.91-6.88(m,1H),4.37(s,2H),4.26-4.21 (m,1H),4.00(s,3H),3.88(dd,J=11.6,7.6Hz,1H),3.66(s,3H),3.57(dd,J=11.6,3.9Hz, 1H),2.91(dd,J=17.8,8.8Hz,1H),2.55(dd,J=17.8,4.7Hz,1H),2.11(s,3H),1.94(s,3H). MS:(ES)C 32 H 33 FN 5 O 4 [M+H] + The calculated m / z is 570.2, the measured value is 570.3.

[0121] Example 2: (S)—N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The compound was purified by HPLC (MeCN / H2O containing 0.1% TFA). 20) to give the desired product, (S)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD 3 OD) δ 11.41(s,1H),8.92(s,1H),8.68(s,1H),8.15-8.13(m,1H),7.39-7.21(m,3H),7.20-7.13(m,1H),7.03-6.86(m,3H),4.41(s,2H) ,4.07-4.01(m,1H),4.00(s,3H),3.66(s,3H),3.28-3.25(m,1H),2.49-2.29(m,3H),2.12(s,3H),1.95(s,3H),1.92-1.88(m,2H). MS:(ES)C 33 H 35 FN 5 O 4 [M+H] + The calculated m / z for this compound was 584.3, the measured value was 584.3.

[0122] Example 3: (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl)-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 20) to give the desired product, (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD 3 OD) δ 11.41(s,1H),8.92(s,1H),8.68(s,1H),8.15-8.13(m,1H),7.39-7.21(m,3H),7.20-7.13(m,1H),7.03-6.86(m,3H),4.41(s,2H) ,4.07-4.01(m,1H),4.00(s,3H),3.66(s,3H),3.28-3.25(m,1H),2.49-2.29(m,3H),2.12(s,3H),1.95(s,3H),1.92-1.88(m,2H). MS:(ES)C 33 H 35 FN 5 O 4 [M+H] + The calculated m / z for this compound was 584.3, and the measured value was 584.3.

[0123] Example 4: (S)—N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((methyl(5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl)-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 20) to give the desired product, (S)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((methyl(5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD 3 OD) δ 11.41(s,1H),8.92(s,1H),8.67(s,1H),8.15-8.11(m,1H),7.39-7.23(m ,3H),7.17(dd,J=7.5,1.5Hz,1H),7.02-6.88(m,3H),4.76-4.67(m,1H),4 .27(s,1H),4.09-4.04(m,1H),4.02(s,3H),4.01(s,2H),3.65(s,3H),3.0 7(s,3H),2.97-2.78(m,2H),2.61-2.33(m,2H),2.11(s,3H),1.96(s,3H). MS:(ES)C 34 H 37 FN 5 O 4 [M+H] + The calculated m / z for this compound was 598.3, the measured value was 598.3.

[0124] Example 5: (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((methyl((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl)-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA).2 0) to give the desired product, (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((methyl((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD 3 OD) δ 11.41(s,1H),8.92(s,1H),8.67(s,1H),8.15-8.11(m,1H),7.39-7.23(m ,3H),7.17(dd,J=7.5,1.5Hz,1H),7.02-6.88(m,3H),4.76-4.67(m,1H),4 .27(s,1H),4.09-4.04(m,1H),4.02(s,3H),4.01(s,2H),3.65(s,3H),3.0 7(s,3H),2.97-2.78(m,2H),2.61-2.33(m,2H),2.11(s,3H),1.96(s,3H). MS:(ES)C 34 H 37 FN 5 O 4 [M+H] + The calculated m / z for this compound was 598.3, the measured value was 598.3.

[0125] Example 6: (S)—N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((((1-methyl-5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl)-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, (S)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((((1-methyl-5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD 3 OD) δ 11.41(s,1H),8.92(s,1H),8.68(s,1H),8.13-8.11(m,1H),7.37-7.23( m,3H),7.14-7.12(m,1H),7.01-6.88(m,3H),4.43(s,2H),4.00(s,3H),3 .97-3.92(m,1H),3.66(s,3H),3.49(dd,J=13.0,3.0Hz,1H),3.38-3.22 (m,1H),2.86(s,3H),2.58-2.26(m,3H),2.12(s,3H),2.00-1.91(m,4H). MS:(ES)C 34 H 37 FN 5 O 4 [M+H] + The calculated m / z for this compound was 598.3, the measured value was 598.3.

[0126] Example 7: N-(4″-((((2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)methyl)amino)methyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl)-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(4″-((((2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)methyl)amino)methyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD 3 OD) δ 11.41(s,1H),8.92(s,1H),8.68(s,1H),8.13-8.11(m,1H),7.66(s,1H),7.34-7.22(m,3H),7.20-7.13(m,1H),6.99(d,J= 7.6Hz,1H),6.91(s,1H),6.89-6.81(m,1H),4.34(s,2H),4.01(s,2H),3.98(s,3H),3.66(s,3H),2.11(s,3H),1.93(s,3H). MS:(ES)C 33 H 32 FN 6 O 5 [M+H] + The calculated m / z for this compound is 611.2, the measured value is 611.2.

[0127] Example 8: (S)—N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((6-oxopiperidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl)-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, (S)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((6-oxopiperidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD 3 OD) δ 11.41(s,1H),8.92(s,1H),8.67(s,1H),8.14-8.07(m,1H),7.38-7.21(m,3H),7.20-7.13(m,1H),7.02-6.86(m,3H),4.48-4.35(m,2H) ),4.00(s,3H),3.79-3.71(m,2H),3.66(s,3H),3.25(s,2H),2.50(dd,J=7.6,6.1Hz,2H),2.42-2.35(m,1H),2.11(s,3H),1.94(s,3H). MS:(ES)C 33 H 35 FN 5 O 4 [M+H] + The calculated m / z for this compound was 584.3, the measured value was 584.3.

[0128] Example 9: (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((6-oxopiperidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl)-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((6-oxopiperidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD 3 OD) δ 11.41(s,1H),8.92(s,1H),8.67(s,1H),8.14-8.07(m,1H),7.38-7.21(m,3H),7.20-7.13(m,1H),7.02-6.86(m,3H),4.48-4.35(m,2H) ),4.00(s,3H),3.79-3.71(m,2H),3.66(s,3H),3.25(s,2H),2.50(dd,J=7.6,6.1Hz,2H),2.42-2.35(m,1H),2.11(s,3H),1.94(s,3H). MS:(ES)C 33 H 35 FN 5 O 4 [M+H] + The calculated m / z for this compound was 584.3, the measured value was 584.3.

[0129] Example 10: N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((2-(2-oxopyrrolidin-1-yl)ethyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl)-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((2-(2-oxopyrrolidin-1-yl)ethyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD 3 OD) δ 11.41(s,1H),8.92(s,1H),8.67(s,1H),8.12(m,1H),7.38-7.22(m,3H),7.17(d,J=7.5Hz,1H),7.03-6.84(m,3H),4.38(s,2H) ),3.99(s,3H),3.65(m,5H),3.52(t,J=7.1Hz,2H),2.42(t,J=8.1Hz,2H),2.46-2.39(m,2H),2.14-2.04(m,5H),1.94(s,3H). MS:(ES)C 34 H 37 FN 5 O 4 [M+H] + The calculated m / z for this compound was 598.3, the measured value was 598.3.

[0130] Example 11: N-(4″-(((3-amino-3-oxopropyl)amino)methyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl)-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(4″-(((3-amino-3-oxopropyl)amino)methyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD 3 OD) δ 11.41(s,1H),8.91(s,1H),8.67(s,1H),8.12(m,1H),7.36-7.27(m,3H),7.20-7.13(m,1H),7.03-6.83(m,3H) ),4.35(s,2H),4.00(s,3H),3.66(s,3H),3.37-3.27(m,2H),2.71(t,J=6.2Hz,2H),2.12(s,3H),1.94(s,3H). MS:(ES)C 31 H 33 FN 5 O 4 [M+H] + The calculated m / z is 558.2, the measured value is 558.3.

[0131] Example 12: N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((oxetan-3-ylamino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl)-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((oxetan-3-ylamino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD 3 OD) δ 11.41(s,1H),8.92(s,1H),8.68(m,1H),7.39-7.13(m,4H),7.12-7.03(m,1H),7.03-6.86(m,3H),4.71- 4.63(m,2H),4.54-4.43(m,1H),4.29(m,2H),4.00(s,3H),3.70-3.63(m,5H),2.12(s,3H),1.94(s,3H). MS:(ES)C 31 H 32 FN 4 O 4 [M+H] + The calculated m / z is 543.2, the measured value is 543.3.

[0132] Example 13: N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((tetrahydro-2H-pyran-4-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl)-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((tetrahydro-2H-pyran-4-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.41(s,1H),8.92(s,1H),8.67(s,1H),8.16-8.07(m,1H),7.36-7.24(m,3H),7.20-7.13(m,1H),7.03-6.84(m,3 H),4.35(s,2H),4.06(m,2H),3.99(s,3H),3.66(s,3H),3.51-3.45(m,3H),2.14(m,5H),1.94(s,3H),1.74(m,2H). MS:(ES)C 33 H 36 FN 4 O 4 [M+H] + The calculated m / z for this compound was 571.3, the measured value was 571.3.

[0133] Example 14: N-(3″-fluoro-4″-(((3-hydroxycyclobutyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl)-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-4″-(((3-hydroxycyclobutyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 8.58(dd,J=7.4,2.2Hz,1H),8.15(dd,J=8.2,1.3Hz,1H),8.00(dd,J=6.6,2.2Hz,1H),7.40-7.22(m,3H),7.17(dd,J=7.5,1.5Hz,1H),7.00 -6.86(m,3H),6.62(dd,J=7.4,6.5Hz,1H),4.64-4.49(m,3H),4.47-4.33(m,2H),4.12-3.95(m,5H),3.70(s,3H),2.13(s,3H),1.94(s,3H). MS:(ES)C 32 H 34 FN 4 O 4 [M+H] + The calculated m / z for this compound was 557.3, the measured value was 557.3.

[0134] Example 15: N-(3″-fluoro-4″-((((1S,2R)-2-hydroxycyclopentyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl)-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-4″-((((1S,2R)-2-hydroxycyclopentyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.41(s,1H),8.92(s,1H),8.67(s,1H),8.16-8.07(m,1H),7.38-7.21(m,3H) ,7.16(dd,J=7.5,1.5Hz,1H),7.03-6.96(m,1H),6.94-6.82(m,2H),4.44-4.28 (m,3H),3.98(s,3H),3.66(s,3H),3.53-3.41(m,2H),3.40-3.30(m,1H),3.30 -3.21(m,1H),2.12(s,3H),1.87(s,3H),1.92-1.77(m,2H),1.73-1.65(m,1H). MS:(ES)C 33 H 36 FN 4 O 4 [M+H] + The calculated m / z for this compound was 571.3, the measured value was 571.3.

[0135] Example 16: N-(3″-fluoro-4″-((((1R,2S)-2-hydroxycyclopentyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl)-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-4″-((((1R,2S)-2-hydroxycyclopentyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.41(s,1H),8.92(s,1H),8.67(s,1H),8.16-8.07(m,1H),7.38-7.21(m,3H) ,7.16(dd,J=7.5,1.5Hz,1H),7.03-6.96(m,1H),6.94-6.82(m,2H),4.44-4.28 (m,3H),3.98(s,3H),3.66(s,3H),3.53-3.41(m,2H),3.40-3.30(m,1H),3.30 -3.21(m,1H),2.12(s,3H),1.87(s,3H),1.92-1.77(m,2H),1.73-1.65(m,1H). MS:(ES)C 33 H 36 FN 4 O 4 [M+H] + The calculated m / z for this compound was 571.3, the measured value was 571.3.

[0136] Example 17: N-(3″-fluoro-4″-((((1S,2S)-2-hydroxycyclopentyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl)-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-4″-((((1S,2S)-2-hydroxycyclopentyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.41(s,1H),8.92(s,1H),8.67(s,1H),8.16-8.07(m,1H),7.38-7.21(m,3H) ,7.16(dd,J=7.5,1.5Hz,1H),7.03-6.96(m,1H),6.94-6.82(m,2H),4.44-4.28 (m,3H),3.98(s,3H),3.66(s,3H),3.53-3.41(m,2H),3.40-3.30(m,1H),3.30 -3.21(m,1H),2.12(s,3H),1.87(s,3H),1.92-1.77(m,2H),1.73-1.65(m,1H). MS:(ES)C 33 H 36 FN 4 O 4 [M+H] + The calculated m / z for this compound was 571.3, the measured value was 571.3.

[0137] Example 18: N-(3″-fluoro-4″-((((1R,2R)-2-hydroxycyclopentyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl)-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-4″-((((1R,2R)-2-hydroxycyclopentyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.41(s,1H),8.92(s,1H),8.67(s,1H),8.16-8.07(m,1H),7.38-7.21(m,3H) ,7.16(dd,J=7.5,1.5Hz,1H),7.03-6.96(m,1H),6.94-6.82(m,2H),4.44-4.28 (m,3H),3.98(s,3H),3.66(s,3H),3.53-3.41(m,2H),3.40-3.30(m,1H),3.30 -3.21(m,1H),2.12(s,3H),1.87(s,3H),1.92-1.77(m,2H),1.73-1.65(m,1H). MS:(ES)C 33 H 36 FN 4 O 4 [M+H] + The calculated m / z for this compound was 571.3, the measured value was 571.3.

[0138] Example 19: N-(3″-fluoro-4″-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl)-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-4″-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.41(s,1H),8.92(s,1H),8.68(s,1H),8.14-8.12(m,1H),7.38-7.21( m,3H),7.16(d,J=7.6Hz,1H),6.99(d,J=7.6Hz,1H),6.95-6.83(m,2H), 4.40(d,J=13.2Hz,1H),4.31(d,J=13.2Hz,1H),4.09-3.93(m,6H),3.65 (s,3H),3.60-3.42(m,3H),2.11(s,3H),1.94(s,3H),1.90-1.82(m,1H). MS:(ES)C 33 H 36 FN 4 O 5 [M+H] + The calculated m / z for this compound was 587.3, the measured value was 587.3.

[0139] Example 20: N-(3″-fluoro-4″-(((2-hydroxyethyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl)-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-4″-(((2-hydroxyethyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.42(s,1H),8.92(s,1H),8.68(s,1H),8.11(dd,J=8.1,1.3Hz,1H),7.38-7.22(m,3H),7.20-7.13(m,1H),7.03-6 .83(m,3H),4.37(s,2H),3.99(s,3H),3.88-3.81(m,2H),3.66(s,3H),3.23-3.15(m,2H),2.12(s,3H),1.95(s,3H). MS:(ES)C 30 H 32 FN 4 O 4 [M+H] + The calculated m / z for this compound was 531.2, the measured value was 531.2.

[0140] Example 21: (R)-N-(3″-fluoro-4″-(((1-hydroxypropan-2-yl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl)-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, (R)-N-(3″-fluoro-4″-(((1-hydroxypropan-2-yl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.42(s,1H),8.92(s,1H),8.68(s,1H),8.14-8.07(m,1H),7.38-7.21(m,3H),7.16(dd,J=7.5,1.5Hz,1H),7.03-6.96(m,1H),6.95-6.83( m,2H),4.36(s,2H),3.98(s,3H),3.91-3.82(m,1H),3.69-3.58(m,4H),3.45-3.21(m,1H),2.11(s,3H),1.94(s,3H),1.38(d,J=6.7Hz,3H). MS:(ES)C 31 H 34 FN 4 O 4 [M+H] + The calculated m / z for this compound was 545.3, the measured value was 545.3.

[0141] Example 22: (R)-N-(3″-fluoro-4″-(((2-hydroxypropyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl)-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, (R)-N-(3″-fluoro-4″-(((2-hydroxypropyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.41(s,1H),8.92(s,1H),8.68(s,1H), 8.13-8.10(m,1H),7.38-7.22(m,3H),7.20-7.13(m,1H),7.03-6.83(m,3H),4.36(s,2H),4.13-4.09(m,1H),3. 98(s,3H),3.66(s,3H),3.17-3.08(m,1H),2.94-2.84(m,1H),2.11(s,3H),1.95(s,3H),1.24(d,J=6.3Hz,3H). MS:(ES)C 31 H 34 FN 4 O 4 [M+H] + The calculated m / z for this compound was 545.3, the measured value was 545.3.

[0142] Example 23: N-(3″-fluoro-4″-(((2-hydroxy-2-methylpropyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl)-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-4″-(((2-hydroxy-2-methylpropyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.41(s,1H),8.92(s,1H),8.68(s,1H),8.13-8.10(m,1H),7.38-7.22(m,3H),7.20-7.13(m,1H),7.03- 6.84(m,3H),4.40(s,2H),4.00(s,3H),3.66(s,3H),3.03(s,2H),2.12(s,3H),1.95(s,3H),1.30(s,6H). MS:(ES)C 32 H 36 FN 4 O 4 [M+H] + The calculated m / z for this compound was 559.3, and the measured value was 559.3.

[0143] Example 24: N-(3″-fluoro-4″-((((1-hydroxycyclopropyl)methyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl)-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-4″-((((1-hydroxycyclopropyl)methyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.41(s,1H),8.92(s,1H),8.67(s,1H),8.13-8.10(s,1H),7.38-7.22(m,3H),7.17(dd,J=7.5,1.5Hz,1H),7.03-6.84(m,3 H),4.44(s,2H),3.99(s,3H),3.66(s,3H),3.20(s,2H),2.12(s,3H),1.95(s,3H),0.92(t,J=6.3Hz,2H),0.78-0.70(m,2H). MS:(ES)C 32 H 34 FN 4 O 4 [M+H] + The calculated m / z for this compound was 557.3, and the measured value was 557.3.

[0144] Example 25: N-(3″-fluoro-4″-(((1-hydroxy-2-methylpropan-2-yl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl)-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-4″-(((1-hydroxy-2-methylpropan-2-yl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.41(s,1H),8.92(s,1H),8.68(s,1H),8.13-8.10(d,J=7.6Hz,1H),7.38-7.21(m,3H),7.16(d,J=7.5H) z,1H),6.99-6.82(m,3H),4.30(s,2H),3.98(s,3H),3.67(s,5H),2.12(s,3H),1.94(s,3H),1.42(s,6H). MS:(ES)C 32 H 36 FN 4 O 4 [M+H] + The calculated m / z for this compound was 559.3, and the measured value was 559.3.

[0145] Example 26: N-(3″-fluoro-4″-(((2-hydroxyethyl)(methyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl)-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-4″-(((2-hydroxyethyl)(methyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.42(s,1H),8.92(s,1H),8.67(s,1H),8.15-8.11(m,1H),7.39-7.23(m,3H),7.17(dd,J=7.5,1.5Hz,1H),7.03-6.87(m,3H), 4.62(d,J=13.4Hz,1H),4.43-4.34(m,1H),4.01-3.86(m,5H),3.65(s,3H),3.43(m,2H),2.89(s,3H),2.12(s,3H),1.95(s,3H). MS:(ES)C 31 H 34 FN 4 O 4 [M+H] + The calculated m / z for this compound was 545.3, and the measured value was 545.3.

[0146] Example 27: N-(3″-fluoro-4″-(((2-hydroxy-2-methylpropyl)(methyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl)-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-4″-(((2-hydroxy-2-methylpropyl)(methyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.42(s,1H),8.92(s,1H),8.68(s,1H),8.13-8.11(m,1H),7.39-7.23(m,3H) ,7.18(dd,J=7.5,1.5Hz,1H),7.03-6.87(m,3H),4.85(d,J=13.2Hz,1H),4.39( d,J=13.2Hz,1H),4.00(s,3H),3.66(s,3H),3.42(d,J=13.5Hz,1H),3.26(d,J= 13.5Hz, 1H), 2.93 (s, 3H), 2.12 (s, 3H), 1.96 (s, 3H), 1.40 (s, 3H), 1.36 (s, 3H). MS:(ES)C 33 H 38 FN 4 O 4 [M+H] + The calculated m / z for this compound was 573.3, and the measured value was 573.3.

[0147] Example 28: 1-((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamido)-[1,1':3',1''-terphenyl]-4-yl)methyl)azetidine-3-carboxylic acid [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl)-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, 1-((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamido)-[1,1':3',1''-terphenyl]-4-yl)methyl)azetidine-3-carboxylic acid, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.41(s,1H),8.92(s,1H),8.67(s,1H),8.15-8.11(m,1H),7.36-7.25(m,3H),7.17(ddd,J=7.5,1.5,0.5Hz,1H),7.02 -6.85(m,3H),4.57(s,2H),4.43-4.41(m,4H),3.99(s,3H),3.73-3.68(m,1H),3.66(s,3H),2.11(s,3H),1.94(s,3H). MS:(ES)C 32 H 32 FN 4 O 5 [M+H] + The calculated m / z for this compound was 571.3, and the measured value was 571.3.

[0148] Example 29: ((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamido)-[1,1':3',1''-terphenyl]-4-yl)methyl)glycine [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl)-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, ((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamido)-[1,1':3',1''-terphenyl]-4-yl)methyl)glycine, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.42(s,1H),8.92(s,1H),8.68(s,1H),8.14-8.11(m,1H),7.36-7.25(m,3H),7.17(dd,J=7.4,1.5Hz, 1H),7.03-6.84(m,3H),4.42(s,2H),3.99(s,3H),3.93(s,2H),3.66(s,3H),2.12(s,3H),1.95(s,3H). MS:(ES)C 30 H 30 FN 4 O 5 [M+H] + The calculated m / z was 545.2, and the measured value was 545.3.

[0149] Example 30: N-(3″-fluoro-4″-(((2-hydroxyethyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl)-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-4″-(((2-hydroxyethyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 8.58(dd,J=7.4,2.1Hz,1H),8.19-8.10(m,1H),8.00(dd,J=6.6,2.1Hz,1H),7.38-7.21(m,3H),7.17(dd,J=7.5,1.5Hz,1H),7.01-6. 83(m,3H),6.66-6.57(m,1H),4.37(s,2H),3.99(s,3H),3.88-3.81(m,2H),3.71(s,3H),3.23-3.15(m,2H),2.13(s,3H),1.95(s,3H). MS:(ES)C 31 H 33 FN 3 O 4 [M+H] + The calculated m / z for this compound was 530.2, and the measured value was 530.2.

[0150] Example 31: N-(3″-fluoro-4″-(((2-hydroxy-2-methylpropyl)amino)methyl)-5″-methoxy-2,2′-dimethyl[-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl)-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-4″-(((2-hydroxy-2-methylpropyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 8.58(dd,J=7.4,2.2Hz,1H),8.19-8.10(m,1H),8.00(ddd,J=6.5,2.1,0.4Hz,1H),7.38-7.22(m,3H),7.17(ddd,J=7.5,1.5,0.5Hz,1H),7.01 -6.84(m,3H),6.62(ddd,J=7.4,6.5,0.8Hz,1H),4.39(s,2H),4.00(s,3H),3.71(s,3H),3.04(s,2H),2.14(s,3H),1.96(s,3H),1.31(s,6H). MS:(ES)C 33 H 37 FN 3 O 4 [M+H] + The calculated m / z for this compound was 558.3, and the measured value was 558.3.

[0151] Example 32: 1-((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamido)-[1,1':3',1''-terphenyl]-4-yl)methyl)azetidine-3-carboxylic acid [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl)-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, 1-((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamido)-[1,1':3',1''-terphenyl]-4-yl)methyl)azetidine-3-carboxylic acid, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 8.60(dd,J=7.3,2.1Hz,1H),8.17-8.15(m,1H),8.01(dd,J=6.5,2.1Hz,1H),7.37-7.25(m,3H),7.18(d,J=7.5Hz,1H),6.9 9-6.81(m,3H),6.62(t,J=6.9Hz,1H),4.57(s,2H),4.43-4.41(m,4H),3.99(s,3H),3.71(m,4H),2.13(s,3H),1.95(s,3H). MS:(ES)C 33 H 33 FN 3 O 5 [M+H] + The calculated m / z was 570.2, and the measured value was 570.3.

[0152] Example 33: ((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamido)-[1,1':3',1''-terphenyl]-4-yl)methyl)glycine [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl)-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, ((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamido)-[1,1':3',1''-terphenyl]-4-yl)methyl)glycine, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 8.58(dd,J=7.4,2.2Hz,1H),8.19-8.10(m,1H),8.02-7.99(m,1H),7.38-7.22(m,3H),7.18-7.16(m,1H),7.01- 6.84(m,3H),6.64-6.61(m,1H),4.42(s,2H),3.99(s,3H),3.93(s,2H),3.71(s,3H),2.14(s,3H),1.95(s,3H). MS:(ES)C 31 H 31 FN 3 O 5 [M+H] + The calculated m / z was 544.2, and the measured value was 544.3.

[0153] Example 34: (S)—N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((5-oxopyrrolidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, (S)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((5-oxopyrrolidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.16(s,1H),8.42(s,1H),8.07-8.05(m,1H),7.38-7.21(m,3H),7.16(dd,J=7 .5,1.5Hz,1H),7.00-6.85(m,3H),4.37(s,2H),4.26-4.21(m,1H),4.00(s,3H), 3.88(dd,J=11.6,7.6Hz,1H),3.57(dd,J=11.6,3.9Hz,1H),3.35(m,3H),2.91( dd,J=17.8,8.8Hz,1H),2.55(dd,J=17.8,4.7Hz,1H),2.10(s,3H),1.94(s,3H). MS:(ES)C 32 H 33 FN 5 O 5 [M+H] + The calculated m / z was 586.2, and the measured value was 586.3.

[0154] Example 35: (S)—N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((methyl((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, (S)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((methyl((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.15(s,1H),8.41(s,1H),8.09-8.05(m,1H),7.36-7.24(m,3H),7.16(dd,J=7.6,1.5Hz,1H),7.01-6.87(m,3H),4.74-4.68(m,1H),4 .08-4.03(m,1H),4.02(s,3H),4.00(s,2H),3.35(s,3H),3.06(s,3H),2.95-2.80(m,2H),2.60-2.32(m,3H),2.10(s,3H),1.95(s,3H). MS:(ES)C 34 H 37 FN 5 O 5 [M+H] + The calculated m / z for this compound was 614.3, and the measured value was 614.3.

[0155] Example 36: (S)—N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((6-oxopiperidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, (S)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((6-oxopiperidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.16(s,1H),8.41(s,1H),8.07-8.05(m,1H),7.36-7.24(m,3H),7.16(d,J=7.9Hz,1H),7.00-6.86(m,3H),4.48-4.35(m,2H),4.0 0(s,3H),3.77-3.74(m,2H),3.52-3.41(m,1H),3.36(s,3H),2.50-2.49(m,2H),2.42-2.38(m,1H),2.14-2.04(m,4H),1.94(s,3H). MS:(ES)C 33 H 35 FN 5 O 5 [M+H] + The calculated m / z was 600.3, and the measured value was 600.3.

[0156] Example 37: (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((6-oxopiperidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((6-oxopiperidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.16(s,1H),8.41(s,1H),8.07-8.05(m,1H),7.36-7.24(m,3H),7.16(d,J=7.9Hz,1H),7.00-6.86(m,3H),4.48-4.35(m,2H),4.0 0(s,3H),3.77-3.74(m,2H),3.52-3.41(m,1H),3.36(s,3H),2.50-2.49(m,2H),2.42-2.38(m,1H),2.14-2.04(m,4H),1.94(s,3H). MS:(ES)C 33 H 35 FN 5 O 5 [M+H] + The calculated m / z was 600.3, and the measured value was 600.3.

[0157] Example 38: N-(4″-(((3-amino-2,2-dimethyl-3-oxopropyl)amino)methyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(4″-(((3-amino-2,2-dimethyl-3-oxopropyl)amino)methyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.16(s,1H),8.42(s,1H),8.07-8.05(m,1H),7.38-7.22(m,3H),7.19-7.12(m,1H),7.01-6.91(m,2H),6.87 (d,J=9.9Hz,1H),4.34(s,2H),4.01(s,3H),3.36(s,3H),3.14(s,2H),2.10(s,3H),1.94(s,3H),1.34(s,6H). MS:(ES)C 33 H 37 FN 5 O 5 [M+H] + The calculated m / z for this compound was 602.3, and the measured value was 602.3.

[0158] Example 39: (S)—N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((tetrahydrofuran-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, (S)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((tetrahydrofuran-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.15(s,1H),8.41(s,1H),8.09-8.05(m,1H),7.37-7.24(m,3H),7.19-7.12(m,1H),6.98-6.87(m,3H),4.34(s,2H),4.07(d,J=9.7Hz,2H ),3.98(s,3H),3.90-3.82(m,1H),3.77-3.71(m,1H),3.34(s,3H),2.50-2.41(m,1H),2.15-2.10(m,1H),2.16-2.07(m,4H),1.94(s,3H). MS:(ES)C 32 H 34 FN 4 O 5 [M+H] + The calculated m / z was 573.2, and the measured value was 573.3.

[0159] Example 40: (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((tetrahydrofuran-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((tetrahydrofuran-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.15(s,1H),8.41(s,1H),8.09-8.05(m,1H),7.37-7.24(m,3H),7.19-7.12(m,1H),6.98-6.87(m,3H),4.34(s,2H),4.07(d,J=9.7Hz,2H ),3.98(s,3H),3.90-3.82(m,1H),3.77-3.71(m,1H),3.34(s,3H),2.50-2.41(m,1H),2.15-2.10(m,1H),2.16-2.07(m,4H),1.94(s,3H). MS:(ES)C 32 H 34 FN 4 O 5 [M+H] + The calculated m / z for is 573.2, the actual Value 573.3.

[0160] Example 41: N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((tetrahydro-2H-pyran-4-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((tetrahydro-2H-pyran-4-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.15(s,1H),8.41(s,1H),8.09-8.05(m,1H),7.37-7.20(m,3H),7.15(dd,J=7.6,1.6Hz,1H),6.96-6.86(m,3H),4.34(s,2H) ),4.10-4.01(m,2H),3.98(s,3H),3.55-3.41(m,3H),3.34(s,3H),2.18-2.11(m,2H),2.10(s,3H),1.93(s,3H),1.73(m,2H). MS:(ES)C 33 H 36 FN 4 O 5 [M+H] + The calculated m / z for this compound was 587.3, and the measured value was 587.3.

[0161] Example 42: N-(3″-fluoro-4″-((((1R,2S)-2-hydroxycyclopentyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-4″-((((1R,2S)-2-hydroxycyclopentyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.16(s,1H),8.42(s,1H),8.07-8.05(m,1H),7.38-7.21(m,3H),7.17-7.15(m,1H),7.01-6.82(m,3H),4.42-4. 30(m,3H),3.98(s,3H),3.53-3.43(m,1H),3.36(s,3H),2.18-2.05(m,5H),2.06-1.61(m,6H),1.40-1.32(m,1H). MS:(ES)C 33 H 36 FN 4 O 5 [M+H] + The calculated m / z for this compound was 587.3, and the measured value was 587.3.

[0162] Example 43: (R)-N-(3″-fluoro-4″-(((2-hydroxypropyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, (R)-N-(3″-fluoro-4″-(((2-hydroxypropyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.16(s,1H),8.42(s,1H),8.07-8.05(m,1H),7.38-7.21(m,3H),7.19-7.12(m,1H),7.01-6.83(m,3H),4.36(s,2H),4.14-4 .04(m,1H),3.98(s,3H),3.36(s,3H),3.16-3.08(m,1H),2.93-2.88(m,1H),2.10(s,3H),1.95(s,3H),1.24(d,J=6.3Hz,3H). MS:(ES)C 31 H 34 FN 4 O 5 [M+H] + The calculated m / z was 561.2, and the measured value was 561.3.

[0163] Example 44: N-(3″-fluoro-4″-(((2-hydroxy-2-methylpropyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-4″-(((2-hydroxy-2-methylpropyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.14(s,1H),8.43(s,1H),8.04-8.02(m,1H),7.37-7.25(m,3H),7.17-7.15(m,1H),6.99-6.86(m ,3H),4.40(s,2H),3.99(s,3H),3.36(s,3H),3.04(s,2H),2.10(s,3H),1.94(s,3H),1.31(s,6H). MS:(ES)C 32 H 36 FN 4 O 5 [M+H] + The calculated m / z for this compound was 575.3, and the measured value was 575.3.

[0164] Example 45: N-(4″-(((3-amino-2,2-dimethyl-3-oxopropyl)amino)methyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(4″-(((3-amino-2,2-dimethyl-3-oxopropyl)amino)methyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.16(s,1H),8.63(s,1H),8.09-8.05(m,1H),7.36-7.25(m,3H),7.17-7.15(m,1H),6.98-6.86(m,3H), 4.34(s,2H),4.02(s,3H),3.55(s,3H),3.39(s,3H),3.15(s,2H),2.10(s,3H),1.94(s,3H),1.35(s,6H). MS:(ES)C 34 H 39 FN 5 O 5 [M+H] + The calculated m / z for this compound was 616.3, and the measured value was 616.3.

[0165] Example 46: (S)—N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((tetrahydrofuran-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, (S)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((tetrahydrofuran-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.16(s,1H),8.62(s,1H),8.09-8.06(m,1H),7.36-7.21(m,3H),7.17-7.15(m,1H),6.98-6.87(m,3H),4.34(s,2H),4.10-4.03(m,2) H),3.98(s,4H),3.89-3.82(m,1H),3.78-3.71(m,1H),3.54(s,3H),3.37(s,3H),2.48-2.38(m,1H),2.15-2.10(m,4H),1.93(s,3H). MS:(ES)C 33 H 36 FN 4 O 5 [M+H] + The calculated m / z for this compound was 587.3, and the measured value was 587.3.

[0166] Example 47: (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((tetrahydrofuran-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((tetrahydrofuran-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.16(s,1H),8.62(s,1H),8.09-8.06(m,1H),7.36-7.21(m,3H),7.17-7.15(m,1H),6.98-6.87(m,3H),4.34(s,2H),4.10-4.03(m,2) H),3.98(s,4H),3.89-3.82(m,1H),3.78-3.71(m,1H),3.54(s,3H),3.37(s,3H),2.48-2.38(m,1H),2.15-2.10(m,4H),1.93(s,3H). MS:(ES)C 33 H 36 FN 4 O 5 [M+H] + The calculated m / z for this compound was 587.3, and the measured value was 587.3.

[0167] Example 48: N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((tetrahydro-2H-pyran-4-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((tetrahydro-2H-pyran-4-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.17(s,1H),8.63(s,1H),8.09-8.05(m,1H),7.36-7.24(m,3H),7.16(d,J=7.5Hz,1H),7.00-6.84(m,3H),4.36(s,2H),4.0 9-4.05(m,2H),3.99(s,3H),3.56(s,3H),3.51-3.43(m,3H),3.38(s,3H),2.18-2.10(m,5H),1.93(s,3H),1.77-1.69(m,2H). MS:(ES)C 34 H 38 FN 4 O 5 [M+H] + The calculated m / z for this compound was 601.3, and the measured value was 601.3.

[0168] Example 49: N-(3″-fluoro-4″-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-4″-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.17(s,1H),8.63(s,1H),8.10-8.06(m,1H),7.36-7.24(m,3H),7.19-7.12(m,1H),7.00-6.82(m,3H),4.43-4.29(m,2 H),4.10-3.95(m,6H),3.61-3.40(m,6H),3.37(s,3H),2.15-2.10(m,1H),2.09(s,3H),1.93(s,3H),1.91-1.82(m,1H). MS:(ES)C 34 H 38 FN 4 O 6 [M+H] + The calculated m / z was 617.3, and the measured value was 618.3.

[0169] Example 50: N-(4″-(((3-amino-2,2-dimethyl-3-oxopropyl)amino)methyl)-2′,3″-difluoro-5″-methoxy-2-methyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] Using a procedure similar to that described in step c of Example 1, the product was prepared from N-(2',3''-difluoro-4''-formyl-5''-methoxy-2-methyl-[1,1':3',1''-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(4″-(((3-amino-2,2-dimethyl-3-oxopropyl)amino)methyl)-2′,3″-difluoro-5″-methoxy-2-methyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.19(s,1H),8.63(s,1H),8.14-8.12(m,1H),7.62-7.57(m,1H),7.42-7.29(m,3H),7.15-7.09(m ,3H),4.34(s,2H),4.04(s,3H),3.56(s,3H),3.39(s,3H),3.13(s,2H),2.20(s,3H),1.34(s,6H). MS:(ES)C 33 H 36 F 2 N 5 O 5 [M+H] + The calculated m / z for this compound was 620.3, and the measured value was 620.3.

[0170] Example 51: (S)—N-(2′,3″-difluoro-5″-methoxy-2-methyl-4″-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] Using a procedure similar to that described in step c of Example 1, the product was prepared from N-(2',3''-difluoro-4''-formyl-5''-methoxy-2-methyl-[1,1':3',1''-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, (S)-N-(2',3''-difluoro-5''-methoxy-2-methyl-4''-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1':3',1''-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.19(s,1H),8.63(s,1H),8.12(t,J=7.5Hz,1H),7.61-7.57(m,1H),7.42-7.29(m,3H),7.17-7.08(m,3H),4.40(s,2H),4.0 8-4.02(m,1H),4.02(s,3H),3.55(s,3H),3.38(s,3H),3.27-3.22(m,2H),2.46-2.34(m,3H),2.20(s,3H),1.96-1.88(m,1H). MS:(ES)C 33 H 34 F 2 N 5 O 5 [M+H] + The calculated m / z was 618.2, and the measured value was 618.3.

[0171] Example 52: (S)—N-(2′,3″-difluoro-5″-methoxy-2-methyl-4″-(((5-oxopyrrolidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] Using a procedure similar to that described in step c of Example 1, the product was prepared from N-(2',3''-difluoro-4''-formyl-5''-methoxy-2-methyl-[1,1':3',1''-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, (S)-N-(2',3''-difluoro-5''-methoxy-2-methyl-4''-(((5-oxopyrrolidin-3-yl)amino)methyl)-[1,1':3',1''-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.18(s,1H),8.63(s,1H),8.12(t,J=7.6Hz,1H),7.61-7.57(m,1H),7.42-7.29(m,3H),7.17-7.08(m,3H),4.37(s,2H),4.28-4.16(m ,1H),4.03(s,3H),3.90-3.82(m,1H),3.60-3.55(m,1H),3.54(s,3H),3.39(s,3H),2.95-2.86(m,1H),2.59-2.52(m,1H),2.20(s,3H). MS:(ES)C 32 H 32 F 2 N 5 O 5 [M+H] + The calculated m / z is 604.2, and the measured value is 604.3.

[0172] Example 53: (S)—N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((((1-methyl-5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide [ka] Using a procedure similar to that described in step c of Example 1, the product was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, (S)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((((1-methyl-5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.08(s,1H),8.10-8.06(m,1H),7.35-7.26(m,3H),7.17(d,J=7.6Hz,1H),7.02( d,J=7.8Hz,1H),6.98-6.86(m,2H),4.44(s,2H),4.01(s,3H),3.99-3.93(m,1H),3 .77(s,3H),3.48(d,J=12.7Hz,1H),3.38(s,3H),3.30(s,3H),3.28-3.22(m,1H),2 .85(s,2H),2.56-2.47(m,1H),2.44-2.30(m,2H),2.00-1.92(m,4H),1.95(s,3H). MS:(ES)C 34 H 38 FN 6 O 5 [M+H] + The calculated m / z for this compound was 629.3, and the measured value was 629.3.

[0173] Example 54: (R)-3-(((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-yl)methyl)amino)pyrrolidin-2-one [ka] The product was prepared from 3-fluoro-5-methoxy-2',2''-dimethyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-carbaldehyde using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, (R)-3-(((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-yl)methyl)amino)pyrrolidin-2-one, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 9.24(s,1H),9.05(s,1H),7.79(d,J=7.1Hz,1H),7.64-7.49(m,3H),7.4 1-7.32(m,2H),7.33-7.20(m,2H),6.96-6.84(m,2H),4.63(d,J=13.1Hz, 1H),4.39(d,J=13.2Hz,1H),4.26-4.17(m,1H),3.98(s,3H),3.49-3.40 (m,2H),2.68-2.59(m,1H),2.28-2.18(m,1H),2.10(s,3H),2.02(s,3H). MS:(ES)C 33 H 32 FN 6 O 2 [M+H] + The calculated m / z for this compound was 563.3, and the measured value was 563.3.

[0174] Example 55: (S)-3-(((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-yl)methyl)amino)pyrrolidin-2-one [ka] The product was prepared from 3-fluoro-5-methoxy-2',2''-dimethyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-carbaldehyde using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, (S)-3-(((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-yl)methyl)amino)pyrrolidin-2-one, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 9.24(s,1H),9.05(s,1H),7.79(d,J=7.1Hz,1H),7.64-7.49(m,3H),7.4 1-7.32(m,2H),7.33-7.20(m,2H),6.96-6.84(m,2H),4.63(d,J=13.1Hz, 1H),4.39(d,J=13.2Hz,1H),4.26-4.17(m,1H),3.98(s,3H),3.49-3.40 (m,2H),2.68-2.59(m,1H),2.28-2.18(m,1H),2.10(s,3H),2.02(s,3H). MS:(ES)C 33 H 32 FN 6 O 2 [M+H] + The calculated m / z for this compound was 563.3, and the measured value was 563.3.

[0175] Example 56: 5-((((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-yl)methyl)amino)methyl)pyrimidine-2,4(1H,3H)-dione [ka] The product was prepared from 3-fluoro-5-methoxy-2',2''-dimethyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-carbaldehyde using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 3O) to give the desired product, 5-((((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-yl)methyl)amino)methyl)pyrimidine-2,4(1H,3H)-dione, as a white solid. MS: (ES) C 34 H 31 FN 7 O 3 [M+H] + The calculated m / z for this compound was 604.2, and the measured value was 604.2.

[0176] Example 57: 1-(2-(((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-yl)methyl)amino)ethyl)pyrrolidin-2-one [ka] The product was prepared from 3-fluoro-5-methoxy-2',2''-dimethyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-carbaldehyde using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, 1-(2-(((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-yl)methyl)amino)ethyl)pyrrolidin-2-one, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 9.25(d,J=2.0Hz,1H),9.05(d,J=2.0Hz,1H),7.79(d,J=7.2Hz,1H),7.6 4-7.49(m,2H),7.40-7.35(m,3H),7.30-7.22(m,2H),6.97-6.84(m,2H), 4.39(s,2H),3.99(s,3H),3.66(t,J=5.8Hz,2H),3.53(t,J=5.8Hz,2H),3 .37-3.27(m,3H),2.42(t,J=8.1Hz,2H),2.17-2.04(m,4H),2.02(s,3H). MS:(ES)C 35 H 36 FN 6 O 2 [M+H] + The calculated m / z was 591.3, and the measured value was 592.3.

[0177] Example 58: N-(4″-((((1H-pyrrol-2-yl)methyl)amino)methyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)pyrido[3,4-b]pyrazin-5-amine [ka] The product was prepared from 3-fluoro-5-methoxy-2',2''-dimethyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-carbaldehyde using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(4''-((((1H-pyrrol-2-yl)methyl)amino)methyl)-3''-fluoro-5''-methoxy-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)pyrido[3,4-b]pyrazin-5-amine, as a white solid. MS: (ES) C 34 H 32 FN 6 O[M+H] + The calculated m / z for this compound was 559.3, and the measured value was 559.3.

[0178] Example 59: 3-(((2',3-difluoro-5-methoxy-2''-methyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-yl)methyl)amino)-2,2-dimethylpropanamide [ka] The product was prepared from 2',3-difluoro-5-methoxy-2''-methyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-carbaldehyde using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, 3-(((2',3-difluoro-5-methoxy-2''-methyl-3''-(pyrido[3,4-b'']pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-yl)methyl)amino)-2,2-dimethylpropanamide, as a white solid. 1 H NMR (400MHz, CD 3OD) δ 9.22(s,1H), 9.04(s,1H),7.83-7.82(m,1H),7.63-7.45(m,3H),7.44-7.28(m,4H),7.10-7 .00(m,2H),4.34(s,2H),4.04(s,3H),3.13(s,2H),2.29(s,3H),1.34(s,6H). MS:(ES)C 33 H 33 F 2 N 6 O 2 [M+H] + The calculated m / z was 583.3, and the measured value was 583.3.

[0179] Example 60: (S)-5-((((2',3-difluoro-5-methoxy-2''-methyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-yl)methyl)amino)methyl)pyrrolidin-2-one [ka] The product was prepared from 2',3-difluoro-5-methoxy-2''-methyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-carbaldehyde using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, (S)-5-((((2',3-difluoro-5-methoxy-2''-methyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-yl)methyl)amino)methyl)pyrrolidin-2-one, as a white solid. 1 H NMR (400MHz, CD 3OD) δ 9.24(s,1H),9.05(s,1H),7.81(d,J=7.1Hz,1H),7.68-7.37(m,7H),7.17-7.12(m,2H),4.41(s ,2H),4.06-4.03(m,4H),3.27-3.23(m,2H),2.44-2.32(m,3H),2.23(s,3H),1.94-1.89(m,1H). MS:(ES)C 33 H 31 F 2 N 6 O 2 [M+H] + The calculated m / z was 581.2, and the measured value was 581.3.

[0180] Example 61: 1-((3-fluoro-3″-(isoquinolin-1-ylamino)-5-methoxy-2′,2″-dimethyl-[1,1′:3′,1″-terphenyl]-4-yl)methyl)azetidine-3-carboxylic acid [ka] The product was prepared from 3-fluoro-3″-(isoquinolin-1-ylamino)-5-methoxy-2′,2″-dimethyl-[1,1′:3′,1″-terphenyl]-4-carbaldehyde using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, 1-((3-fluoro-3″-(isoquinolin-1-ylamino)-5-methoxy-2′,2″-dimethyl-[1,1′:3′,1″-terphenyl]-4-yl)methyl)azetidine-3-carboxylic acid, as a white solid. 1 H NMR (400MHz, CD 3OD) δ 8.67-8.63(m,1H),8.11-7.99(m,2H),7.93-7.89(m,1H),7.61-7.45(m,3H),7.44-7.22(m,5H),6.97-6 .86(m,2H),4.56(s,2H),4.43-4.41(m,4H),3.98(s,3H),3.73-3.68(m,1H),2.07(s,3H),2.03(s,3H). MS:(ES)C 35 H 33 FN 3 O 3 [M+H] + The calculated m / z was 562.2, and the measured value was 562.3.

[0181] Example 62: 1-((3″-((1,6-naphthyridin-8-yl)amino)-3-fluoro-5-methoxy-2′,2″-dimethyl-[1,1′:3′,1″-terphenyl]-4-yl)methyl)azetidine-3-carboxylic acid [ka] The product was prepared from 3″-((1,6-naphthyridin-8-yl)amino)-3-fluoro-5-methoxy-2′,2″-dimethyl-[1,1′:3′,1″-terphenyl]-4-carbaldehyde using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, 1-((3″-((1,6-naphthyridin-8-yl)amino)-3-fluoro-5-methoxy-2′,2″-dimethyl-[1,1′:3′,1″-terphenyl]-4-yl)methyl)azetidine-3-carboxylic acid, as a white solid. 1 H NMR (400MHz, CD 3OD) δ 9.34(dd,J=4.3,1.7Hz,1H),8.92(s,1H),8.72(dd,J=8.4,1.7Hz,1H),7.97(dd,J=8.4,4.3Hz,1H),7.73(s,1H),7.55-7.32(m,3H) ,7.31-7.16(m,3H),6.97-6.86(m,2H),4.56(s,2H),4.43-4.40(m,4H),3.98(s,3H),3.75-3.65(m,1H),2.08(s,3H),2.01(s,3H). MS:(ES)C 34 H 32 FN 4 O 3 [M+H] + The calculated m / z was 563.2, and the measured value was 563.3.

[0182] Example 63: 1-((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(quinoxalin-5-ylamino)-[1,1':3',1''-terphenyl]-4-yl)methyl)azetidine-3-carboxylic acid [ka] The product was prepared from 3-fluoro-5-methoxy-2',2''-dimethyl-3''-(quinoxalin-5-ylamino)-[1,1':3',1''-terphenyl]-4-carbaldehyde using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, 1-((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(quinoxalin-5-ylamino)-[1,1':3',1''-terphenyl]-4-yl)methyl)azetidine-3-carboxylic acid, as a white solid. 1 H NMR (400MHz, CD 3OD) δ 8.87(s,1H),8.82(s,1H),7.64-7.62(m,1H),7.50(dd,J=7.9,1.4Hz,1H),7.41-7.29(m,3H),7.25-7.21(m,2H) ,7.04-6.86(m,4H),4.57(s,2H),4.46-4.39(m,4H),3.99(s,3H),3.74-3.66(m,1H),2.05(s,3H),2.01(s,3H). MS:(ES)C 34 H 32 FN 4 O 3 [M+H] + The calculated m / z was 563.2, and the measured value was 563.3.

[0183] Example 64: 1-((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(quinazolin-8-ylamino)-[1,1':3',1''-terphenyl]-4-yl)methyl)azetidine-3-carboxylic acid [ka] The product was prepared from 3-fluoro-5-methoxy-2',2''-dimethyl-3''-(quinazolin-8-ylamino)-[1,1':3',1''-terphenyl]-4-carbaldehyde using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, 1-((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(quinazolin-8-ylamino)-[1,1':3',1''-terphenyl]-4-yl)methyl)azetidine-3-carboxylic acid, as a white solid. 1 H NMR (400MHz, CD 3OD) δ 9.41(s,1H),9.20(s,1H),7.58-7.46(m,2H),7.45-7.29(m,3H),7.29-7.09(m,3H),7.01(dd,J=7.4,1.3Hz,1H) ,6.97-6.85(m,2H),4.51(s,2H),4.43-4.28(m,4H),3.98(s,3H),3.52-3.44(m,1H),2.05(s,3H),2.00(s,3H). MS:(ES)C 34 H 32 FN 4 O 3 [M+H] + The calculated m / z was 563.2, and the measured value was 563.3.

[0184] Example 65: 1-((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(pyrido[3,2-d]pyrimidin-4-ylamino)-[1,1':3',1''-terphenyl]-4-yl)methyl)azetidine-3-carboxylic acid [ka] The product was prepared from 3-fluoro-5-methoxy-2',2''-dimethyl-3''-(pyrido[3,2-d]pyrimidin-4-ylamino)-[1,1':3',1''-terphenyl]-4-carbaldehyde using a procedure similar to that described in step c of Example 1. The resulting compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, 1-((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(pyrido[3,2-d]pyrimidin-4-ylamino)-[1,1':3',1''-terphenyl]-4-yl)methyl)azetidine-3-carboxylic acid, as a white solid. MS: (ES) C 33 H 31 FN 5 O 3 [M+H] + The calculated m / z for this compound was 564.2, and the measured value was 564.2.

[0185] Example 66: (S)—N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((methyl(5-oxopyrrolidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide [ka] Step d: To a stirred solution of 3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-"1,1'-biphenyl]-4-carbaldehyde (75 mg, 0.203 mmol) and (S)-4-aminopyrrolidin-2-one (41 mg, 0.406 mmol) in MeOH:DCE (2 mL) was added NaBH(OAc) 3 (86 mg, 0.406 mmol) and AcOH (5 drops) were added. The reaction mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and the residue was purified by silica gel flash chromatography (0% to 20% MeOH / DCM) to give a yellow solid of (S)-4-(((3-fluoro-5-methoxy-2'-methyl)-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)amino)pyrrolidin-2-one. MS: (ES) C 25 H 33 BFN 2 O 4 [M+H] + The calculated m / z was 455.2, and the measured value was 455.3.

[0186] Step e: To a stirred solution of (S)-4-(((3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)amino)pyrrolidin-2-one (86 mg, 0.189 mmol) and 37% aqueous paraformaldehyde (78 μL) in MeOH:DCE (2 mL), was added NaBH(OAc) 3(201 mg, 0.945 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the residue was purified by silica gel flash chromatography (0% to 20% MeOH / DCM) to give a yellow solid of (S)-4-(((3-fluoro-5-methoxy-2'-methyl)-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)pyrrolidin-2-one. MS: (ES) C 26 H 35 BFN 2 O 4 [M+H] + The calculated m / z for this compound was 469.3, and the measured value was 469.3.

[0187] Step f: (S)-4-(((3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl"-4-yl)methyl)(methyl)amino)pyrrolidin-2-one (78 mg, 0.167 mmol), N-(3-bromo-2-methylphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide (54 mg, 0.167 mmol) and 2M K 2 CO 3 A mixture of (0.25 mL, 0.501 mmol) in p-dioxane (5 mL) was added to dichloromethane and Pd(dppf)Cl 2 The complex of 1H 2 O (20 mg, 0.022 mmol) was added. The reaction mixture was degassed (N 2 ) and N 2 The reaction mixture was stirred at 95 °C for 5 h under 5% CO. The reaction mixture was diluted with EtOAc, filtered through Celite, washed with brine, and washed with MgSO. 4 The solvent was removed under reduced pressure and the residue was purified by silica gel flash chromatography (0% to 20% methanol / dichloromethane) followed by HPLC (MeCN / H2O with 0.1% TFA). 20) to give (S)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((methyl(5-oxopyrrolidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 8.92(s,1H),8.67(s,1H),8.15-8.11(m,1H),7.39-7.23(m,3H),7.17(dd,J=7.7,1.7Hz,1H),7.03-6.90(m,3H),4.47(s,2H),4.39(d,J =7.4Hz,1H),4.01(s,3H),3.96-3.87(m,1H),3.78-3.71(m,1H),3.65(s,3H),2.91(s,3H),2.85-2.74(m,1H),2.12(s,3H),1.96(s,3H). MS:(ES)C 33 H 35 FN 5 O 4 [M+H] + The calculated m / z for this compound was 584.3, and the measured value was 584.3.

[0188] Example 67: (S)—N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((methyl(5-oxopyrrolidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyrimidine-3-carboxamide [ka] The product was prepared from N-(3-bromo-2-methylphenyl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide using a procedure similar to that described in step f of Example 66. The resulting compound was purified by HPLC (MeCN / H 20) to give the desired product, (S)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((methyl(5-oxopyrrolidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyrimidine-3-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 12.19(s,1H),8.60(dd,J=7.3,2.0Hz,1H),8.17-8.14(m,1H),8.02-8.0 0(m,1H),7.38-7.24(m,3H),7.19(dd,J=7.6,1.6Hz,1H),7.00-6.94(m,3 H),4.48-4.40(m,3H),4.01(s,3H),3.95-3.85(m,1H),3.77-3.73(m,2H) ,3.70(s,3H),2.90(s,3H),2.82-2.78(m,1H),2.13(s,3H),1.95(s,3H). MS:(ES)C 34 H 36 FN 4 O 4 [M+H] + The calculated m / z was 583.3, and the measured value was 583.3. Example 68: N-(4″-(aminomethyl)-3″-fluoro-5″-methoxy-2,2″-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyrimidine-3-carboxamide [ka]

[0189] Step a: To a solution of 1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (0.36 g, 2.35 mmol), 3-bromo-2-methylaniline (0.43 g, 2.35 mmol) in DMF (5.0 mL) was added HATU (1.34 g, 3.52 mmol) and diisopropylethylamine (0.75 g, 5.87 mmol). The reaction was stirred at room temperature for 16 hours. After completion of the reaction, half of the solvent was removed and the mixture was diluted with water (15 ml) and stirred for 20 minutes. The resulting solid was filtered through a plastic funnel, washed with water (10 ml) and dried under vacuum.

[0190] Step b: N-(3-bromo-2-methylphenyl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (100 mg, 0.31 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 (146 mg, 0.31 mmol) and 2M K 2 CO 3 (0.38 mL, 0.77 mmol) in p-dioxane (3 mL) with dichloromethane and Pd(dppf)Cl 2 (26 mg, 0.032 mmol) was added. The reaction mixture was degassed (N 2 ) and N 2 The reaction mixture was stirred at 95 °C for 4 h under reduced pressure, and the mixture was diluted with EtOAc, filtered through Celite, washed with brine, and diluted with MgSO 4 The solvent was removed under reduced pressure and the residue was purified by silica gel flash chromatography (5-20%-40% EtOAc / Hexanes) to give tert-butyl ((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamido)-[1,1':3',1''-terphenyl]-4-yl)carbamate. MS: (ES) C 33 H 37 FN 3 O 5 [M+H] +The calculated m / z was 586.3, and the measured value was 586.2.

[0191] Step c: To a stirred solution of tert-butyl ((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamido)-[1,1':3',1''-terphenyl]-4-yl)carbamate (75 mg, 0.123 mmol) in anhydrous dichloromethane (2.5 mL) at room temperature, TFA (141 mg, 1.23 mmol) was added dropwise over 5 min. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the solvent was removed in vacuo to give a viscous residue. This material was purified by HPLC (MeCN / H 2 0) to give N-(4″-(aminomethyl)-3″-fluoro-5″-methoxy-2,2″-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (48 mg, 77%). 1 H NMR (400MHz, CD 3 OD) δ 12.19(s,1H),8.59(dd,J=7.4,2.2Hz,1H),8.14(d,J=8.2Hz,1H),8.00(d d,J=2.2,6.6Hz,1H),7.38-7.21(m,3H),7.15(d,J=7.2Hz,1H),6.96(d,J= 7.2Hz,1H),6.91(s,1H),6.86(d,J=9.8Hz,1H),6.62(ddd,J=7.5,6.5,0.8 Hz, 1H), 4.22 (s, 2H), 3.97 (s, 3H), 3.71 (s, 3H), 2.12 (s, 3H), 1.93 (s, 3H). MS:(ES)C 29 H 29 FN 3 O 3 [M+H] + The calculated m / z for this compound was 486.2, and the measured value was 486.2.

[0192] Example 69: 6-amino-N-(3″-fluoro-4″-(((2-hydroxyethyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)nicotinamide [ka] Process a:CH 2 Cl 2 To a stirred suspension of 6-aminonicotinic acid (0.75 g, 5.34 mmol) in hexanes (10 mL) was added oxalyl chloride (1.02 g, 8.15 mmol) at room temperature. The resulting mixture was stirred for 4 h. The solvent was removed under reduced pressure and the resulting residue was dried under vacuum and used directly in the next step. The residue was added to a solution of 3-bromo-2-methylaniline (1.0 g, 6.41 mmol) and N,N-diisopropylethylamine (2.06 mg, 16.0 mmol) in THF (15 mL) and the mixture was stirred at room temperature overnight. The reaction was then worked up by washing with water and extraction with EtOAc. The crude product was purified by silica gel chromatography (20-100% EtOAc / Hexanes) to give the desired product 6-amino-N-(3-bromo-2-methylphenyl)nicotinamide. MS: (ES) C 13 H 13 BrN 3 O[M+H] + The calculated m / z was 306.0, and the measured value was 306.1.

[0193] Step b: 6-amino-N-(3-bromo-2-methylphenyl)nicotinamide (150 mg, 0.49 mmol), 3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (199 mg, 0.53 mmol) and 2M K 2 CO 3 A mixture of (0.61 mL, 1.22 mmol) of Pd(dppf)Cl in p-dioxane (15 mL) was 2 (40 mg, 0.049 mmol) was added. The reaction mixture was degassed (N2 ) and N 2 The reaction mixture was stirred at 95 °C for 3 h under reduced pressure, and the mixture was diluted with EtOAc, filtered through Celite, washed with brine, and diluted with MgSO 4 The solvent was removed under reduced pressure and the residue was purified by silica gel flash chromatography (5-20%-40% EtOAc / Hexanes) to give 6-amino-N-(3''-fluoro-4''-formyl-5''-methoxy-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)nicotinamide. MS: (ES) C 28 H 25 FN 3 O 3 [M+H] + The calculated m / z was 470.2, the measured value was 470.2.

[0194] Step c: To a solution of 6-amino-N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)nicotinamide (50 mg, 0.106 mmol) and ethanolamine (26 mg, 0.42 mmol) in DMF (2 mL) was added NaBH(OAc) under stirring. 3 (56 mg, 0.26 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and the residue was purified by HPLC (0-40%-100% MeCN / H 2 O) to give 6-amino-N-(3″-fluoro-4″-(((2-hydroxyethyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)nicotinamide. 1 H NMR (400MHz, CD 3 OD) δ 8.55-8.49(m,1H),8.38(dd,J=9.4,2.3Hz,1H),7.38-7.21(m,4H),7.15-7.02(m,3H),6.94-6.82(m ,2H),4.36(s,2H),3.98(s,3H),3.88-3.81(m,2H),3.19(t,J=5.2Hz,2H),2.05(s,3H),1.98(s,3H). MS:(ES)C 30 H32 FN 4 O 3 [M+H] + The calculated m / z for this compound was 515.2, and the measured value was 515.2.

[0195] Example 70: 1-((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(pyrimidine-4-carboxamido)-[1,1':3',1''-terphenyl]-4-yl)methyl)azetidine-3-carboxylic acid [ka] Step a: Pyrimidine-4-carboxylic acid (0.5 g, 4.03 mmol) in CH 2 Cl 2 To the (10 mL) suspension was added oxalyl chloride (0.76 g, 6.04 mmol) at room temperature. The resulting mixture was stirred for 4 h. The solvent was removed under reduced pressure and dried under vacuum, and the resulting residue was used directly in the next step. The residue was added to a solution of 3-bromo-2-methylaniline (0.72 g, 3.90 mmol) and N,N-diisopropylethylamine (1.14 mg, 8.85 mmol) in THF (15 mL). The reaction mixture was stirred overnight at room temperature. After stirring was complete, the reaction was worked up by washing with water and extracted with EtOAc. The crude product was purified by silica gel chromatography (20-100% EtOAc / Hexanes) to give the desired product N-(3-bromo-2-methylphenyl)pyrimidine-4-carboxamide. MS: (ES) C 12 H 11 BrN 3 O[M+H] + The calculated m / z for this compound was 292.0, and the measured value was 292.0.

[0196] Step b: N-(3-bromo-2-methylphenyl)pyrimidine-4-carboxamide (150 mg, 0.49 mmol), 3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (199 mg, 0.53 mmol) and 2M K2 CO 3 A mixture of (0.61 mL, 1.22 mmol) in p-dioxane (15 mL) was added to dichloromethane and Pd(dppf)Cl 2 (40 mg, 0.049 mmol) was added. The reaction mixture was degassed (N 2 ) and N 2 The reaction mixture was stirred at 95 °C for 3 h under reduced pressure, and the mixture was diluted with EtOAc, filtered through Celite, washed with brine, and diluted with MgSO 4 The solvent was removed under reduced pressure and the residue was purified by silica gel flash chromatography (5-20%-40% EtOAc / Hexanes) to give N-(3''-fluoro-4''-formyl-5''-methoxy-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)pyrimidine-4-carboxamide. MS: (ES) C 27 H 23 FN 3 O 3 [M+H] + The calculated m / z for this compound was 456.2, and the measured value was 456.2.

[0197] Step c: In a solution of N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)pyrimidine-4-carboxamide (50 mg, 0.106 mmol) and azetidine-3-carboxylic acid (26 mg, 0.42 mmol) in DMF (2 mL), NaBH(OAc) was added under stirring. 3 (56 mg, 0.26 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and the residue was purified by HPLC (0-40%-100% MeCN / H 2 0) to give 1-((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(pyrimidine-4-carboxamido)-[1,1':3',1''-terphenyl]-4-yl)methyl)azetidine-3-carboxylic acid. 1 H NMR (400MHz, CD 3OD) δ 9.34(d,J=1.4Hz,1H),9.09(d,J=5.1Hz,1H),8.21(dd,J=5.2,1.4Hz,1H),7.80(t,J=8.7Hz,1H),7.34(d,J=7.7Hz,2H),7.26(d,J=7.9Hz,1H),7 .22-7.15(m,1H),7.12-7.05(m,1H),6.97-6.85(m,2H),4.56(s,2H),4. 41(d,J=9.7Hz,4H),3.98(s,3H),3.69(s,1H),2.09(s,3H),1.96(s,3H). MS:(ES)C 31 H 30 FN 4 O 3 [M+H] + The calculated m / z for this compound was 541.2, and the measured value was 541.2.

[0198] Example 71: N-(4″-(aminomethyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)nicotinamide [ka] This compound was prepared using a procedure similar to that described in Example 68. The resulting compound was purified by HPLC (MeCN / H 2 O containing 0.1% TFA). 2 O) to give the desired product, N-(4″-(aminomethyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)nicotinamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 9.18(s,1H),8.83-8.76(m,1H),8.52(d,J=8.1Hz,1H),7.72(dd,J=8.0,5.0Hz,1H),7.43-7.29(m ,3H),7.29-7.09(m,3H),6.93-6.80(m,2H),4.22(s,2H),3.97(s,3H),2.04(s,3H),1.96(s,3H). MS:(ES)C 28 H 27 FN 3 O2 [M+H] + The calculated m / z for this compound was 456.2, and the measured value was 456.2.

[0199] Example 72: N-(4″-(aminomethyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)isonicotinamide [ka] This compound was prepared using a procedure similar to that described in Example 68. The resulting compound was purified by HPLC (MeCN / H 2 O containing 0.1% TFA). 2 O) to give the desired product, N-(4″-(aminomethyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)isonicotinamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 9.18(s,1H),8.82(d,J=5.1Hz,1H),8.07(d,J=4.3Hz,1H),7.44-7.29(m,3H),7.28-7.09(m,3H), 6.90(d,J=1.3Hz,1H),6.84(d,J=9.9Hz,2H),4.22(s,2H),3.97(s,3H),2.03(s,3H),1.96(s,3H). MS:(ES)C 28 H 27 FN 3 O 2 [M+H] + The calculated m / z for this compound was 456.2, and the measured value was 456.2.

[0200] Example 73: N-(4″-(aminomethyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-6-methylpicolinamide [ka] This compound was prepared using a procedure similar to that described in Example 68. The resulting compound was purified by HPLC (MeCN / H 2 O containing 0.1% TFA). 2 O) to give the desired product, N-(4″-(aminomethyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-6-methylpicolinamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 8.03(d,J=5.1Hz,1H),7.95-7.86(m,2H),7.49(d,J=7.8Hz,1H),7.33(dt,J=7.7,3.1Hz,2H),7.28-7.14(m,2H),7.04( d,J=7.5Hz,1H),6.91(s,1H),6.85(d,J=9.9Hz,1H),4.22(s,2H),3.97(s,3H),2.64(s,3H),2.11(s,3H),1.96(s,3H). MS:(ES)C 29 H 29 FN 3 O 2 [M+H] + The calculated m / z for this compound is 470.2, and the measured value is 453.1 [M-17].

[0201] Example 74: 4″-(aminomethyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-N-(pyridin-2-yl)-[1,1′:3′,1″-terphenyl]-3-carboxamide [ka] This compound was prepared using a procedure similar to that described in Example 68. The resulting compound was purified by HPLC (MeCN / H 2 O containing 0.1% TFA). 2 0) to give the desired product, 4″-(aminomethyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-N-(pyridin-2-yl)-[1,1′:3′,1″-terphenyl]-3-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3OD) δ 9.18(s,1H),8.82(d,J=5.1Hz,1H),8.07(d,J=4.3Hz,1H),7.44-7.29(m,3H),7.28-7.09(m,3H), 6.90(d,J=1.3Hz,1H),6.84(d,J=9.9Hz,2H),4.22(s,2H),3.97(s,3H),2.03(s,3H),1.96(s,3H). MS:(ES)C 28 H 27 FN 3 O 2 [M+H] + The calculated m / z for this compound was 456.2, and the measured value was 439.0 [M-17].

[0202] Example 75: N-(4″-(aminomethyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)pyridine-2-carboxamide [ka] This compound was prepared using a procedure similar to that described in Example 68. The resulting compound was purified by HPLC (MeCN / H 2 O containing 0.1% TFA). 2 0) to give the desired product, N-(4″-(aminomethyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)pyridine-2-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 9.02(d,J=5.0Hz,2H),7.87-7.80(m,1H),7.70(t,J=4.9Hz,1H),7.39-7.29(m,2H),7.28-7.14(m,2H),7. 12-7.04(m,1H),6.90(s,1H),6.84(d,J=9.9Hz,1H),4.21(s,2H),3.97(s,3H),2.10(s,3H),1.96(s,3H). MS:(ES)C 27 H 26 FN 4 O 2 [M+H] +The calculated m / z for this compound was 457.2, and the measured value was 440.0 [M-17].

[0203] Example 76: N-(4″-(aminomethyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)pyridine-4-carboxamide [ka] This compound was prepared using a procedure similar to that described in Example 68. The resulting compound was purified by HPLC (MeCN / H 2 O containing 0.1% TFA). 2 0) to give the desired product, N-(4″-(aminomethyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)pyridine-4-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 9.34(d,J=1.4Hz,1H),9.09(d,J=5.1Hz,1H),8.21(dd,J=5.1,1.4Hz,1H),7.85-7.77(m,1H),7.34(t,J=7.9Hz,1H),7.28-7.21(m,1 H),7.18(dd,J=7.6,1.1Hz,1H),7.08(dd,J=7.8,1.2Hz,1H),6.93-6.81(m,2H),4.22(s,2H),3.97(s,3H),2.09(s,3H),1.95(s,3H). MS:(ES)C 27 H 26 FN 4 O 2 [M+H] + The calculated m / z for this compound was 457.2, and the measured value was 440.0 [M-17].

[0204] Example 77: N-(4″-(aminomethyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)pyrazine-2-carboxamide [ka] This compound was prepared using a procedure similar to that described in Example 68. The resulting compound was purified by HPLC (MeCN / H 2 O containing 0.1% TFA). 2 0) to give the desired product, N-(4″-(aminomethyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)pyrazine-2-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 9.36(d,J=1.4Hz,1H),8.85(d,J=2.4Hz,1H),8.75(dd,J=2.5,1.4Hz,1H),7.76(t,J=8.3Hz,1H),7.38-7.29(m,2H),7 .28-7.14(m,2H),7.08(dd,J=7.8,1.2Hz,1H),6.93-6.81(m,2H),4.22(s,2H),3.97(s,3H),2.08(s,3H),1.96(s,3H). MS:(ES)C 27 H 26 FN 4 O 2 [M+H] + The calculated m / z for this compound was 457.2, and the measured value was 440.0 [M-17].

[0205] Example 78: N-(4″-(aminomethyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)tetrahydro-2H-pyran-2-carboxamide [ka] This compound was prepared using a procedure similar to that described in Example 68. The resulting compound was purified by HPLC (MeCN / H 2 O containing 0.1% TFA). 2 0) to give the desired product, N-(4″-(aminomethyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)tetrahydro-2H-pyran-2-carboxamide, as a white solid. 1H NMR (400MHz, CD 3 OD) δ 7.52-7.43(m,1H),7.36-7.19(m,3H),7.13(d,J=7.4Hz,1H),7.06-6.99(m,1H),6.92-6.79(m,2H),4.22(s,2H),4.14(dd,J =11.4,3.5Hz,1H),3.96(s,4H),3.61(t,J=10.1Hz,1H),2.10(d,J=13.4Hz,1H),1.96(s,3H),1.96(s,3H),1.71-1.58(m,4H) 1.53(d,J=11.7Hz,1H). MS:(ES)C 28 H 32 FN 2 O 3 [M+H] + The calculated m / z for this compound was 463.2, and the measured value was 463.2.

[0206] Example 79: ((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(pyrimidine-4-carboxamido)-[1,1':3',1''-terphenyl]-4-yl)methyl)glycine [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)pyrimidine-4-carboxamide using a procedure similar to that described in step c of Example 1. The compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, ((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(pyrimidine-4-carboxamido)-[1,1':3',1''-terphenyl]-4-yl)methyl)glycine, as a white solid. 1 H NMR (400MHz, CD 3OD) δ 9.35(d,J=1.4Hz,1H),9.09(d,J=5.1Hz,1H),8.21(dd,J=5.1,1.4Hz,1H),7.82(d,J=7.9Hz,1H),7.35(t,J=7.7Hz,2H),7.26(dd,J=7.8,1.4 Hz,1H),7.22-7.15(m,1H),7.12-7.05(m,1H),6.96-6.84(m,2H),4.41 (d,J=1.2Hz,2H),3.98(s,3H),3.93(s,2H),2.10(s,3H),1.95(s,3H). MS:(ES)C 29 H 28 FN 4 O 4 [M+H] + The calculated m / z was 515.2, and the measured value was 515.5.

[0207] Example 80: N-(3″-fluoro-4″-(((2-hydroxyethyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)pyrimidine-4-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)pyrimidine-4-carboxamide using a procedure similar to that described in step c of Example 1. The compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-4″-(((2-hydroxyethyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)pyrimidine-4-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3OD) δ 9.35(d,J=1.4Hz,1H),9.09(d,J=5.1Hz,1H),8.21(dd,J=5.1,1.4Hz,1H),7.82(dd, J=8.1,1.1Hz,1H),7.34(t,J=7.7Hz,2H),7.26(dd,J=7.8,1.5Hz,1H),7.18(dd,J=7 .5,1.5Hz,1H),7.09(dd,J=7.8,1.3Hz,1H),6.96-6.84(m,2H),4.36(d,J=1.2Hz,2H ),3.98(s,3H),3.88-3.81(m,2H),3.19(t,J=5.2Hz,2H),2.10(s,3H),1.95(s,3H). MS:(ES)C 29 H 30 FN 4 O 3 [M+H] + The calculated m / z is 501.2, and the measured value is 501.5.

[0208] Example 81: N-(3″-fluoro-4″-(((3-hydroxyazetidin-1-yl)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)pyrimidine-4-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)pyrimidine-4-carboxamide using a procedure similar to that described in step c of Example 1. The compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-4″-(((3-hydroxyazetidin-1-yl)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)pyrimidine-4-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3OD) δ 9.35(d,J=1.4Hz,1H),9.09(d,J=5.1Hz,1H),8.21(dd,J=5.1,1.4Hz,1H), 7.81(d,J=8.1Hz,1H),7.35(t,J=7.6Hz,2H),7.30-7.22(m,1H),7.22-7.1 5(m,1H),7.08(d,J=7.4Hz,1H),6.97-6.86(m,2H),4.64-4.49(m,3H),4.4 6-4.33(m,2H),4.11-4.01(m,2H),3.98(s,3H),2.09(s,3H),1.96(s,3H). MS:(ES)C 30 H 30 FN 4 O 3 [M+H] + The calculated m / z was 513.2, and the measured value was 513.5.

[0209] Example 82: 6-((3″-fluoro-4″-(((2-hydroxyethyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)carbamoyl)nicotinic acid [ka] This compound was prepared using a procedure similar to that described in Example 1. The resulting compound was purified by HPLC (MeCN / H2O containing 0.1% TFA). 2 0) to give the desired product, 6-((3″-fluoro-4″-(((2-hydroxyethyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)carbamoyl)nicotinic acid, as a white solid. 1 H NMR (400MHz, CD 3OD) δ 9.25(d,J=1.4Hz,1H),8.58(dd,J=8.1,2.1Hz,1H),8.33(d,J=8.1Hz,1H),7.90-7.81(m,1H),7.34(t,J=7.4Hz,2H),7.29-7.15(m,2H), 7.07(d,J=7.6Hz,1H),6.96-6.84(m,2H),4.36(s,2H),3.99(s,3H),3.88-3.81(m,2H),3.19(t,J=5.3Hz,2H),2.11(s,3H),1.97(s,3H). MS:(ES)C 31 H 31 FN 3 O 5 [M+H] + The calculated m / z was 544.2, and the measured value was 544.5.

[0210] Example 83: 1-((3″-(5-aminopyrazine-2-carboxamido)-3-fluoro-5-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-4-yl)methyl)azetidine-3-carboxylic acid [ka] This compound was prepared using a procedure similar to that described in Example 1. The resulting compound was purified by HPLC (MeCN / H2O containing 0.1% TFA). 2 0) to give the desired product, 1-((3″-(5-aminopyrazine-2-carboxamido)-3-fluoro-5-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-4-yl)methyl)azetidine-3-carboxylic acid, as a white solid. 1 H NMR (400MHz, CD 3OD) δ 8.65(d,J=1.4Hz,1H),7.97(d,J=1.4Hz,1H),7.82-7.72(m,1H),7.38-7.21(m,3H),7.21-7.14(m,1H),7.06-6.99(m,1H) ,6.97-6.85(m,2H),4.56(s,2H),4.41(d,J=10.8Hz,4H),3.98(s,3H),3.70(t,J=10.2Hz,1H),2.06(s,3H),1.96(s,3H). MS:(ES)C 31 H 31 FN 5 O 4 [M+H] + The calculated m / z was 556.2, and the measured value was 556.5.

[0211] Example 84: 1-((3″-(2-aminopyrimidine-4-carboxamido)-3-fluoro-5-methoxy-2′,2″-dimethyl-[1,1′:3′,1″-terphenyl]-4-yl)methyl)azetidine-3-carboxylic acid [ka] This compound was prepared using a procedure similar to that described in Example 1. The resulting compound was purified by HPLC (MeCN / H2O containing 0.1% TFA). 2 0) to give the desired product, 1-((3″-(2-aminopyrazine-4-carboxamido)-3-fluoro-5-methoxy-2′,2″-dimethyl-[1,1′:3′,1″-terphenyl]-4-yl)methyl)azetidine-3-carboxylic acid, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 8.52(d,J=5.1Hz,1H),7.85-7.78(m,1H),7.39-7.21(m,4H),7.21-7.14(m,1H),7.10-7.03(m,1H),6.97-6 .85(m,2H),4.56(s,2H),4.45-4.40(m,4H),3.98(s,3H),3.71(t,J=11.4Hz,1H),2.09(s,3H),1.96(s,3H). MS:(ES)C 31 H31 FN 5 O 4 [M+H] + The calculated m / z was 556.2, and the measured value was 556.5.

[0212] Example 85: 1-((3-fluoro-5-methoxy-2,2'-dimethyl-3''-(thiazole-2-carboxamido)-[1,1':3',1''-terphenyl]-4-yl)methyl)azetidine-3-carboxylic acid [ka] This compound was prepared using a procedure similar to that described in Example 1. The resulting compound was purified by HPLC (MeCN / H2O containing 0.1% TFA). 2 0) to give the desired product, 1-((3-fluoro-5-methoxy-2,2'-dimethyl-3''-(thiazole-2-carboxamido)-[1,1':3',1''-terphenyl]-4-yl)methyl)azetidine-3-carboxylic acid, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 8.02(d,J=3.1Hz,1H),7.92(d,J=3.1Hz,1H),7.66(dd,J=7.9,1.3Hz,1H),7.39-7.21(m,3H),7.18(dd,J=7.4,1.5Hz,1H),7.09( dd,J=7.6,1.3Hz,1H),6.99-6.86(m,2H),4.56(s,2H),4.45-4.40(m,4H),3.98(s,3H),3.74(bs,1H),2.07(s,3H),1.96(s,3H). MS:(ES)C 30 H 29 FN 3 O 4 S[M+H] + The calculated m / z for this compound was 546.2, and the measured value was 546.2.

[0213] Example 86: 1-((3-fluoro-5-methoxy-3″-(5-methoxypicolinamido)-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-4-yl)methyl)azetidine-3-carboxylic acid [ka] This compound was prepared using a procedure similar to that described in Example 1. The resulting compound was purified by HPLC (MeCN / H2O containing 0.1% TFA). 2 0) to give the desired product, 1-((3-fluoro-5-methoxy-3″-(5-methoxypicolinamido)-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-4-yl)methyl)azetidine-3-carboxylic acid, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 8.36(dd,J=2.8,0.6Hz,1H),8.18(dd,J=8.7,0.7Hz,1H),7.90-7.83(m,1H),7.55(dd,J=8.7,2.9Hz,1H),7.38-7.14(m,4H),7.07- 6.99(m,1H),6.97-6.86(m,2H),4.56(s,2H),4.45-4.40(m,4H),3.97(s,3H),3.95(s,3H),3.70(bs,1H),2.09(s,3H),1.96(s,3H). MS:(ES)C 33 H 33 FN 3 O 5 [M+H] + The calculated m / z was 570.2, and the measured value was 570.2.

[0214] Example 87: 1-((3-fluoro-5-methoxy-2,2'-dimethyl-3''-(5-methoxypicolinamido)-[1,1':3',1''-terphenyl]-4-yl)methyl)azetidine-3-carboxylic acid [ka] This compound was prepared using a procedure similar to that described in Example 1. The resulting compound was purified by HPLC (MeCN / H2O containing 0.1% TFA). 2 0) to give the desired product, 1-((3-fluoro-5-methoxy-2,2'-dimethyl-3''-(5-methoxypicolinamido)-[1,1':3',1''-terphenyl]-4-yl)methyl)azetidine-3-carboxylic acid, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 8.54(dt,J=2.2,0.8Hz,1H),8.11(d,J=8.7Hz,1H),7.92-7.83(m,2H),7.38-7.14(m,4H),7.07-7.00(m,1H),6.96 -6.86(m,2H),4.56(s,2H),4.45-4.40(m,4H),3.98(s,3H),3.70(bs,1H),2.46(s,3H),2.09(s,3H),1.96(s,3H). MS:(ES)C 33 H 33 FN 3 O 4 [M+H] + The calculated m / z for this compound was 554.2, and the measured value was 554.2.

[0215] Example 88: N-(3″-fluoro-4″-(((2-hydroxyethyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide [ka] This compound was prepared using a procedure similar to that described in Example 1. The resulting compound was purified by HPLC (MeCN / H2O containing 0.1% TFA). 2 0) to give the desired product, N-(3''-fluoro-4''-(((2-hydroxyethyl)amino)methyl)-5''-methoxy-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide, as a white solid.1 H NMR (400MHz, CD 3 OD) δ 8.82(s,1H),8.31(d,J=6.2Hz,1H),8.18(dd,J=8.1,2.2Hz,1H),7.90-7.79(m ,1H),7.34(t,J=7.7Hz,2H),7.26(dd,J=7.7,1.5Hz,1H),7.18(dd,J=7.5,1.5 Hz,1H),7.07-7.03(m,1H),6.96-6.84(m,2H),4.43(s,2H),4.36(s,2H),3.98 (s,3H),3.88-3.81(m,4H),3.21(dt,J=5.3Hz,4H),2.09(s,3H),1.97(s,3H). MS:(ES)C 33 H 38 FN 4 O 4 [M+H] + The calculated m / z was 573.28, and the measured value was 573.5.

[0216] Example 89: 4-(((3-fluoro-3″-(5-(((2-hydroxyethyl)amino)methyl)picolinamide)-5-methoxy-2′,2″-dimethyl-[1,1′:3′,1″-terphenyl]-4-yl)methyl)amino)butanoic acid [ka] This compound was prepared using a procedure similar to that described in Example 1. The resulting compound was purified by HPLC (MeCN / H2O containing 0.1% TFA). 2 0) to give the desired product, 4-(((3-fluoro-3″-(5-(((2-hydroxyethyl)amino)methyl)picolinamide)-5-methoxy-2′,2″-dimethyl-[1,1′:3′,1″-terphenyl]-4-yl)methyl)amino)butanoic acid, as a white solid. 1 H NMR (400MHz, CD 3OD) δ 8.82(s,1H),8.31(d,J=8.1Hz,1H),8.18(dd,J=8.1,2.2Hz,1H),7.84(d,J=8.0 Hz,1H),7.34(t,J=7.7Hz,2H),7.29-7.22(m,1H),7.21-7.15(m,1H),7.10-7.03 (m,1H),6.96-6.84(m,2H),4.43(s,2H),4.33(s,2H),3.98(s,3H),3.88-3.81(m ,2H),3.27-3.12(m,4H),2.49(t,J=6.9Hz,2H),2.10(s,3H),1.97-2.05(m,5H). MS:(ES)C 35 H 40 FN 4 O 5 [M+H] + The calculated m / z was 615.3, and the measured value was 615.2.

[0217] Example 90: 2-(((3-fluoro-3″-(5-(((2-hydroxyethyl)amino)methyl)picolinamide)-5-methoxy-2′,2″-dimethyl-[1,1′:3′,1″-terphenyl]-4-yl)methyl)amino)ethane-1-sulfonic acid [ka] This compound was prepared using a procedure similar to that described in Example 1. The resulting compound was purified by HPLC (MeCN / H2O containing 0.1% TFA). 2 0) to give the desired product, 2-(((3-fluoro-3″-(5-(((2-hydroxyethyl)amino)methyl)picolinamide)-5-methoxy-2′,2″-dimethyl-[1,1′:3′,1″-terphenyl]-4-yl)methyl)amino)ethane-1-sulfonic acid, as a white solid. 1 H NMR (400MHz, CD 3OD) δ 8.82(s,1H),8.31(d,J=8.3Hz,1H),8.18(dd,J=8.2,2.2Hz,1H),7.86(d,J= 8.2Hz,1H),7.34(t,J=7.7Hz,2H),7.29-7.22(m,1H),7.17(dd,J=8.2,2.2Hz 1H),7.07(dd,J=8.2,2.2Hz,1H),6.96-6.84(m,2H),4.41(s,2H),4.38(s,2H),3.99(s,3H),3.88-3.81 (m,2H),3.49(t,J=6.2Hz,2H),3.24(q,J=7.2Hz,2H),3.15(t,J=6.3Hz,2H),2.09(s,3H),1.97(s,3H). MS:(ES)C 33 H 38 FN 4 O 6 S[M+H] + The calculated m / z for this compound was 637.2, and the measured value was 637.2.

[0218] Example 91: N-(3″-fluoro-4″-((isopropylamino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)pyrido[3,4-b]pyrazin-5-amine [ka] A mixture of 3-fluoro-5-methoxy-2',2''-dimethyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-carbaldehyde (24 mg, 0.042 mmol), propan-2-amine (30 mg, 0.51 mmol) and HOAc (90 mg, 1.50 mmol) in EtOH (1.5 mL) was heated at 70 °C for 0.5 h. The mixture was cooled to 0 °C and NaBH 3 CN (45 mg, 0.71 mmol) was added. The mixture was stirred at room temperature for 20 min and then concentrated in vacuo. The resulting residue was purified by HPLC (MeCN / H 20) to give N-(3″-fluoro-4″-((isopropylamino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)pyrido[3,4-b]pyrazin-5-amine (TFA salt). 1 H NMR (400MHz, CD 3 OD) δ 9.25(d,J=2.0Hz,1H),9.05(d,J=2.0Hz,1H),7.79(d,J=7.6Hz,1H),7.59(d, J=7.6Hz,1H),7.53(t,J=7.8Hz,1H),7.40-7.34(m,3H),7.28(d,J=7.6Hz,1H) ,7.24(d,J=7.2Hz,1H),6.93(s,1H),6.87(d,J=10.0Hz,1H),4.30(s,2H),3.9 8(s,3H),3.55-3.44(m,1H),2.10(s,3H),2.01(s,3H),1.42(d,J=6.8Hz,6H). MS:(ES)C 32 H 33 FN 5 O[M+H] + The calculated m / z for this compound was 522.3, and the measured value was 522.3.

[0219] Example 92: N-(3″-fluoro-4″-((isopropylamino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide [ka] Step a: N-(3-bromo-2-methylphenyl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (500 mg, 1.48 mmol), 3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (600 mg, 1.63 mmol), and 2M K 2 CO 3(1.85 mL, 3.7 mmol) in p-dioxane (10 mL) with dichloromethane and Pd(dppf)Cl 2 (121 mg, 0.148 mmol) was added. The reaction mixture was degassed (N 2 ) and N 2 The reaction mixture was stirred at 95 °C for 5 h under 5% CO. The reaction mixture was diluted with EtOAc, filtered through Celite, washed with brine, and washed with MgSO. 4 The solvent was removed under reduced pressure and the residue was purified by silica gel flash chromatography (5-20%-100% EtOAc / Hexanes) to give N-(3''-fluoro-4''-formyl-5''-methoxy-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide. MS: (ES) C 29 H 25 FN 2 O 4 [M+H] + The calculated m / z for this compound was 485.2, and the measured value was 485.2.

[0220] Step b: To a solution of N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (40 mg, 0.082 mmol) and propan-2-amine (10 mg, 0.16 mmol) in MeOH:DCE (2 mL) was added NaBH(OAc) under stirring. 3 (52 mg, 0.24 mmol) and AcOH (5 drops) were added. The reaction mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and the residue was purified by HPLC (0-40%-100% MeCN / H 2 0) to give N-(3″-fluoro-4″-((isopropylamino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide. 1 H NMR (400MHz, CD 3OD) δ 12.18(s,1H),8.59(dd,J=7.3,2.0Hz,1H),8.13(d,J=8.2Hz,1H),7.99(dd,J=6.3 ,2.0Hz,1H),7.36-7.24(m,3H),7.15(d,J=7.2Hz,1H),6.96(d,J=7.4Hz,1H),6.9 3(s,1H),6.86(d,J=9.8Hz,1H),6.61(t,J=7.5Hz,1H),4.29(s,2H),3.98(s,3H), 3.70(s,3H),3.55-3.45(m,1H),2.12(s,3H),1.93(s,3H),1.41(d,J=6.3Hz,6H). MS:(ES)C 32 H 35 FN 3 O 3 [M+H] + The calculated m / z was 528.3, and the measured value was 528.2.

[0221] Example 93: (S)—N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((5-oxopyrrolidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide using a procedure similar to that described in step c of Example 1. The compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, (S)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((5-oxopyrrolidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide, as a white solid. 1H NMR (400MHz, CD 3 OD) δ 12.18(s,1H),8.59(dd,J=8.2,2.4Hz,1H),8.14(d,J=8.2Hz,1H),7.98(dd,J=6.3,2.0Hz,1H),7.36-7.24 (m,3H),7.16(d,J=7.2Hz,1H),6.97(d,J=7.4Hz,1H),6.95(s,1H),6.88(d,J=9.8Hz,1H),6.61(t,J=7.5H z,1H),4.36(s,2H),4.28-4.20(m,1H),3.99(s,3H),3.87(dd,J=11.8,7.5Hz,1H),3.70(s,3H),3.56(dd, J=12.0,4.4Hz,1H),2.89(dd,J=18.0,9.0Hz,1H),2.54(dd,J=17.6,4.7Hz,1H),2.12(s,3H),1.93(s,3H). MS:(ES)C 33 H 34 FN 4 O 4 [M+H] + The calculated m / z for this compound was 569.3, and the measured value was 569.3.

[0222] Example 94: (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((5-oxopyrrolidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide using a procedure similar to that described in step c of Example 1. The compound was purified by HPLC (MeCN / H with 0.1% TFA). 20) to give the desired product, (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((5-oxopyrrolidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 12.18(s,1H),8.59(dd,J=8.2,2.4Hz,1H),8.14(d,J=8.2Hz,1H),7.98(dd,J=6.3,2.0Hz,1H),7.36-7.25 (m,3H),7.16(d,J=7.8Hz,1H),6.96(d,J=7.4Hz,1H),6.95(s,1H),6.88(d,J=9.8Hz,1H),6.61(t,J=7.5H z,1H),4.36(s,2H),4.28-4.20(m,2H),3.99(s,3H),3.87(dd,J=11.8,7.5Hz,1H),3.70(s,3H),3.56(dd, J=12.0,4.4Hz,1H),2.90(dd,J=18.0,9.0Hz,1H),2.54(dd,J=17.6,4.7Hz,1H),2.12(s,3H),1.93(s,3H). MS:(ES)C 33 H 34 FN 4 O 4 [M+H] + The calculated m / z for this compound was 569.3, and the measured value was 569.3.

[0223] Example 95: (S)—N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide using a procedure similar to that described in step c of Example 1. The compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, (S)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 12.18(s,1H),8.57(d,J=7.0Hz,1H),8.16(t,J=8.2Hz,1H),7.98(d,J=6.2Hz,1H), 7.36-7.24(m,2H),7.16(d,J=7.4Hz,1H),6.98-6.92(m,2H),6.95(s,1H),6.89(d,J =9.8Hz,1H),6.60(t,J=7.5Hz,1H),4.39(s,2H),4.10-4.05(m,1H),3.99(s,3H),3. 70(s,3H),3.26(dd,J=6.8,2.7Hz,2H),2.45-2.35(m,3H),2.13(s,3H),1.94(s,3H) 1.93-1.89(m,1H). MS:(ES)C 34 H 36 FN 4 O 4 [M+H] + The calculated m / z was 583.3, and the measured value was 583.3.

[0224] Example 96: (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide using a procedure similar to that described in step c of Example 1. The compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 12.18(s,1H),8.57(dd,J=7.8,2.4Hz,1H),8.16(t,J=8.2Hz,1H),8.01(dd,J=6.2,1.9Hz, 1H),7.36-7.24(m,3H),7.16(d,J=7.2Hz,1H),6.98(d,J=7.4Hz,1H),6.95(s,1H),6.82(d,J=9.8Hz,1H),6.60(t,J=7.5Hz,1 H),4.39(s,2H),4.10-4.00(m,1H),3.99(s,3H),3.70(s,3H),3.30-3.25(m,2H),2.45-2.30(m,3H),2.13(s,3H),1.94(s,3H) 1.92-1.85(m,1H). MS:(ES)C 34 H 36 FN 4 O 4 [M+H] + The calculated m / z was 583.3, and the measured value was 583.3.

[0225] Example 97: (S)—N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((methyl(5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide using a procedure similar to that described in step c of Example 1. The compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, (S)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((methyl(5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 12.18(s,1H),8.58(dd,J=7.8,2.4Hz,1H),8.15(t,J=7.7Hz,1H),7.98(dd,J=6 .3,2.0Hz,1H),7.35-7.24(m,3H),7.17(d,J=7.4Hz,1H),7.00-6.90(m,3H),6.6 2(t,J=7.5Hz,1H),4.60-4.40(m,2H),4.30-4.25(m,1H),4.01(s,3H),3.70(s,3 H),3.55-3.35(m,2H),2.94(s,3H),2.50-2.32(m,3H),2.13(s,3H),1.94(s,3H) 1.92-1.85(m,1H). MS:(ES) C 35 H 38 FN 4 O 4 [M+H] +The calculated m / z for this compound was 597.3, and the measured value was 597.3.

[0226] Example 98: (S)—N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((((1-methyl-5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide using a procedure similar to that described in step c of Example 1. The compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, (S)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((((1-methyl-5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3OD) δ 12.18(s,1H),8.58(dd,J=7.8,2.4Hz,1H),8.15(t,J=8.2Hz,1H),8.01(dd,J=6.6,1.9Hz,1H),7. 35-7.24(m,3H),7.16(d,J=7.4Hz,1H),6.97(d,J=7.4Hz,1H),6.96(s,1H),6.89(d,J=9.8Hz,1H), 6.62(t,J=7.5Hz,1H),4.43(m,2H),4.00(s,3H),3.98-3.90(m,1H),3.70(s,3H),3.46(dd,J=7.8,4.0Hz,1H), 3.25-3.20(m,1H),2.85(s,3H),2.60-2.35(m,3H),2.13(s,3H),1.93(s,3H),1.98-1.90(m,1H). MS:(ES)C 35 H 38 FN 4 O 4 [M+H] + The calculated m / z for this compound was 597.3, and the measured value was 597.3.

[0227] Example 99: N-(4″-((((2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)methyl)amino)methyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide using a procedure similar to that described in step c of Example 1. The compound was purified by HPLC (MeCN / H with 0.1% TFA). 20) to give the desired product, N-(4″-((((2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)methyl)amino)methyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 12.18(s,1H),8.57(d,J=7.8Hz,1H),8.12(t,J=7.5Hz,1H),7.99(dd,J=6. 7Hz,1H),7.65(s,1H),7.35-7.24(m,3H),7.15(d,J=6.2Hz,1H),6.95(d,J= 7.8Hz,1H),6.91(s,1H),6.84(d,J=9.8Hz,1H),6.62(t,J=7.0Hz,1H),4.4 3(s,2H),4.00(s,2H),3.98(s,3H),3.70(s,3H),2.11(s,3H),1.93(s,3H). MS:(ES)C 34 H 36 FN 5 O 5 [M+H] + The calculated m / z was 610.3, and the measured value was 610.2.

[0228] Example 100: N-(3″-fluoro-4″-(((1-hydroxy-2-methylpropan-2-yl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide using a procedure similar to that described in step c of Example 1. The compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-4″-(((1-hydroxy-2-methylpropan-2-yl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 12.18(s,1H),8.59(dd,J=7.8,2.4Hz,1H),8.14(t,J=8.2Hz,1H),7.99(d,J =6.8Hz,1H),7.36-7.24(m,3H),7.15(d,J=7.4Hz,1H),6.96(d,J=7.4Hz,1H) ,6.91(s,1H),6.84(d,J=9.8Hz,1H),6.60(t,J=7.5Hz,1H),4.29(s,2H),3. 97(s,3H),3.70(s,3H),3.66(s,2H),2.12(s,3H),1.93(s,3H),1.42(s,6H). MS:(ES)C 33 H 37 FN 3 O 4 [M+H] + The calculated m / z was 558.3, and the measured value was 558.2.

[0229] Example 101: N-(3″-fluoro-4″-(((2-hydroxyethyl)(methyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide using a procedure similar to that described in step c of Example 1. The compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-4″-(((2-hydroxyethyl)(methyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 12.18(s,1H),8.57(dd,J=7.8,2.4Hz,1H),8.16(t,J=8.2Hz,1H),7.99(dd,J=6.3,2.0Hz,1H ),7.36-7.24(m,3H),7.16(d,J=7.4Hz,1H),6.97(d,J=7.4Hz,1H),6.96(s,1H),6.89(d,J=9. 8Hz,1H),6.61(t,J=13.7Hz,1H),4.60(d,J=13.0Hz,1H),4.37(d,J=13.3Hz,1H),3.98(s,3H) ),3.95-3.85(m,2H),3.70(s,3H),3.45-3.30(m,2H),2.89(s,3H),2.13(s,3H),1.95(s,3H). MS:(ES)C 32 H 35 FN 3 O 4 [M+H] + The calculated m / z was 544.3, and the measured value was 544.2.

[0230] Example 102: N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((oxetan-3-ylamino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide using a procedure similar to that described in step c of Example 1. The compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((oxetan-3-ylamino)methyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 12.18(s,1H),8.59(dd,J=7.3,2.0Hz,1H),8.13(t,J=8.2Hz,1H),7.99(dd,J=6.3,2.0Hz,1H),7. 36-7.24(m,3H),7.16(d,J=7.4Hz,1H),6.96(d,J=7.4Hz,1H),6.92(s,1H),6.88(d,J=9.8Hz,1H), 6.60(t,J=7.5Hz,1H),4.65(dd,J=8.2,5.5Hz,2H),4.55-4.45(m,3H),4.29(s,2H),3.99(s,3H),3.70(s,3H),2.13(s,3H),1.94(s,3H). MS:(ES)C 32 H 33 FN 3 O 4 [M+H] + The calculated m / z for this compound was 542.2, and the measured value was 542.2.

[0231] Example 103: N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((tetrahydrofuran-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide using a procedure similar to that described in step c of Example 1. The compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((tetrahydrofuran-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 12.18(s,1H),8.59(dd,J=7.8,2.4Hz,1H),8.14(t,J=8.2Hz,1H),7.98(dd,J=6.3,2.0Hz,1H),7. 36-7.24(m,3H),7.16(d,J=7.2Hz,1H),6.96(d,J=7.4Hz,1H),6.94(s,1H),6.87(d,J=9.8Hz,1H), 6.61(t,J=7.5Hz,1H),4.33(s,2H),4.10-4.05(m,2H),4.04-4.00(m,1H),3.98(s,3H),3.85(dd,J=10.4,5.6Hz ,1H),3.73(dd,J=8.2,4.0Hz,1H),3.70(s,3H),2.50-2.41(m,1H),2.12(s,3H),2.10-2.05(m,1H),1.94(s,3H). MS:(ES)C 33 H 35 FN 3 O 4 [M+H] + The calculated m / z was 556.3, and the measured value was 556.2.

[0232] Example 104: N-(4″-(aminomethyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] Step a: To a mixture of 3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (0.36 g, 2.35 mmol) and 3-bromo-2-methylaniline (0.43 g, 2.35 mmol) in a vial containing DMF (5.0 mL) was added HATU (1.34 g, 3.52 mmol) and diisopropylethylamine (0.75 g, 5.87 mmol). The reaction was stirred at room temperature for 16 hours. After completion of the reaction, half of the solvent was removed, diluted with water (15 ml) and the mixture was stirred for 20 minutes. The solid was filtered through a plastic funnel, washed with water (10 ml) and dried under vacuum to give N-(3-bromo-2-methylphenyl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide.

[0233] Step b: N-(3-bromo-2-methylphenyl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (100 mg, 0.31 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 (146 mg, 0.31 mmol) and 2M K 2 CO 3 To a mixture of (0.38 mL, 0.77 mmol) of Pd(dppf)Cl in p-dioxane (4 mL) with dichloromethane 2 The complex (26 mg, 0.032 mmol) was added. The reaction mixture was degassed (N 2 ) and N 2The mixture was stirred at 95 °C for 4 h under reduced pressure, and the mixture was diluted with EtOAc, filtered through Celite, washed with brine, and MgSO 4 The solvent was removed under reduced pressure and the residue was purified by silica gel flash chromatography (5-20%-40% EtOAc / Hexanes) to give tert-butyl ((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide)-[1,1':3',1''-terphenyl]-4-yl)methyl)carbamate. MS: (ES) C 33 H 36 FN 4 O 6 [M+H] + The calculated m / z for this compound was 603.3, and the measured value was 603.3.

[0234] Step c: To tert-butyl ((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide)-[1,1':3',1''-terphenyl]-4-yl)methyl)carbamate (75 mg, 0.123 mmol) in anhydrous dichloromethane (2.5 mL) was added dropwise over 5 min under stirring at room temperature. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the solvent was removed in vacuo to give a viscous compound, which was purified by HPLC (MeCN / H 2 O containing 0.1% TFA). 2 0) to give N-(4″-(aminomethyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD 3OD) δ 11.19(s,1H),8.41(s,1H),8.06(d,J=6.2Hz,1H),7.38-7.21(m,3H),7.15(dd,J=7.5,1.5Hz,1H),6.96(d,J=7. 2Hz,1H),6.93(s,1H),6.86(d,J=8.2Hz,1H),4.22(s,2H),3.97(s,3H),3.36(s,3H),2.10(s,3H),1.93(s,3H). MS:(ES)C 28 H 28 FN 4 O 4 [M+H] + The calculated m / z for this compound was 503.2, and the measured value was 486.2 [M-17].

[0235] Example 105: N-(3″-fluoro-4″-((isopropylamino)-methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] Step a: N-(3-bromo-2-methylphenyl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (500 mg, 1.48 mmol), 3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-"1,1'-biphenyl"-4-carbaldehyde (939 mg, 2.53 mmol), and 2M K 2 CO 3 (1.85 mL, 3.7 mmol) in p-dioxane (10 mL) with dichloromethane and Pd(dppf)Cl 2 (121 mg, 0.148 mmol) was added. The reaction mixture was degassed (N 2 ) and N 2 The reaction mixture was stirred at 95 °C for 5 h under 5% CO. The reaction mixture was diluted with EtOAc, filtered through Celite, washed with brine, and washed with MgSO. 4The solvent was removed under reduced pressure and the residue was purified by silica gel flash chromatography (5-20%-40% EtOAc / Hexanes) to give N-(3''-fluoro-4''-formyl-5''-methoxy-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. MS: (ES) C 28 H 25 FN 3 O 5 [M+H] + The calculated m / z is 502.2, the measured value is 502.2.

[0236] Step b: To a solution of N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (40 mg, 0.079 mmol) and propan-2-amine (10 mg, 0.16 mmol) in MeOH:DCE (2 mL) was added NaBH(OAc) under stirring. 3 (33 mg, 0.16 mmol) and AcOH (4 drops) were added. The reaction mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC (0-40%-100% MeCN / H 2 0) to give a white solid of N-(3″-fluoro-4″-((isopropylamino)-methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD 3OD) δ 11.15(s,1H),8.41(s,1H),8.05(d,J=8.0Hz,1H),7.39-7.24(m,3H),7.15(d,J=6.2Hz,1H),6.96(d,J=7.4Hz,1H),6.94(s,1H),6.86( d,J=9.7Hz,1H),4.30(d,J=1.5Hz,2H),3.56-3.46(m,1H),3.98(s,3H),3.36(s,3H),2.10(s,3H),1.93(s,3H),1.42(d,J=6.5Hz,6H). MS:(ES)C 31 H 34 FN 4 O 4 [M+H] + The calculated m / z was 544.3, and the measured value was 544.2.

[0237] Example 106: N-(4″-((dimethylamino)methyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxooxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The compound was purified by HPLC (MeCN / H2O containing 0.1% TFA). 2 0) to give the desired product, N-(4″-((dimethylamino)methyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3OD) δ 11.15(s,1H),8.41(s,1H),8.05(d,J=8.0Hz,1H),7.39-7.24(m,3H),7.17(d,J=6.2Hz,1H),6.96(d,J=7.4Hz,1H), 6.94(s,1H),6.86(d,J=9.7Hz,1H),4.43(s,2H),3.99(s,3H),3.36(s,3H),2.93(s,6H),2.10(s,3H),1.93(s,3H). MS:(ES)C 30 H 32 FN 4 O 4 [M+H] + The calculated m / z for this compound was 531.2, and the measured value was 531.2.

[0238] Example 107: N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(morpholinomethyl)-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxooxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The compound was purified by HPLC (MeCN / H2O containing 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(morpholinomethyl)-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3OD) δ 11.15(s,1H),8.41(s,1H),8.05(d,J=8.0Hz,1H),7.39-7.24(m,3H),7.16 (d,J=6.2Hz,1H),6.96(d,J=7.0Hz,1H),6.95(s,1H),6.88(d,J=9.7Hz,1H ),4.47(d,J=1.5Hz,2H),4.06(d,J=11.0Hz,2H),3.99(s,3H),3.77(t,J=1 2.5Hz, 2H), 3.49 (d, J=12.7Hz, 4H), 3.36 (s, 3H), 2.10 (s, 3H), 1.93 (s, 3H). MS:(ES)C 32 H 34 FN 4 O 5 [M+H] + The calculated m / z for this compound was 572.2, and the measured value was 572.2.

[0239] Example 108: N-(4″-((3-aminopyrrolidin-1-yl)methyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxoxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The compound was purified by HPLC (MeCN / H2O containing 0.1% TFA). 2 0) to give the desired product, N-(4″-((3-aminopyrrolidin-1-yl)methyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3 OD) δ 11.16(s,1H),8.40(d,J=11.2Hz,1H),8.05(d,J=7.7Hz,1H),7.39-7.24(m,3H),7.16(dd,J=7.4,1.5Hz,1H),6.98(d,J=7.0Hz,1H),6.95(s,1 H),6.85(d,J=9.7Hz,1H),4.55-4.50(m,2H),4.45-4.39(m,2H),4.30- 4.20(m,3H),3.98(s,3H),3.40-3.17(m,5H),2.10(s,3H),1.93(s,3H). MS:(ES)C 32 H 35 FN 5 O 4 [M+H] + The calculated m / z was 572.3, and the measured value was 572.2.

[0240] Example 109: N-(4″-(((2-aminoethyl)amino)methyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxoxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The compound was purified by HPLC (MeCN / H2O containing 0.1% TFA). 2 0) to give the desired product, N-(4″-(((2-aminoethyl)amino)methyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3 OD) δ 11.15(s,1H),8.42(s,1H),8.05(d,J=7.8Hz,1H),7.39-7.24(m,3H),7.16(d,J=7.3Hz,1H),6.96(d,J=7.0Hz,1H),6. 95(s,1H),6.88(d,J=9.7Hz,1H),4.41(s,2H),3.98(s,3H),3.77-3.68(m,4H),3.36(s,3H),2.10(s,3H),1.93(s,3H). MS:(ES)C 30 H 33 FN 5 O 4 [M+H] + The calculated m / z was 546.2, and the measured value was 564.2.

[0241] Example 110: N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((oxetan-3-ylamino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxooxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The compound was purified by HPLC (MeCN / H2O containing 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((oxetan-3-ylamino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3OD) δ 11.15(s,1H),8.41(s,1H),8.05(d,J=8.2Hz,1H),7.38-7.21(m,3H),7.16(d,J=7.3Hz,1H), 6.96(d,J=7.0Hz,1H),6.94(s,1H),6.88(d,J=9.7Hz,1H),4.90(d,J=7.0Hz,1H),4.71-4.63 (m,2H),4.49-4.41(m,2H),4.29(s,2H),4.00(s,3H),3.36(s,3H),2.10(s,3H),1.93(s,3H). MS:(ES)C 31 H 32 FN 4 O 5 [M+H] + The calculated m / z for this compound was 559.2, and the measured value was 559.2.

[0242] Example 111: N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((tetrahydrofuran-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxooxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The compound was purified by HPLC (MeCN / H2O containing 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((tetrahydrofuran-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3OD) δ 11.15(s,1H),8.42(s,1H),8.05(d,J=8.2Hz,1H),7.38-7.21(m,3H),7.16( dd,J=7.3,1.5Hz,1H),7.01-6.85(m,3H),4.33(s,2H),4.07(dd,J=8.6,3.3H z,2H),3.99(s,3H),3.86(dd,J=10.8,5.7Hz,1H),3.80-3.67(m,1H),3.36(s ,3H),3.30-3.20(m,1H),2.48-2.38(m,1H),2.15-2.05(m,4H),1.93(s,3H). MS:(ES)C 32 H 34 FN 4 O 5 [M+H] + The calculated m / z for this compound was 573.2, and the measured value was 573.2.

[0243] Example 112: N-(3″-fluoro-4″-((((1-hydroxycyclopropyl)methyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxoxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The compound was purified by HPLC (MeCN / H2O containing 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-4″-((((1-hydroxycyclopropyl)methyl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid.1 H NMR (400MHz, CD 3 OD) δ 11.15(s,1H),8.42(s,1H),8.04(d,J=8.1Hz,1H),7.38-7.21(m,3H),7.14(dd,J=7.3,1.5Hz,1H),6.96(d,J=7.0Hz,1H) ,6.93(s,1H),6.85(d,J=9.7Hz,1H),4.43(s,2H),3.98(s,3H),3.36(s,3H),3.20(s,1H),2.11-2.08(m,4H),1.93(s,3H) 0.89-0.94(m,2H),0.70-0.78(m,2H). MS:(ES)C 32 H 34 FN 4 O 5 [M+H] + The calculated m / z for this compound was 573.2, and the measured value was 573.2.

[0244] Example 113: N-(3″-fluoro-4″-((3-hydroxyazetidin-1-yl)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxoxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The compound was purified by HPLC (MeCN / H2O containing 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-4″-((3-hydroxyazetidin-1-yl)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid.1 H NMR (400MHz, CD 3 OD) δ 11.15(s,1H),8.41(s,1H),8.05(d,J=8.2Hz,1H),7.38-7.21(m,3H),7.16(d,J=7.3Hz,1H),6.96(d,J=7.0Hz,1H),6.94(s,1H),6.88(d,J= 9.7Hz,1H),4.90(d,J=7.0Hz,1H),4.71-4.63(m,2H),4.49-4.41(m,2H),4.29(s,2H),4.00(s,3H),3.36(s,3H),2.10(s,3H),1.93(s,3H). MS:(ES)C 31 H 32 FN 4 O 5 [M+H] + The calculated m / z for this compound was 559.2, and the measured value was 559.2.

[0245] Example 114: (S)—N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxoxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The compound was purified by HPLC (MeCN / H2O containing 0.1% TFA). 20) to give the desired product, (S)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 O.D.) δ11.17(s,1H),8.41(s,1H),8.04(d,J=8.2Hz,1H),7.38-7.21(m,3H),7.15(d,J=7.3Hz,1H),7.01-6.85(m,3H),4.40(s ,2H),4.20-4.10(m,1H),3.98(s,3H),3.36(s,3H),3.20-3.30(m,1H),2.45-2.35(m,3H),2.10(s,3H),1.97-1.87(m,4H) 1.90-1.85(m,1H). MS:(ES)C 33 H 35 FN 5 O 5 [M+H] + The calculated m / z was 600.3, and the measured value was 600.2.

[0246] Example 115: (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxooxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The compound was purified by HPLC (MeCN / H2O containing 0.1% TFA).2 0) to give the desired product, (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 O.D.) δ11.17(s,1H),8.41(s,1H),8.04(d,J=8.2Hz,1H),7.38-7.21(m,3H),7.15(d,J=9.0Hz,1H),7.01-6.85(m,3H),4.39(s ,2H),4.10-4.05(m,1H),3.99(s,3H),3.36(s,3H),3.30-3.25(m,1H),2.45-2.35(m,3H),2.10(s,3H),1.97-1.89(m,4H) 1.92-1.89(m,1H). MS:(ES)C 33 H 35 FN 5 O 5 [M+H] + The calculated m / z was 600.3, and the measured value was 600.2.

[0247] Example 116: N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((3-oxopiperazin-1-yl)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxoxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The compound was purified by HPLC (MeCN / H2O containing 0.1% TFA). 20) to give the desired product, N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((3-oxopiperazin-1-yl)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.15(s,1H),8.41(s,1H),8.04(d,J=7.4Hz,1H),7.38-7.21(m,3H),7.16(dd,J=1.5,7.3Hz,1H),7.01-6.85(m,3H), 4.55(s,2H),3.99(s,3H),3.94(s,2H),3.45-3.65(m,3H),3.36(s,3H),3.30-3.20(m,1H),2.10(s,3H),1.95(s,3H). MS:(ES)C 32 H 33 FN 5 O 5 [M+H] + The calculated m / z for this compound was 585.2, and the measured value was 585.2.

[0248] Example 117: (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((5-oxopyrrolidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxoxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The compound was purified by HPLC (MeCN / H2O containing 0.1% TFA). 20) to give the desired product, (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((5-oxopyrrolidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.15(s,1H),8.41(s,1H),8.04(d,J=8.2Hz,1H),7.38-7.21(m,3H),7.15(d,J =7.3Hz,1H),7.01-6.85(m,3H),4.36(s,2H),4.26-4.20(m,1H),3.99(s,3H),3 .87(dd,J=11.3,7.4Hz,1H),3.56(dd,J=11.7,3.9Hz,1H),3.36(s,3H),2.90(d d,J=11.3,7.4Hz,1H),2.53(dd,J=18.0,5.1Hz,1H),2.10(s,3H),1.93(s,3H). MS:(ES)C 32 H 33 FN 5 O 5 [M+H] + The calculated m / z for this compound was 586.2, and the measured value was 586.2.

[0249] Example 118: N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxoxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The compound was purified by HPLC (MeCN / H2O containing 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.17(s,1H),8.41(s,1H),8.04(d,J=8.2Hz,1H),7.38-7.21(m,3H),7.15(d,J=7.8Hz,1H),7. 01-6.85(m,3H),4.49(s,2H),4.32(s,2H),3.98(s,3H),3.36(s,3H),2.09(s,3H),1.93(s,3H). MS:(ES)C 31 H 30 FN 6 O 6 [M+H] + The calculated m / z for this compound was 601.2, and the measured value was 601.2.

[0250] Example 119: N-(3″-fluoro-4″-((((3R,4R)-4-hydroxytetrahydrofuran-3-yl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxoxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The compound was purified by HPLC (MeCN / H2O containing 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-4″-((((3R,4R)-4-hydroxytetrahydrofuran-3-yl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 O.D.) δ11.15(s,1H),8.41(s,1H),8.04(d,J=8.2Hz,1H),7.38-7.21(m,3H),7 .15(d,J=7.2Hz,1H),7.01-6.85(m,3H),4.88-4.47(m,1H),4.39(dd,J= 22.0,13.4Hz,2H),4.20-4.05(m,2H),4.01-3.95(m,4H),3.75-3.70(m, 1H), 3.60 (dd, J=9.8, 4.3Hz, 1H), 3.36 (s, 3H), 2.09 (s, 3H), 1.93 (s, 3H). MS:(ES)C 32 H 34 FN 4 O 6 [M+H] + The calculated m / z for this compound was 589.2, and the measured value was 589.2.

[0251] Example 120: N-(3″-fluoro-4″-((((3R,4R)-3-hydroxytetrahydrofuran-2H-pyran-4-yl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxoxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The compound was purified by HPLC (MeCN / H2O containing 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-4″-((((3R,4R)-3-hydroxytetrahydrofuran-2H-pyran-4-yl)amino)methyl)-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.15(s,1H),8.41(s,1H),8.05(d,J=7.1Hz,1H),7.38-7.21(m,3H),7. 15(d,J=7.4Hz,1H),7.01-6.85(m,3H),4.39(d,J=13.7Hz,1H),4.29(d, J=13.3Hz,1H),4.10-3.96(m,2H),3.98(s,3H),3.60-3.40(m,2H),3.35 (s,3H),2.15-2.05(m,2H),2.09(s,3H),1.93(s,3H),1.90-1.85(m,2H). MS:(ES)C 33 H 36 FN 4 O 6 [M+H] + The calculated m / z is 603.3, the measured value is 603.2.

[0252] Example 121: 1-((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide)-[1,1':3',1''-terphenyl]-4-yl)methyl]azetidine-3-carboxylic acid [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-3-methyl-2,4-dioxoxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step c of Example 1. The compound was purified by HPLC (MeCN / H2O containing 0.1% TFA). 2 0) to give the desired product, 1-((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-[1,1':3',1''-terphenyl]-4-yl)methyl]azetidine-3-carboxylic acid, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.15(s,1H),8.41(s,1H),8.05(d,J=8.1Hz,1H),7.38-7.21(m,3H),7.16(d,J=7.5Hz,1H),7.01-6.85(m,3H),4.56 (s,2H),4.42(t,J=9.1Hz,4H),3.98(s,3H),3.71(s,1H),3.36(s,3H),2.10(s,3H),1.93(s,3H). MS:(ES)C 32 H 32 FN 4 O 6 [M+H] + The calculated m / z for this compound was 589.2, and the measured value was 589.2.

[0253] Example 122: N-(4″-(aminomethyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] Step a: To a mixture of 1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (0.3 g, 2.35 mmol), 3-bromo-2-methylaniline (0.43 g, 2.35 mmol) in DMF (8 mL) was added HATU (1.34 g, 3.52 mmol) and diisopropylethylamine (0.75 g, 5.87 mmol). The reaction was stirred at room temperature for 16 hours. After completion of the reaction, half of the solvent was removed and diluted with water (15 ml). The mixture was stirred for 20 minutes, then the solid was filtered, washed with water (10 ml) and dried under vacuum to give N-(3-bromo-2-methylphenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide.

[0254] Step b: N-(3-bromo-2-methylphenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (100 mg, 0.31 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 (146 mg, 0.31 mmol) and 2M K 2 CO 3 To a mixture of (0.38 mL, 0.77 mmol) of Pd(dppf)Cl in p-dioxane (4 mL) with dichloromethane 2 The complex (26 mg, 0.032 mmol) was added. The reaction mixture was degassed (N 2 ) and N 2 The reaction mixture was stirred at 95 °C for 4 h under reduced pressure, and the mixture was diluted with EtOAc, filtered through Celite, washed with brine, and diluted with MgSO 4The solvent was removed under reduced pressure and the residue was purified by silica gel flash chromatography (5-20%-60% EtOAc / hexanes) to give tert-butyl ((3″-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-3-fluoro-5-methoxy-2′,2″-dimethyl-“1,1′:3′,1″-terphenyl]-4-yl)methyl)carbamate.

[0255] Step c: To a stirred solution of tert-butyl ((3″-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-3-fluoro-5-methoxy-2′,2″-dimethyl-[1,1′:3′,1″-terphenyl]-4-yl)methyl)carbamate (75 mg, 0.123 mmol) in anhydrous dichloromethane (2.5 mL) at room temperature was added TFA (141 mg, 1.23 mmol) dropwise over 5 min. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the solvent was removed in vacuo to give a viscous compound, which was purified by HPLC (MeCN / H 2 O containing 0.1% TFA). 2 0) to give N-(4″-(aminomethyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD 3 OD) δ 11.16(s,1H),8.63(s,1H),8.05(d,J=6.2Hz,1H),7.37-7.21(m,3H),7.15(d,J=7.4,1.5Hz,1H), 7.01-6.85(m,3H),4.22(s,2H),3.97(s,3H),3.55(s,3H),3.39(s,3H),2.09(s,3H),1.93(s,3H). MS:(ES)C 29 H 30 FN 4 O 4 [M+H] + The calculated m / z for this compound was 517.2, and the measured value was 500.1 [M-17].

[0256] Example 123: (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((6-oxopiperidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] Step a: N-(3-bromo-2-methylphenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (500 mg, 1.48 mmol), 3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-"1,1'-biphenyl"-4-carbaldehyde (939 mg, 2.53 mmol) and 2M K 2 CO 3 To a mixture of (1.85 mL, 3.7 mmol) of Pd(dppf)Cl in p-dioxane (10 mL) with dichloromethane 2 The complex (121 mg, 0.148 mmol) was added. The reaction mixture was degassed (N 2 ) and N 2 The reaction mixture was stirred at 95 °C for 5 h under 5% CO. The reaction mixture was diluted with EtOAc, filtered through Celite, washed with brine, and washed with MgSO. 4 The solvent was removed under reduced pressure and the residue was purified by silica gel flash chromatography (5-20%-40% EtOAc / Hexanes) to give N-(3''-fluoro-4''-formyl-5''-methoxy-2,2'-dimethyl)-[1,1':3',1''-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. MS: (ES) C 29 H 27 FN 3 O 5 [M+H] + The calculated m / z for this compound was 516.2, and the measured value was 516.2.

[0257] Step b: In a solution of N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (40 mg, 0.079 mmol) and (R)-5-aminopiperidin-2-one (20 mg, 0.16 mmol) in MeOH:DCE (2 mL) was added NaBH(OAc) under stirring. 3 (45 mg, 0.16 mmol) and AcOH (4 drops) were added. The reaction mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC (0-40%-100% MeCN / HO) to give a white solid of (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((6-oxopiperidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD 3 OD) δ 11.16(s,1H),8.63(s,1H),8.05(d,J=6.2Hz,1H),7.37-7.21(m,3H),7.15(d,J=6 .2Hz,1H),7.01-6.85(m,3H),4.41(dd,J=13.7,5.1Hz,2H),4.00(s,3H),3.77-3. 55(m,2H),3.54(s,3H),3.50-3.45(m,1H),3.38(s,3H),3.31-3.29(m,1H),2.50( t,J=7.2Hz,1H),2.42-2.35(m,1H),2.15-2.05(m,1H),2.09(s,3H),1.93(s,3H). MS:(ES)C 34 H 37 FN 5 O 5 [M+H] + The calculated m / z for this compound was 614.3, and the measured value was 614.2.

[0258] Example 124: (S)—N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((6-oxopiperidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step b of Example 123. The compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, (S)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((6-oxopiperidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.16(s,1H),8.63(s,1H),8.05(d,J=6.2Hz,1H),7.37-7.21(m,3H),7.15( d,J=6.2Hz,1H),7.01-6.85(m,3H),4.41(dd,J=13.7,5.1Hz,2H),4.00(s,3 H),3.77-3.55(m,2H),3.54(s,3H),3.50-3.45(m,1H),3.38(s,3H),2.50(t,J =7.2Hz,2H),2.42-2.35(m,1H),2.12-2.07(m,1H),2.10(s,3H),1.93(s,3H). MS:(ES)C 34 H 37 FN 5 O 5 [M+H] +The calculated m / z for this compound was 614.3, and the measured value was 614.2.

[0259] Example 125: N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((((1-methyl-1H-pyrazol-5-yl)methyl)amino)-methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step b of Example 123. The compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((((1-methyl-1H-pyrazol-5-yl)methyl)amino)-methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 O.D.) δ11.15(s,1H),8.62(s,1H),8.04(d,J=8.1Hz,1H),7.54(d,J=2.1Hz,1H),7. 38-7.21(m,3H),7.14(dd,J=7.4,1.2Hz,1H),6.96(d,J=7.0Hz,1H),6.93(s,1 H),6.88(d,J=9.7Hz,1H),6.56(d,J=2.0Hz,1H),4.49(s,2H),4.40(s,2H),3 .97(s,3H),3.92(s,3H),3.55(s,3H),3.38(s,3H),2.10(s,3H),1.93(s,3H). MS:(ES)C 34 H36 FN 6 O 4 [M+H] + The calculated m / z was 611.3, and the measured value was 611.2.

[0260] Example 126: N-(4″-(((2,5-dioxopyrrolidin-3-yl)amino)methyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step b of Example 123. The compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(4″-(((2,5-dioxopyrrolidin-3-yl)amino)methyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3OD) δ 11.16(s,1H),8.62(s,1H),8.04(d,J=6.2Hz,1H),7.37-7.21(m,3H),7.15(d,J=6.2Hz,1H),7.01-6.85(m,3H),4.68-4.59(m,2H),4.43(d,J =13.7Hz,1H),3.99(s,3H),3.54(s,3H),3.31(s,3H),3.16(dd,J=18.0,9.0Hz,1H),2.80(dd,J=18.0,5.9Hz,1H),2.09(s,3H),1.93(s,3H). MS:(ES)C 33 H 33 FN 5 O 6 [M+H] + The calculated m / z for this compound was 614.2, and the measured value was 614.2.

[0261] Example 127: N-(4″-((((2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)methyl)amino)methyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step b of Example 123. The compound was purified by HPLC (MeCN / H with 0.1% TFA). 20) to give the desired product, N-(4″-((((2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)methyl)amino)methyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 O.D.) δ11.16(s,1H),8.62(s,1H),8.04(d,J=8.1Hz,1H),7.65(s,1H),7.38-7.21(m,3H),7.15(d,J=6.2Hz,1H),6.96(d,J=7.8Hz,1H), 6.91(s,1H),6.83(d,J=10.2Hz,1H),4.33(s,2H),4.00(s,2H),3.98(s,3H),3.55(s,3H),3.31(s,3H),2.10(s,3H),1.93(s,3H). MS:(ES)C 34 H 34 FN 6 O 6 [M+H] + The calculated m / z for this compound was 641.2, and the measured value was 641.2.

[0262] Example 128: N-(4″-((((1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)methyl)-amino)methyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in step b of Example 123. The compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(4″-((((1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)methyl)-amino)methyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide as a white solid. 1 H NMR (400MHz, CD 3 O.D.) 11.16(s,1H),8.62(s,1H),8.07(d,J=8.2Hz,1H),7.83(s,1H),7.38-7.21(m,3H),7.15(d,J=6.2Hz,1H),6.95(d,J=7.8Hz,1H),6.92(s ,1H),6.84(d,J=10.2Hz,1H),4.34(s,2H),4.03(s,2H),3.98(s,3H),3.55(s,3H),3.38(s,3H),3.30(s,6H),2.10(s,3H),1.93(s,3H). MS:(ES)C 36 H 38 FN 6 O 6 [M+H] + The calculated m / z was 669.3, and the measured value was 669.2.

[0263] Example 129: (S)—N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((5-oxopyrrolidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide [ka] Step a: To a solution of 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid (380 mg, 2.4 mmol) in anhydrous DMF (7 mL) was added methyl iodide (1.2 mL, 19 mmol) and potassium carbonate (2.0 g, 14 mmol) at room temperature under stirring. After stirring at 60° C. for 2 h, the mixture was poured into water (25 mL) and diluted with 60 mL of CHCl. 3 The crude material was purified by silica gel chromatography (45-60% EtOAc / Hexanes) to give the desired product, methyl 2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylate.

[0264] Step b: In a vial containing methyl 2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylate (284 mg, 1.4 mmol), acetic acid (2 mL) and 12 M HCl (2 mL) were added at room temperature. The mixture was heated at 60° C. for 2 hours, then concentrated under reduced pressure and dried in vacuum. The residue, methyl 2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylate, was used in the next step without purification.

[0265] Step c: To a mixture of 2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid (238 mg, 1.28 mmol) and 3-bromo-2-methylaniline (287 mg, 1.54 mmol) in DMF (6.0 mL) was added HATU (730 mg, 1.92 mmol) along with diisopropylethylamine (330 mg, 2.56 mmol). The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was removed by half and diluted with water (15 mL) and the mixture was stirred for 20 minutes. The solid was filtered, washed with water (10 ml) and dried under vacuum to give a white solid of N-(3-bromo-2-methylphenyl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide.

[0266] Step d: N-(3-bromo-2-methylphenyl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (450 mg, 1.27 mmol), 3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (550 mg, 1.27 mmol), and K 2 CO 3 (500mg, 3.17mmol) in p-dioxane / H 2 Pd(dppf)Cl with dichloromethane in 2H2O (9:1 mL) 2 The complex (120 mg, 0.127 mmol) was added. The reaction mixture was degassed (N 2 ) and N 2 The reaction mixture was stirred at 95 °C for 5 h under 5% CO. The reaction mixture was diluted with EtOAc, filtered through Celite, washed with brine, and washed with MgSO. 4The solvent was removed under reduced pressure and the residue was purified by silica gel flash chromatography (20% to 100% EtOAc / Hexanes) to give N-(3''-fluoro-4''-formyl-5''-methoxy-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide. MS: (ES) C 28 H 26 FN 4 O 5 [M+H] + The calculated m / z for this compound was 517.2, and the measured value was 517.2.

[0267] Step e: To a stirred solution of N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide (125 mg, 0.32 mmol) and (S)-4-aminopyrrolidin-2-one hydrochloride (23 mg, 0.155 mmol) in MeOH:DCE (1:1 mL) was added diisopropylethylamine (25 mg, 0.231 mmol), NaBH(OAc), 3 (49 mg, 0.231 mmol) and AcOH (5 drops) were added. The reaction mixture was stirred at room temperature for 3 h. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC (0%-40%-100% MeCN / H 2 0) to give a white solid of (S)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((5-oxopyrrolidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide. 1 H NMR (400MHz, CD 3OD) δ 11.08(s,1H),8.07(d,J=8.2Hz,1H),7.37-7.29(m,2H),7.24(d,J=7.8Hz,1H),7.16(d,J=8.2H z,1H),7.01(d,J=7.8Hz,1H),6.95(s,1H),6.88(d,J=9.8Hz,1H),4.36(s,2H),4.26-4.20(m,1 H),3.99(s,3H),3.87(dd,J=11.7,7.8Hz,1H),3.77(s,3H),3.56(dd,J=11.4,4.0Hz,1H),3.38 (s,3H),2.92(dd,J=18.6,4.7Hz,1H),2.52(dd,J=18.0,4.7Hz,1H),2.11(s,3H),1.94(s,3H). MS:(ES)C 32 H 34 FN 6 O 5 [M+H] + The calculated m / z is 601.3, and the measured value is 601.2.

[0268] Example 130: (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((5-oxopyrrolidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide and (S)-4-aminopyrrolidin-2-one-hydrochloride-carboxamide using a procedure similar to that described in step e of Example 129. The compound was purified by HPLC (MeCN / H 2 O containing 0.1% TFA). 20) to give the desired product, (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((5-oxopyrrolidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.07(s,1H),8.05(t,J=7.8Hz,1H),7.37-7.29(m,2H),7.24(d,J=8.2Hz,1H),7.16(d ,J=7.4Hz,1H),7.01(d,J=7.8Hz,1H),6.94(s,1H),6.88(d,J=9.3Hz,1H),4.36(s,2H) ,4.26-4.20(m,1H),3.99(s,3H),3.92-3.85(m,1H),3.77(s,3H),3.60-3.50(m,1H),3 .38(s,3H),2.92(dd,J=18.0,9.0Hz,1H),2.60-2.52(m,1H),2.11(s,3H),1.94(s,3H). MS:(ES)C 32 H 34 FN 6 O 5 [M+H] + The calculated m / z is 601.3, and the measured value is 601.2.

[0269] Example 131: (S)—N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide and (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride using a procedure similar to that described in step e of Example 129. The compound was purified by HPLC (MeCN / H2O containing 0.1% TFA). 2 0) to give the desired product, (S)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.08(s,1H),8.07(t,J=7.8Hz,1H),7.37-7.26(m,2H),7.24(d,J=8.2Hz,1H), 7.16(d,J=7.8Hz,1H),7.01(d,J=7.2Hz,1H),6.95(s,1H),6.88(d,J=9.4Hz,1H ),4.40(s,2H),4.10-4.02(m,1H),4.00(s,3H),3.77(s,3H),3.39(s,3H),3.30 -3.25(m,2H),2.46-2.34(m,3H),2.11(s,3H),1.94(s,3H),1.92-1.89(m,1H). MS:(ES)C 32 H 36 FN 6 O 5 [M+H] + The calculated m / z was 615.3, and the measured value was 615.2.

[0270] Example 132: (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide and (R)-5-(aminomethyl)pyrrolidin-2-one hydrochloride using a procedure similar to that described in step e of Example 129. The compound was purified by HPLC (MeCN / H2O containing 0.1% TFA). 2 0) to give the desired product, (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.08(s,1H),8.07(t,J=8.2Hz,1H),7.37-7.26(m,2H),7.24(d,J=8.2Hz,1H), 7.16(d,J=7.8Hz,1H),7.01(d,J=7.8Hz,1H),6.95(s,1H),6.88(d,J=9.0Hz,1H ),4.39(s,2H),4.05-4.00(m,1H),3.99(s,3H),3.77(s,3H),3.38(s,3H),3.30 -3.20(m,2H),2.46-2.34(m,3H),2.11(s,3H),1.94(s,3H),1.92-1.89(m,1H). MS:(ES)C 32 H 36FN 6 O 5 [M+H] + The calculated m / z was 615.3, and the measured value was 615.2.

[0271] Example 133: (S)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((methyl(5-oxopyrrolidin-2-yl)-methyl)amino)methyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using a procedure similar to that described in step e of Example 129. The compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, (S)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((methyl(5-oxopyrrolidin-2-yl)-methyl)amino)methyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3OD) δ 11.08(s,1H),8.07(t,J=8.5Hz,1H),7.37-7.22(m,3H),7.17(d,J=7.1Hz,1H) ,7.01(d,J=8.2Hz,1H),6.99(s,1H),6.93(d,J=9.7Hz,1H),4.65-4.55(m,1H) ,4.50-4.42(m,2H),4.30-4.20(m,2H),4.01(s,3H),3.77(s,3H),3.38(s,3H) ,2.94(s,3H),2.55-2.30(m,3H),2.11(s,3H),1.95(s,3H),1.90-1.85(m,1H). MS:(ES)C 34 H 38 FN 6 O 5 [M+H] + The calculated m / z was 629.3, and the measured value was 629.2.

[0272] Example 134: (S)—N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((6-oxopiperidin-3-yl)amino)methyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide and (S)-5-aminopiperidin-2-one using a procedure similar to that described in step e of Example 129. The compound was purified by HPLC (MeCN / H with 0.1% TFA). 20) to give the desired product, (S)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((6-oxopiperidin-3-yl)amino)methyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.09(s,1H),8.07(t,J=7.8Hz,1H),7.37-7.26(m,2H),7.24(d,J=7.0Hz,1H),7.16(d,J =7.8Hz,1H),7.01(d,J=7.8Hz,1H),6.95(s,1H),6.88(d,J=9.7Hz,1H),4.41(dd,J=18.4, 12.9Hz,2H),3.99(s,3H),3.77(s,3H),3.75-3.70(m,1H),3.50-3.45(m,1H),3.38(s,3H) ),2.50(t,J=6.2Hz,2H),2.45-2.35(m,2H),2.11(s,3H),2.15-2.05(m,1H),1.94(s,3H). MS:(ES)C 33 H 36 FN 6 O 5 [M+H] + The calculated m / z was 615.3, and the measured value was 615.2.

[0273] Example 135: (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((6-oxopiperidin-3-yl)amino)methyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide and (R)-5-aminopiperidin-2-one using a procedure similar to that described in step e of Example 129. The compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((6-oxopiperidin-3-yl)amino)methyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.09(s,1H),8.06(t,J=8.2Hz,1H),7.37-7.26(m,2H),7.24(d,J=7.0Hz,1H),7.15(d,J =7.2Hz,1H),7.01(d,J=7.8Hz,1H),6.94(s,1H),6.88(d,J=10.1Hz,1H),4.40(dd,J=12.6 ,5.4Hz,2H),3.99(s,3H),3.77(s,3H),3.75-3.65(m,2H),3.50-3.45(m,1H),3.38(s,3H) ),2.50(t,J=7.1Hz,2H),2.45-2.35(m,1H),2.11(s,3H),2.10-2.00(m,1H),1.94(s,3H). MS:(ES)C 33 H 36 FN 6 O 5 [M+H] + The calculated m / z is 615.3, and the measured value is 615.2.

[0274] Example 136: (1S,2R)-2-(((3-fluoro-5-methoxy-2,2'-dimethyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-yl)methyl)amino)cyclopentan-1-ol [ka] 3-Fluoro-5-methoxy-2',2''-dimethyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-carbaldehyde (23 mg, 0.041 mmol), (1S,2R)-2-aminocyclopentan-1-ol hydrochloride (30 mg, 0.22 mmol), EtOH (1.5 mL). 3 A mixture of N (15 mg, 0.15 mmol) and HOAc (75 mg, 1.25 mmol) was heated at 70 °C for 0.5 h. The mixture was cooled to 0 °C and NaBH(OAc) 3 (70 mg, 0.33 mmol) was added. After stirring at room temperature for 30 min, the mixture was concentrated in vacuo. The resulting residue was purified by HPLC (MeCN / H 2 0) to give (1S,2R)-2-(((3-fluoro-5-methoxy-2,2′-dimethyl-3″-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)amino)cyclopentan-1-ol (TFA salt). 1 H NMR (400MHz, CD 3OD) δ 9.25(d,J=2.0Hz,1H),9.06(d,J=2.0Hz,1H),7.78(d,J=7.6Hz,1H),7.60-7.51(m,2H ),7.41-7.34(m,3H),7.28(dd,J=7.6,1.2Hz,1H),7.23(dd,J=7.2,1.2Hz,1H),6.92( s,1H),6.86(dd,J=9.6,1.2Hz,1H),4.44-4.28(m,3H),3.97(s,3H),3.52-3.44(m,1H) ),2.18-2.07(m,1H),2.10(s,3H),2.02(s,3H),2.00-1.77(m,4H),1.62-1.74(m,1H). MS:(ES)C 34 H 35 FN 5 O 2 [M+H] + The calculated m / z for this compound was 564.3, and the measured value was 564.3.

[0275] Example 137: (S)—N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((2-(5-oxopyrrolidin-2-yl)ethyl)amino)methyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide and (S)-5-(2-aminoethyl)pyrrolidin-2-one hydrochloride using a procedure similar to that described in step e of Example 129. The compound was purified by HPLC (MeCN / H with 0.1% TFA). 20) to give the desired product, (S)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((2-(5-oxopyrrolidin-2-yl)ethyl)amino)methyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.08(s,1H),8.07(t,J=8.7Hz,1H),7.37-7.26(m,2H),7.24(d,J=7.0Hz,1H),7.15 (d,J=7.8Hz,1H),7.01(d,J=7.8Hz,1H),6.94(s,1H),6.87(d,J=10.2Hz,1H),4.34( s,2H),3.98(s,3H),3.77(s,3H),3.80-3.70(m,2H),3.38(s,3H),3.25-3.10(m,2H) ,2.40-2.30(m,3H),2.12(s,3H),2.10-1.95(m,1H),1.94(s,3H),1.85-1.75(m,1H). MS:(ES)C 34 H 38 FN 6 O 5 [M+H] + The calculated m / z was 629.3, and the measured value was 629.2.

[0276] Example 138: N-(4″-(((3-amino-3-oxopropyl)amino)methyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide and 3-aminopropanamide using a procedure similar to that described in step e of Example 129. The compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(4″-(((3-amino-3-oxopropyl)amino)methyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.09(s,1H),8.08(t,J=7.4Hz,1H),7.37-7.26(m,2H),7.25(d,J=6.6Hz,1H),7.15(d,J=7.1Hz,1H),7.01(d,J=7.2Hz,1H),6.93(s,1H),6.8 6(d,J=10.2Hz,1H),4.35(s,2H),3.99(s,3H),3.77(s,3H),3.38(s,3H) ),3.34-3.30(m,2H),2.70(d,J=12.0Hz,2H),2.11(s,3H),1.94(s,3H). MS:(ES)C 31 H 34 FN 6 O 5 [M+H] + The calculated m / z was 589.3, and the measured value was 589.2.

[0277] Example 139: (S)—N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((3-oxoisoxazolidin-4-yl)amino)methyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide and (S)-4-aminoisoxazolidin-3-one using a procedure similar to that described in step e of Example 129. The compound was purified by HPLC (MeCN / H2O containing 0.1% TFA). 2 0) to give the desired product, (S)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((3-oxoisoxazolidin-4-yl)amino)methyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.08(s,1H),8.07(t,J=7.8Hz,1H),7.37-7.26(m,2H),7.24(d,J=8.2Hz,1H),7.16(d,J=7.2Hz,1H),7.01(d,J=7.8Hz,1H),6.94(s,1H),6.8 5(d,J=9.7Hz,1H),4.73(s,2H),4.70-4.61(m,1H),4.39(d,J=10.7Hz, 2H),3.98(s,3H),3.77(s,3H),3.38(s,3H),2.11(s,3H),1.94(s,3H). MS:(ES)C 31 H 32 FN 6 O 6 [M+H] + The calculated m / z for this compound was 603.2, and the measured value was 603.2.

[0278] Example 140: (S)—N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((2-oxopiperidin-3-yl)amino)methyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide and (S)-3-aminopiperidin-2-one hydrochloride using a procedure similar to that described in step e of Example 129. The compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, (S)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((2-oxopiperidin-3-yl)amino)methyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.08(s,1H),8.07(t,J=8.2Hz,1H),7.37-7.26(m,2H),7.15(d,J=7.2Hz,1H),7. 01(d,J=8.2Hz,1H),6.92(s,1H),6.85(d,J=10.5Hz,1H),4.49(d,J=13.2Hz,1H),4 .40(d,J=13.1Hz,1H),4.05-3.90(m,1H),3.99(s,3H),3.77(s,3H),3.38(s,3H),3 .37-3.15(m,2H),2.45-2.38(m,1H),2.12(s,3H),2.01-1.97(m,3H),1.94(s,3H). MS:(ES)C 33 H 36 FN6 O 5 [M+H] + The calculated m / z is 615.3, and the measured value is 615.2.

[0279] Example 141: (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((2-oxopiperidin-3-yl)amino)methyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide and (R)-3-aminopiperidin-2-one hydrochloride using a procedure similar to that described in step e of Example 129. The compound was purified by HPLC (MeCN / H2O containing 0.1% TFA). 2 0) to give the desired product, (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((2-oxopiperidin-3-yl)amino)methyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3OD) δ 11.08(s,1H),8.07(t,J=8.2Hz,1H),7.37-7.26(m,2H),7.15(d,J=7.2Hz,1H),7.01(d ,J=8.2Hz,1H),6.92(s,1H),6.85(d,J=10.5Hz,1H),4.47(d,J=13.5Hz,1H),4.37(d,J= 12.6Hz,1H),4.10-3.90(m,1H),3.99(s,3H),3.77(s,3H),3.38(s,3H),3.35-3.05(m,2 H),2.45-2.38(m,1H),2.15-2.10(m,1H),2.12(s,3H),1.90-2.00(m,2H),1.94(s,3H). MS:(ES)C 33 H 36 FN 6 O 5 [M+H] + The calculated m / z was 615.3, and the measured value was 615.2.

[0280] Example 142: (S)—N-(4″-(((2,6-dioxopiperidin-3-yl)amino)methyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide and 3-aminopiperidine-2,6-dione hydrochloride using a procedure similar to that described in step e of Example 129. The compound was purified by HPLC (MeCN / H2O containing 0.1% TFA). 20) to give the desired product, (S)-N-(4″-(((2,6-dioxopiperidin-3-yl)amino)methyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.08(s,1H),8.06(t,J=8.2Hz,1H),7.33-7.26(m,3H),7.15(d,J=7.0Hz,1 H),7.00(d,J=8.2Hz,1H),6.93(s,1H),6.87(d,J=10.1Hz,1H),4.55(d,J=14 .1Hz,1H),4.50-4.42(m,2H),3.99(s,3H),3.77(s,3H),3.38(s,3H),2.85-2 .79(m,2H),2.50-2.42(m,1H),2.30-2.20(m,1H),2.11(s,3H),1.94(s,3H). MS:(ES)C 33 H 34 FN 6 O 6 [M+H] + The calculated m / z is 629.2, and the measured value is 629.1.

[0281] Example 143: N-(4″-(((2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)methyl)amino)methyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide and 5-(aminomethyl)pyrimidine-2,4(1H,3H)-dione hydrochloride using a procedure similar to that described in step e of Example 129. The compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(4″-(((2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)methyl)amino)methyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.08(s,1H),8.07(t,J=7.8Hz,1H),7.65(s,1H),7.30(dd,J=17.2,7.8Hz,2H),7.24(d,J=7.4Hz,1H),7.14(d,J=7.0Hz,1H),7.00(d,J=7 .8Hz,1H),6.90(s,1H),6.83(d,J=9.8Hz,1H),4.33(s,2H),4.00(s,2H),3.98(s,3H),3.77(s,3H),3.38(s,3H),2.11(s,3H),1.94(s,3H). MS:(ES)C 33 H 33 FN 7 O 6 [M+H] + The calculated m / z is 642.2, and the measured value is 642.1.

[0282] Example 144: N-(4″-(((2,4-dioxohexahydropyrimidin-5-yl)amino)methyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide [ka] The compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide and 5-aminodihydropyrimidine-2,4(1H,3H)-dione using a procedure similar to that described in step e of Example 129. The compound was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, N-(4″-(((2,4-dioxohexahydropyrimidin-5-yl)amino)methyl)-3″-fluoro-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.08(s,1H),8.06(t,J=8.0Hz,1H),7.39-7.22(m,3H),7.15(d,J=7.0Hz,1H),7.00(d,J=6.2Hz,1H),6.93(s,1H),6.87(d,J=10.1Hz,1H ),4.66-4.58(m,1H),4.55-4.42(m,2H),3.99(s,3H),3.86-3.75(m,4H),3.55(t,J=12.2Hz,1H),3.38(s,3H),2.12(s,3H),1.94(s,3H). MS:(ES)C 32 H 33 FN 7 O 6 [M+H]+ The calculated m / z for this compound was 630.2, and the measured value was 630.2.

[0283] Example 145: (S)—N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((5-oxopyrrolidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] To a solution of N-(3''-fluoro-4''-formyl-5''-methoxy-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (46 mg, 0.089 mmol) in 1:1 MeOH:DCE (2 mL) was added (S)-4-aminopyrrolidin-2-one (28 mg, 0.28 mmol). After stirring at room temperature for 75 min, sodium triacetoxyborohydride (82 mg, 0.39 mmol) was added. The reaction mixture was concentrated in vacuo and the crude residue was purified by HPLC (MeCN / H2O with 0.1% TFA). 2 0) to give (S)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((5-oxypyrrolidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (TFA salt). 1 H NMR (400MHz, CD 3OD) δ 11.17(s,1H),8.63(s,1H),8.06(d,J=7.9Hz,1H),7.38-7.21(m,3H),7.16(d, J=7.7Hz,1H),7.00-6.86(m,3H),4.37(s,2H),4.23(m,1H),4.00(s,3H),3.88 (dd,J=11.7,7.6Hz,1H),3.60-3.55(m,1H),3.55(s,3H),3.39(s,3H),2.91(d d,J=17.8,8.8Hz,1H),2.55(dd,J=17.8,4.7Hz,1H),2.09(s,3H),1.94(s,3H). MS:(ES)C 33 H 35 FN 5 O 5 [M+H] + The calculated m / z was 600.3, and the measured value was 600.3.

[0284] Example 146: (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((5-oxopyrrolidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] Using a procedure similar to that described in the step of Example 145, this compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The compound obtained was purified by HPLC (MeCN / H containing 0.1% TFA). 20) to give the desired product, (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((5-oxopyrrolidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 11.16(s,1H),8.63(s,1H),8.06(d,J=8.2Hz,1H),7.38-7.21(m,3H),7.16(d, J=7.5Hz,1H),7.00-6.86(m,3H),4.37(s,2H),4.23(m,1H),4.00(s,3H),3.88 (dd,J=11.7,7.6Hz,1H),3.60-3.55(m,1H),3.55(s,3H),3.39(s,3H),2.91(d d,J=17.8,8.8Hz,1H),2.55(dd,J=17.8,4.7Hz,1H),2.09(s,3H),1.94(s,3H). MS:(ES)C 33 H 35 FN 5 O 5 [M+H] + The calculated m / z was 600.3, and the measured value was 600.2.

[0285] Example 147: (S)—N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((methyl(5-oxopyrrolidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] To a solution of (S)-N-(3''-fluoro-5''-methoxy-2,2'-dimethyl-4''-(((5-oxopyrrolidin-3-yl)amino)methyl)-[1,1':3',1''-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (87 mg, 0.15 mmol) in 1:1 MeOH:DCE (2 mL) was added 37% aqueous formalin (210 mg, 2.6 mmol). After stirring at room temperature for 30 min, sodium triacetoxyborohydride (128 mg, 0.60 mmol) was added. After stirring for a further 18 h, the solvent was removed under reduced pressure and the residue was purified by HPLC (MeCN / H2O with 0.1% TFA). 2 0) to give the desired product, (S)—N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((methyl(5-oxopyrrolidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD 3 OD) δ 11.16(s,1H),8.63(s,1H),8.06(d,J=7.7Hz,1H),7.39-7.23(m,3H),7.21- 7.13(m,1H),7.01-6.90(m,3H),4.47(s,2H),4.43-4.35(m,1H),4.01(s,3H) ,3.93(bs,1H),3.75(dd,J=11.6,5.1Hz,1H),3.55(s,3H),3.39(s,3H),2.97 -2.88(m,1H),2.91(s,3H),2.81(d,J=6.0Hz,1H),2.10(s,3H),1.95(s,3H). MS:(ES)C 34 H 37 FN 5 O 5 [M+H] + The calculated m / z was 614.3, and the measured value was 614.2.

[0286] Example 148: (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((methyl(5-oxopyrrolidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] Using a procedure similar to that described in the step of Example 147, this compound was prepared from (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((5-oxopyrrolidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The compound obtained was purified by HPLC (MeCN / H containing 0.1% TFA). 2 0) to give the desired product, (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((methyl(5-oxopyrrolidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD 3 OD) δ 11.16(s,1H),8.63(s,1H),8.06(d,J=7.7Hz,1H),7.39-7.23(m,3H),7.21- 7.13(m,1H),7.01-6.90(m,3H),4.47(s,2H),4.43-4.35(m,1H),4.01(s,3H) ,3.93(bs,1H),3.75(dd,J=11.6,5.1Hz,1H),3.55(s,3H),3.39(s,3H),2.97 -2.88(m,1H),2.91(s,3H),2.81(d,J=6.0Hz,1H),2.10(s,3H),1.95(s,3H). MS:(ES)C 34 H 37 FN 5 O 5 [M+H]+ The calculated m / z was 614.3, and the measured value was 614.2.

[0287] Example 149: (S)—N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] To a solution of N-(3''-fluoro-4''-formyl-5''-methoxy-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (46 mg, 0.089 mmol) in 1:1 MeOH:DCE (2 mL) was added (S)-5-aminomethylpyrrolidin-2-one hydrochloride (57 mg, 0.38 mmol) and diisopropylethylamine (0.066 mL, 0.38 mmol). The mixture was stirred at room temperature for 1 h, at which point sodium triacetoxyborohydride (111 mg, 0.52 mmol) was added. After stirring at room temperature for 2 days, the solvent was removed under reduced pressure and the residue was purified by HPLC (MeCN / H2O with 0.1% TFA). 2 0) to give the desired product, (S)—N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD 3OD) δ 11.17(s,1H),8.63(s,1H),8.06(d,J=7.7Hz,1H),7.38-7.21(m,3H),7.16(d,J=7.4Hz,1H),7.00-6.86(m,3H),4.40(s,2H),4.0 8-4.03(m,1H),4.00(s,3H),3.55(s,3H),3.39(s,3H),3.26(dd,J=6.2,2.0Hz,2H),2.46-2.34(m,3H),2.09(s,3H),1.94(s,4H). MS:(ES)C 34 H 37 FN 5 O 5 [M+H] + The calculated m / z for this compound was 614.3, and the measured value was 614.3.

[0288] Example 150: (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] Using a procedure similar to that described in the step of Example 149, this compound was prepared from N-(3″-fluoro-4″-formyl-5″-methoxy-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The compound obtained was purified by HPLC (MeCN / H containing 0.1% TFA). 2 0) to give the desired product, (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD3 OD) δ 11.17(s,1H),8.63(s,1H),8.06(d,J=7.7Hz,1H),7.38-7.21(m,3H),7.16(d,J=7.4Hz,1H),7.00-6.86(m,3H),4.40(s,2H),4.0 8-4.03(m,1H),4.00(s,3H),3.55(s,3H),3.39(s,3H),3.26(dd,J=6.2,2.0Hz,2H),2.46-2.34(m,3H),2.09(s,3H),1.94(s,4H). MS:(ES)C 34 H 37 FN 5 O 5 [M+H] + The calculated m / z for this compound was 614.3, and the measured value was 614.2.

[0289] Example 151: (S)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((methyl(5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] To a solution of N-(3''-fluoro-4''-formyl-5''-methoxy-2,2'-dimethyl-[1,1':3',1''-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (46 mg, 0.089 mmol) in 1:1 MeOH:DCE (2 mL) was added (5S)-5-[(methylamino)methyl]pyrrolidin-2-one hydrochloride (58 mg, 0.35 mmol) and diisopropylethylamine (0.061 mL, 0.35 mmol). After stirring at room temperature for 1 h, sodium triacetoxyborohydride (78 mg, 0.37 mmol) was added and the reaction mixture was stirred for an additional 2 days. The solvent was removed under reduced pressure and the residue was purified by HPLC (MeCN / H2O with 0.1% TFA). 20) to give (S)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((methyl(5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD 3 OD) δ 8.63(s,1H),8.08(d,J=7.5Hz,1H),7.34(t,J=7.6Hz,1H),7.30-7.25(m,2H),7.17(dd,J=7.4,1.5Hz,1 H),7.02-6.92(m,3H),4.49(bs,2H),4.27(bs,1H),4.01(s,3H),3.55(s,3H),3.44(bs,2H),3.38(s,3H) 2.95(s,3H),2.53-2.33(m,3H),2.10(s,3H),1.95(s,3H),1.94(bs,1H). MS:(ES)C 35 H 39 FN 5 O 5 [M+H] + The calculated m / z for this compound was 628.3, and the measured value was 628.3.

[0290] Example 152: (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((methyl(5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] The compound was prepared from (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(((5-oxopyrrolidin-2yl)methyl)amino)methyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide using a procedure similar to that described in Example 147. The compound obtained was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product, (R)-N-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-((methyl(5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD 3 OD) δ 11.17(s,1H),8.63(s,1H),8.08(d,J=7.5Hz,1H),7.34(t,J=7.6Hz,1H),7.30-7.25(m,2H),7.17(dd,J=7.4,1 .5Hz,1H),7.02-6.92(m,3H),4.49(bs,2H),4.27(bs,1H),4.01(s,3H),3.55(s,3H),3.44(bs,2H),3.38(s,3H) 2.95(s,3H),2.53-2.33(m,3H),2.10(s,3H),1.95(s,3H),1.94(bs,1H). MS:(ES)C 35 H 39 FN 5 O 5 [M+H] + The calculated m / z for this compound was 628.3, and the measured value was 628.3.

[0291] Example 153: (S)-4-(((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-yl)methyl)amino)pyrrolidin-2-one [ka] Step a: In a 100 mL round bottom flask, 5-chloropyrido[3,4-b]pyrazine (1.1 g, 6.6 mmol), 3-bromo-2-methylaniline (2.9 g, 16 mmol), cesium carbonate (6.6 g, 20 mmol) and DMSO (25 mL) were combined and mixed. The mixture was stirred at 60 °C for 42 h. After cooling to room temperature, the reaction mixture was poured into water (100 mL) and extracted with 20% THF in EtOAc (3 x 200 mL). The combined extracts were concentrated and the residue was purified by silica gel flash chromatography (6-25% EtOAc / hexanes) to give N-(3-bromo-2-methylphenyl)pyrido[3,4-b]pyrazin-5-amine.

[0292] Step b: N-(3-bromo-2-methylphenyl)pyrido[3,4-b]pyrazin-5-amine (700 mg, 2.2 mmol), 3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (1.0 g, 2.7 mmol) and 2M K in p-dioxane (10 mL). 2 CO 3 To a mixture of (2.5 mL, 5.0 mmol) Pd(dppf)Cl with dichloromethane 2 The complex (300 mg, 0.37 mmol) was added. The mixture was then cooled to 5°C. 2 The mixture was degassed at rt and then stirred at 90 °C for 2 h. After cooling to room temperature, the mixture was diluted with ethyl acetate and water. The organic phase was concentrated and purified by silica gel flash chromatography (16-100% EtOAc / Hexanes, then 10% MeOH / DCM) followed by a second silica gel flash chromatography (4-6% EtOAc / DCM) to give the desired product, 3-fluoro-5-methoxy-2',2''-dimethyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-carbaldehyde.

[0293] Step c: In a 40 mL round bottom flask, 3-fluoro-5-methoxy-2',2''-dimethyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-carbaldehyde (44 mg, 0.092 mmol), (S)-4-amino-2-pyrrolidinone (54 mg, 0.54 mmol), and 1:1 MeOH:DCE (2 mL) were mixed. The mixture was heated until completely dissolved and then stirred at room temperature for 30 min. Sodium triacetoxyborohydride (82 mg, 0.39 mmol) was added and the mixture was stirred for an additional 1.5 h. The solvent was removed under reduced pressure and the residue was purified by HPLC (MeCN / H2O with 0.1% TFA). 2 0) to give (S)-4-(((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-yl)methyl)amino)pyrrolidin-2-one. 1 H NMR (400MHz, CD 3 OD) δ 9.23(d,J=2.0Hz,1H),9.04(d,J=2.0Hz,1H),7.80(d,J=7.1Hz,1H),7.65-7.58(m,1 H),7.57-7.48(m,1H),7.42-7.20(m,5H),6.98-6.86(m,2H),4.37(s,2H),4.27-4.1 9(m,1H),3.99(s,3H),3.88(dd,J=11.6,7.6Hz,1H),3.58(dd,J=11.6,3.9Hz,1H),2 .90(dd,J=17.8,8.8Hz,1H),2.56(dd,J=17.8,4.7Hz,1H),2.10(s,3H),2.01(s,3H). MS:(ES)C 33 H 32 FN 6 O 2 [M+H] + The calculated m / z for this compound was 563.3, and the measured value was 563.3.

[0294] Example 154: (S)-5-((((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-yl)methyl)amino)methyl)pyrrolidin-2-one [ka] This compound was prepared from 3-fluoro-5-methoxy-2',2''-dimethyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-carbaldehyde and (S)-5-aminomethylpyrrolidin-2-one hydrochloride using a procedure similar to that described in step c of Example 153. The product was purified by HPLC (MeCN / H2O containing 0.1% TFA). 2 0) to give (S)-5-((((3-fluoro-5-methoxy-2',2''-dimethyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-yl)methyl)amino)methyl)pyrrolidin-2-one. 1 H NMR (400MHz, CD 3 OD) δ 9.24(d,J=2.0Hz,1H),9.05(d,J=2.0Hz,1H),7.79(d,J=7.1Hz,1H),7.6 4-7.49(m,2H),7.42-7.33(m,3H),7.26(ddd,J=19.6,7.6,1.5Hz,2H),6. 98-6.85(m,2H),4.40(s,2H),4.10-4.02(m,1H),3.99(s,3H),3.28-3.23 (m,2H),2.48-2.32(m,3H),2.10(s,3H),2.02(s,3H),1.96-1.87(m,1H). C 34 H 34 FN 6 O 2 [M+H] + The calculated m / z was 577.3, and the measured value was 577.2.

[0295] Example 155: (S)-4-(((2″-chloro-3-fluoro-5-methoxy-2′-methyl-3″-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)amino)pyrrolidin-2-one [ka] Step a: A mixture of 5-chloropyrido[3,4-b]pyrazine (250 mg, 1.5 mmol), 3-bromo-2-chloroaniline (800 mg, 3.9 mmol) and cesium carbonate (900 mg, 2.8 mmol) in DMSO (2.5 mL) was stirred at 60 °C for 19 h. Upon completion of the reaction, the mixture was cooled and diluted with ethyl acetate and water. The organic phase was separated and purified by silica gel flash chromatography (4-34% DCM / hexanes) followed by a second silica gel flash chromatography purification (2-10% MeOH / DCM) to give N-(3-bromo-2-chlorophenyl)pyrido[3,4-b]pyrazin-5-amine.

[0296] Step b: N-(3-bromo-2-chlorophenyl)pyrido[3,4-b]pyrazin-5-amine (320 mg, 0.94 mmol), 3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (400 mg, 1.1 mmol), and 2M K 2 CO 3 To a mixture of (1.5 mL, 3.0 mmol) of Pd(dppf)Cl in dioxane (4 mL) with dichloromethane 2 Complex (220 mg, 0.27 mmol) was added. The mixture was then cooled to 5°C. 2The mixture was degassed at rt and stirred at 90 °C for 75 min. Upon completion of the reaction, the mixture was diluted with ethyl acetate and water. The organic phase was separated, dried, and concentrated to give a residue which was purified by flash chromatography on silica gel (4-30% EtOAc / Hexanes followed by 2-5% MeOH / DCM) to give 2''-chloro-3-fluoro-5-methoxy-2'-methyl-3''-pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-carbaldehyde.

[0297] Step c: To a solution of 2″-chloro-3-fluoro-5-methoxy-2′-methyl-3″-pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′:3′,1″-terphenyl]-4-carbaldehyde (40 mg, 0.084 mmol) in 1:1 MeOH:DCE (2 mL) was added (S)-4-aminopyrrolidin-2-one (40 mg, 0.40 mmol). The mixture was stirred at room temperature for 1.5 h and sodium triacetoxyborohydride (123 mg, 0.58 mmol) was added. The mixture was stirred for an additional 20 min. The solvent was removed under reduced pressure and the residue was purified by HPLC (MeCN / H with 0.1% TFA). 2 0) to give the desired product (S)-4-(((2″-chloro-3-fluoro-5-methoxy-2′-methyl-3″-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)amino)pyrrolidin-2-one. 1 H NMR (400MHz, CD 3OD) δ 9.11(d,J=1.9Hz,1H),8.93(d,J=1.9Hz,1H),8.82-8.74(m,1H),8.27(d,J=6.3Hz,1H),7.51(t ,J=7.9Hz,1H),7.38(dd,J=9.2,6.8Hz,2H),7.33-7.21(m,2H),7.12(dd,J=7.5,1.5Hz,1H),6. 98-6.87(m,2H),4.37(s,2H),4.24(m,1H),4.00(s,3H),3.88(dd,J=11.7,7.6Hz,1H),3.57(dd ,J=11.6,3.9Hz,1H),2.91(dd,J=17.8,8.8Hz,1H),2.55(dd,J=17.8,4.6Hz,1H),2.03(s,3H). MS:(ES)C 32 H 29 FClN 6 O 2 [M+H] + The calculated m / z was 583.2, and the measured value was 583.1.

[0298] Example 156: 3-(((2″-chloro-3-fluoro-5-methoxy-2′-methyl-3″-pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)amino)-2,2-dimethylpropanamide [ka] This compound was prepared from 2″-chloro-3-fluoro-5-methoxy-2′-methyl-3″-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′:3′,1″-terphenyl]-4-carbaldehyde and 3-amino-2,2-dimethylpropanamide using a procedure similar to that described in step c of Example 155. The reaction mixture was purified by HPLC (MeCN / H2O containing 0.1% TFA). 2 0) to give the desired compound 3-(((2″-chloro-3-fluoro-5-methoxy-2′-methyl-3″-pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)amino)-2,2-dimethylpropanamide.1 H NMR (400MHz, CD 3 OD) δ 9.11(d,J=1.9Hz,1H),8.94(d,J=1.9Hz,1H),8.72(d,J=8.2Hz,1H),8.28-8.21(m,1H),7.51(t,J=7.9Hz,1H),7.42-7.21(m ,4H),7.18-7.11(m,1H),6.94(s,1H),6.91-6.83(m,1H),4.34(s,2H),4.02(s,3H),3.14(s,2H),2.04(s,3H),1.34(s,6H). MS:(ES)C 33 H 33 FClN 6 O 2 [M+H] + The calculated m / z was 599.2, and the measured value was 599.1.

[0299] Example 157: (S)-5-((((2″-chloro-3-fluoro-5-methoxy-2′-methyl-3″-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)amino)methyl)pyrrolidin-2-one [ka] This compound was prepared from 2″-chloro-3-fluoro-5-methoxy-2′-methyl-3″-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′:3′,1″-terphenyl]-4-carbaldehyde and (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride using a procedure similar to that described in step c of Example 155. The reaction mixture was purified by HPLC (MeCN / H 2 O containing 0.1% TFA). 2 0) to give the desired compound, (S)-5-((((2″-chloro-3-fluoro-5-methoxy-2′-methyl-3″-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)amino)methyl)pyrrolidin-2-one. 1 H NMR (400MHz, CD 3OD) δ 9.13(d,J=1.9Hz,1H),8.95(d,J=1.9Hz,1H),8.66(d,J=8.3Hz,1H),8.22(d,J= 6.4Hz,1H),7.53(t,J=7.9Hz,1H),7.38(dd,J=11.7,7.0Hz,2H),7.33-7.22(m, 2H),7.21-7.14(m,1H),6.98-6.86(m,2H),4.40(s,2H),4.09-4.03(m,1H),4.0 0(s,3H),3.28-3.24(m,2H),2.48-2.34(m,3H),2.04(s,3H),1.95-1.88(m,1H). MS:(ES)C 33 H 31 FClN 6 O 2 [M+H] + The calculated m / z for this compound was 597.2, and the measured value was 597.2.

[0300] Example 158: (S)—N-(2-chloro-3″-fluoro-5″-methoxy-2′-methyl-4″-(((5-oxopyrrolidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] Step a: 3-bromo-2-chloroaniline (240 mg, 1.2 mmol), 3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (370 mg, 1.0 mmol), and 2M K 2 CO 3 A mixture of (1.5 mL, 3.0 mmol) of Pd(dppf)Cl in dioxane (8 mL) with dichloromethane was 2 The complex (120 mg, 0.15 mmol) was added. The mixture was then cooled to 5°C. 2The mixture was degassed at rt and stirred at 90° C. for 2.5 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and water, and the organic phase was separated and purified by silica gel flash chromatography to give 3″-amino-3-fluoro-5-methoxy-2′,2″-dimethyl-[1,1′:3′,1″-terphenyl]-4-carbaldehyde.

[0301] Step b: To a solution of 1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonyl chloride in THF (4 mL) was added a solution of 3″-amino-3-fluoro-5-methoxy-2′,2″-dimethyl-[1,1′:3′,1″-terphenyl]-4-carbaldehyde (200 mg, 0.54 mmol) and pyridine (0.12 mmol, 1.5 mmol). The mixture was sonicated, heated briefly, and allowed to stand at room temperature for 4 days. The solvent was removed to give N-(2-chloro-3″-fluoro-4″-formyl-5″-methoxy-2′-methyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide.

[0302] Step c: A mixture of the crude aldehyde, N-(2-chloro-3″-fluoro-4″-formyl-5″-methoxy-2′-methyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (ca. 0.11 mmol) and (S)-4-aminopyrrolidin-2-one (36 mg, 0.36 mmol) in 1:1 MeOH:DCE (1.4 mL) was briefly heated, sonicated and then stirred at room temperature for 15 min. Sodium triacetoxyborohydride (81 mg, 0.38 mmol) was added and the mixture was stirred at room temperature for an additional 15 min. The solvent was removed under reduced pressure and the residue was purified by HPLC (MeCN / H2O with 0.1% TFA). 20) to give (S)-N-(2-chloro-3″-fluoro-5″-methoxy-2′-methyl-4″-(((5-oxopyrrolidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD 3 OD) δ 11.68(s,1H),8.66(s,1H),8.50(d,J=8.5Hz,1H),7.44-7.24(m,3H),7.19(d,J =7.6Hz,1H),7.09-7.02(m,1H),6.97-6.85(m,2H),4.37(s,2H),4.23(s,1H),3. 99(s,3H),3.88(dd,J=11.7,7.7Hz,1H),3.61-3.58(m,1H),3.55(s,3H),3.38( s,3H),2.91(dd,J=17.6,9.1Hz,1H),2.56(dd,J=17.7,4.6Hz,1H),1.98(s,3H). MS:(ES)C 32 H 32 FClN 5 O 5 [M+H] + The calculated m / z is 620.2, and the measured value is 620.1.

[0303] Example 159: N-(4″-(((3-amino-2,2-dimethyl-3-oxopropyl)amino)methyl)-2-chloro-3″-fluoro-5″-methoxy-2′-methyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] This compound was prepared from N-(2-chloro-3″-fluoro-4″-formyl-5″-methoxy-2′-methyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and 3-amino-2,2-dimethylpropanamide using a procedure similar to that described in step c of Example 158. The crude residue was purified by HPLC (MeCN / H2O containing 0.1% TFA). 2 0) to give the desired compound, N-(4″-(((3-amino-2,2-dimethyl-3-oxopropyl)amino)methyl)-2-chloro-3″-fluoro-5″-methoxy-2′-methyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD 3 OD) δ 11.63(s,1H),8.61(s,1H),8.45(dd,J=8.3,1.6Hz,1H),7.39-7.20(m,3H),7.17-7.10(m,1H),7.01(dd,J=7.2,1.6Hz,1H), 6.88(s,1H),6.85-6.77(m,1H),4.28(s,2H),3.96(s,3H),3.50(s,3H),3.33(s,3H),3.09(s,2H),1.93(s,3H),1.29(s,6H). MS:(ES)C 33 H 36 FClN 5 O 5 [M+H] + The calculated m / z was 636.2, and the measured value was 636.3.

[0304] Example 160: (S)—N-(2-chloro-3″-fluoro-5″-methoxy-2′-methyl-4″-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] This compound was prepared from N-(2-chloro-3″-fluoro-4″-formyl-5″-methoxy-2′-methyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (S)-5-(aminomethyl)pyrrolidin-2-one using a procedure similar to that described in step c of Example 158. The crude residue was purified by HPLC (MeCN / H2O containing 0.1% TFA). 2 0) to give the desired compound, (S)-N-(2-chloro-3″-fluoro-5″-methoxy-2′-methyl-4″-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD 3 OD) δ 11.61(s,1H),8.59(s,1H),8.47-8.40(m,1H),7.37-7.18(m,3H),7.12(d,J=7.6Hz,1H),6.99(d,J=7.7Hz,1H),6.91-6.78(m,2H),4.33( s,2H),4.03-3.95(m,1H),3.93(s,3H),3.48(s,3H),3.31(s,3H),3.25-3.16(m,2H),2.39-2.27(m,3H),1.92(s,3H),1.89-1.81(m,1H). MS:(ES)C 33 H 34 ClFN 5 O 5 [M+H] + The calculated m / z is 634.2, and the measured value is 634.1.

[0305] Example 161: (S)—N-(2-chloro-3″-fluoro-5″-methoxy-2′-methyl-4″-(((6-oxopiperidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] This compound was prepared from N-(2-chloro-3″-fluoro-4″-formyl-5″-methoxy-2′-methyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (S)-5-(aminomethyl)piperidin-2-one using a procedure similar to that described in step c of Example 158. The crude residue was purified by HPLC (MeCN / H2O containing 0.1% TFA). 2 0) to give the desired compound (S)-N-(2-chloro-3″-fluoro-5″-methoxy-2′-methyl-4″-(((6-oxopiperidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD 3 OD) δ 11.61(s,1H),8.59(s,1H),8.44(d,J=8.3Hz,1H),7.37-7.18(m,3H),7.1 6-7.09(m,1H),7.03-6.95(m,1H),6.90-6.78(m,2H),4.42-4.29(m,2H), 3.93(s,3H),3.73-3.64(m,2H),3.48(s,3H),3.45-3.36(m,1H),3.31(s, 3H), 2.44 (t, J=6.9Hz, 2H), 2.32 (bs, 1H), 2.10-1.97 (m, 1H), 1.92 (s, 3H). MS:(ES)C 33 H 34 ClFN 5 O 5 [M+H] +The calculated m / z for this compound was 634.2, and the measured value was 634.2.

[0306] Example 162: N-(2'-chloro-3''-fluoro-4''-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-5''-methoxy-2-methyl-[1,1':3',1''-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] Step a: 2-fluoro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (511 mg, 1.82 mmol), 1,3-dibromo-2-chlorobenzene (750 mg, 2.77 mmol), K 2 CO 3 (756 mg, 5.48 mmol) and Pd(dppf)Cl with dichloromethane 2 A mixture of the complex (200 mg, 0.24 mmol) in dioxane (9 mL) and water (1.3 mL) was dissolved in N 2 The mixture was stirred at 95° C. for 8 hours under reduced pressure. The mixture was cooled to room temperature and purified by silica gel flash chromatography (0-100% EtOAc / hexanes) to give 3'-bromo-2'-chloro-3-fluoro-5-methoxy-[1,1'-biphenyl]-4-carbaldehyde. MS: (ES) C 14 H 9 BrClFO 2 Na[M+Na] + The calculated m / z for this compound was 365.0, and the measured value was 365.0.

[0307] Step b: Pd(dppf)Cl with 3'-bromo-2'-chloro-3-fluoro-5-methoxy-[1,1'-biphenyl]-4-carbaldehyde (330 mg, 0.96 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (270 mg, 1.06 mmol), KOAc (236 mg, 2.40 mmol) and dichloromethane 2 A mixture of the complex (120 mg, 0.15 mmol) in dioxane (5 mL) was 2 The mixture was stirred at 95° C. for 5 h under 5% CO. The mixture was cooled to room temperature and purified by silica gel flash chromatography (0-100% EtOAc / hexanes) to give 2'-chloro-3-fluoro-5-methoxy-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde. MS: (ES) C 20 H 22 BClFO 4 [M+H] + The calculated m / z was 391.1, and the measured value was 391.0.

[0308] Step c: 2'-chloro-3-fluoro-5-methoxy-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (80 mg, 0.20 mmol), N-(3-bromo-2-methylphenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (70 mg, 0.20 mmol), K 2 CO 3 (100 mg, 0.72 mmol) and dichloromethanePd(dppf)Cl 2 A mixture of the complex (45 mg, 0.055 mmol) in dioxane (3 mL) and water (0.45 mL) was dissolved in N 2The mixture was stirred at 95° C. for 2.5 h under 100% EtOAc / hexanes. The mixture was cooled to room temperature and purified by silica gel flash chromatography (0-100% EtOAc / hexanes) to give N-(2'-chloro-3''-fluoro-4''-formyl-5''-methoxy-2-methyl-[1,1':3',1''-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. MS: (ES) C 28 H 23 ClFN 3 O 5 [M+H] + The calculated m / z for this compound was 536.1, and the measured value was 536.1.

[0309] Step d: N-(2'-chloro-3''-fluoro-4''-formyl-5''-methoxy-2-methyl-[1,1':3',1''-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (20 mg, 0.037 mmol), (3R,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (12 mg, 0.078 mmol), Et 3 A mixture of N (15 mg, 0.15 mmol) and HOAc (90 mg, 1.5 mmol) in EtOH (1.5 mL) was heated at 70 °C for 0.5 h. The mixture was cooled to 0 °C and NaBH 3 CN (45 mg, 0.71 mmol) was added. After stirring at 0° C. for 3 min, the mixture was concentrated in vacuo. The resulting residue was purified by HPLC (MeCN / H 2 0) to give N-(2'-chloro-3''-fluoro-4''-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-5''-methoxy-2-methyl-[1,1':3',1''-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (TFA salt). 1 H NMR (400MHz, CD 3OD) δ 8.62(s,1H),8.11(d,J=7.2Hz,1H),7.49(t,J=7.4Hz,1H),7.43(dd,J=7.2,2.0Hz,1H),7. 34(dd,J=7.6,2.0Hz,1H),7.29(t,J=8.0Hz,1H),7.03(s,1H),7.05-6.97(m,2H),4.41(d,J =13.2Hz,1H),4.33(d,J=13.2Hz,1H),4.07(s,1H),3.99(s,3H),4.04-3.94(m,2H),3.55( s,3H),3.60-3.42(m,3H),3.39(s,3H),2.13(s,3H),2.17-2.05(m,1H),1.90-1.85(m,1H). MS:(ES)C 33 H 35 ClFN 4 O 6 [M+H] + The calculated m / z for this compound was 637.2, and the measured value was 637.2.

[0310] Example 163: (S)—N-(2′-chloro-3″-fluoro-5″-methoxy-2-methyl-4″-(((6-oxopiperidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] N-(2'-chloro-3''-fluoro-4''-formyl-5''-methoxy-2-methyl-[1,1':3',1''-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (20 mg, 0.037 mmol), (S)-5-aminopiperidin-2-one hydrochloride (10 mg, 0.066 mmol), Et 3 A mixture of N (15 mg, 0.15 mmol) and HOAc (75 mg, 1.25 mmol) in EtOH (1.5 mL) was heated at 70 °C for 0.5 h. The mixture was cooled to 0 °C and NaBH 3CN (45 mg, 0.71 mmol) was added. After stirring at 0° C. for 3 min, the mixture was concentrated in vacuo. The resulting residue was purified by HPLC (MeCN / H 2 0) to give (S)-N-(2'-chloro-3''-fluoro-5''-methoxy-2-methyl-4''-(((6-oxopiperidin-3-yl)amino)methyl)-[1,1':3',1''-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (TFA salt). 1 H NMR (400MHz, CD 3 OD) δ 11.17(s,1H), 8.63(s,1H),8.09(d,J=7.6Hz,1H),7.49(t,J=7.4Hz,1H),7.43(dd,J=7.6,1.6Hz,1 H),7.34(dd,J=7.2,2.0Hz,1H),7.29(t,J=8.0Hz,1H),7.05(s,1H),6.97-7.20(m,2H) ),4.47-4.37(m,2H),4.01(s,3H),3.80-3.72(m,2H),3.55(s,3H),3.50-3.42(m,1H) ,3.39(s,3H),2.53-2.47(m,2H),2.44-2.34(m,1H),2.13(s,3H),2.14-2.02(m,1H). MS:(ES)C 33 H 34 ClFN 5 O 5 [M+H] + The calculated m / z for this compound was 634.2, and the measured value was 634.2.

[0311] Example 164: N-(4″-(((3-amino-2,2-dimethyl-3-oxopropyl)amino)methyl)-2′-chloro-3″-fluoro-5″-methoxy-2-methyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] A mixture of N-(2'-chloro-3''-fluoro-4''-formyl-5''-methoxy-2-methyl-[1,1':3',1''-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (25 mg, 0.046 mmol), 3-amino-2,2-dimethylpropanamide (25 mg, 0.021 mmol) and HOAc (120 mg, 2.0 mmol) in EtOH (1.5 mL) was heated at 70°C for 0.5 h. The mixture was cooled to 0°C and diluted with NaBH 3 CN (40 mg, 0.63 mmol) was added. After stirring at 0° C. for 3 min, the mixture was concentrated in vacuo. The resulting residue was purified by HPLC (MeCN / H 2 0) to give N-(4″-(((3-amino-2,2-dimethyl-3-oxopropyl)amino)methyl)-2′-chloro-3″-fluoro-5″-methoxy-2-methyl-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (TFA salt). 1 H NMR (400MHz, CD 3 O.D.) δ8.56(s,1H),8.05(d,J=8.0Hz,1H),7.43-7.34(m,2H),7.19-7.27(m,2H),6.93(d,J=7.2Hz,1H),6.87(s,1H),6.79(d ,J=9.6,1H),5.43(s,1H),3.92(s,2H),3.88(s,3H),3.49(s,3H),3.32(s,3H),2.69(s,2H),2.07(s,3H),1.14(s,6H). MS:(ES)C 33 H 36 ClFN 5 O 5 [M+H] + The calculated m / z for this compound was 636.2, and the measured value was 636.2.

[0312] Example 165: (S)—N-(2′-chloro-3″-fluoro-5″-methoxy-2-methyl-4″-(((5-oxopyrrolidin-3-yl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] A mixture of N-(2'-chloro-3''-fluoro-4''-formyl-5''-methoxy-2-methyl-[1,1':3',1''-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (19 mg, 0.035 mmol), (S)-4-aminopyrrolidin-2-one (10 mg, 0.010 mmol) and HOAc (60 mg, 1.0 mmol) in EtOH (1.5 mL) was heated at 70°C for 0.5 h. The mixture was cooled to 0°C and NaBH 3 CN (40 mg, 0.63 mmol) was added. After stirring at 0° C. for 3 min, the mixture was concentrated in vacuo. The resulting residue was purified by HPLC (MeCN / H2O with 0.1% TFA) to give (S)-N-(2'-chloro-3''-fluoro-5''-methoxy-2-methyl-4''-(((5-oxopyrrolidin-3-yl)amino)methyl)-[1,1':3',1''-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (TFA salt). 1 H NMR (400MHz, CD 3O.D. δ11.10(s,1H),8.56(s,1H),8.05(dd,J=7.2,7.2Hz,1H),7.46-7.35(m,2H),7.2 8(d,J=7.2Hz,1H),7.23(t,J=7.8Hz,1H),6.99(s,1H),6.96-6.90(m,2H),4.31( s,2H),4.18(bs,1H),3.94(s,3H),3.78-3.86(m,1H),3.60-3.40(m,1H),3.48(s ,3H),3.32(s,3H),2.85-2.80(m,1H),2.50(d,J=18.0,4.0Hz,1H),2.06(s,3H). MS:(ES)C 32 H 32 ClFN 5 O 5 [M+H] + The calculated m / z is 620.2, and the measured value is 620.1.

[0313] Example 166: (S)-N-(2'-chloro-3''-fluoro-5''-methoxy-2-methyl-4''-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1':3',1''-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] N-(2'-chloro-3''-fluoro-4''-formyl-5''-methoxy-2-methyl-[1,1':3',1''-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (22 mg, 0.040 mmol), (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride (15 mg, 0.10 mmol), Et 3 A mixture of N (15 mg, 0.15 mmol) and HOAc (75 mg, 1.25 mmol) in EtOH (1.5 mL) was heated at 70 °C for 0.5 h. The mixture was cooled to 0 °C and NaBH 3CN (45 mg, 0.71 mmol) was added. After stirring at 0° C. for 3 min, the mixture was concentrated in vacuo. The resulting residue was purified by HPLC (MeCN / H 2 0) to give (S)-N-(2'-chloro-3''-fluoro-5''-methoxy-2-methyl-4''-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1':3',1''-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (TFA salt). 1 H NMR (400MHz, CD 3 O.D.) δ11.08(s,1H),8.54(s,1H),8.02(t,J=7.0Hz,1H),7.43-7.32(m,2H),7 .25(d,J=6.8Hz,1H),7.20(t,J=8.0Hz,1H),6.97(s,1H),6.93-6.88(m,2 H),4.32(s,2H),4.10-3.93(m,1H),3.92(s,3H),3.46(s,3H),3.29(s,3H) ),3.20-3.15(m,2H),2.40-2.24(m,3H),2.04(s,3H),1.90-1.78(m,1H). MS:(ES)C 33 H 34 ClFN 5 O 5 [M+H] + The calculated m / z for this compound was 634.2, and the measured value was 634.2.

[0314] Example 167: (S)-5-((((2'-chloro-3-fluoro-5-methoxy-2''-methyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-yl)methyl)amino)methyl)pyrrolidin-2-one [ka] Step a: 2'-chloro-3-fluoro-5-methoxy-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (86 mg, 0.22 mmol), N-(3-bromo-2-methylphenyl)pyrido[3,4-b]pyrazin-5-amine (70 mg, 0.22 mmol), K 2 CO 3 (92 mg, 0.67 mmol) and Pd(dppf)Cl with dichloromethane 2 A mixture of the complex (45 mg, 0.049 mmol) in dioxane (3 mL) and water (0.45 mL) was dissolved in N 2 The mixture was stirred at 95° C. for 2 h under reduced pressure. The mixture was cooled to room temperature and purified by silica gel flash chromatography (0-100% EtOAc / hexanes) to give 2′-chloro-3-fluoro-5-methoxy-2″-methyl-3″-(pyrido[3,4-b]pyrazin-5-ylamino]-[1,1′:3′,1″-terphenyl]-4-carbaldehyde. MS: (ES) C 28 H 21 ClFN 4 O 2 [M+H] + The calculated m / z for this compound is 499.1, and the measured value is 499.0.

[0315] Step b: 2'-chloro-3-fluoro-5-methoxy-2''-methyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-carbaldehyde (20 mg, 0.040 mmol), (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride (11 mg, 0.073 mmol), Et 3 A mixture of N (15 mg, 0.15 mmol) and HOAc (90 mg, 1.5 mmol) in EtOH (1.5 mL) was heated at 70 °C for 0.5 h. The mixture was cooled to 0 °C and NaBH(OAc) 3 (50 mg, 0.24 mmol) was added. After stirring at 0° C. for 5 min, the mixture was concentrated in vacuo. The resulting residue was purified by HPLC (MeCN / H 20) to give (S)-5-((((2'-chloro-3-fluoro-5-methoxy-2''-methyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-yl)methyl)amino)methyl)pyrrolidin-2-one (TFA salt). 1 H NMR (400MHz, CD 3 OD) δ 9.01(d,J=2.0Hz,1H),8.86(d,J=2.0Hz,1H),8.14(d,J=5.6Hz,1H),8.03(d,J=7.2 ,1H),7.50-7.40(m,2H),7.40-7.32(m,2H),7.20(d,J=6.0Hz,1H),7.05(d,J=6.8H z,1H),6.91(s,1H),6.83(dd,J=10.0,1.6Hz,1H),3.91(s,3H),3.90(s,2H),3.88- 3.78(m,1H),2.73-2.60(m,2H),2.38-2.20(m,3H),2.13(s,3H),1.82-1.70(m,1H). MS:(ES)C 33 H 31 ClFN 6 O 2 [M+H] + The calculated m / z for this compound was 597.2, and the measured value was 597.2.

[0316] Example 168: (S)-4-(((2'-chloro-3-fluoro-5-methoxy-2''-methyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-yl)methyl)amino)pyrrolidin-2-one [ka] A mixture of 2'-chloro-3-fluoro-5-methoxy-2''-methyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino]-[1,1':3',1''-terphenyl]-4-carbaldehyde (26 mg, 0.052 mmol), (S)-4-aminopyrrolidin-2-one (15 mg, 0.15 mmol) and HOAc (75 mg, 1.25 mmol) in EtOH (1.5 mL) was heated at 70°C for 0.5 h. The mixture was cooled to 0°C and NaBH(OAc) 3 (45 mg, 0.21 mmol) was added. After stirring at 0° C. for 5 min, the mixture was concentrated in vacuo. The resulting residue was purified by HPLC (MeCN / H 2 0) to give (S)-4-(((2'-chloro-3-fluoro-5-methoxy-2''-methyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-yl)methyl)amino)pyrrolidin-2-one (TFA salt). 1 H NMR (400MHz, CD 3 OD) δ 9.24(d,J=2.0Hz,1H),9.05(d,J=2.0Hz,1H),7.79(d,J=7.2Hz,1H),7.63(dd,J=7.9,1.4 Hz,1H),7.58-7.51(m,2H),7.48(dd,J=7.7,1.9Hz,1H),7.44-7.37(m,3H),7.05(s,1H), 6.90(dd,J=10.4,1.2Hz,1H),4.37(s,2H),4.28-4.20(m,1H),4.00(s,3H),3.86-3.83(m,1H) ,3.58(dd,J=11.6,3.6Hz,1H),2.94-2.86(m,1H),2.57(dd,J=18.0,4.8Hz,1H),2.15(s,3H). MS:(ES)C 32 H 29 ClFN 6 O 2 [M+H] + The calculated m / z was 583.2, and the measured value was 583.2.

[0317] Example 169: (3R,4R)-4-(((2'-chloro-3-fluoro-5-methoxy-2"-methyl-3"-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1"-terphenyl]-4-yl)methyl)amino)tetrahydro-2H-pyran-3-ol [ka] 2'-Chloro-3-fluoro-5-methoxy-2''-methyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino]-[1,1':3',1''-terphenyl]-4-carbaldehyde (20 mg, 0.04 mmol), (3R,4R)-4-aminotetrahydro-2H-pyran-3-ol (13 mg, 0.085 mmol), Et 3 A mixture of N (15 mg, 0.15 mmol) and HOAc (90 mg, 1.5 mmol) in EtOH (1.5 mL) was heated at 70 °C for 0.5 h. The mixture was cooled to 0 °C and NaBH(OAc) 3 (45 mg, 0.21 mmol) was added. After stirring at 0° C. for 5 min, the mixture was concentrated in vacuo. The resulting residue was purified by HPLC (MeCN / H 2 0) to give (3R,4R)-4-(((2'-chloro-3-fluoro-5-methoxy-2''-methyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-terphenyl]-4-yl)methyl)amino)tetrahydro-2H-pyran-3-ol (TFA salt). 1 H NMR (400MHz, CD 3OD) δ 9.24(d,J=2.0Hz,1H),9.05(d,J=2.0Hz,1H),7.78(d,J=7.2Hz,1H),7.63(d,J=7.2,1.4 Hz,1H),7.58-7.51(m,2H),7.48(dd,J=7.6,2.0Hz,1H),7.43-7.37(m,3H),7.03(s,1H), 6.98(dd,J=9.6Hz,1H),4.41(d,J=13.6Hz,1H),4.32(d,J=13.2Hz,1H),4.08(s,3H),4. 10-3.94(m,3H),3.60-3.40(m,3H),2.15(s,3H),2.20-2.00(m,1H),1.95-1.91(m,1H). MS:(ES)C 33 H 31 ClFN 5 O 2 [M+H] + The calculated m / z was 583.2, and the measured value was 583.1.

[0318] Example 170: (S)-N-(2,2'-dichloro-3''-fluoro-5''-methoxy-4''-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1':3',1''-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ka] Step a: 2'-chloro-3-fluoro-5-methoxy-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (110 mg, 0.28 mmol), N-(3-bromo-2-chlorophenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (110 mg, 0.30 mmol), K 2 CO 3 (116 mg, 0.84 mmol) and Pd(dppf)Cl with dichloromethane 2 A mixture of the complex (45 mg, 0.055 mmol) in dioxane (3 mL) and water (0.45 mL) was dissolved in N2 The mixture was stirred at 95° C. for 3 h under reduced pressure. The mixture was cooled to room temperature and purified by silica gel flash chromatography (0-100% EtOAc / hexanes) to give N-(2,2′-dichloro-3″-fluoro-4″-formyl-5″-methoxy-[1,1′:3′,1″-terphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. MS: (ES) m / z C 27 H 21 Cl 2 FN 3 O 5 [M+H] + The calculated m / z for this compound is 556.1, and the measured value is 556.0.

[0319] Step b: N-(2,2'-dichloro-3''-fluoro-4''-formyl-5''-methoxy-[1,1':3',1''-ter...

Claims

1. Compounds of formula (Ia), (Ib), (Ic), or (Id): 【Chemistry 1】 【Chemistry 2】 【Chemistry 3】 【Chemistry 4】 or a pharma- ceutically acceptable salt thereof: R 1a , R 1b , R 1C and R 1d are each independently H, halogen, or C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 selected from the group consisting of alkoxy and CN; X 1 Optionally, one or two C 1-2 Alkyl or CO 2 C substituted with H 1-3 is alkylene; R 2a and R 2b are each independently H, C 1-8 Alkyl, C 1-8 Haloalkyl, -Y, -X 2 -C(O) 2 R a , -X 2 -OR a , -X 2 -NR a R b , -X 2 -CONR a R b , -X 2 -SO 2 R a , -X 2 -SO 2 N.R. a R b , -X 2 -SO 3 R 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, SO 2 N.H. 2 , C.O.N.H. 2 ,C(O)NHOH,PO 3 H 2 , COO-C 1-8 Alkyl or CO 2 H, and each Y is optionally further substituted with one or two substituents independently selected from C 3-6 Cycloalkyl, C 4-8 heterocyclyl and 5-6 membered heteroaryl groups, 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, SO 2 N.H. 2 , C.O.N.H. 2 ,C(O)NHOH,PO 3 H 2 , COO-C 1-8 Alkyl, SO 3 H and CO 2 H; or R 2a and R 2b are combined to form a 4-10 membered ring or an 8-10 membered spiro ring, optionally with one or two additional ring vertices selected from O, N, and S, 2a and R 2b The 4- to 10-membered ring or 8- to 10-membered spiro ring formed by combining 1-8 Alkyl, C 1―8 Haloalkyl, C 1-8 Hydroxyalkyl, -X 3 -C(O) 2 R a , -X 3 -OR a , -X 3 -NR a R b , -X 3 -CONR a R b , -X 3 -SO 2 R a , -X 3 -SO 2 N.R. a R b , and -X 3 -SO 3 R a (In the formula, X 3 is a single bond or C 1-6 alkylene); R 3 and R 4 are F, Cl, CN, and CH 3 , O.C.H. 3 , C.H. 2 CH 3 and C.F. 3 are independently selected from the group consisting of: A is -N(R a )-, -C(=O)N(R a )-,-S(O)N(R a ) - and -S(O) 2 N (R a )- selected from the group consisting of; Z is selected from the group: i) optionally substituted with one or two oxo groups, and optionally up to four R a and / or R b a monocyclic, bicyclic or spirocyclic non-aromatic heterocycle substituted with ii) optionally 1 to 3 R c a monocyclic 5- or 6-membered heteroaryl ring substituted with iii) optionally 1 to 3 R c A fused bicyclic heteroaryl ring substituted with -N(R a )-, Z optionally represents 1 to 3 R c is a fused bicyclic heteroaryl ring substituted with 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-CO 2 H and C 1-6 Alkylene-SO 3 H; 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-CO 2 H and C 1-6 Alkylene-SO 3 H, each of which is independently selected from the group consisting of OH, SO 2 N.H. 2 , C.O.N.H. 2 ,C(O)NHOH,PO 3 H 2 , COO-C 1-8 Alkyl and CO 2 Optionally further substituted with 1 or 2 substituents independently selected from H; and R a and R b are optionally combined when attached to the same nitrogen atom and are optionally halogen, OH, SO 2 N.H. 2 , C.O.N.H. 2 ,C(O)NHOH,PO 3 H 2 , COO-C 1-8 Alkyl or CO 2 forming a 4-8 membered ring or an 8-10 membered spiro ring substituted with H; Each R c is H, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -Y 1 , -X 4 -C(O) 2 R a , -O-X 4 -C(O) 2 R a , -X 4 -OR a , -X 4 -NR a R b , -X 4 -CONR a R b , -O-X 4 -CONR a R b , -X 4 -SO 2 R a , -X 4 -SO 2 N.R. a R b , -X 4 -SO 3 R a , and -N(R a ) -X 4 -C(O) 2 R a wherein each X is independently selected from the group consisting of 4 is a single bond or C 1-6 alkylene), each Y 1 is C 3-6 Cycloalkyl and C 4-8 heterocyclyl; and Optionally, two R on adjacent ring vertices c or a pharma- ceutically acceptable salt thereof, wherein:

2. Compounds of formula (Ia), (Ib), (Ic), or (Id): 【Chemistry 5】 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】 or a pharma- ceutically acceptable salt thereof: R 1a , R 1b , R 1C and R 1d are each independently H, halogen, or C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 selected from the group consisting of alkoxy and CN; X 1 Optionally, one or two C 1-2 Alkyl or CO 2 C substituted with H 1-3 is an alkylene group; R 2a and R 2b are each independently H, C 1-8 Alkyl, C 1-8 Haloalkyl, -Y, -X 2 -C(O) 2 R a , -X 2 -OR a , -X 2 -NR a R b , -X 2 -CONR a R b , -X 2 -SO 2 R a , -X 2 -SO 2 N.R. a R b , -X 2 -SO 3 R 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, SO 2 N.H. 2 , C.O.N.H. 2 ,C(O)NHOH,PO 3 H 2 , COO-C 1-8 Alkyl or CO 2 H, and each Y is optionally further substituted with one or two substituents independently selected from C 3-6 Cycloalkyl, C 4-8 heterocyclyl and 5-6 membered heteroaryl groups, 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, SO 2 N.H. 2 , C.O.N.H. 2 ,C(O)NHOH,PO 3 H 2 , COO-C 1-8 Alkyl, SO 3 H and CO 2 H; or R 2a and R 2b are combined to form a 4-9 membered ring or an 8-10 membered spiro ring, optionally with one or two additional ring vertices selected from O, N, and S, 2a and R 2b The 4- to 9-membered ring or 8- to 10-membered spiro ring formed by combining 1-8 Alkyl, C 1―8 Haloalkyl, C 1-8 Hydroxyalkyl, -X 3 -C(O) 2 R a , -X 3 -OR a , -X 3 -NR a R b , -X 3 -CONR a R b , -X 3 -SO 2 R a , -X 3 -SO 2 N.R. a R b , and -X 3 -SO 3 R a (In the formula, X 3 is a single bond or C 1-6 alkylene); R 3 and R 4 are F, Cl, CN, and CH 3 , O.C.H. 3 , C.H. 2 CH 3 and C.F. 3 are independently selected from the group consisting of: A is -N(R a )-, -C(=O)N(R a )-,-S(O)N(R a ) - and -S(O) 2 N (R a )- selected from the group consisting of; Z is selected from the group: i) optionally substituted with one or two oxo groups, and optionally up to four R a and / or R b a monocyclic, bicyclic or spirocyclic non-aromatic heterocycle substituted with ii) optionally 1 to 3 R c a monocyclic 5- or 6-membered heteroaryl ring substituted with iii) optionally 1 to 3 R c A fused bicyclic heteroaryl ring substituted with -N(R a )-, Z optionally represents 1 to 3 R c is a fused bicyclic heteroaryl ring substituted with 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-CO 2 H and C 1-6 Alkylene-SO 3 H; 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-CO 2 H and C 1-6 Alkylene-SO 3 H, each of which is independently selected from the group consisting of OH, SO 2 N.H. 2 , C.O.N.H. 2 ,C(O)NHOH,PO 3 H 2 , COO-C 1-8 Alkyl and CO 2 Optionally further substituted with 1 or 2 substituents independently selected from H; and R a and R b are optionally combined when attached to the same nitrogen atom and are optionally halogen, OH, SO 2 N.H. 2 , C.O.N.H. 2 ,C(O)NHOH,PO 3 H 2 , COO-C 1-8 Alkyl or CO 2 forming a 4- to 8-membered ring or an 8- to 10-membered spiro ring substituted with H; Each R c is H, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -Y 1 , -X 4 -C(O) 2 R a , -O-X 4 -C(O) 2 R a , -X 4 -OR a , -X 4 -NR a R b , -X 4 -CONR a R b , -O-X 4 -CONR a R b , -X 4 -SO 2 R a , -X 4 -SO 2 N.R. a R b , -X 4 -SO 3 R a , and -N(R a ) -X 4 -C(O) 2 R a wherein each X is independently selected from the group consisting of 4 is a single bond or C 1-6 alkylene), each Y 1 is C 3-6 Cycloalkyl and C 4-8 heterocyclyl; and Optionally, two R on adjacent ring vertices c or a pharma- ceutically acceptable salt thereof, wherein:

3. (a) Group R 1a OCH 3 and R 1b is F; (b) A is -C(=O)N(R a )- and Z is the group consisting of: i) a 5- or 6-membered non-aromatic heterocycle optionally substituted with one or two oxo groups and optionally substituted with up to four R a and / or R b ; and ii) a monocyclic 5- or 6-membered heteroaryl ring optionally substituted with 1-3 R c ; (c) Z is the group consisting of: 【Chemistry 9】 is a non-aromatic heterocycle having a formula selected from (d) Z is a monocyclic 5- or 6-membered heteroaryl ring optionally substituted with 1-3 R c , and said heteroaryl ring is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, and pyrazolyl groups; (e) The compound of claim 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein Z is a non-aromatic heterocycle selected from the group consisting of piperidinyl, morpholinyl, tetrahydropyranyl, and tetrahydrofuranyl groups, each of which is optionally substituted with up to four R and / or R.

4. A is -N(R a )—and Z is optionally 1 to 3 R c 3. The compound of claim 1 or 2, wherein R is a fused bicyclic heteroaryl ring substituted with R, or a pharma- ceutically acceptable salt thereof.

5. Z is the group consisting of: 【Chemistry 10】 5. The compound of claim 1 or 4, wherein the fused bicyclic heteroaryl ring has a formula selected from:

6. (i) R 2a and R 2b are each H, or (ii) R 2a and R 2b are combined to form a 4- to 9-membered or 8- to 10-membered spiro ring, optionally having one or two additional ring vertices selected from O, N and S, said 4- to 9-membered or 8- to 10-membered spiro ring being selected from oxo, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, -X 3 -C(O) 2 R a , -X 3 -OR a , -X 3 -NR a R b , -X 3 -CONR a R b , -X 3 -SO 2 R a , -X 3 -SO 2 N.R. a R b , and -X 3 -SO 3 R a (In the formula, X 3 is a single bond or C 1-6 alkylene; (iii) -N(R 2a )(R 2b ) is the group consisting of: 【Chemistry 11】 Selected from or (iv) -N(R 2a )(R 2b ) is the group consisting of: 【Chemistry 12】 or (v) -N(R 2a )(R 2b ) is the group consisting of: 【Chemistry 13】 6. The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, selected from:

7. R 2a is H or C 1-8 is alkyl; and R 2b is -Y or -X 2 The compound according to any one of claims 1 to 5, wherein Y is -Y, or a pharma- ceutically acceptable salt thereof.

8. 8. The compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof, wherein the compound is an optically pure or enriched isomer.

9. Y is C 3-6 Cycloalkyl and C 4-8 heterocyclyl, 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, SO 2 N.H. 2 , C.O.N.H. 2 ,C(O)NHOH,PO 3 H 2 , COO-C 1-8 Alkyl, SO 3 H and CO 2 9. The compound of claim 8, or a pharma- ceutically acceptable salt thereof, optionally further substituted with 1 to 4 substituents independently selected from the group consisting of H groups.

10. A is -C(=O)N(R a )—and (i) Z is optionally substituted with one or two oxo groups, and optionally R a and / or R b or a 5- or 6-membered non-aromatic heterocycle substituted with (ii) Z is optionally one to three R c or a monocyclic 5- or 6-membered heteroaryl ring substituted with (iii) Z is optionally substituted with one or two oxo groups, and optionally R a and / or R b and R 1c , R 6 , R 7 , R 8 each of (iv) Z is optionally 1 to 3 R c and R is a monocyclic 5- or 6-membered heteroaryl ring substituted with 1c , R 6 , R 7 , R 8 each of (v) Z is optionally substituted with one or two oxo groups, and optionally R a and / or R b wherein the non-aromatic heterocycle is selected from the group consisting of piperidinyl, morpholinyl, tetrahydropyranyl, and tetrahydrofuranyl groups; or (vi) Z is optionally one to three R c 3. The compound of claim 1 or 2, wherein R is a monocyclic 5- or 6-membered heteroaryl ring substituted with R, ...

11. A compound selected from the following (i) or (ii), or a pharma- ceutically acceptable salt thereof: 【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】 【Table 1-18】 【Table 1-19】 【Table 1-20】 【Table 1-21】 【Table 1-22】 【Table 1-23】 【Table 1-24】 【Table 1-25】 【Table 1-26】 【Table 1-27】 【Table 1-28】 【Table 1-29】 【Table 1-30】 【Table 1-31】 【Table 1-32】 【Table 1-33】 【Table 1-34】 【Table 1-35】 【Table 1-36】 【Table 1-37】 【Table 1-38】 【Table 1-39】 【Table 1-40】 【Table 1-41】 【Table 1-42】 【Table 1-43】 【Table 1-44】 【Table 1-45】 【Table 1-46】 【Table 2-1】 【Table 2-2】 【Table 2-3】 【Table 2-4】 【Table 2-5】 【Table 2-6】 【Table 2-7】 【Table 2-8】 【Table 2-9】 【Table 2-10】 【Table 2-11】 【Table 2-12】 【Table 2-13】 【Table 2-14】

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

13. 13. The pharmaceutical composition of claim 12, further comprising one or more additional therapeutic agents, wherein the one or more additional therapeutic agents are selected from the group consisting of antibacterial agents, antiviral agents, cytotoxic agents, gene expression modulating agents, chemotherapeutic agents, anticancer agents, antiangiogenic agents, immunotherapeutic agents, antihormonal agents, antifibrotic agents, radiation therapy, radiotherapeutic agents, antitumor agents, and antiproliferative agents.

14. (i) modulates an immune response mediated by the PD-1 signaling pathway in a subject; (ii) enhancing, stimulating, modulating and / or increasing an immune response in a subject in need thereof; (iii) inhibiting the growth, proliferation, or metastasis of cancer cells in a subject in need thereof; or (iv) treating a subject suffering from or susceptible to a disease or disorder mediated by the PD-1 signaling pathway. A composition comprising a compound according to any one of claims 1 to 11 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12 or 13, for use in a method comprising: the subject is afflicted with 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, and optionally the method further comprises administering to the subject a therapeutically effective amount of one or more additional therapeutic agents; The disease or disorder is 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, synovium, meningioma, leiomyosarcoma, rhabdomyosarcoma, malignant soft tissue sarcoma, tumor, 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, follicular 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 (SCLC), non-squamous NSCLC, colorectal cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, pancreatic cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, head and neck squamous cell carcinoma, head and neck cancer, gastrointestinal tract, gastric cancer, HIV, hepatitis A, hepatitis B, hepatitis C , hepatitis D, herpes virus, papilloma virus, influenza, bone cancer, skin cancer, rectal cancer, anal cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, small intestine cancer, endocrine system cancer, urethral cancer, penile cancer, bladder cancer , kidney cancer, ureteral cancer, renal pelvic cancer, central nervous system (CNS) tumor, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, epidermoid carcinoma, asbestos carcinoma, carcinoma, adenocarcinoma, papillary carcinoma, cystadenocarcinoma, bronchogenic carcinoma, renal cell carcinoma, transitional cell carcinoma, choroidal carcinoma, seminoma, embryonal carcinoma, Wilms' tumor, pleomorphic adenoma, hepatocellular papilloma, renal tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma, and fibroma, and The composition, or pharmaceutical composition, wherein the optional one or more additional therapeutic agents are selected from the group consisting of antibacterial agents, antiviral agents, cytotoxic agents, gene expression modulating agents, chemotherapeutic agents, anticancer agents, antiangiogenic agents, immunotherapeutic agents, antihormonal agents, antifibrotic agents, radiation therapy, radiotherapy agents, antitumor agents, and antiproliferative agents.

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