Triaryl compounds for the treatment of pd-l1 diseases

Abstract

Compounds useful as immunomodulators are provided. The compounds have the structure of Formula (I), including stereoisomers and pharmaceutically acceptable salts thereof, wherein 1a , R 1b , R 1c , 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 of making and uses related to such compounds, as well as pharmaceutical compositions comprising such compounds.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 62 / 848,114, filed May 15, 2019, pursuant to 35 USC §119(e), the entire contents of which are incorporated herein by reference.

[0003] Declaration of rights to inventions made under federally funded research and development

[0004] not applicable

[0005] Refer to the "Sequence List," table, or computer program list appendix submitted on the CD.

[0006] not applicable Background Technology

[0007] Programmed cell death protein-1 (PD-1) is a member of the CD28 superfamily that transmits negative signals through interaction with its ligands PD-L1 or PD-L2. PD-1 and its ligands are widely expressed and play broad immunomodulatory roles in T cell activation and tolerance. PD-1 and its ligands are involved in reducing infectious and tumor immunity, and promoting chronic infection and tumor progression.

[0008] PD-1 pathway regulation has therapeutic potential in various human diseases (Hyun-Tak Jin et al., Current Topics in Microbiology and Immunology (Curr Top Microbiol Immunol.) (2011); 350:17-37). Blocking the PD-1 pathway has become an attractive target in cancer therapy. Therapeutic antibodies that block the programmed cell death protein-1 (PD-1) immune checkpoint pathway can prevent T cell downregulation and promote anti-cancer immune responses. Several PD-1 pathway inhibitors have shown potent activity at different stages of clinical trials (RD Harvey, Clinical Pharmacology and Therapeutics (2014); 96(2), 214-223).

[0009] Drugs are needed to block the interaction between PD-L1 and PD-1 or CD80. Some antibodies have been developed and commercialized. Several patent applications for non-peptide small molecule drugs have been published (BMS WO 2015 / 160641, WO 2015 / 034820 and WO 2017 / 066227 and WO2018 / 009505; Aurigene WO 2015 / 033299 and WO 2015 / 033301; Incyte WO2017 / 070089, WO 2017 / 0145025, WO...). WO2017 / 106634, US2017 / 0174679, WO2017 / 192961, WO2017 / 222976, WO2017 / 205464, WO2017 / 112730, WO2017 / 041899 and WO2018 / 013789, Maxinovel's WO2018 / 006795 and our ChemoCentryx's WO2018 / 005374 have been disclosed. However, there is still a need for alternative compounds, such as small molecules, as PD-L1 inhibitors that offer advantages in terms of oral administration, stability, bioavailability, therapeutic index, and toxicity. Summary of the Invention

[0010] In one respect, this article provides compounds having the structure of formula (I), or pharmaceutically acceptable salts thereof:

[0011]

[0012] Among them, A, Z, X 1 R 1a R 1b R 1c R 1d R 2a R 2b R 3 R 3a R 4 R 6 R 7 R 8 The subscript n is as defined in this article.

[0013] In addition to the compounds provided herein, this disclosure also provides pharmaceutical compositions comprising one or more such compounds and methods relating to the preparation and use of such compounds. In some embodiments, the compounds are used in treatment methods for diseases associated with the PD-1 / PD-L1 pathway.

[0014] Brief description of the attached figures

[0015] not applicable Detailed Implementation

[0016] Abbreviations and Definitions

[0017] As used herein, the terms “a,” “an,” or “the” include not only aspects having one member but also aspects having multiple members. For example, unless the context clearly specifies otherwise, the singular forms “a,” “an,” and “the” include the plural forms. Thus, for example, a reference to “a cell” includes multiple such cells, while a reference to “the reagent” includes a reference to one or more reagents known to those skilled in the art, and so on.

[0018] The terms "approximately" and "approximately" generally refer to an acceptable degree of error in a measured quantity for a given property or precision. Typical, exemplary error levels are within 20% of a given value or range, preferably within 10%, and more preferably within 5%. Alternatively, particularly in biological systems, the terms "approximately" and "approximately" may indicate a value within an order of magnitude of a given value, preferably within 5 times, and more preferably within 2 times. The numerical values ​​given herein are approximate, and unless otherwise stated, this means that the terms "approximately" or "approximately" can be inferred without explicit specification.

[0019] Unless otherwise stated, the term "alkyl", either on its own or as part of another substituent, refers to an alkyl group having a specified number of carbon atoms (i.e., C40, C50, C60, C70, C6 ... 1-8 Alkyl groups refer to straight-chain or branched hydrocarbons with 1 to 8 carbon atoms. Examples of alkyl groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. 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, crotonyl, 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 higher homologues and isomers. The term "cycloalkyl" refers to a group having a specified number of ring atoms (e.g., C1, C2, C3, C4, C5, C6, C6, C6, C7 ... 3-6 A cycloalkyl group is a hydrocarbon ring that is fully saturated or has no more than one double bond between its vertices. "Cycloalkyl" can also refer to bicyclic and polycyclic hydrocarbon rings, for example, bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, etc. Bicyclic or polycyclic rings can be fused rings, bridged rings, spirocyclic rings, or combinations thereof. The term "heterocyclic alkyl" or "heterocyclic group" refers to a cycloalkyl group containing 1 to 5 heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. The heterocyclic alkyl group can be a monocyclic, bicyclic, or polycyclic system. Bicyclic or polycyclic rings can be fused rings, bridged rings, spirocyclic rings, or combinations thereof. It should be understood that C 4-12The description of heterocyclic groups refers to groups having 4 to 12 ring members, wherein at least one ring member is a heteroatom. Non-limiting examples of heterocyclic alkyl groups include: pyrrolidine, imidazoline, pyrazolidine, butyrolactam, valproic acid, imidazolinone, tetrazolone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrrolidine, thiaran, pyranone, tetrahydrofuran, tetrahydrothiophene, quinine ring, and similar groups. Heterocyclic alkyl groups can be linked to other parts of the molecule via a cyclic carbon or a heteroatom.

[0020] The term "alkylene" itself, or as part of another substituent, refers to a divalent group derived from an alkane, such as -CH2CH2CH2CH2-. Alkylenes can be straight-chain or branched. An example of the latter is -CH2C(CH3)2CH2-, -CH2C(CH3)2-, or -CH(CH3)CH2CH2-. Typically, alkyl (or alkylene) groups have 1 to 12 carbon atoms, with those having 8 or fewer carbon atoms preferred in this disclosure. Similarly, "alkenyl" and "alkynyl" refer to the unsaturated form of an alkylene group having a double or triple bond, respectively.

[0021] Unless otherwise stated, the term "heteroalkyl" on its own or in combination with another term refers to a stable straight-chain, branched, or cyclic hydrocarbon group, or a combination thereof, consisting of the stated number of carbon atoms and one to three heteroatoms selected from O, N, Si, and S, wherein nitrogen and sulfur atoms may optionally be oxidized, and nitrogen heteroatoms may optionally be quaternized. Heteroatoms O, N, and S may be located at any internal position of the heteroalkyl group. Heteroatoms Si may be located at any position of the heteroalkyl group, including the position where the alkyl group is attached to the rest of the molecule. Examples include: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2,-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. At most two heteroatoms can be consecutive, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Similarly, unless otherwise stated, the terms "heteroalkenyl" and "heteroyynyl" on their own or in combination with another term refer to an alkenyl or ynyl group containing the stated number of carbon atoms and having one to three heteroatoms selected from O, N, Si, and S, wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatoms O, N, and S may be located at any internal position of the heteroalkyl group.

[0022] The term "heteroalkylene" itself, or as part of another substituent, refers to a saturated, unsaturated, or polyunsaturated divalent group derived from a heteroalkyl group, such as -CH2-CH2-S-CH2CH2- and -CH2-S-CH2-CH2-NH-CH2-, -O-CH2-CH=CH-, -CH2-CH=C(H)CH2-O-CH2-, and -S-CH2-C≡C-. For heteroalkylene, the heteroatom can also be one or both located at the end of the chain (e.g., alkeneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.).

[0023] The terms "alkoxy," "alkamino," and "alkathio" (or thioalkoxy) take their conventional meaning to refer to alkyl groups that are attached to other parts of a molecule via an oxygen, amino, or sulfur atom, respectively. Additionally, for dialkylamino groups, the alkyl moiety can be the same or different and can form 3-7 membered rings by combining with the nitrogen atoms to which they are attached. Therefore, -NR is used. a R b The groups represented include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl, and similar groups.

[0024] Unless otherwise stated, the terms "halogenated" or "halogen," either on their own or as part of another substituent, refer to a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "halogenated alkyl" are intended to include both monohalogenated and polyhalogenated alkyl groups. For example, the term "C"... 1-4 "Halogenated alkyl" refers to compounds including trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, and 3-bromopropyl.

[0025] The term "hydroxyalkyl" or "alkyl-OH" refers to an alkyl group as defined above, wherein at least one (and at most three) hydrogen atoms are replaced by a hydroxyl group. For an alkyl group, the hydroxyalkyl group can have any suitable number of carbon atoms, such as C0. 1-6 Exemplary hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl (wherein the hydroxyl group is at the 1 or 2 position), hydroxypropyl (wherein the hydroxyl group is at the 1, 2 or 3 position), and 2,3-dihydroxypropyl.

[0026] Term "C" 1-3 "alkyl-guanidinyl" refers to the C group as described above. 1-3 Alkyl group, wherein at least one hydrogen atom is replaced by a guanidinyl group (-NHC(NH)NH2).

[0027] Unless otherwise stated, the term "aryl" refers to a polyunsaturated, typically aromatic, hydrocarbon group, which can be monocyclic or fused together or covalently linked polycyclic (up to three rings). The term "heteroaryl" refers to an aryl group (or ring) containing one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. Heteroaryl groups can be linked to other parts of the molecule via heteroatoms. It should be understood that C 5-10 The description of a heteroaryl group refers to a heteroaryl group having 5 to 10 ring members, wherein at least one ring member is a heteroatom. Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl; and non-limiting examples of heteroaryl groups include pyridyl, pyrazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purine, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzoisoxazoleyl, isobenzofuranyl, isoindoleyl, indoleazine. dolizinyl), benzotriazinyl, thienopyridyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridyl, benzothiaxolyl, benzofuranyl, benzothiopheneyl, indolyl, quinolinyl, isoquinolinyl, isothiazolyl, pyrazolyl, indazoleyl, pteridinyl, imidazoyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazoyl, pyrroleyl, thiazoyl, furanyl, thiopheneyl, and similar groups. The substituents used in each of the aryl and heteroaryl ring systems described above are selected from the acceptable substituents described below.

[0028] The terms "carbocyclic," "carbocyclic," or "carbocyclic group" refer to a cyclic portion with only a carbon atom at the apex. The carbocyclic portion can be saturated or unsaturated and may be aromatic. Typically, the carbocyclic portion has 3 to 10 ring members. Carbocyclic portions with polycyclic structures (e.g., bicyclic) may include cycloalkyl rings fused to an aromatic ring (e.g., 1,2,3,4-tetrahydronaphthalene). Therefore, carbocyclic groups include cyclopentyl, cyclohexenyl, naphthyl, and 1,2,3,4-tetrahydronaphthalene. The term "heterocyclic" refers to both "heterocyclic alkyl" and "heteroaryl" portions. Therefore, heterocyclic groups can be saturated or unsaturated and may be aromatic. Typically, heterocyclic groups have 4 to 10 ring members, including piperidinyl, tetrazinyl, pyrazolyl, and indoleyl.

[0029] When any of the above terms (e.g., "alkyl", "aryl", and "heteroaryl") are referred to as "substituted" without further notation on the substituent, the substituted form of the shown group is as follows.

[0030] The substituents of alkyl groups (including those commonly referred to as alkylene, alkenyl, ynyl, and cycloalkyl) can be zero to (2m'+1) groups selected from the group consisting of: halogen, -OR', -NR'R”, -SR', -SiR'R”R”', -OC(O)R', -C(O)R', -CO2R', -CONR'R”, -OC(O)NR'R”, -NR”C(O)R', -NR'-C( The following are listed: -NR”R”', -NR”C(O)2R’, -NH-C(NH2)=NH, -NR’C(NH2)=NH, -NH-C(NH2)=NR’, -S(O)R’, -S(O)2R’, -S(O)2NR’R”, -NR’S(O)2R”, -CN, and -NO2, where m’ is the total number of carbon atoms in the group. R’, R”, and R”’ each independently refer to hydrogen, unsubstituted carbon, and unsubstituted carbon. 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 Thioalkoxy or unsubstituted aryl-C 1-4 Alkyl groups. When R' and R” are attached to the same nitrogen atom, they can combine with the nitrogen atom to form 3, 4, 5, 6, or 7-membered rings. For example, -NR'R” means including 1-pyrrolidinyl and 4-morpholinyl. The term “acyl” is used alone or as part of another group, referring to an alkyl group where the two substituents on the carbon closest to the group's attachment point are replaced by the substituent =O (e.g., -C(O)CH3, -C(O)CH2CH2OR', etc.).

[0031] Similarly, the substituents of aryl and heteroaryl groups are varied and generally selected from: -halogen, -OR', -OC(O)R', -NR'R”, -SR', -R', -CN, -NO2, -CO2R', CONR'R”, -C(O)R', -OC(O)NR'R”, -NR”C(O)R', -NR”C(O)2R', -NR'-C(O)NR”R”', NHC( NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', S(O)2NR'R”, NR'S(O)2R”, N3, perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl, ranging from zero to the total number of open valences on the aromatic ring system; and R', R” and R”' are independently selected from: hydrogen, C 1-8 Alkyl, C 3-6 cycloalkyl, C 2-8 alkenyl, C 2-8 Alkynyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-C 1-4Alkyl groups and unsubstituted aryl groups -C 1-4 Alkyl groups. Other suitable substituents include the aforementioned aryl substituents connected to the ring atom via an alkylene group of 1-4 carbon atoms.

[0032] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be of the formula -TC(O)-(CH2). q The substituent is replaced by a -U- substituent, where T and U are independently -NH-, -O-, -CH2-, or a single bond, and q is an integer from 0 to 2. Optionally, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally replaced by the formula -A-(CH2). r The substituents of -B- are substituted, wherein A and B are independently -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-, -S(O)2NR' or single bonds, and r is an integer from 1 to 3. One of the single bonds in the newly formed ring may optionally be substituted with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be substituted with the formula -(CH2). s -X-(CH2) t The substituent is replaced by a substituent, where s and t are independent integers from 0 to 3, and X is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituent R' in NR'- and -S(O)2NR'- is selected from hydrogen or unsubstituted C. 1-6 alkyl.

[0033] As used in this article, the term “heteroatoms” is intended to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si).

[0034] The present invention also relates to its prodrugs and bioisosteres. For example, suitable bioisosteres will include carboxylic acid substitutes (phosphonic acids, hypophosphonic acids, sulfonic acids, sulfinic acids, and acidic heterocyclic groups, such as tetrazolium). Suitable prodrugs will include conventional groups known to hydrolyze and / or oxidize under physiological conditions to provide a compound of formula I.

[0035] The terms “patient” and “subject” include primates (especially humans), domesticated companion animals (such as dogs, cats, horses, etc.), and livestock (such as cattle, pigs, sheep, etc.).

[0036] As used herein, the term “treatment” or “treatment” includes both treating a disease and treating symptoms, either of which can be preventative (i.e., before the onset of symptoms, to prevent, delay, or reduce the severity of symptoms) or therapeutic (i.e., after the onset of symptoms, to reduce the severity and / or duration of symptoms).

[0037] The term "pharmaceutically acceptable salt" refers to salts of active compounds prepared with relatively non-toxic acids or bases, depending on the specific substituents present on the compounds described herein. When the compounds of this disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of these compounds with a sufficient amount of the desired base in a solvent-free environment or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, trivalent manganese, divalent manganese, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, and naturally occurring amines, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and similar groups. When the compounds of this disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of these compounds with a sufficient amount of the desired acid, which may be solvent-free or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphoric acid, sulfuric acid, monohydrosulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, succinic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Also included are salts of amino acids, such as arginine, and salts of organic acids, such as glucuronic acid or galacturonic acid (see, for example, Berge, SM, et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of this disclosure contain both basic and acidic functional groups, allowing the compounds to be converted into either basic or acid addition salts.

[0038] The neutral form of a compound can be regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of a compound differs from its various salt forms in some physical properties, such as solubility in polar solvents, but for the purposes of this disclosure, the salt is equivalent to the parent form of the compound in other respects.

[0039] Some compounds of this disclosure may exist in both solvated and hydrated forms, including hydrated forms. Generally, the hydrated form is equivalent to the hydrated form and is intended to be included within the scope of this disclosure. Some compounds of this disclosure may exist in polycrystalline or amorphous forms. Generally, all physical forms are equivalent to the intended use of this invention and are intended to fall within the scope of this invention.

[0040] Certain compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regio isomers, and single isomers (e.g., individual enantiomers) are all intended to be included within the scope of the present invention. When a stereochemical description is shown, it means a compound in which one isomer is present and which is substantially free of the other isomer. “Substantially free” of the other isomer means a ratio of at least 80 / 20 between the two isomers, more preferably 90 / 10 or 95 / 5 or more. In some embodiments, the content of one isomer is at least 99%.

[0041] The compounds disclosed herein may also contain atomic isotopes in non-natural proportions on one or more atoms constituting these compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention. For example, the compounds can be prepared by subjecting any number of hydrogen atoms to deuterium (… 2 H) Isotope substitution. The compounds of this disclosure may also contain atomic isotopes in non-natural proportions on one or more atoms constituting these compounds. Non-natural proportions of isotopes can be defined as amounts ranging from those found in nature to those consisting of 100% of the atoms in question. For example, the compounds may be doped with radioactive isotopes (e.g., tritium). 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C)) or non-radioactive isotopes (such as deuterium) 2 H) or carbon-13 ( 13 C)). Such isotopic variations can provide additional utility for those described elsewhere in this application. For example, isotopic variants of the compounds disclosed herein may be found to have other uses, including but not limited to, as diagnostic and / or imaging agents, or as therapeutic agents for cytotoxicity / radiotoxicity. Additionally, isotopic variants of the compounds disclosed herein may have altered pharmacokinetic and pharmacodynamic characteristics, which may contribute to improved safety, tolerability, or efficacy during treatment. All isotopic variants of the compounds of this invention, whether radioactive or not, are intended to be included within the scope of this invention.

[0042] compound

[0043] In one aspect, this disclosure provides compounds having the structure of formula (I), or pharmaceutically acceptable salts, prodrugs, or bioelectron isosteres thereof:

[0044]

[0045] in:

[0046] R 1a R 1b R 1c and R 1d Each is independently selected from the following groups: H, halogens, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and CN;

[0047] X 1 It is C 1-3 Alkylene, optionally surrounded by one or two Cs 1-2 Alkyl or CO2H substitution;

[0048] R 2a and R 2b Each is independently selected from the following groups: H, C 1-8 Alkyl, C 1-8 Halogenated alkyl groups, -Y, -X 2 -C(O)2R a -X 2 -OR a -X 2 -NR a R b -X 2 -CONR a R b -X 2 -SO2R a -X 2 -SO2NR a R b -X 2 -SO3R a and –X 2 -Y, where each X 2 It is C 1-6 Alkylene and any C 1-8 Alkyl or C 1-6 Alkyl groups, optionally further substituted with one or two members independently selected from the group consisting of: OH, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 Alkyl or CO2H, and each Y is selected from the following group: C 3-6Cycloalkyl, C4-8 heterocyclic and 5- to 6-membered heteroaryl, wherein each is optionally further substituted by one to four independent substituents 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 Halogenated alkoxy groups, C 1-4 Hydroxylalkoxy, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 Alkyl groups, SO3H, and CO2H;

[0049] Or R 2a and R 2b They combine to form 4 to 10-membered rings or helices, optionally having one or two additional ring vertices selected from O, N or S;

[0050] Among them, R 2a and R 2b The resulting ring is substituted by 0-4 independent substituents selected from the following group: oxo, C-, ... 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, -X 3 -C(O)2R a -X 3 -OR a -X 3 -NR a R b -X 3 -CONR a R b -X 3 -SO2R a -X 3 -SO2NR a R b and –X 3 -SO3R a ;where X 3 For key or C 1-6 Alkylene; R 3 and R 4 Each of the following is independently selected: F, Cl, CN, CH3, OCH3, CH2CH3, and CF3;

[0051] The subscript n is 0, 1, 2, or 3;

[0052] Each R 3a Select independently from the following groups: H, F, Cl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C1-3 Halogenated alkoxy groups, C 2-3 alkenyl and CN;

[0053] R 6 R 7 and R 8 Each of the following groups is independently selected: H, F, Cl, CN, CH3, OCH3, CH2CH3, and CF3;

[0054] A is selected from the following group: –N(R) a )-、-C(=O)N(R a )-、-S(O)N(R a )- and -S(O)2N(R a )-;

[0055] Z is selected from the following group:

[0056] i) A monocyclic, bicyclic, or spirocyclic non-aromatic heterocycle, optionally substituted with one or two oxo groups and optionally with up to four R groups. a and / or R b replace;

[0057] ii) 5 or 6-membered heterocyclic aromatic monocyclic compounds, optionally covered with 1-3 Rs c Replace; and

[0058] iii) Dense bicyclic heterocyclic aromatic rings, optionally surrounded by 1-3 R... c replace;

[0059] Where A is –N(R) a When )-, then Z is arbitrarily controlled by 1-3 R. c Substituted fused bicyclic heterocyclic aromatic rings;

[0060] Each R a Each is independently selected from the following groups: H, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkylene-CO2H, C 1-6 Alkylene-SO3H;

[0061] Each R b Each is independently selected from the following groups: H, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkylene-CO2H and C 1-6Alkylene-SO3H, wherein each is optionally further substituted by one or two members independently selected from the group consisting of: OH, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 Alkyl groups and CO2H;

[0062] Furthermore, when R is attached to the same nitrogen atom, a and R b They can optionally combine to form 4-8 membered rings or spiro rings, optionally bonded by halogens, OH, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 Alkyl or CO2H substitution;

[0063] Each R c Each is independently selected from the following groups: H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, Y 1 -X 4 -C(O)2R a -OX 4 -C(O)2R 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 -SO2R a -X 4 -SO2NR a R b -X 4 -SO3R a , and -N(R a )-X 4 -C(O)2R a , where each X 4 Is it a key or C? 1-6 Alkylene, and each Y 1 Selected from the following group: C 3-6 cycloalkyl and C 4-8 Heterocyclic base; and optionally, two R on adjacent ring vertices c They combine to form fused 5- or 6-membered heterocycles.

[0064] In one aspect, this disclosure provides compounds having the structure of formula (I), or pharmaceutically acceptable salts, prodrugs, or bioelectron isosteres thereof:

[0065]

[0066] in:

[0067] R 1a R 1b R 1c and R 1d Each is independently selected from the following groups: H, halogens, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and CN;

[0068] X 1 It is C 1-3 Alkylene, optionally surrounded by one or two Cs 1-2 Alkyl or CO2H substitution;

[0069] R 2a and R 2b Each is independently selected from the following groups: H, C 1-8 Alkyl, C 1-8 Halogenated alkyl groups, -Y, -X 2 -C(O)2R a -X 2 -OR a -X 2 -NR a R b -X 2 -CONR a R b -X 2 -SO2R a -X 2 -SO2NR a R b -X 2 -SO3R a and –X 2 -Y, where each X 2 It is C 1-6 Alkylene and any C 1-8 Alkyl or C 1-6 Alkyl groups, optionally further substituted with one or two members independently selected from the group consisting of: OH, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 Alkyl or CO2H, and each Y is selected from the following group: C 3-6 cycloalkyl, C 4-8 Heterocyclic group and 5- to 6-membered heteroaryl group, wherein each is optionally further substituted by one to four independent substituents selected from the group consisting of: oxo, OH, C 1-4 Alkyl, C 1-4Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Hydroxylalkoxy, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 Alkyl groups, SO3H, and CO2H;

[0070] Or R 2a and R 2b They combine to form 4 to 9-membered rings or helices, optionally having one or two additional ring vertices selected from O, N or S;

[0071] Among them, R 2a and R 2b The resulting ring is substituted by 0-4 independent substituents selected from the following group: oxo, C-, ... 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, -X 3 -C(O)2R a -X 3 -OR a -X 3 -NR a R b -X 3 -CONR a R b -X 3 -SO2R a -X 3 -SO2NR a R b and –X 3 -SO3R a ;where X 3 For key or C 1-6 Alkylene;

[0072] R 3 and R 4 Each of the following is independently selected: F, Cl, CN, CH3, OCH3, CH2CH3, and CF3;

[0073] The subscript n is 0, 1, 2, or 3;

[0074] Each R 3a Select independently from the following groups: H, F, Cl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 2-3 alkenyl and CN;

[0075] R6 R 7 and R 8 Each of the following groups is independently selected: H, F, Cl, CN, CH3, OCH3, CH2CH3, and CF3;

[0076] A is selected from the following group: –N(R) a )-、-C(=O)N(R a )-、-S(O)N(R a )- and -S(O)2N(R a )-;

[0077] Z is selected from the following group:

[0078] i) A monocyclic, bicyclic, or spirocyclic non-aromatic heterocycle, optionally substituted with one or two oxo groups and optionally with up to four R groups. a and / or R b replace;

[0079] ii) 5 or 6-membered heterocyclic aromatic monocyclic compounds, optionally covered with 1-3 Rs c Replace; and

[0080] iii) Dense bicyclic heterocyclic aromatic rings, optionally surrounded by 1-3 R... c replace;

[0081] Where A is –N(R) a When )-, then Z is arbitrarily controlled by 1-3 R. c Substituted fused bicyclic heterocyclic aromatic rings;

[0082] Each R a Each is independently selected from the following groups: H, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkylene-CO2H, C 1-6 Alkylene-SO3H;

[0083] Each R b Each is independently selected from the following groups: H, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkylene-CO2H and C 1-6 Alkylene-SO3H, wherein each is optionally further substituted by one or two members independently selected from the group consisting of: OH, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 Alkyl groups and CO2H;

[0084] Furthermore, when R is attached to the same nitrogen atom, a and R b They can optionally combine to form 4-8 membered rings or spiro rings, optionally bonded by halogens, OH, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 Alkyl or CO2H substitution;

[0085] Each R c Each is independently selected from the following groups: H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, Y 1 -X 4 -C(O)2R a -OX 4 -C(O)2R 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 -SO2R a -X 4 -SO2NR a R b -X 4 -SO3R a , and -N(R a )-X 4 -C(O)2R a , where each X 4 Is it a key or C? 1-6 Alkylene, and each Y 1 Selected from the following group: C 3-6 cycloalkyl and C 4-8 Heterocyclic base; and optionally, two R on adjacent ring vertices c They combine to form fused 5- or 6-membered heterocycles.

[0086] In some embodiments, this disclosure provides compounds of formula (I) represented by formula (Ia):

[0087]

[0088] Among them, group R 1a R 1b R 1c R1d R 2a R 2b R 3 R 4 A, X 1 Z has the meaning provided by equation (I).

[0089] In some embodiments, this disclosure provides compounds of formula (I) represented by formula (Ib):

[0090]

[0091] Among them, group R 1a R 1b R 1c R 2a R 2b R 3 R 4 A, X 1 Z has the meaning provided by equation (I).

[0092] In some embodiments, this disclosure provides compounds of formula (I) represented by formula (Ic):

[0093]

[0094] Among them, group R 1a R 1b R 2a R 2b R 3 R 4 A, X 1 Z has the meaning provided by equation (I).

[0095] In some embodiments, this disclosure provides compounds of formula (I) represented by formula (Id):

[0096]

[0097] Among them, group R 1a R 1b R 2a R 2b R 3 R 4 A and Z have the meaning provided by equation (I).

[0098] In some selected embodiments, in compounds of formula (I), (Ia), (Ib), (Ic), or (Id), Z is a non-aromatic heterocycle whose structural formula is selected from the group consisting of:

[0099]

[0100] In some preferred embodiments, in compounds of formula (I), (Ia), (Ib), (Ic), or (Id), Z is a non-aromatic heterocycle selected from the group consisting of piperidinyl, morpholinyl, tetrahydropyranyl, and tetrahydrofuranyl, wherein each is optionally surrounded by up to four R groups. a and / or R b replace.

[0101] In some selected embodiments, in compounds of formula (I), (Ia), (Ib), (Ic), or (Id), Z is a fused bicyclic heteroaromatic ring selected from the group consisting of:

[0102]

[0103] In some selected embodiments, in compounds of formula (I), (Ia), (Ib), (Ic), or (Id), Z is optionally surrounded by 1-3 R. c A substituted 5- or 6-membered monocyclic heteroaryl ring; said heterocycle is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, and pyrazolyl.

[0104] In selected embodiments, including any of the embodiments described above concerning compounds of formula (I), (Ia), (Ib), (Ic), or (Id), in additional embodiments, A is -C(=O)N(R) a )-.

[0105] In selected embodiments, including any of the embodiments described above relating to compounds of formula (I), (Ia), (Ib), (Ic), or (Id), in additional embodiments, R 1a It is OCH3 and R 1b It is F.

[0106] In selected embodiments, including any of the embodiments described above relating to compounds of formula (I), (Ia), (Ib), (Ic), or (Id), in additional embodiments, R 2a and R 2b Each is represented by H.

[0107] In selected embodiments, including any of the embodiments described above relating to compounds of formula (I), (Ia), (Ib), (Ic), or (Id), in further embodiments, R 2a and R 2b The rings or spirocycles are combined to form 4-9 membered rings or spirocycles, optionally having one or two additional ring vertices selected from O, N, or S; wherein the rings or spirocycles are substituted by 0-4 independent substituents selected from the group consisting of: oxo, C, ... 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, -X 2-C(O)2R a -X 2 -OR a -X 2 -NR a R b -X 2 -CONR a R b -X 2 -SO2R a -X 2 -SO2NR a R b and –X 2 -SO3R a ; where X 2 Is it a key or C? 1-6 Alkylene.

[0108] In selected embodiments, including any of the embodiments described above relating to compounds of formula (I), (Ia), (Ib), (Ic), or (Id), in further embodiments, –N(R 2a (R) 2b Selected from the following group:

[0109]

[0110] In selected embodiments, including any of the embodiments described above relating to compounds of formula (I), (Ia), (Ib), (Ic), or (Id), in further embodiments, –N(R 2a (R) 2b Selected from the following group:

[0111]

[0112] In selected embodiments, including any of the embodiments described above relating to compounds of formula (I), (Ia), (Ib), (Ic), or (Id), in further embodiments, –N(R 2a (R) 2b Selected from the following group:

[0113]

[0114] In selected embodiments, including any of the embodiments described above relating to compounds of formula (I), (Ia), (Ib), (Ic), or (Id), in other embodiments, R 2a Is it H or C? 1-8 Alkyl; R 2b Is it -Y or -X? 2 -Y.

[0115] In selected embodiments, including any of the embodiments described above relating to compounds of formula (I), (Ia), (Ib), (Ic), or (Id), in further embodiments, R 2a Is it H or C? 1-8 Alkyl; R 2b Is it -Y or -X? 2 -Y; and Y is selected from the following group: C 3-6 cycloalkyl and C 4-8 Heterocyclic groups, each of which is optionally further substituted by 1-4 independent substituents 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 Halogenated alkoxy groups, C 1-4 Hydroxylalkoxy, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 Alkyl groups and CO2H.

[0116] In selected embodiments, including any of the embodiments described above concerning compounds of formula (I), (Ia), (Ib), (Ic), or (Id), in further embodiments, A is -C(=O)N(R) a )-, Z is a 5- or 6-membered non-aromatic heterocycle, optionally substituted with one or two oxo groups, and optionally with R a and / or R b replace.

[0117] In selected embodiments, including any of the embodiments described above concerning compounds of formula (I), (Ia), (Ib), (Ic), or (Id), in further embodiments, A is -C(=O)N(R) a Z is a 5- or 6-membered monocyclic heterocyclic aromatic ring, optionally surrounded by 1-3 R groups. c replace.

[0118] In selected embodiments, including any of the embodiments described above concerning compounds of formula (I), (Ia), (Ib), (Ic), or (Id), in further embodiments, A is -C(=O)N(R) a Z is a 5- or 6-membered non-aromatic heterocycle, optionally substituted with one or two oxo groups, and optionally with R. a and / or R b Replace; each R 1c R 6 R 7 and R 8 For H.

[0119] In selected embodiments, including any of the embodiments described above concerning compounds of formula (I), (Ia), (Ib), (Ic), or (Id), in further embodiments, A is -C(=O)N(R) a Z is a 5- or 6-membered monocyclic heteroaryl ring, optionally bounded by 1-3 R groups. c Replace; while R 1c R 6 R 7 and R 8 Each of them is H.

[0120] In selected embodiments, including any of the embodiments described above concerning compounds of formula (I), (Ia), (Ib), (Ic), or (Id), in further embodiments, A is -C(=O)N(R) a Z is a 5- or 6-membered non-aromatic heterocycle, optionally substituted with one or two oxo groups, and optionally with R. a and / or R b Substitution; the non-aromatic heterocycle is selected from the group consisting of piperidinyl, morpholinyl, tetrahydropyranyl, and tetrahydrofuranyl.

[0121] In selected embodiments, including any of the embodiments described above concerning compounds of formula (I), (Ia), (Ib), (Ic), or (Id), in further embodiments, A is -C(=O)N(R) a Z is a 5- or 6-membered monocyclic heteroaryl ring, optionally surrounded by 1-3 R groups. c Substitution; the heterocycle is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, and pyrazolyl.

[0122] In selected embodiments, any of the embodiments described above relating to compounds of formula (I), (Ia), (Ib), (Ic), or (Id) is included; in further embodiments, the compounds are selected from Table 1. In selected embodiments, any of the embodiments described above relating to compounds of formula (I), (Ia), (Ib), (Ic), or (Id) is included; in other embodiments, the compounds are selected from Table 2.

[0123] In selected embodiments, any of the embodiments described above relating to compounds of formula (I), (Ia), (Ib), (Ic), or (Id) is included. In other embodiments, the compounds are selected from Table 1 and have ++ or +++ activity. In selected embodiments, any of the embodiments described above relating to compounds of formula (I), (Ia), (Ib), (Ic), or (Id) is included. In other embodiments, the compounds are selected from Table 2 and have ++ or +++ activity.

[0124] In selected embodiments, any of the embodiments described above relating to compounds of formula (I), (Ia), (Ib), (Ic), or (Id) is included. In other embodiments, the compounds are selected from Table 1 and have +++ activity. In selected embodiments, any of the embodiments described above relating to compounds of formula (I), (Ia), (Ib), (Ic), or (Id) is included. In other embodiments, the compounds are selected from Table 2 and have +++ activity.

[0125] In addition to the compounds provided above, pharmaceutically acceptable salts of these compounds are also provided. In some embodiments, the pharmaceutically acceptable salt is 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-ethomorpholine, N-ethoperidine, glucosamine, glucosamine, histidine, hepatoamide, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, hydrochloric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphoric acid, acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, succinic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, arginine, glucuronic acid, and galacturonic acid. In some embodiments, the pharmaceutically acceptable salt is selected from the group consisting of: ammonium, calcium, magnesium, potassium, sodium, hydrochloric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, succinic acid, octanoic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, arginine, glucuronic acid, and galacturonic acid. In some embodiments, the pharmaceutically acceptable salt is sodium or hydrochloric acid.

[0126] In addition to salt form, this disclosure provides compounds existing in prodrug form. The prodrugs of the compounds described in this application are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of this disclosure. Furthermore, prodrugs can be converted into the compounds of this disclosure in an in vitro environment by chemical or biochemical methods. For example, when a prodrug is placed in a transdermal patch reservoir containing suitable enzymes or chemical reagents, the prodrug will slowly convert into the compounds of this disclosure.

[0127] Esters can be used as prodrugs for the corresponding carboxylic acids. C 1-10 Alkyl esters or C 1-10 Halogenated alkyl esters can be used as prodrugs for the corresponding carboxylic acids. The following esters can be used: tert-butyl ester, methyl ester, ethyl ester, and isopropyl ester.

[0128] Pharmaceutical Composition

[0129] In addition to the compounds provided herein, compositions of these compounds typically contain a drug carrier or diluent.

[0130] As used herein, the term "composition" is intended to cover products containing specific amounts of specific ingredients, and any product produced directly or indirectly from a combination of specific amounts of specific ingredients. "Pharmaceutically acceptable" means that the carrier, diluent, or excipient must be compatible with the other components of the formulation and harmless to its recipients.

[0131] In another embodiment, a pharmaceutical composition comprising the compounds of the present invention and pharmaceutically acceptable excipients is provided, said compounds comprising compounds of formula (I), (Ia), (Ib), (Ic) or (Id) or pharmaceutically acceptable salts thereof.

[0132] In some embodiments, the pharmaceutical composition further comprises one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of: antimicrobial agents, antiviral agents, cytotoxic agents, gene expression regulators, chemotherapeutic agents, anticancer agents, antiangiogenic agents, immunotherapeutic agents, antihormonal agents, antifibrotic agents, radiotherapy, radiotherapy agents, antitumor agents, and antiproliferative agents. In some embodiments, the one or more additional therapeutic agents are antagonists of chemokines and / or chemokine 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. Chemokines and / or chemokine receptor antagonists are known in the art, for example WO2007 / 002667, WO2007 / 002293, WO / 2003 / 105853, WO / 2007 / 022257, WO / 2007 / 059108, WO / 2007 / 044804, WO2007 / 115232, WO2007 / 115231, WO2008 / 14 7815、WO2010 / 030815、WO2010 / 075257、WO2011 / 163640、WO2010 / 054006、WO2010 / 051561、 WO2011 / 035332, WO2013 / 082490, WO2013 / 082429, WO2014 / 085490, WO2014 / 100735, WO2014 / 089495、WO2015 / 084842、WO2016 / 187393、WO2017 / 127409、WO2017 / 087607、WO2017 / 0876 10. WO2017 / 176620, WO2018 / 222598, WO2018 / 222601, WO2013 / 130811, WO2006 / 076644, WO2 008 / 008431, WO2009 / 038847, WO2008 / 008375, WO2008 / 008374, WO2008 / 010934, WO2009 / 0 09740, WO2005 / 112925, WO2005 / 112916, WO2005 / 113513, WO2004 / 085384, WO2004 / 046092.Chemokines and / or chemokine 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.

[0133] Pharmaceutical compositions for administering the compounds disclosed herein can be conveniently present in unit dosage forms and can be prepared by any method known in the fields of pharmacy and drug delivery. All methods involve the step of binding the active ingredient to a carrier constituting one or more excipients. Generally, pharmaceutical compositions are prepared by uniformly and tightly binding the active ingredient to a liquid carrier or a finely fragmented solid carrier, or both, and then, if desired, shaping the product into the desired formulation. In the pharmaceutical composition, the amount of the active target compound is sufficient to produce the desired effect on the course or condition of a disease.

[0134] Pharmaceutical compositions containing an active ingredient can be in forms suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions and self-emulsifiers, hard or soft capsules, syrups, elixirs, solutions, oral patches, oral gels, chewing gum, chewable tablets, effervescent powders, and effervescent tablets, as described in U.S. Patent Application 2002-0012680. Compositions for oral administration can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions can contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, antioxidants, and preservatives to provide a pharmaceutically palatable formulation. Tablets contain the active ingredient mixed with a non-toxic, pharmaceutically acceptable excipient suitable for manufacturing tablets. These excipients can be, for example, inert diluents such as cellulose, silica, alumina, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginate; binders such as PVP, cellulose, PEG, starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. The tablets can be uncoated or coated, enteric-coated, or otherwise used to delay disintegration and absorption in the gastrointestinal tract using known techniques to provide a longer-lasting effect. For example, delaying materials such as glyceryl monostearate or glyceryl distearate can be used. Coating can also be performed using the techniques described in U.S. Patent Nos. 4,256,108, 4,166,452, and 4,265,874 to form permeable therapeutic tablets for controlled release.

[0135] Oral formulations can also be in the form of hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, polyethylene glycol (PEG) of varying average sizes (e.g., PEG400, PEG4000), and certain surfactants such as levofloxacin or solute alcohols; or in the form of soft gelatin capsules, in which the active ingredient is mixed with an aqueous or oil medium such as peanut oil, liquid paraffin, or olive oil. Furthermore, emulsions can be prepared using non-aqueous miscible components such as oils and stabilized with surfactants such as monoglycerides or diglycerides, PEG esters, etc.

[0136] The aqueous suspension contains an active substance mixed with excipients suitable for making the aqueous suspension. Such excipients can be suspending agents, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic; dispersants or wetting agents, such as naturally occurring phospholipids (e.g., lecithin) or condensation products of ethylene oxides and fatty acids (e.g., polyoxyethylene stearate), or condensation products of ethylene oxides and long-chain fatty alcohols (e.g., heptadecanethoxycetyl alcohol), or condensation products of ethylene oxides and esters derived from fatty acids and hexitols (e.g., polyoxyethylene sorbitan monooleate), or condensation products of ethylene oxides and esters derived from fatty acids and hexitol anhydrides (e.g., polyvinyl dehydrated sorbitan monooleate). The aqueous suspension may also contain one or more preservatives, such as ethyl, or n-propyl, p-hydroxybenzoates, one or more colorants, one or more flavoring agents, and one or more sweeteners, such as sucrose or saccharin.

[0137] Oily suspensions can be formulated by suspending the active ingredient in vegetable oils (such as peanut oil, olive oil, sesame oil, or coconut oil) or mineral oils (such as liquid paraffin). Oil suspensions may contain thickeners such as beeswax, hard paraffin, or hexadecyl alcohol. Sweeteners and flavorings, such as those mentioned above, can be added to provide palatable oral formulations. These compositions can be preserved by adding antioxidants, such as ascorbic acid.

[0138] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water provide active ingredients that can be mixed with dispersants or wetting agents, suspending agents, and one or more preservatives. Examples of suitable dispersants or wetting agents and suspending agents are described above. Additional excipients, such as sweeteners, flavoring agents, and coloring agents, may also be present.

[0139] The pharmaceutical compositions disclosed herein 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 may be naturally occurring gums, such as gum arabic or tragacanth; naturally occurring phospholipids, such as soybean or lecithin; and esters or metaesters derived from fatty acids and hexitan anhydrides, such as sorbitan monooleate; and condensation products of said metaesters with vinyl oxides, such as polyoxyethylene dehydrated sorbitan monooleate. The emulsion may also contain sweeteners and flavorings.

[0140] Syrups and elixirs can be formulated with sweeteners such as glycerin, propylene glycol, sorbitol, or sucrose. These formulations may also contain modifiers, preservatives, flavoring agents, and coloring agents. Oral solutions can be prepared in combination with, for example, cyclodextrin, polyethylene glycol, and surfactants.

[0141] Pharmaceutical compositions may be in the form of sterile injectable aqueous solutions or oily suspensions. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents mentioned above, according to known techniques. Sterile injectable formulations may also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents (e.g., solutions in 1,3-butanediol). Acceptable solvents and media may include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile non-volatile oils are commonly used as solvents or suspension media. For this purpose, any mild non-volatile oil, including synthetic monoglycerides or diglycerides, may be used. Furthermore, fatty acids such as oleic acid may be used in the preparation of injectable formulations.

[0142] The compounds disclosed herein can also be administered in the form of rectal suppositories. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, thus melting in the rectum to release the drug. These materials include cocoa butter and polyethylene glycol. Furthermore, the compounds can be administered via ocular delivery as a solution or ointment. Further, transdermal delivery of the compounds can be accomplished using iontophoresis patches, etc. For topical use, creams, ointments, gels, solutions, or suspensions containing the compounds of the present invention are used. As used herein, topical application also means including the use of mouthwash and mouth rinse solutions.

[0143] The compounds disclosed herein can also be coupled with a carrier, which is a suitable polymer for targeted drug delivery. Such polymers may include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl-methacrylamide phenol, polyhydroxyethyl-asparagine, or polyoxyethylene-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention can be coupled with a carrier that is a class of biodegradable polymers suitable for achieving controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polycaprolactone, polyhydroxybutyric acid, polyvinyl acetate, polyacetal, polydihydropyran, polycyanoacrylate, and crosslinked or amphiphilic block copolymers of hydrogels. The polymer and semi-permeable polymer matrix can be formed into molded articles, such as valves, stents, catheters, prostheses, etc. In one embodiment of the invention, the compounds of the present invention are coupled with a polymer or semi-permeable polymer matrix formed as a stent or stent graft device.

[0144] Methods of treating diseases and symptoms

[0145] The compounds of this invention can be used as immunomodulators. The compounds of this invention can be used as agonists, antagonists, partial agonists, inverse agonists, and inhibitors of PD-1 and / or PD-L1 in various in vitro and in vivo conditions. In some embodiments, the compounds of this invention can be used as inhibitors of protein-protein interactions between PD-1 and PD-L1 proteins. In some embodiments, the compounds of this invention can be used as inhibitors of PD-L1. In some embodiments, the compounds of this invention can be used as inhibitors of protein-protein interactions between CD80 and PD-L1 proteins. In some embodiments, the compounds of this invention can be used to inhibit the interactions between PD-1 and PD-L1 and / or PD-1 and CD80 and / or PD-1 and PD-L2 in vivo or in vitro. In some embodiments, the compounds of this invention can be used to inhibit VISTA and / or TIM-3. In some embodiments, the compounds of this invention can be used as inhibitors of protein-protein interactions between PD-1 and PD-L1 proteins and inhibitors of VISTA and / or TIM-3. In some embodiments, in addition to acting as inhibitors of protein-protein interactions of PD-1 / PD-L1 proteins, the compounds of the present invention 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 galactoglucoside-9 and / or CD86 and / or PD-L2 and / or VISTA and / or TIM-3 and / or CD80.

[0146] The compounds of the present invention can be contacted with receptors that interact with them in aqueous solutions and under conditions suitable for ligand-receptor binding. Receptors may be present in suspensions (e.g., in isolated membrane or cell preparations), in cultured or isolated cells, or in tissues or organs.

[0147] Preferably, the amount of the compound of the invention in contact with the receptor should be sufficient to inhibit PD-1 / PD-L1 binding as measured in vitro, for example, by ELISA. The receptor may be present in solution or suspension, in cultured or isolated cell preparations, or in a patient.

[0148] In some embodiments, the compounds of the present invention can be used to restore and enhance T cell activation. In some embodiments, the compounds of the present invention can be used to enhance the immune response of a patient. In some embodiments, the compounds of the present invention can be used to treat, prevent, or slow the progression of diseases or conditions in various therapeutic areas, such as cancer and infectious diseases.

[0149] In some embodiments, the compounds of the present invention can be used to treat patients with diseases that respond to modulation of protein-protein interactions of PD-1 / PD-L1 proteins.

[0150] In some embodiments, the present invention provides a method for modulating an immune response mediated by the PD-1 signaling pathway in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, said compound comprising a compound of formula (I), (Ia), (Ib), (Ic) or (Id) or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of formula (I), (Ia), (Ib), (Ic) or (Id) or a pharmaceutically acceptable salt thereof.

[0151] In some embodiments, the present invention provides a method for enhancing, stimulating, modulating, and / or increasing an immune response in a subject requiring an immune response, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, said compound comprising a compound of formula (I), (Ia), (Ib), (Ic), or (Id) or a pharmaceutically acceptable salt thereof, or a composition of compounds of the present invention, said compound comprising a compound of formula (I), (Ia), (Ib), (II), (Ia), or (Ib) or a pharmaceutically acceptable salt thereof.

[0152] In some embodiments, the present invention provides a method for inhibiting the growth, proliferation, or metastasis of cancer cells in a subject in need, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, said compound comprising a compound of formula (I), (Ia), (Ib), (Ic), or (Id) or a pharmaceutically acceptable salt thereof, or a composition of compounds of the present invention, said compound comprising a compound of formula (I), (Ia), (Ib), (Ic), or (Id) or a pharmaceutically acceptable salt thereof.

[0153] In some embodiments, the present invention provides a method of treating a subject in need, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, said compound comprising a compound of formula (I), (Ia), (Ib), (Ic) or (Id) or a pharmaceutically acceptable salt thereof, or a composition of compounds of the present invention, said compound comprising a compound of formula (I), (Ia), (Ib), (Ic) or (Id) or a pharmaceutically acceptable salt thereof.

[0154] In some implementations, the subject suffers from a disease or condition selected from the group consisting of: infectious diseases, bacterial infectious diseases, viral infectious diseases, fungal infectious diseases, solid tumors, hematologic malignancies, immune diseases, inflammatory diseases, and cancer. In some implementations, the disease or condition is selected from the group consisting of: melanoma, glioblastoma, esophageal tumors, nasopharyngeal carcinoma, uveal melanoma, lymphoma, lymphocytic lymphoma, primary central nervous system 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, osteosarcoma, angiosarcoma, lymphangiosarcoma, synovial tumor, meningioma, leiomyosarcoma, and rhabdomyosarcoma. Soft tissue sarcoma, sarcoma, sepsis, biliary tract tumors, basal cell carcinoma, thymic tumors, thyroid cancer, parathyroid cancer, uterine cancer, adrenal cancer, liver infection, Merkel cell carcinoma, neurotumor, 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 tumors, myelodysplastic syndrome, malignant melanoma of the skin or eye, renal cell carcinoma, small cell lung cancer. Lung cancer, mesothelioma, breast cancer, squamous non-small cell lung cancer (SCLC), non-squamous non-small cell lung cancer, colorectal cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma, squamous cell carcinoma of the head and neck, head and neck cancer, gastrointestinal cancer, stomach cancer, HIV, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes simplex virus, human papillomavirus (HPV), 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 cancers. Urethra cancer, penile cancer, bladder cancer, kidney cancer, ureteral cancer, renal pelvis cancer, central nervous system tumors (CNS), tumor angiogenesis, spinal axis tumors, brainstem glioma, pituitary adenoma, epidermoid carcinoma, asbestosis, carcinoma, adenocarcinoma, papillary carcinoma, cystadenocarcinoma, bronchial carcinoma, renal cell carcinoma, transitional cell carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, nephroblastoma, pleomorphic adenoma, hepatocellular papilloma, renal tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma, and fibroma.

[0155] In some embodiments, the subject is further administered a therapeutically effective amount of one or more adjunctive therapeutic agents. In some embodiments, the one or more adjunctive therapeutic agents are selected from the group consisting of: antibacterial agents, antiviral agents, cytotoxic agents, gene expression regulators, chemotherapeutic agents, anticancer agents, antiangiogenic agents, immunotherapeutic agents, antihormonal agents, antifibrotic agents, radiotherapy, radiotherapy agents, antitumor agents, and antiproliferative agents. In some embodiments, the one or more adjunctive therapeutic agents are antagonists of chemokines and / or chemokine 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. Chemokines and / or chemokine receptor antagonists are known in the art, for example WO2007 / 002667, WO2007 / 002293, WO / 2003 / 105853, WO / 2007 / 022257, WO / 2007 / 059108, WO / 2007 / 044804, WO2007 / 115232, WO2007 / 115231, WO2008 / 147 815、WO2010 / 030815、WO2010 / 075257、WO2011 / 163640、WO2010 / 054006、WO2010 / 051561、WO 2011 / 035332、WO2013 / 082490、WO2013 / 082429、WO2014 / 085490、WO2014 / 100735、WO2014 / 0 89495、WO2015 / 084842、WO2016 / 187393、WO2017 / 127409、WO2017 / 087607、WO2017 / 087610、 WO2017 / 176620, WO2018 / 222598, WO2018 / 222601, WO2013 / 130811, WO2006 / 076644, WO2008 The following are described in / 008431, WO2009 / 038847, WO2008 / 008375, WO2008 / 008374, WO2008 / 010934, WO2009 / 009740, WO2005 / 112925, WO2005 / 112916, WO2005 / 113513, WO2004 / 085384, and WO2004 / 046092.Chemokines and / or chemokine 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.

[0156] In some embodiments, the compounds of the present invention can be used to inhibit infectious diseases. These infectious diseases include, but are not limited to, HIV, influenza, herpes, Giardia, malaria, Leishmaniasis, viral hepatitis (A, B, and C), herpesviruses (e.g., VZV, HSV-I, HAV-6, HSV-II, and CMV, Epstein-Barr virus), adenovirus, influenza virus, flavivirus, echovirus, rhinovirus, Coxsackie virus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscvirus, poliovirus, rabies virus, JC virus and arbovirus encephalitis virus, chlamydial infection, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumococci, meningococci and cocci, Klebsiella, and others. Bacillus, Serratia, Pseudomonas, Escherichia coli, Legionella, diphtheria, Salmonella, Bacillus, cholera, tetanus, botulism, anthrax, plague, leptospirosis, Lyme disease, pathogenic infections of Candida (Candida albicans, Candida krusei, Candida glabrata, Candida tropicalis, etc.), Cryptococcus neoformans, Aspergillus (Fumica mold, Niger mold, etc.), Mucor (Mucor, Pyrophyllus) Rhizopus, Schenck's Sporothrix, Blastomyces dermatitidis, Blastomyces brasiliensis, Coccidioides immitis and Histoplasma capsulatum, pathogenic infections of parasitic endoamyces, Escherichia coli, Naegleria folliculorum, Acanthamoeba, Lambda flagellates, Cryptosporidium, Pneumocystis carinii, Plasmodium vivax, Babesia microbabesia, Trypanosoma brevicornu, Trypanosoma krusei, Leishmania donovani, Toxoplasma gondii, and Hookworm brasiliensis.

[0157] In some embodiments, the compounds of the present invention can be used to inhibit HIV infection, slow the progression of AIDS, deplete the HIV viral reservoir, or reduce the symptoms or severity of HIV infection and AIDS.

[0158] The compounds of this invention can be used to treat cancer and precancerous conditions in subjects.

[0159] The treatments described herein typically involve administering an effective amount of one or more compounds described herein to a patient. Suitable patients include those who have or are susceptible to (i.e., for preventative treatment) one of the conditions or diseases described herein. Typical patients for the treatments described herein include mammals, especially primates, and particularly humans. Other suitable patients include domesticated companion animals such as dogs, cats, horses, etc., or livestock such as cattle, pigs, sheep, etc.

[0160] Typically, the treatment methods described herein involve administering an effective amount of one or more compounds provided herein to a patient. In a preferred embodiment, the compounds of this disclosure are preferably administered intravenously, orally, or topically to a patient (e.g., a human). An effective amount may be sufficient to modulate the PD-1 / PD-L1 interaction and / or sufficient to reduce or alleviate the symptoms presented by the patient. Preferably, the administered amount is sufficient to produce sufficiently high plasma concentrations of the compound (or its active metabolite, if the compound is a prodrug) to modulate the PD-1 / PD-L1 interaction. Treatment regimens may vary depending on the compound used and the specific condition being treated; for the treatment of most diseases, a dosing frequency of four times daily or less is preferred. Generally, a twice-daily dosing regimen is more preferred, and a once-daily dosing regimen is particularly preferred. However, it should be understood that the specific dose level and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health condition, sex, diet, time of administration, route of administration, excretion rate, combination of drugs (i.e., other drugs given to the patient), and the severity of the specific disease being treated, as well as the prescribing physician's judgment. Generally, it is preferred to use the minimum dose sufficient to provide effective treatment. The effectiveness of a patient's treatment can usually be monitored using medical or veterinary standards appropriate for the disease being treated or prevented.

[0161] Composition

[0162] Companion drugs comprising the compounds of this invention and other drugs can be administered as combination formulations, wherein both components are contained in a single formulation, or as single formulations. Single formulation administration includes simultaneous administration and administration at time intervals. In the case of administration at time intervals, the compound of this invention can be administered first, followed by another drug, or another drug can be administered first, followed by the disclosed compound. The administration methods for each drug can be the same or different.

[0163] The dosage of other drugs may be appropriately selected based on the clinically used dosage. The ratio of the compound of the present invention to other drugs may be appropriately selected according to the age and weight of the recipient, the method of administration, the time of administration, the disease being treated, the symptoms, and their combinations. For example, based on 1 part by weight of the compound of the present invention, 0.01 to 100 parts by weight of other drugs may be used. The other drug may be a combination of two or more drugs in an appropriate proportion.

[0164] The compounds described in this invention may be used or used in combination with one or more therapeutic agents, such as antibacterial agents, antiviral agents, cytotoxic agents, gene expression regulators, chemotherapeutic agents, anticancer agents, antiangiogenic agents, immunotherapeutic agents, antihormonal agents, antifibrotic agents, radiotherapy, radiotherapy agents, antitumor agents, and antiproliferative agents. These therapeutic agents may be in the form of compounds, antibodies, peptides, or polynucleotides.

[0165] The compounds described herein may be used in combination with one or more therapeutic antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins (e.g., Fab derivatives), antibody-drug conjugates (ADCs), viruses, oncolytic viruses, gene-modifying agents or editing agents such as CRISPR (including CRISPRCas9), zinc finger nucleases or synthetic nucleases (TALENs), CAR (chimeric antigen receptor) T-cell immunotherapies, or any combination thereof.

[0166] Examples of chemotherapy include alkylating agents, nitrosoureas, antimetabolites, anticancer antibiotics, plant-derived alkaloids, topoisomerase inhibitors, hormonal drugs, hormone antagonists, aromatase inhibitors, P-glycoprotein inhibitors, platinum complex derivatives, other immunotherapeutic agents, and other anticancer drugs.

[0167] The compounds described herein may be used, either in combination or in mixtures with adjuvants to cancer treatment, such as leukopenia (neutropenia), thrombocytopenia, antiemetics, and cancer pain interventions.

[0168] The compounds described herein may be used or used in combination with kinase inhibitors.

[0169] In one embodiment, the compounds of the present invention may be used simultaneously or in mixtures with other immunomodulators and / or enhancers. Examples of said immunomodulators include various cytokines, vaccines, and adjuvants. Examples of said cytokines, vaccines, and adjuvants that stimulate immune responses include, but are not limited to, GM-CSF, M-CSF, G-CSF, interferon-α, β, or γ, IL-1, IL-2, IL-3, IL-12, Poly(I:C), and CPG. Enhancers include cyclophosphamide and cyclophosphamide analogs, anti-TGF and imatinib (Gleevac), mitotic inhibitors such as 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.

[0170] In some embodiments, the compounds described herein may be used, or in combination with one or more of the following modifiers: CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CCR11, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, ChemR23, C5aR, C5a, and C5. In some embodiments, the modifiers are antagonists.

[0171] In some embodiments, the compounds described herein may be used, or in combination with one or more chemokines and / or chemokine receptor antagonists, such as WO2007 / 002667, WO2007 / 002293, WO / 2003 / 105853, WO / 2007 / 022257, WO / 2007 / 059108, WO / 2007 / 044804, WO2007 / 115232, WO200 7 / 115231、WO2008 / 147815、WO2010 / 030815、WO2010 / 075257、WO2011 / 163640、WO2010 / 054006 , WO2010 / 051561, WO2011 / 035332, WO2013 / 082490, WO2013 / 082429, WO2014 / 085490, WO2014 / 1 00735、WO2014 / 089495、WO2015 / 084842、WO2016 / 187393、WO2017 / 127409、WO2017 / 087607、WO 2017 / 087610, WO2017 / 176620, WO2018 / 222598, WO2018 / 222601, WO2013 / 130811, WO2006 / 0766 44. WO2008 / 008431, WO2008 / 038847, WO2008 / 008375, WO2008 / 008374, WO2008 / 010934, WO200 9 / 009740, WO2005 / 112925, WO2005 / 112916, WO2005 / 113513, WO2004 / 085384, WO2004 / 046092. The chemokines and / or chemokine receptor antagonists that can be used in this invention 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.

[0172] dose

[0173] Dosage levels of approximately 0.1 mg to approximately 140 mg per kilogram of body weight per day can be used to treat or prevent conditions involving PD-1 / PD-L1 interaction (approximately 0.5 mg to approximately 7 g per person per day). The amount of active ingredient that can be combined with a carrier material to produce a single dosage form can vary depending on the host being treated and the specific route of administration. Dosage units typically contain approximately 1 mg to approximately 500 mg of the active ingredient. For compounds administered orally, transdermally, intravenously, or subcutaneously, preferably, an adequate amount of the compound is administered to achieve a serum concentration of 5 ng (nanograms) / mL to 10 μg (micrograms) / mL serum; more preferably, an adequate amount of the compound is administered to achieve a serum concentration of 20 ng to 1 μg / mL serum; and most preferably, an adequate amount of the compound should be 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), an adequate amount of the compound should be administered to achieve a local concentration of approximately 1 micromolar.

[0174] The frequency of dosing can also vary depending on the compound used and the specific disease being treated. However, for the treatment of most diseases, a dosing regimen of four, three, or fewer times daily is preferred, with a particularly preferred regimen of once or twice daily. However, it should be understood that the specific dose level for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health condition, sex, diet, time of administration, route of administration and excretion rate, drug combination (i.e., other medications given to the patient), the severity of the specific disease being treated, and other factors including the prescribing physician's judgment.

[0175] In another aspect of the invention, the compounds of the present invention can be used for various non-pharmaceutical in vivo and in vitro applications. The compounds of the present invention can also be used as positive controls for PD-1 / PD-L1 interaction activity assays, i.e., as standards for determining the binding ability of candidate reagents to PD-1 and / or PD-L1, or as radiotracers for positron emission tomography (PET) imaging or single-photon emission computed tomography (SPECT).

[0176] The scope of this invention also includes kits and instructions for use containing compounds of the invention or pharmaceutically acceptable salts thereof. The kits may further contain at least one additional reagent. Kits typically include a label indicating the intended use of the kit contents. Terminology labels include any text or documentation provided on or with the kit, or any materials accompanying the kit.

[0177] Example

[0178] The following examples illustrate various methods for preparing the compounds of the present invention, including compounds of formula (I), (Ia), (Ib), (Ic), or (Id). The examples are provided for illustrative purposes only and are not intended to limit the claimed disclosure.

[0179] The reagents and solvents used below are commercially available, such as Aldrich Chemical Company (Milwaukee, Wisconsin, USA). Recorded on a Varian Mercury 400MHz NMR spectrometer. 1 1H-NMR spectra are provided. Significant peaks relative to TMS are presented and listed in the following order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplicity) and proton number. Mass spectrometry results are reported as mass-to-charge ratios. In the examples, individual m / z values ​​are reported for M+H (or MH, as described above) ions containing the most common atomic isotopes. Isotope modes conform to the expected formula in all cases. Electrospray ionization (ESI) mass spectrometry was performed on a HP MSD electrospray mass spectrometer, with sample delivery using an HP1100 HPLC. Typically, analytes were dissolved in methanol or CH3CN at a concentration of 0.1 mg / mL, and 1 μL was injected into the mass spectrometer along with the transfer solvent, with a scan range of 100–1000 Daltons. All compounds were analyzed using positive or negative electrospray ionization with acetonitrile / water and 1% formic acid as transfer solvents.

[0180] The following abbreviations are used in the examples and throughout the description of this invention: TLC refers to thin-layer chromatography.

[0181] Compounds within the scope of this invention can be synthesized as described below, using various 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 target compounds of this invention, and that the methods described herein are not exhaustive, but do provide broadly applicable and practical routes for the relevant compounds.

[0182] Some of the molecules claimed in this patent may exist in different enantiomeric and diastereomeric forms, unless a particular enantiomer is specified, and all variants of these compounds are claimed.

[0183] In this paper, a detailed description of the experimental procedures for synthesizing key compounds leads to molecules described by the physical data that identify them and the associated structural descriptions.

[0184] Those skilled in the art will also recognize that acids and bases are frequently used in standard processing procedures in organic chemistry. In the experimental procedures described in this patent, salts of the parent compound may sometimes be produced if the parent compound possesses the necessary inherent acidity or basicity.

[0185] Example 1: (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((5-oxopyrrolidone-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide

[0186]

[0187] Step a: HATU (2.22 g, 5.84 mmol) and diisopropylethylamine (0.94 g, 7.30 mmol) were added to a mixture of 1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid (0.75 g, 4.87 mmol) and 3-bromo-2-methylaniline (0.91 g, 4.87 mmol) in DMF (30 mL). The reaction was stirred at room temperature for 16 hours. After the reaction was complete, 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, CD3OD) δ8.89(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)m / z C 13 H 13 BrN3O2[M+H] + Calculated value: 322.0, measured value: 322.0.

[0188] Step b: A complex of Pd(dppf)Cl2 and dichloromethane (456 mg, 0.559 mmol) was added to a mixture of N-(3-bromo-2-methylphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-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-dioxoboron-2-yl)-[1,1'-biphenyl]-4-yl)methyl)carbamate (1.4 g, 3.72 mmol), and 2M K2CO3 (5.6 mL, 11.2 mmol) in 32 mL of p-dioxane. The reaction mixture was degassed (N2) for 2 min and stirred at 95 °C under N2 for 5 h. The reaction mixture was diluted with EtOAc, filtered through diatomaceous earth, washed with brine, and dried over MgSO4. The solvent was removed under reduced pressure, and the residue was purified by silica gel rapid chromatography column (5%-20%-40% ethyl acetate / n-hexane) to give N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a brown solid. 1 HNMR (400MHz, CD3OD) δ10.40 (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)m / zC 28 H 25 FN3O4[M+H] + Calculated value: 486.2, measured value: 486.2.

[0189] Step c: Acetic acid (5 drops) was added to a stirred solution of N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide (100 mg, 0.206 mmol) and (S)-4-aminopyrrolidone-2-one (82 mg, 0.824 mmol) in ethanol (1 mL). The reaction mixture was stirred at 70 °C for 1 hour. The mixture was then cooled to 0 °C, and NaCNBH3 (13 mg, 0.206 mmol) was slowly added. 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 / water) to give (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((5-oxopyrrolidone-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. 1 H NMR(400MHz,CD3OD)δ11.41(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)m / z C 32 H 33 FN5O4[M+H] + Calculated value: 570.2; Measured value: 570.3.

[0190] Example 2: (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide

[0191]

[0192] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD) δ11.41(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)m / zC 33 H 35 FN5O4[M+H] + Calculated value: 584.3, measured value: 584.3.

[0193] Example 3: (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide

[0194]

[0195] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD) δ11.41(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)m / zC 33 H 35 FN5O4[M+H] + Calculated value: 584.3, measured value: 584.3.

[0196] Example 4: (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((methyl((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide

[0197]

[0198] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((methyl((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR(400MHz,CD3OD)δ11.41(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),4.76–4.6 7(m,1H),4.27(s,1H),4.09–4.04(m,1H),4.02(s,3H),4.01(s,2H),3.65(s,3H ),3.07(s,3H),2.97–2.78(m,2H),2.61–2.33(m,2H),2.11(s,3H),1.96(s,3H). MS:(ES)m / z C 34 H 37 FN5O4[M+H] + Calculated value: 598.3, measured value: 598.3.

[0199] Example 5: (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((methyl((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide

[0200]

[0201] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((methyl((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR(400MHz,CD3OD)δ11.41(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),4.76–4.6 7(m,1H),4.27(s,1H),4.09–4.04(m,1H),4.02(s,3H),4.01(s,2H),3.65(s,3H ),3.07(s,3H),2.97–2.78(m,2H),2.61–2.33(m,2H),2.11(s,3H),1.96(s,3H). MS:(ES)m / z C 34 H 37 FN5O4[M+H] + Calculated value: 598.3, measured value: 598.3.

[0202] Example 6: (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((((1-methyl-5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide

[0203]

[0204] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((((1-methyl-5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR(400MHz,CD3OD)δ11.41(s,1H),8.92(s,1H),8.68(s,1H),8.13–8.11(m,1 H),7.37–7.23(m,3H),7.14–7.12(m,1H),7.01–6.88(m,3H),4.43(s,2H),4.0 0(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)m / z C 34 H 37 FN5O4[M+H] + Calculated value: 598.3, measured value: 598.3.

[0205] 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”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-5-carboxamide

[0206]

[0207] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(4”-((((2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)methyl)amino)methyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR(400MHz,CD3OD)δ11.41(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)m / z C 33 H 32 FN6O5[M+H] + Calculated value: 611.2, measured value: 611.2.

[0208] Example 8: (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((6-oxopiperidin-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide

[0209]

[0210] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) 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”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD) δ11.41(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)m / zC 33 H 35 FN5O4[M+H] + Calculated value: 584.3, measured value: 584.3.

[0211] Example 9: (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((6-oxopiridine-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide

[0212]

[0213] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) 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”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD) δ11.41(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(d,2h). J=7.6,6.1Hz,2H),2.42-2.35(m,1H),2.11(s,3H),1.94(s,3H). MS: (ES)m / zC 33 H 35 FN5O4[M+H] + Calculated value: 584.3, measured value: 584.3.

[0214] Example 10: N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((2-(2-oxopyrrolidone-1-yl)ethyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide

[0215]

[0216] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((2-(2-oxopyrrolidone-1-yl)ethyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD) δ11.41(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)m / z C 34 H 37 FN5O4[M+H] + Calculated value: 598.3, measured value: 598.3.

[0217] Example 11: N-(4”-(((3-amino-3-oxopropyl)amino)methyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide

[0218]

[0219] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(4”-((((3-amino-3-oxopropyl)amino)methyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid.1 H NMR (400MHz, CD3OD) δ11.41(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)m / z C 31 H 33 The calculated value of FN5O4[M+H]+ is 558.2, and the measured value is 558.3.

[0220] Example 12: N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((oxocyclobutane-3-ylamino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide

[0221]

[0222] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((oxocyclobutane-3-ylamino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD) δ11.41(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)m / z C 31 H 32 The calculated value of FN4O4[M+H]+ is 543.2, and the measured value is 543.3.

[0223] Example 13: N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((tetrahydro-2H-pyran-4-yl)amino)methyl)-[1,1':3',1''-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide

[0224]

[0225] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((4H-2H-pyran-4-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD) δ11.41(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,3H),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)m / z C 33 H 36 FN4O4[M+H] + Calculated value: 571.3, measured value: 571.3.

[0226] Example 14: N-(3”-fluoro-4”-(((3-hydroxycyclobutyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide

[0227]

[0228] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(3”-fluoro-4''-((3-hydroxycyclobutyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxy-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD) δ8.58(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)m / z C 32 H 34 FN4O4[M+H] + Calculated value: 557.3, measured value: 557.3.

[0229] Example 15: N-(3”-fluoro-4”-((((1S,2R)-2-hydroxycyclopentyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide

[0230]

[0231] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(3”-fluoro-4”-((((1S,2R)-2-hydroxycyclopentyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD) δ11.41(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)m / z C 33 H 36 FN4O4[M+H] + Calculated value: 571.3, measured value: 571.3.

[0232] Example 16: N-(3”-fluoro-4”-((((1R,2S)-2-hydroxycyclopentyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide

[0233]

[0234] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(3”-fluoro-4”-((((1R,2S)-2-hydroxycyclopentyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD) δ11.41(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)m / z C 33 H 36 FN4O4[M+H] + Calculated value: 571.3, measured value: 571.3.

[0235] Example 17: N-(3”-fluoro-4”-((((1S,2S)-2-hydroxycyclopentyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide

[0236]

[0237] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(3”-fluoro-4”-((((1S,2S)-2-hydroxycyclopentyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD) δ11.41(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)m / z C 33 H 36 FN4O4[M+H] + Calculated value: 571.3, measured value: 571.3.

[0238] Example 18: N-(3”-fluoro-4”-((((1R,2R)-2-hydroxycyclopentyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide

[0239]

[0240] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(3”-fluoro-4”-((((1R,2R)-2-hydroxycyclopentyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD) δ11.41(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)m / z C 33 H 36 FN4O4[M+H] + Calculated value: 571.3, measured value: 571.3.

[0241] 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”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide

[0242]

[0243] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) 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”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR(400MHz,CD3OD)δ11.41(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)m / z C 33 H 36 FN4O5[M+H] + Calculated value: 587.3, measured value: 587.3.

[0244] Example 20: N-(3”-fluoro-4”-(((2-hydroxyethyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide

[0245]

[0246] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(3”-fluoro-4”-(((2-hydroxyethyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD) δ11.42(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,1 H),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)m / z C 30 H 32 FN4O4[M+H] + Calculated value: 531.2, measured value: 531.2.

[0247] Example 21: (R)-N-(3”-fluoro-4”-(((1-hydroxypropyl-2-yl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide

[0248]

[0249] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (R)-N-(3”-fluoro-4”-(((1-hydroxypropane)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1H NMR(400MHz,CD3OD)δ11.42(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)m / zC 31 H 34 FN4O4[M+H] + Calculated value: 545.3, measured value: 545.3.

[0250] Example 22: (R)-N-(3”-fluoro-4”-(((2-hydroxypropyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide

[0251]

[0252] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (R)-N-(3”-fluoro-4”-(((2-hydroxypropyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1H NMR (400MHz, CD3OD) δ11.41(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),4.3 6(s,2H),4.13–4.09(m,1H),3.98(s,3H),3.66(s,3H),3.17–3.08(m,1 H), 2.94–2.84 (m, 1H), 2.11 (s, 3H), 1.95 (s, 3H), 1.24 (d, J = 6.3Hz, 3H). MS: (ES)m / z C 31 H 34 FN4O4[M+H] + Calculated value: 545.3, measured value: 545.3.

[0253] Example 23: N-(3”-fluoro-4”-(((2-hydroxy-2-methylpropyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide

[0254]

[0255] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(3”-fluoro-4”-(((2-hydroxy-2-methylpropyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD) δ11.41(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)m / z C 32 H 36FN4O4[M+H] + Calculated value: 559.3, measured value: 559.3.

[0256] Example 24: N-(3”-fluoro-4”-((((1-hydroxycyclopropyl)methyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide

[0257]

[0258] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(3”-fluoro-4”-((((1-hydroxycyclopropyl)methyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD) δ11.41(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,3H),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)m / z C 32 H 34 FN4O4[M+H] + Calculated value: 557.3, measured value: 557.3.

[0259] Example 25: N-(3”-fluoro-4”-(((1-hydroxy-2-methylpropane-2-yl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide

[0260]

[0261] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(3”-fluoro-4”-(((1-hydroxy-2-methylpropane-2-yl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1 HNMR(400MHz,CD3OD)δ11.41(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=7.5Hz,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)m / z C 32 H 36 FN4O4[M+H] + Calculated value: 559.3, measured value: 559.3.

[0262] Example 26: N-(3”-fluoro-4”-(((2-hydroxyethyl)(methyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide

[0263]

[0264] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(3”-fluoro-4”-(((2-hydroxyethyl)(methyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1H NMR (400MHz, CD3OD) δ11.42(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)m / z C 31 H 34 FN4O4[M+H] + Calculated value: 545.3, measured value: 545.3.

[0265] Example 27: N-(3”-fluoro-4”-(((2-hydroxy-2-methylpropyl)(methyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide

[0266]

[0267] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) 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”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1H NMR (400MHz, CD3OD) δ11.42(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)m / z C 33 H 38 FN4O4[M+H] + Calculated value: 573.3, measured value: 573.3.

[0268] Example 28: 1-((3-fluoro-5-methoxy-2′,2″-dimethyl-3″-(1-methyl-6-oxo-1,6-dihydropyrimidin-5-carboxamido)-[1,1′:3′,1″-triphenyl]-4-yl)methyl)azacyclobutane-3-carboxylic acid

[0269]

[0270] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product 1-((3-fluoro-5-methoxy-2′,2″-dimethyl-3″-(1-methyl-6-oxo-1,6-dihydropyrimidin-5-carboxamido)-[1,1′:3′,1″-triphenyl]-4-yl)methyl)azacyclobutane-3-carboxylic acid, as a white solid. 1H NMR (400MHz, CD3OD) δ11.41(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)m / z C 32 H 32 FN4O5[M+H] + Calculated value: 571.3, measured value: 571.3.

[0271] Example 29: (3-fluoro-5-methoxy-2′,2″-dimethyl-3″-(1-methyl-6-oxo-1,6-dihydropyrimidin-5-carbamate)-[1,1′:3′,1″-triphenyl]-4-yl)methyl)glycine

[0272]

[0273] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (3-fluoro-5-methoxy-2′,2″-dimethyl-3″-(1-methyl-6-oxo-1,6-dihydropyrimidin-5-carboxamido)-[1,1′:3′,1″-triphenyl]-4-yl)methyl)glycine, as a white solid. 1 H NMR (400MHz, CD3OD) δ11.42(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)m / zC 30 H 30 FN4O5[M+H] + Calculated value: 545.2; Measured value: 545.3.

[0274] Example 30: N-(3”-fluoro-4”-(((2-hydroxyethyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

[0275]

[0276] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(3”-fluoro-4”-(((2-hydroxyethyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD) δ8.58(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)m / z C 31 H 33 FN3O4[M+H] + Calculated value: 530.2, measured value: 530.2.

[0277] Example 31: N-(3”-fluoro-4”-(((2-hydroxy-2-methylpropyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

[0278]

[0279] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(3”-fluoro-4”-(((2-hydroxy-2-methylpropyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD) δ8.58(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)m / zC 33 H 37 FN3O4[M+H] + Calculated value: 558.3, measured value: 558.3.

[0280] Example 32: 1-((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamido)-[1,1':3',1”-triphenyl]-4-yl)methyl)azacyclobutane-3-carboxylic acid

[0281]

[0282] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2’-dimethyl-[1,1’:3’,1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) 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”-triphenyl]-4-yl)methyl)azacyclobutane-3-carboxylic acid, as a white solid.1 H NMR (400MHz, CD3OD) δ8.60(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=7.5H z,1H),6.99–6.81(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)m / z C 33 H 33 FN3O5[M+H] + Calculated value: 570.2; Measured value: 570.3.

[0283] Example 33: (3-fluoro-5-methoxy-2',2”-dimethyl-3”-(1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamido)-[1,1':3',1”-triphenyl]-4-yl)methyl)glycine

[0284]

[0285] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2’-dimethyl-[1,1’:3’,1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) 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”-triphenyl]-4-yl)methyl)glycine, as a white solid. 1 H NMR (400MHz, CD3OD) δ8.58(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)m / z C 31 H 31 FN3O5[M+H] +Calculated value: 544.2; Measured value: 544.3.

[0286] Example 34: (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((5-oxopyrrolidone-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0287]

[0288] This compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((5-oxopyrrolidone-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR(400MHz,CD3OD)δ11.16(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)m / z C 32 H 33 FN5O5[M+H] + Calculated value: 586.2; Measured value: 586.3.

[0289] Example 35: (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((methyl((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0290]

[0291] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((methyl((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD) δ11.15(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),4.74–4.6 8(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)m / z C 34 H 37 FN5O5[M+H] + Calculated value: 614.3, measured value: 614.3.

[0292] Example 36: (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((6-oxopiridine-3-yl)amino)methyl)-[1,1':3',1”-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0293]

[0294] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) 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”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD) δ11.16(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),4.00(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)m / z C 33 H 35 FN5O5[M+H] + Calculated value: 600.3, measured value: 600.3.

[0295] Example 37: (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((6-oxopiperidin-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0296]

[0297] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) 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”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD) δ11.16(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),4.00(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)m / z C 33 H 35 FN5O5[M+H] + Calculated value: 600.3, measured value: 600.3.

[0298] Example 38: N-(4”-(((3-amino-2,2-dimethyl-3-oxopropyl)amino)methyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0299]

[0300] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) 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”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD) δ11.16(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)m / z C 33 H 37 FN5O5[M+H] + Calculated value: 602.3, measured value: 602.3.

[0301] Example 39: (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((tetrahydrofuran-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0302]

[0303] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((tetrahydrofuran-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR(400MHz,CD3OD)δ11.15(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,3 H),2.50–2.41(m,1H),2.15–2.10(m,1H),2.16-2.07(m,4H),1.94(s,3H). MS: (ES)m / z C 32 H 34 FN4O5[M+H] + Calculated value: 573.2; Measured value: 573.3.

[0304] Example 40: (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((tetrahydrofuran-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0305]

[0306] This compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((tetrahydrofuran-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR(400MHz,CD3OD)δ11.15(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,3 H),2.50–2.41(m,1H),2.15–2.10(m,1H),2.16-2.07(m,4H),1.94(s,3H). MS: (ES)m / z C 32 H 34 FN4O5[M+H] + Calculated value: 573.2; Measured value: 573.3.

[0307] Example 41: N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((tetrahydro-2H-pyran-4-yl)amino)methyl)-[1,1':3',1''-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0308]

[0309] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) 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”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD) δ11.15(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)m / z C 33 H 36 FN4O5[M+H] + Calculated value: 587.3, measured value: 587.3.

[0310] Example 42: N-(3”-fluoro-4”-((((1R,2S)-2-hydroxycyclopentyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0311]

[0312] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(3”-fluoro-4”-((((1R,2S)-2-hydroxycyclopentyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD) δ11.16(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)m / z C 33 H 36 FN4O5[M+H] + Calculated value: 587.3, measured value: 587.3.

[0313] Example 43: (R)-N-(3”-fluoro-4”-(((2-hydroxypropyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0314]

[0315] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (R)-N-(3”-fluoro-4”-(((2-hydroxypropyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid.1 H NMR (400MHz, CD3OD) δ11.16(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,2 H),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)m / z C 31 H 34 FN4O5[M+H] + Calculated value: 561.2; measured value: 561.3.

[0316] Example 44: N-(3”-fluoro-4”-(((2-hydroxy-2-methylpropyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0317]

[0318] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(3”-fluoro-4”-(((2-hydroxy-2-methylpropyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD) δ11.14(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)m / z C 32 H36 FN4O5[M+H] + Calculated value: 575.3, measured value: 575.3.

[0319] Example 45: N-(4”-(((3-amino-2,2-dimethyl-3-oxopropyl)amino)methyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0320]

[0321] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) 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”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD) δ11.16(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)m / z C 34 H 39 FN5O5[M+H] + Calculated value: 616.3, measured value: 616.3.

[0322] Example 46: (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((tetrahydrofuran-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0323]

[0324] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((tetrahydrofuran-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD) δ11.16(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,2H),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)m / z C 33 H 36 FN4O5[M+H] + Calculated value: 587.3, measured value: 587.3.

[0325] Example 47: (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((tetrahydrofuran-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0326]

[0327] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((tetrahydrofuran-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD) δ11.16(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,2H),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)m / z C 33 H 36 FN4O5[M+H] + Calculated value: 587.3, measured value: 587.3.

[0328] Example 48: N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((tetrahydro-2H-pyran-4-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0329]

[0330] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) 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”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD) δ11.17(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),4.09–4.05(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)m / zC 34 H 38 FN4O5[M+H] + Calculated value: 601.3, measured value: 601.3.

[0331] 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”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0332]

[0333] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) 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”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD) δ11.17(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,2H),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)m / z C 34 H 38 FN4O6[M+H] + Calculated value: 617.3; Measured value: 618.3.

[0334] Example 50: N-(4”-(((3-amino-2,2-dimethyl-3-oxopropyl)amino)methyl)-2′,3″-difluoro-5'′-methoxy-2-methyl-[1,1′:3′,1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0335]

[0336] The compound was prepared using a process similar to step c of Example 1, with N-(2′,3″-difluoro-4″-formyl-5″-methoxy-2-methyl-[1,1′:3′,1″-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) 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″-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD) δ11.19(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)m / z C 33 H 36 F2N5O5[M+H] + The calculated value is 620.3, and the measured value is 620.3.

[0337] Example 51: (S)-N-(2',3”-difluoro-5”-methoxy-2-methyl-4”-((((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0338]

[0339] The compound was prepared using a process similar to step c of Example 1, with N-(2′,3”-difluoro-4”-formyl-5”-methoxy-2-methyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (S)-N-(2',3”-difluoro-5”-methoxy-2-methyl-4”-((((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD) δ11.19(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),4.08–4.02(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)m / z C 33 H 34 F2N5O5[M+H] + The calculated value is 618.2, and the measured value is 618.3.

[0340] Example 52: (S)-N-(2',3”-difluoro-5”-methoxy-2-methyl-4”-(((5-oxopyrrolidone-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0341]

[0342] The compound was prepared using a process similar to step c of Example 1, with N-(2′,3”-difluoro-4”-formyl-5”-methoxy-2-methyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (S)-N-(2',3”-difluoro-5”-methoxy-2-methyl-4”-(((5-oxopyrrolidone-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD) δ11.18(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)m / z C 32 H 32 F2N5O5[M+H] + The calculated value is 604.2, and the measured value is 604.3.

[0343] Example 53: (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((((1-methyl-5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide

[0344]

[0345] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((((1-methyl-5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-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, CD3OD) δ11.08 (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),3.99–3.9 3(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)m / z C 34 H 38 FN6O5[M+H] + Calculated value: 629.3, measured value: 629.3.

[0346] Example 54: (R)-3-(((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-yl)methyl)amino)pyrrolidone-2-one

[0347]

[0348] The compound was prepared using a process similar to step c of Example 1, with 3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-carboxaldehyde. The product was purified by HPLC (MeCN / water and 0.1% TFA) 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”-triphenyl]-4-yl)methyl)amino)pyrrolidone-2-one, a white solid. 1 H NMR(400MHz,CD3OD)δ9.24(s,1H),9.05(s,1H),7.79(d,J=7.1Hz,1H),7.64–7 .49(m,3H),7.41–7.32(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)m / z C 33 H 32 FN6O2[M+H] + Calculated value: 563.3, measured value: 563.3.

[0349] Example 55: (S)-3-(((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-yl)methyl)amino)pyrrolidone-2-one

[0350]

[0351] The compound was prepared using a process similar to step c of Example 1, with 3-fluoro-5-methoxy-2',2”-dimethyl-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-carboxaldehyde. The product was purified by HPLC (MeCN / H2O and 0.1% TFA) 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”-triphenyl]-4-yl)methyl)amino)pyrrolidone-2-one as a white solid. 1H NMR(400MHz,CD3OD)δ9.24(s,1H),9.05(s,1H),7.79(d,J=7.1Hz,1H),7.64–7 .49(m,3H),7.41–7.32(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)m / z C 33 H 32 FN6O2[M+H] + Calculated value: 563.3, measured value: 563.3.

[0352] Example 56: 5-((((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-(1,1':3',1”-triphenyl]-4-yl)methyl)amino)methyl)pyrimidine-2,4(1H,3H)-dione

[0353]

[0354] This compound was prepared using a procedure similar to step c of Example 1, with 3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-carboxaldehyde. The product was purified by HPLC (MeCN / water and 0.1% TFA) 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”-triphenyl]-4-yl)methyl)amino)methyl)pyrimidine-2,4(1H,3H)-dione, as a white solid. MS: (ES) m / z C 34 H 31 FN7O3[M+H] + Calculated value: 604.2, measured value: 604.2.

[0355] Example 57: 1-(2-(((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-yl)methyl)amino)ethyl)pyrrolidone-2-one

[0356]

[0357] The compound was prepared using a process similar to step c of Example 1, with 3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-carboxaldehyde. The product was purified by HPLC (MeCN / water and 0.1% TFA) 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”-triphenyl]-4-yl)methyl)amino)ethyl)pyrrolidine-2-one, as a white solid. 1 H NMR (400MHz, CD3OD) δ9.25 (d, J=2.0Hz, 1H), 9.05 (d, J=2.0Hz, 1H), 7.79 (d, J= 7.2Hz,1H),7.64-7.49(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)m / z C 35 H 36 FN6O2[M+H] + Calculated value: 591.3, measured value: 592.3.

[0358] Example 58: N-(4”-((((1H-pyrrolo-2-yl)methyl)amino)methyl)-3''-fluoro-5''-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)pyrido[3,4-b]pyrazine-5-amine

[0359]

[0360] This compound was prepared using a procedure similar to step c of Example 1, with 3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-carboxaldehyde. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(4”-((((1H-pyrrolo-2-yl)methyl)amino)methyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)pyrido[3,4-b]pyrazin-5-amine, as a white solid. MS: (ES) m / z C 34 H 32 FN6O[M+H] + Calculated value: 559.3, measured value: 559.3.

[0361] Example 59: 3-(((2',3-difluoro-5-methoxy-2”-methyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-(1,1':3',1”-triphenyl]-4-yl)methyl)amino)-2,2-dimethylpropylamine

[0362]

[0363] The compound was prepared using a process similar to step c of Example 1, with 2',3-difluoro-5-methoxy-2”-methyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-carboxaldehyde. The product was purified by HPLC (MeCN / water and 0.1% TFA) 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”-triphenyl]-4-yl)methyl)amino)-2,2-dimethylpropylamine, as a white solid. 1 H NMR (400MHz, CD3OD) δ9.22(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)m / z C 33 H 33 F2N6O2[M+H] + Calculated value: 583.3, measured value: 583.3.

[0364] Example 60: (S)-5-((((2′,3-difluoro-5-methoxy-2″-methyl-3″-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-yl)methyl)amino)methyl)pyrrolidone-2-one

[0365]

[0366] The compound was prepared using a process similar to step c of Example 1, with 2',3-difluoro-5-methoxy-2″-methyl-3″-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-carboxaldehyde. The product was purified by HPLC (MeCN / water and 0.1% TFA) 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”-triphenyl]-4-yl)methyl)amino)methyl)pyrrolidone, as a white solid. 1 H NMR (400MHz, CD3OD) δ9.24(s,1H),9.05(s,1H),7.81(d,J=7.1Hz,1H),7.68–7.37(m,7H),7.17–7.12(m,2 H),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)m / z C 33 H 31 F2N6O2[M+H] + Calculated value: 581.2; Actual measured value: 581.3.

[0367] Example 61: 1-((3-fluoro-3”-(isoquinoline-1-ylamino)-5-methoxy-2',2”-dimethyl-[1,1':3',1”-triphenyl]-4-yl)methyl)azacyclobutane-3-carboxylic acid

[0368]

[0369] The compound was prepared using a process similar to step c of Example 1, with 3-fluoro-3”-(isoquinoline-1-ylamino)-5-methoxy-2',2”-dimethyl-[1,1':3',1”-triphenyl]-4-carboxaldehyde. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product 1-((3-fluoro-3”-(isoquinoline-1-ylamino)-5-methoxy-2',2”-dimethyl-[1,1':3',1”-triphenyl]-4-yl)methyl)azacyclobutane-3-carboxylic acid as a white solid. 1 H NMR (400MHz, CD3OD) δ8.67–8.63(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,5 H),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)m / z C 35 H 33 FN3O3[M+H] + Calculated value: 562.2; Measured value: 562.3.

[0370] Example 62: 1-((3”-((1,6-naphthid-8-yl)amino)-3-fluoro-5-methoxy-2',2”-dimethyl-[1,1':3',1”-triphenyl]-4-yl)methyl)azacyclobutane-3-carboxylic acid

[0371]

[0372] The compound was prepared using a process similar to step c of Example 1, with 3”-((1,6-naphthid-8-yl)amino)-3-fluoro-5-methoxy-2',2”-dimethyl-[1,1':3',1”-triphenyl]-4-carboxaldehyde. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product 1-((3”-((1,6-naphthid-8-yl)amino)-3-fluoro-5-methoxy-2',2”-dimethyl-[1,1':3',1”-triphenyl]-4-yl)methyl)azacyclobutane-3-carboxylic acid as a white solid. 1H NMR (400MHz, CD3OD) δ9.34(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)m / z C 34 H 32 FN4O3[M+H] + Calculated value: 563.2; measured value: 563.3.

[0373] Example 63: 1-((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(quinoxalo-5-ylamino)-[1,1':3',1”-triphenyl]-4-yl)methyl)azacyclobutane-3-carboxylic acid

[0374]

[0375] The compound was prepared using a process similar to step c of Example 1, with 3-fluoro-5-methoxy-2',2”-dimethyl-3”-(quinoxalo-5-ylamino)-[1,1':3',1”-triphenyl]-4-carboxaldehyde. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product 1-((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(quinoxalo-5-ylamino)-[1,1':3',1”-triphenyl]-4-yl)methyl)azacyclobutane-3-carboxylic acid as a white solid. 1 H NMR (400MHz, CD3OD) δ8.87(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)m / z C 34 H 32 FN4O3[M+H] + Calculated value: 563.2; measured value: 563.3.

[0376] Example 64: 1-((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(quinazolin-8-ylamino)-[1,1':3',1”-triphenyl]-4-yl)methyl)azacyclobutane-3-carboxylic acid

[0377]

[0378] The compound was prepared using a process similar to step c of Example 1, with 3-fluoro-5-methoxy-2',2”-dimethyl-3”-(quinazoline-8-ylamino)-[1,1':3',1”-triphenyl]-4-carboxaldehyde. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product 1-((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(quinazoline-8-ylamino)-[1,1':3',1”-triphenyl]-4-yl)methyl)azacyclobutane-3-carboxylic acid as a white solid. 1 H NMR (400MHz, CD3OD) δ9.41(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)m / z C 34 H 32 FN4O3[M+H] + Calculated value: 563.2; measured value: 563.3.

[0379] Example 65: 1-((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrido[3,2-d]pyrimidin-4-ylamino)-[1,1':3',1”-triphenyl]-4-yl)methyl)azacyclobutane-3-carboxylic acid

[0380]

[0381] This compound was prepared using a procedure similar to step c of Example 1, with 3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrido[3,2-d]pyrimidin-4-ylamino)-[1,1':3',1”-triphenyl]-4-carboxaldehyde. The product was purified by HPLC (MeCN / water and 0.1% TFA) 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”-triphenyl]-4-yl)methyl)azacyclobutane-3-carboxylic acid as a white solid. MS: (ES) m / z C 33 H 31 FN5O3[M+H] + Calculated value: 564.2, measured value: 564.2.

[0382] Example 66: (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((methyl(5-oxopyrrolidone-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide

[0383]

[0384] Step d: To a stirred solution of 3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxoron-2-yl)-[1,1'-biphenyl]-4-carboxaldehyde (75 mg, 0.203 mmol) and (S)-4-aminopyrrolidone-2-one (41 mg, 0.406 mmol) in MeOH:DCE (2 mL), NaBH(OAc)3 (86 mg, 0.406 mmol) and AcOH (5 drops) were added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel rapid chromatography (0%–20% MeOH / DCM) to give (S)-4-(((3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxorbacon-2-yl)-[1,1'-biphenyl]-4-yl)methyl)amino)pyrrolidine-2-one as a yellow solid. MS: (ES) m / z C 25 H 33 BFN2O4[M+H] + Calculated value: 455.2; measured value: 455.3.

[0385] Step e: Add NaBH(OAc)3 (201 mg, 0.945 mmol) to a stirred solution of (S)-4-(((3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-[1,1'-biphenyl]-4-yl)methyl)amino)pyrrolidone-2-one (86 mg, 0.189 mmol) and 37% paraformaldehyde aqueous solution in MeOH:DCE (2 mL). The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel rapid chromatography (0%–20% MeOH / DCM) to give (S)-4-(((3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxoron-2-yl)-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)pyrrolidone-2-one as a yellow solid. MS: (ES) m / z C 26 H 35 BFN2O4[M+H] + Calculated value: 469.3, measured value: 469.3.

[0386] Step f: To a mixture of (S)-4-(((3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxoron-2-yl)-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)pyrrolidone-2-one (78 mg, 0.167 mmol), N-(3-bromo-2-methylphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-5-carboxamide (54 mg, 0.167 mmol), and 2M K2CO3 (0.25 mL, 0.501 mmol) in a solution of p-dioxane (5 mL), a complex of Pd(dppf)Cl2 and dichloromethane (20 mg, 0.022 mmol) was added. The reaction mixture was degassed (N2) for 2 min and stirred at 95 °C under N2 for 5 h. The reaction mixture was diluted with EtOAc, filtered through diatomaceous earth, washed with brine, and dried over MgSO4. Solvent was removed under reduced pressure, and the residue was purified by silica gel rapid chromatography (0-20% methanol / dichloromethane) and high-performance liquid chromatography (MeCN / H2O and 0.1% TFA) to give (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((methyl(5-oxopyrrolidone-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide, as a white solid. 1H NMR (400MHz, CD3OD) δ8.92(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)m / z C 33 H 35 FN5O4[M+H] + Calculated value: 584.3, measured value: 584.3.

[0387] Example 67: (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((methyl(5-oxopyrrolidone-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

[0388]

[0389] The compound was prepared using a process similar to step f in Example 66, with N-(3-bromo-2-methylphenyl)-1-methyl-2-oxo-1,2-dihydropyrimidine-3-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((methyl(5-oxopyrrolidone-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyrimidine-3-carboxamide, as a white solid. 1HNMR(400MHz,CD3OD)δ12.19(s,1H),8.60(dd,J=7.3,2.0Hz,1H),8.17–8.14( m,1H),8.02–8.00(m,1H),7.38–7.24(m,3H),7.19(dd,J=7.6,1.6Hz,1H),7.00 –6.94(m,3H),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)m / z C 34 H 36 FN4O4[M+H] + Calculated value: 583.3, measured value: 583.3.

[0390] Example 68: N-(4”-(aminomethyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

[0391]

[0392] Step a: HATU (1.34 g, 3.52 mmol) and diisopropylethylamine (0.75 g, 5.87 mmol) were added to a solution of 1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (0.36 g, 2.35 mmol) and 3-bromo-2-methylaniline (0.43 g, 2.35 mmol) in DMF (5.0 mL). The reaction was stirred at room temperature for 16 hours. After the reaction was complete, half of the solvent was removed, the mixture was diluted with water (15 mL), and then stirred for 20 minutes. The resulting solid was filtered through a plastic funnel, washed with water (10 mL), and dried under vacuum.

[0393] Step b: A complex of Pd(dppf)Cl2 and dichloromethane (26 mg, 0.032 mmol) was added to a solution of 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-dioxoboron-2-yl)-[1,1'-biphenyl]-4-yl)methyl)carbamate (146 mg, 0.31 mmol) and 2M K2CO3 (0.38 mL, 0.77 mmol) in p-dioxane (3 mL). The reaction mixture was degassed (N2) for 2 min and stirred at 95 °C under N2 for 4 h. The reaction mixture was diluted with EtOAc, filtered through diatomaceous earth, washed with brine, and dried over MgSO4. Solvent was removed under reduced pressure, and the residue was purified by silica gel rapid chromatography (5%-20%-40% acetic acid / hexane) to give tert-butyl((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(1-methyl-2-oxo-1,2-dihydropyridine-3-carbamate)-[1,1':3',1”-triphenyl]-4-yl)methyl)carbamate. MS: (ES) m / z C 33 H 37 FN3O5[M+H] + The calculated value is 586.3, and the measured value is 586.2.

[0394] Step c: At room temperature, TFA (141 mg, 1.23 mmol) was added dropwise to a stirred solution of tert-butyl (3-fluoro-5-methoxy-2',2”-dimethyl-3”-(1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide)-(1,1':3',1”-triphenyl)-4-yl)methyl)carbamate (75 mg, 0.123 mmol) in anhydrous dichloromethane (2.5 mL) over 5 minutes. The reaction mixture... The compound was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed under vacuum, yielding a viscous residue. The material was purified by high performance liquid chromatography (MeCN / water and 0.1% TFA) to give N-(4”-(aminomethyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (48 mg, 77%). 1H NMR (400MHz, CD3OD) δ12.19(s,1H),8.59(dd,J=7.4,2.2Hz,1H),8.14(d,J=8.2 Hz,1H),8.00(dd,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. 5,0.8Hz,1H),4.22(s,2H),3.97(s,3H),3.71(s,3H),2.12(s,3H),1.93(s,3H). MS: (ES)m / z C 29 H 29 FN3O3[M+H] + Calculated value: 486.2, measured value: 486.2.

[0395] Example 69: 6-Amino-N-(3”-Fluoro-4”-(((2-hydroxyethyl)amino)methyl)-5”-Methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)nicotinamide

[0396]

[0397] Step a: At room temperature, oxaloyl chloride (1.02 g, 8.15 mmol) was added to a stirred suspension of 6-aminonicotinic acid (0.75 g, 5.34 mmol) in dichloromethane (10 mL). The resulting mixture was stirred for 4 hours. The solvent was removed under reduced pressure, and the 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 overnight at room temperature. After the reaction was complete, the reaction mixture was washed with water and extracted with EtOAc. The crude product was purified by silica gel chromatography (20-100% ethyl acetate / n-hexane) to give the desired product 6-amino-N-(3-bromo-2-methylphenyl)nicotinamide. MS: (ES) m / z C 13 H 13 BrN3O[M+H] + Calculated value: 306.0, measured value: 306.1.

[0398] Step b: A complex of Pd(dppf)Cl2 and dichloromethane (40 mg, 0.049 mmol) was added to a mixture of 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-dioxoboron-2-yl)-[1,1'-biphenyl]-4-carboxaldehyde (199 mg, 0.53 mmol), and 2M K2CO3 (0.61 mL, 1.22 mmol) in 15 mL of p-dioxane. The reaction mixture was degassed (N2) for 2 min and stirred at 95 °C under N2 for 3 h. The reaction mixture was diluted with EtOAc, filtered through diatomaceous earth, washed with brine, and dried over MgSO4. Solvent was removed under reduced pressure, and the residue was purified by silica gel rapid chromatography (5–20%–40% EtOAc / n-hexane) to give 6-amino-N-(3”-fluoro-4”-formyl-5”-methoxy-2,2’-dimethyl-[1,1’:3’,1”-triphenyl]-3-yl)nicotinamide. MS: (ES) m / z C 28 H 25 FN3O3[M+H] + Calculated value: 470.2, measured value: 470.2.

[0399] Step c: NaBH(OAc)3 (56 mg, 0.26 mmol) was added to a stirred solution of 6-amino-N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)nicotinamide (50 mg, 0.106 mmol) and ethanolamine (26 mg, 0.42 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by HPLC (0-40%-100% MeCN / H2O) to give 6-amino-N-(3”-fluoro-4”-(((2-hydroxyethyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)nicotinamide. 1 H NMR(400MHz, CD3OD)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),6.9 4–6.82(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)m / z C 30 H 32 FN4O3[M+H]+ Calculated value: 515.2, measured value: 515.2.

[0400] Example 70: 1-((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrimidin-4-carboxamido)-[1,1':3',1”-triphenyl]-4-yl)methyl)azacyclobutane-3-carboxylic acid

[0401]

[0402] Step a: At room temperature, oxaloyl chloride (0.76 g, 6.04 mmol) was added to a stirred suspension of pyrimidine-4-carboxylic acid (0.5 g, 4.03 mmol) in dichloromethane (10 mL). The resulting mixture was stirred for 4 hours. The solvent was removed under reduced pressure, and the mixture was dried under vacuum. The 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 the reaction was complete, the mixture was washed with water and extracted with EtOAc. The crude product was purified by silica gel chromatography (20-100% ethyl acetate / n-hexane) to give the desired product N-(3-bromo-2-methylphenyl)pyrimidine-4-carboxamide. MS: (ES) m / z C 12 H 11 BrN3O[M+H] + Calculated value: 292.0, measured value: 292.0.

[0403] Step b: A dichloromethane complex of Pd(dppf)Cl2 (40 mg, 0.049 mmol) was added to a mixture of N-(3-bromo-2-methylphenyl)pyrimidin-4-carboxamide (150 mg, 0.49 mmol), 3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-[1,1'-biphenyl]-4-carboxaldehyde (199 mg, 0.53 mmol), and 2M K2CO3 (0.61 mL, 1.22 mmol) in 15 mL of p-dioxane. The reaction mixture was degassed (N2) for 2 min and stirred at 95 °C under N2 for 3 h. The reaction mixture was diluted with EtOAc, filtered through diatomaceous earth, washed with brine, and dried over MgSO4. Solvent was removed under reduced pressure, and the residue was purified by silica gel rapid chromatography column (5%-20%-40% ethyl acetate / n-hexane) to give N-(3”-fluoro-4”-formyl-5”-methoxy-2,2’-dimethyl-[1,1’:3’,1”-triphenyl]-3-yl)pyrimidin-4-carboxamide. MS: (ES) m / z C 27 H 23FN3O3[M+H] + Calculated value: 456.2, measured value: 456.2.

[0404] Step c: Add NaBH(OAc)3 (56 mg, 0.26 mmol) to a stirred solution of N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-4-yl)pyrimidin-4-carboxamide (50 mg, 0.106 mmol) and aziridine-3-carboxylic acid (26 mg, 0.42 mmol) in DMF (2 mL). Stir the reaction mixture at room temperature for 2 hours. Remove the solvent under reduced pressure, and purify the residue by HPLC (0–40%–100% MeCN / H2O) to give 1-((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrimidin-4-carboxamide)-[1,1':3',1”-triphenyl]-4-yl)methyl)aziridine-3-carboxylic acid. 1 H NMR (400MHz, CD3OD) δ9.34(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)m / z C 31 H 30 FN4O3[M+H] + Calculated value: 541.2, measured value: 541.2.

[0405] Example 71: N-(4”-(aminomethyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)nicotinamide

[0406]

[0407] The compound was prepared using a method similar to that described in Example 68. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(4”-(aminomethyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)nicotinamide as a white solid. 1H NMR (400MHz, CD3OD)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)m / zC 28 H 27 FN3O2[M+H] + Calculated value: 456.2, measured value: 456.2.

[0408] Example 72: N-(4”-(aminomethyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)isonicotinamide

[0409]

[0410] The compound was prepared using a method similar to that described in Example 68. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(4”-(aminomethyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)nicotinamide as a white solid. 1 H NMR (400MHz, CD3OD)9.18(s,1H),8.82(d,J=5.1Hz,1H),8.07(d,J=4.3Hz,1H),7.44–7.29(m,3H),7.28–7.0 9(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). S: (ES)m / z C 28 H 27 FN3O2[M+H] + Calculated value: 456.2, measured value: 456.2.

[0411] Example 73: N-(4”-(aminomethyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-6-methylpyridine amide

[0412]

[0413] The target compound was prepared using a method similar to that described in Example 68. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(4”-(aminomethyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-6-methylpyridine amide as a white solid. 1 H NMR(400MHz, CD3OD)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)m / z C 29 H 29 FN3O2[M+H] + Calculated value 470.2, measured value 453.1 [M-17].

[0414] Example 74: 4”-(aminomethyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-N-(pyridin-2-yl)-[1,1':3',1”-triphenyl]-3-carboxamide

[0415]

[0416] The compound was prepared using a method similar to that described in Example 68. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product, 4”-(aminomethyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-N-(pyridin-2-yl)-[1,1':3',1”-triphenyl]-3-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD)9.18(s,1H),8.82(d,J=5.1Hz,1H),8.07(d,J=4.3Hz,1H),7.44–7.29(m,3H),7.28–7.0 9(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)m / z C 28 H 27 FN3O2[M+H] +Calculated value 456.2, measured value 439.0 [M-17].

[0417] Example 75: N-(4”-(aminomethyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)pyrimidine-2-carboxamide

[0418]

[0419] The compound was prepared using a method similar to that described in Example 68. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(4”-(aminomethyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)pyrimidine-2-carboxamide as a white solid. 1 H NMR(400MHz, CD3OD)δ9.02(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:

[0420] (ES)m / z C 27 H 26 FN4O2[M+H] + Calculated value 457.2, measured value 440.0 [M-17].

[0421] Example 76: N-(4”-(aminomethyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)pyrimidine-4-carboxamide

[0422]

[0423] The compound was prepared using a method similar to that described in Example 68. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(4”-(aminomethyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)pyrimidine-4-carboxamide as a white solid. 1H NMR(400MHz, CD3OD)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,1H),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)m / z C 27 H 26 FN4O2[M+H] + Calculated value 457.2, measured value 440.0 [M-17].

[0424] Example 77: N-(4”-(aminomethyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)pyrazine-2-carboxamide

[0425]

[0426] The compound was prepared using a method similar to that described in Example 68. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(4”-(aminomethyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)pyrazine-2-carboxamide as a white solid. 1 H NMR(400MHz, CD3OD)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)m / z C 27 H 26 FN4O2[M+H] + Calculated value 457.2, measured value 440.0 [M-17].

[0427] Example 78: N-(4”-(aminomethyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)tetrahydro-2H-pyran-2-carboxamide

[0428]

[0429] The compound was prepared using a method similar to that described in Example 68. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(4”-(aminomethyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)tetrahydro-2H-pyran-2-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD)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=1 1.4,3.5Hz,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)m / z C 28 H 32 FN2O3[M+H] + Calculated value: 463.2, measured value: 463.2.

[0430] Example 79: ((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrimidin-4-carbamate)-[1,1':3',1”-triphenyl]-4-yl)methyl)glycine

[0431]

[0432] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2’-dimethyl-[1,1’:3’,1”-triphenyl]-3-yl)pyrimidin-4-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product ((3-fluoro-5-methoxy-2’,2”-dimethyl-3”-(pyrimidin-4-carboxamido)-[1,1’:3’,1”-triphenyl]-4-yl)methyl)glycine, as a white solid. 1H NMR(400MHz, CD3OD)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 =7.8,1.4Hz,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)m / z C 29 H 28 FN4O4[M+H] + Calculated value: 515.2; Actual measured value: 515.5.

[0433] Example 80: N-(3”-fluoro-4”-(((2-hydroxyethyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)pyrimidin-4-carboxamide

[0434]

[0435] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2’-dimethyl-[1,1’:3’,1”-triphenyl]-3-yl)pyrimidine-4-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(3”-fluoro-4”-(((2-hydroxyethyl)amino)methyl)-5”-methoxy-2,2’-dimethyl-[1,1’:3’,1”-triphenyl]-3-yl)pyrimidine-4-carboxamide, as a white solid. 1H NMR(400MHz, CD3OD)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=1.2 Hz, 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)m / z C 29 H 30 FN4O3[M+H] + Calculated value: 501.2, measured value: 501.5.

[0436] Example 81: N-(3”-fluoro-4”-((3-hydroxyazacyclobutane-1-yl)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)pyrimidin-4-carboxamide

[0437]

[0438] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)pyrimidine-4-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(3”-fluoro-4”-((3-hydroxyazacyclobutane-1-yl)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)pyrimidine-4-carboxamide, as a white solid. 1H NMR(400MHz, CD3OD)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) ,7.22–7.15(m,1H),7.08(d,J=7.4Hz,1H),6.97–6.86(m,2H),4.64–4.49(m,3H ),4.46–4.33(m,2H),4.11–4.01(m,2H),3.98(s,3H),2.09(s,3H),1.96(s,3H). MS:(ES)m / z C 30 H 30 FN4O3[M+H] + Calculated value: 513.2; Measured value: 513.5.

[0439] Example 82: 6-((3”-fluoro-4”-(((2-hydroxyethyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)carbamoyl)nicotinic acid

[0440]

[0441] The compound was prepared using a method similar to that described in Example 1. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product, 6-((3”-fluoro-4”-(((2-hydroxyethyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)carbamoyl)nicotinic acid, as a white solid. 1 H NMR(400MHz, CD3OD)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),7.29–7.1 5(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)m / z C 31 H 31 FN3O5[M+H] + Calculated value: 544.2; Measured value: 544.5.

[0442] Example 83: 1-((3”-(5-aminopyrazine-2-carboxamido)-3-fluoro-5-methoxy-2',2”-dimethyl-[1,1':3',1”-triphenyl]-4-yl)methyl)azacyclobutane-3-carboxylic acid

[0443]

[0444] The compound was prepared using a method similar to that described in Example 1. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product 1-((3”-(5-aminopyrazin-2-carboxamido)-3-fluoro-5-methoxy-2',2”-dimethyl-[1,1':3',1”-triphenyl]-4-yl)methyl)azacyclobutane-3-carboxylic acid as a white solid. 1 H NMR(400MHz, CD3OD)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)m / z C 31 H 31 FN5O4[M+H] + Calculated value: 556.2; measured value: 556.5.

[0445] Example 84: 1-((3”-(2-aminopyrimidine-4-carboxamido)-3-fluoro-5-methoxy-2',2”-dimethyl-[1,1':3',1”-triphenyl]-4-yl)methyl)azacyclobutane-3-carboxylic acid

[0446]

[0447] The compound was prepared using a method similar to that described in Example 1. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product 1-((3”-(2-aminopyrimidin-4-carboxamido)-3-fluoro-5-methoxy-2',2”-dimethyl-[1,1':3',1”-triphenyl]-4-yl)methyl)azacyclobutane-3-carboxylic acid as a white solid. 1H NMR(400MHz, CD3OD)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)m / z C 31 H 31 FN5O4[M+H] + Calculated value: 556.2; measured value: 556.5.

[0448] Example 85: 1-((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(thiazolyl-2-carboxamido)-[1,1':3',1”-triphenyl]-4-yl)methyl)azacyclobutane-3-carboxylic acid

[0449]

[0450] The compound was prepared using a method similar to that described in Example 1. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product 1-((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(thiazolyl-2-carboxamido)-[1,1':3',1”-triphenyl]-4-yl)methyl)azacyclobutane-3-carboxylic acid as a white solid. 1 H NMR(400MHz, CD3OD)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)m / z C 30 H 29 FN3O4S[M+H] + Calculated value: 546.2; Measured value: 546.2.

[0451] Example 86: 1-((3-fluoro-5-methoxy-3”-(5-methoxypyridinamido)-2',2”-dimethyl-[1,1':3',1”-triphenyl]-4-yl)methyl)azacyclobutane-3-carboxylic acid

[0452]

[0453] The compound was prepared using a method similar to that described in Example 1. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product 1-((3-fluoro-5-methoxy-3”-(5-methoxypyridinamido)-2',2”-dimethyl-[1,1':3',1”-triphenyl]-4-yl)methyl)azacyclobutane-3-carboxylic acid as a white solid. 1 H NMR(400MHz, CD3OD)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,4 H),7.07–6.99(m,1H),6.97–6.86(m,2H),4.56(s,2H),4.45–4.40(m,4 H),3.97(s,3H),3.95(s,3H),3.70(bs,1H),2.09(s,3H),1.96(s,3H). MS: (ES)m / z C 33 H 33 FN3O5[M+H] + Calculated value: 570.2, measured value: 570.2.

[0454] Example 87: 1-((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(5-methylpyridinamido)-[1,1':3',1”-triphenyl]-4-yl)methyl)azacyclobutane-3-carboxylic acid

[0455]

[0456] The compound was prepared using a method similar to that described in Example 1. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product 1-((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(5-methylpyridinamido)-[1,1':3',1”-triphenyl]-4-yl)methyl)azacyclobutane-3-carboxylic acid as a white solid. 1H NMR(400MHz, CD3OD)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)m / z C 33 H 33 FN3O4[M+H] + Calculated value: 554.2, measured value: 554.2.

[0457] Example 88: N-(3”-fluoro-4”-(((2-hydroxyethyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)pyridineamide

[0458]

[0459] The compound was prepared using a method similar to that described in Example 1. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(3”-fluoro-4”-(((2-hydroxyethyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)pyridineamide, as a white solid. 1 HNMR(400MHz,CD3OD)8.82(s,1H),8.31(d,J=6.2Hz,1H),8.18(dd,J=8.1,2.2Hz,1 H),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=7.5,1.5Hz,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)m / zC 33 H 38 FN4O4[M+H] + Calculated value: 573.28; Measured value: 573.5.

[0460] Example 89: 4-(((3-fluoro-3”-(5-((((2-hydroxyethyl)amino)methyl)pyridinamido)-5-methoxy-2',2”-dimethyl-[1,1':3',1”-triphenyl]-4-yl)methyl)amino)butyric acid

[0461]

[0462] The compound was prepared using a method similar to that described in Example 1. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product, 4-(((3-fluoro-3”-(5-((((2-hydroxyethyl)amino)methyl)pyridinamido)-5-methoxy-2',2”-dimethyl-[1,1':3',1”-triphenyl]-4-yl)methyl)amino)butyric acid, as a white solid. 1 H NMR(400MHz, CD3OD)8.82(s,1H),8.31(d,J=8.1Hz,1H),8.18(dd,J=8.1,2.2Hz,1H), 7.84(d,J=8.0Hz,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)m / zC 35 H 40 FN4O5[M+H] + Calculated value: 615.3, measured value: 615.2.

[0463] Example 90: 2-(((3-fluoro-3”-(5-((((2-hydroxyethyl)amino)methyl)pyridinamido)-5-methoxy-2',2”-dimethyl-[1,1':3',1”-triphenyl]-4-yl)methyl)amino)ethane-1-sulfonic acid

[0464]

[0465] The compound was prepared using a method similar to that described in Example 1. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product, 2-(((3-fluoro-3”-(5-((((2-hydroxyethyl)amino)methyl)pyridinamido)-5-methoxy-2',2”-dimethyl-[1,1':3',1”-triphenyl]-4-yl)methyl)amino)ethane-1-sulfonic acid, as a white solid. 1 H NMR (400MHz, CD3OD)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=8.2,2.2Hz1H),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)m / z C 33 H 38 FN4O6S[M+H] + Calculated value: 637.2; Measured value: 637.2.

[0466] Example 91: N-(3”-fluoro-4”-((isopropylamino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)pyrido[3,4-b]pyrazine-5-amine

[0467]

[0468] A mixture of 1.5 mL of ethanol solution containing 3-fluoro-5-methoxy-2′,2″-dimethyl-3″-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′:3′,1″-triphenyl]-4-carboxaldehyde (24 mg, 0.042 mmol), propane-2-amine (30 mg, 0.51 mmol), and HOAc (90 mg, 1.50 mmol) was heated at 70 °C for 0.5 hours. The mixture was then cooled to 0 °C. Then NaBH3CN (45 mg, 0.71 mmol) was added. After stirring at room temperature for 20 minutes, the mixture was concentrated under vacuum. The resulting residue was purified by HPLC (MeCN / water and 0.1% TFA) to give N-(3”-fluoro-4”-((isopropylamino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)pyrido[3,4-b]pyrazin-5-amine (TFA salt). 1 H NMR (400MHz, CD3OD) δ9.25(d,J=2.0Hz,1H),9.05(d,J=2.0Hz,1H),7.79(d,J=7.6H z,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 ), 3.98 (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)m / z C 32 H 33 FN5O[M+H] + Calculated value: 522.3; Actual measured value: 522.3.

[0469] Example 92: N-(3”-fluoro-4”-(isopropylamino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

[0470]

[0471] Step a: A dichloromethane complex of Pd(dppf)Cl2 (121 mg, 0.148 mmol) was added to a solution of 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-dioxoboron-2-yl)-[1,1'-biphenyl]-4-carboxaldehyde (600 mg, 1.63 mmol), and 2M K2CO3 (1.85 mL, 3.7 mmol) in 10 mL of p-dioxane. The reaction mixture was degassed (N2) for 2 min and stirred at 95 °C under N2 for 5 h. The reaction mixture was diluted with EtOAc, filtered through diatomaceous earth, washed with brine, and dried over MgSO4. Solvent was removed under reduced pressure, and the residue was purified by silica gel rapid chromatography column (5%-20%-100% ethyl acetate / n-hexane) to give N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide. MS: (ES) m / z C 29 H 25 FN₂O₄[M+H] + Calculated value: 485.2, measured value: 485.2.

[0472] Step B: To a stirred solution of N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (40 mg, 0.082 mmol) and propane-2-amine (10 mg, 0.16 mmol) in MeOH:DCE (2 mL), NaBH(OAc)3 (52 mg, 0.24 mmol) and AcOH (5 drops) were added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by HPLC (0-40%-100% MeCN / water) to obtain N-(3”-fluoro-4”-((isopropylamino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide. 1H NMR(400MHz, CD3OD)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=7.4H z,1H),6.93(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)m / z C 32 H 35 FN3O3[M+H] + Calculated value: 528.3; Measured value: 528.2.

[0473] Example 93: (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((5-oxopyrrolidone-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

[0474]

[0475] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((5-oxopyrrolidone-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide, as a white solid. 1H NMR(400MHz, CD3OD)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=7.5Hz,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)m / z C 33 H 34 FN4O4[M+H] + Calculated value: 569.3, measured value: 569.3.

[0476] Example 94: (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((5-oxopyrrolidone-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

[0477]

[0478] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((5-oxopyrrolidone-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide, as a white solid. 1H NMR (400MHz, CD3OD) δ12.18(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=7.5Hz,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)m / z C 33 H 34 FN4O4[M+H] + Calculated value: 569.3, measured value: 569.3.

[0479] Example 95: (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

[0480]

[0481] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide, as a white solid. 1H NMR (400MHz, CD3OD) δ12.18(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)m / zC 34 H 36 FN4O4[M+H] + Calculated value: 583.3, measured value: 583.3.

[0482] Example 96: (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

[0483]

[0484] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide, as a white solid. 1H NMR (400MHz, CD3OD) δ12.18(s,1H),8.57(dd,J=7.8,2.4Hz,1H),8.16(t,J=8.2Hz,1H),8.01(d d,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,1 H),6.82(d,J=9.8Hz,1H),6.60(t,J=7.5Hz,1H),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)m / z C 34 H 36 FN4O4[M+H] + Calculated value: 583.3, measured value: 583.3.

[0485] Example 97: (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((methyl(5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

[0486]

[0487] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((methyl(5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide, as a white solid. 1H NMR (400MHz, CD3OD) δ12.18(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. 62(t,J=7.5Hz,1H),4.60–4.40(m,2H),4.30–4.25(m,1H),4.01(s,3H),3.70(s,3H),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)m / z C 35 H 38 FN4O4[M+H] + Calculated value: 597.3, measured value: 597.3.

[0488] Example 98: (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((((1-methyl-5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

[0489]

[0490] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((((1-methyl-5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide, as a white solid. 1H NMR (400MHz, CD3OD) δ12.18(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)m / z C 35 H 38 FN4O4[M+H] + Calculated value: 597.3, measured value: 597.3.

[0491] 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”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

[0492]

[0493] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) 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”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide, as a white solid. 1H NMR (400MHz, CD3OD)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) ,4.43(s,2H),4.00(s,2H),3.98(s,3H),3.70(s,3H),2.11(s,3H),1.93(s,3H). MS:(ES)m / z C 34 H 36 FN5O5[M+H] + Calculated value: 610.3, measured value: 610.2.

[0494] Example 100: N-(3”-fluoro-4”-(((1-hydroxy-2-methylpropyl-2-yl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

[0495]

[0496] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(3”-fluoro-4”-(((1-hydroxy-2-methylpropyl-2-yl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide, as a white solid. 1H NMR (400MHz, CD3OD)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)m / z C 33 H 37 FN3O4[M+H] + Calculated value: 558.3, measured value: 558.2.

[0497] Example 101: N-(3”-fluoro-4”-(((2-hydroxyethyl)(methyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

[0498]

[0499] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(3”-fluoro-4”-(((2-hydroxyethyl)(methyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide, as a white solid. 1H NMR(400MHz, CD3OD)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)m / z C 32 H 35 FN3O4[M+H] + Calculated value: 544.3, measured value: 544.2.

[0500] Example 102: N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((oxetane-3-ylamino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

[0501]

[0502] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((oxocyclobutane-3-ylamino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide, as a white solid. 1H NMR(400MHz, CD3OD)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,1 H),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,2 H),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)m / z C 32 H 33 FN3O4[M+H] + Calculated value: 542.2, measured value: 542.2.

[0503] Example 103: N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((tetrahydrofuran-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

[0504]

[0505] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((tetrahydrofuran-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide, as a white solid. 1H NMR(400MHz, CD3OD)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),6.6 1(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,1 H),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)m / z C 33 H 35 FN3O4[M+H] + Calculated value: 556.3, measured value: 556.2.

[0506] Example 104: N-(4”-(aminomethyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0507]

[0508] Step a: HATU (1.34 g, 3.52 mmol) and diisopropylethylamine (0.75 g, 5.87 mmol) were added to a mixture containing 15 mL of DMF in a vial. The reaction was stirred at room temperature for 16 hours. After the reaction was complete, half of the solvent was removed, and the mixture was diluted with water (15 mL). 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.

[0509] Step b: A dichloromethane complex of Pd(dppf)Cl2 (26 mg, 0.032 mmol) was added to a mixture of N-(3-bromo-2-methylphenyl)-3-methyl-2,4-oxo-1,2,3,4-tetrahydropyrimidin-5-carboxamide (100 mg, 0.31 mmol), tert-butyl(3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-[1,1'-biphenyl]-4-yl)methyl)carbamate (146 mg, 0.31 mmol), and 2M K2CO3 (0.38 mL, 0.77 mmol) in 4 mL of p-dioxane. The reaction mixture was degassed (N2) for 2 min and stirred at 95 °C under N2 for 4 h. The reaction mixture was diluted with EtOAc, filtered through diatomaceous earth, washed with brine, and dried over MgSO4. The solvent was removed under reduced pressure, and the residue was purified by silica gel rapid chromatography (5%–20%–40% acetic acid / hexane) to give tert-butyl((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(3-methyl-2,4-dioxo-1,2,3,4-dihydropyrimidin-5-carbamate)-[1,1':3',1”-triphenyl]-4-yl)methyl)carbamate. MS: (ES) m / z C 33 H 36 FN4O6[M+H] + Calculated value: 603.3, measured value: 603.3.

[0510] Step c: At room temperature, TFA (141 mg, 1.23 mL) was added dropwise to a stirred solution of tert-butyl ((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-carbamate)-[1,1':3',1”-triphenyl]-4-yl)-methyl)-carbamate (75 mg, 0.123 mmol) in anhydrous dichloromethane (2.5 mL). The reaction mixture was stirred for 5 minutes at room temperature. After the reaction was complete, the solvent was removed under vacuum to obtain a viscous compound, which was purified by HPLC (MeCN / H2O and 0.1% TFA) to give N-(4”-(aminomethyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, CD3OD)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)m / zC 28 H 28 FN4O4[M+H] + Calculated value 503.2, measured value 486.2 [M-17].

[0511] Example 105: N-(3”-fluoro-4”-((isopropylamino)-methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0512]

[0513] Step a: A dichloromethane complex of Pd(dppf)Cl2 (121 mg, 0.148 mmol) was added to a mixture of N-(3-bromo-2-methylphenyl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-carboxamide (500 mg, 1.48 mmol), 3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-[1,1'-biphenyl]-4-carboxaldehyde (939 mg, 2.53 mmol), and 2M K2CO3 (1.85 mL, 3.7 mmol) in 10 mL of p-dioxane. The reaction mixture was degassed (N2) for 2 min and stirred at 95 °C under N2 for 5 h. The reaction mixture was diluted with EtOAc, filtered through diatomaceous earth, washed with brine, and dried over MgSO4. Solvent was removed under reduced pressure, and the residue was purified by silica gel rapid chromatography column (5%-20%-40% ethyl acetate / n-hexane) to give N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. MS: (ES) m / z C 28 H 25 FN3O5[M+H] + Calculated value: 502.2; Measured value: 502.2

[0514] Step b: To a stirred solution of N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (40 mg, 0.079 mmol) and propane-2-amine (10 mg, 0.16 mmol) in MeOH:DCE (2 mL), NaBH(OAc)3 (33 mg, 0.16 mmol) and AcOH (4 drops) were added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC (0–40%–100% MeCN / water) to obtain N-(3”-fluoro-4”-((isopropylamino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyridine-5-carboxamide, which was a white solid. 1 H NMR (400MHz, CD3OD)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)m / zC 31 H 34 FN4O4[M+H] + Calculated value: 544.3, measured value: 544.2.

[0515] Example 106: N-(4”-(dimethylamino)methyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0516]

[0517] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(4”-(dimethylamino)methyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR(400MHz, CD3OD)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)m / z C 30 H 32 FN4O4[M+H] + Calculated value: 531.2, measured value: 531.2.

[0518] Example 107: N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(morpholinomethyl)-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0519]

[0520] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(morpholinomethyl)-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1H NMR (400MHz, CD3OD)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=12.5Hz,2H),3.49(d,J=12.7Hz,4H),3.36(s,3H),2.10(s,3H),1.93(s,3H). MS:(ES)m / z C 32 H 34 FN4O5[M+H] + Calculated value: 572.2, measured value: 572.2.

[0521] Example 108: N-(4”-((3-aminopyrrolidone-1-yl)methyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0522]

[0523] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(4”-((3-aminopyrrolidone-1-yl)methyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1H NMR(400MHz,CD3OD)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,1H),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)m / z C 32 H 35 FN5O4[M+H] + Calculated value: 572.3; Measured value: 572.2.

[0524] Example 109: N-(4”-(((2-aminoethyl)amino)methyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0525]

[0526] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(4”-(((2-aminoethyl)amino)methyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1H NMR (400MHz, CD3OD)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=7.0H z,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)m / z C 30 H 33 FN5O4[M+H] + Calculated value: 546.2; Measured value: 564.2.

[0527] Example 110: N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((oxocyclobutane-3-ylamino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0528]

[0529] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((oxocyclobutane-3-ylamino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1H NMR (400MHz, CD3OD)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),4.49–4.4 1(m,2H),4.29(s,2H),4.00(s,3H),3.36(s,3H),2.10(s,3H),1.93(s,3H). MS: (ES)m / z C 31 H 32 FN4O5[M+H] + Calculated value: 559.2, measured value: 559.2.

[0530] Example 111: N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((tetrahydrofuran-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0531]

[0532] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((tetrahydrofuran-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1H NMR (400MHz, CD3OD)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= 8.6,3.3Hz,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)m / z C 32 H 34 FN4O5[M+H] + Calculated value: 573.2, measured value: 573.2.

[0533] Example 112: N-(3”-fluoro-4”-((((1-hydroxycyclopropyl)methyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0534]

[0535] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(3”-fluoro-4”-((((1-hydroxycyclopropyl)methyl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1H NMR (400MHz, CD3OD)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)m / z C 32 H 34 FN4O5[M+H] + Calculated value: 573.2, measured value: 573.2.

[0536] Example 113: N-(3”-fluoro-4”-((3-hydroxyazacyclobutane-1-yl)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0537]

[0538] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(3”-fluoro-4”-((3-hydroxyazacyclobutane-1-yl)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1H NMR (400MHz, CD3OD)11.15(s,1H),8.41(s,1H),8.05(d,J=8.2 Hz,1H),7.38–7.21(m,3H),7.16(d,J=7.3 Hz,1H),6.96(d,J=7.0 Hz,1H),6.94(s,1H),6.88(d,J=9.7 Hz,1H),4.90(d,J=7.0 Hz,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)m / z C 31 H 32 The calculated value of FN4O5[M+H]+ is 559.2, and the measured value is also 559.2.

[0539] Example 114: (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0540]

[0541] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1H NMR(400 MHz, CD3OD)11.17(s,1H),8.41(s,1H),8.04(d,J=8.2 Hz,1H),7.38–7.21(m,3H),7.15(d,J=7.3 Hz,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)m / z C 33 H 35 The calculated value of FN5O5[M+H]+ is 600.3, and the measured value is 600.2.

[0542] Example 115: (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0543]

[0544] This compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1H NMR(400MHz, CD3OD)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=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)m / z C 33 H 35 FN5O5[M+H] + Calculated value: 600.3, measured value: 600.2.

[0545] Example 116: N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((3-oxopiperazin-1-yl)methyl)-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0546]

[0547] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((3-oxopirain-1-yl)methyl)-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD)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)m / z C32 H 33 FN5O5[M+H] + Calculated value: 585.2, measured value: 585.2.

[0548] Example 117: (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((5-oxopyrrolidone-3-yl)amino)methyl)-[1,1':3',1”-terphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0549]

[0550] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((5-oxopyrrolidone-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, CD3OD)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),3.9 9(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(dd,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)m / z C 32 H 33 FN5O5[M+H] + Calculated value: 586.2, measured value: 586.2.

[0551] 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”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0552]

[0553] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) 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”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 HNMR (400MHz, CD3OD)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=7.8 Hz,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)m / z C 31 H 30 FN6O6[M+H] + Calculated value: 601.2, measured value: 601.2.

[0554] Example 119: N-(3”-fluoro-4”-((((3R,4R)-4-hydroxytetrahydrofuran-3-yl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0555]

[0556] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) 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”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD)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=7.2Hz,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),3.75–3.7 0(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)m / z C 32 H 34 FN4O6[M+H] + Calculated value: 589.2; Measured value: 589.2.

[0557] Example 120: N-(3”-fluoro-4”-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0558]

[0559] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) 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”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD)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)m / z C 33 H 36 FN4O6[M+H] + Calculated value: 603.3, measured value: 603.2.

[0560] Example 121: 1-((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-carboxamido)-[1,1':3',1”-triphenyl]-4-yl)methyl)azacyclobutane-3-carboxylic acid

[0561]

[0562] The compound was prepared using a process similar to step c of Example 1, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) 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”-triphenyl]-4-yl)methyl)azacyclobutane-3-carboxylic acid, as a white solid. 1 H NMR(400MHz, CD3OD)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),7.0 1–6.85(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). S: (ES)m / z C 32 H 32 FN4O6[M+H] + Calculated value: 589.2; Measured value: 589.2.

[0563] Example 122: N-(4”-(aminomethyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0564]

[0565] Step a: HATU (1.34 g, 3.52 mmol) and diisopropylethylamine (0.75 g, 5.87 mmol) were added to a mixture of 1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (0.3 g, 2.35 mmol) and 3-bromo-2-methylaniline (0.43 g, 2.35 mmol) in DMF (8 mL). The reaction was stirred at room temperature for 16 hours. After the reaction was complete, half of the solvent was removed and the mixture was 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.

[0566] Step b: A dichloromethane complex of Pd(dppf)Cl2 (26 mg, 0.032 mmol) was added to a mixture of N-(3-bromo-2-methylphenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-carboxamide (100 mg, 0.31 mmol), tert-butyl((3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-[1,1'-biphenyl]-4-yl)methyl)carbamate (146 mg, 0.31 mmol), and 2M K2CO3 (0.38 mL, 0.77 mmol) in 4 mL of p-dioxane. The reaction mixture was degassed (N2) for 2 min and stirred at 95 °C under N2 for 4 h. The reaction mixture was diluted with EtOAc, filtered through diatomaceous earth, washed with brine, and dried over MgSO4. The solvent was removed under reduced pressure, and the residue was purified by silica gel rapid chromatography (5%-20%-60% acetic acid / hexane) to give tert-butyl((3”-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide)-3-fluoro-5-methoxy-2',2”-dimethyl-[1,1':3',1”-triphenyl]-4-yl)methyl)carbamate.

[0567] Step c: At room temperature, add TFA (141 mg, 1.23 mL) dropwise to a stirred solution of tert-butyl ((3”-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-carbamate)-3-fluoro-5-methoxy-2',2”-dimethyl-[1,1':3',1”-triphenyl]-4-yl)methyl)carbamate (75 mg, 0.123 mmol) in anhydrous dichloromethane (2.5 mL). The reaction mixture was stirred for 5 minutes at room temperature for 2 hours. After the reaction was complete, the solvent was removed under vacuum to obtain a viscous compound, which was purified by HPLC (MeCN / water and 0.1% TFA) to give N-(4”-(aminomethyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, CD3OD)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)m / z C 29 H 30 FN4O4[M+H] + Calculated value 517.2, measured value 500.1 [M-17].

[0568] Example 123: (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((6-oxopiperidin-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0569]

[0570] Step a: A dichloromethane complex of Pd(dppf)Cl2 (121 mg, 0.148 mmol) was added to a mixture of N-(3-bromo-2-methylphenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-carboxamide (500 mg, 1.48 mmol), 3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-[1,1'-biphenyl]-4-carboxaldehyde (939 mg, 2.53 mmol), and 2M K2CO3 (1.85 mL, 3.7 mmol) in 10 mL of p-dioxane. The reaction mixture was degassed (N2) for 2 min and stirred at 95 °C under N2 for 5 h. The reaction mixture was diluted with EtOAc, filtered through diatomaceous earth, washed with brine, and dried over MgSO4. Solvent was removed under reduced pressure, and the residue was purified by silica gel rapid chromatography column (5%-20%-40% ethyl acetate / n-hexane) to give N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide). MS: (ES) m / z C 29 H 27 FN3O5[M+H] + Calculated value: 516.2; Measured value: 516.2

[0571] Step b: To a stirred solution of N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-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), NaBH(OAc)3 (45 mg, 0.16 mmol) and AcOH (4 drops) were added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC (0–40%–100% MeCN / water) to obtain (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((6-oxopiridin-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, which was a white solid. 1 H NMR(400MHz, CD3OD)11.16(s,1H),8.63(s,1H),8.05(d,J=6.2Hz,1H),7.37–7.21(m,3 H),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)m / z C 34 H 37 FN5O5[M+H] + Calculated value: 614.3, measured value: 614.2.

[0572] Example 124: (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((6-oxopiperidin-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0573]

[0574] The compound was prepared using a procedure similar to step b of Example 123, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) 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”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD)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),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)m / z C 34 H 37 FN5O5[M+H] + Calculated value: 614.3, measured value: 614.2.

[0575] Example 125: N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((1-methyl-1H-pyrazol-5-yl)methyl)-amino)-methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0576]

[0577] The compound was prepared using a procedure similar to step b of Example 123, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) 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”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR(400MHz, CD3OD)11.15(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,1H),6.88(d,J=9.7Hz,1H),6.56(d,J=2.0Hz,1H),4.49(s,2H),4.40(s,2 H),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)m / z C 34 H 36 FN6O4[M+H] + Calculated value: 611.3, measured value: 611.2.

[0578] Example 126: N-(4”-(((2,5-dioxopyrrolidone-3-yl)amino)methyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0579]

[0580] The compound was prepared using a procedure similar to step b of Example 123, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(4”-(((2,5-dioxopyrrolidine-3-yl)amino)methyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD) 11.16 (s, 1H), 8.62 (s, 1H), 8.04 (d, J = 6.2Hz, 1H), 7.3 7–7.21(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)m / z C 33 H 33 FN5O6[M+H] + Calculated value: 614.2, measured value: 614.2.

[0581] 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”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-carboxamide

[0582]

[0583] The compound was prepared using a procedure similar to step b of Example 123, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(4”-((((2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)methyl)amino)methyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1 H NMR (400MHz, CD3OD)11.16(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)m / z C 34 H 34 FN6O6[M+H] + Calculated value: 641.2, measured value: 641.2.

[0584] 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”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-carboxamide

[0585]

[0586] The compound was prepared using a process similar to step b of Example 123, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to obtain 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”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-carboxamide, which was a white solid. 1 H NMR (400MHz, CD3OD)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,1 H),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)m / z C 36 H 38 FN6O6[M+H] + The calculated value is 669.3, and the measured value is 669.2.

[0587] Example 129: (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((5-oxopyrrolidone-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide

[0588]

[0589] Step a: At room temperature, iodomethane (1.2 mL, 19 mmol) and potassium carbonate (2.0 g, 14 mmol) were added to a stirred solution of anhydrous DMF (7 mL) of 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid (380 mg, 2.4 mmol) and stirred at 60 °C for 2 hours. The mixture was then poured into water (25 mL) and extracted with 60 mL of HCl 3:2-propanol (2:1). The crude product was purified by silica gel chromatography (45-60% ethyl acetate / n-hexane) to give the desired product, methyl 2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid.

[0590] Step b: At room temperature, acetic acid (2 mL) and 12 M hydrochloric acid (2 mL) were added to a vial containing methyl 2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid (284 mg, 1.4 mmol). The mixture was heated at 60 °C for 2 hours, then concentrated under reduced pressure and dried under vacuum. The remaining 2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid was used unpurified in subsequent steps.

[0591] Step c: HATU (730 mg, 1.92 mmol) and diisopropylethylamine (330 mg, 2.56 mmol) were added 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). The reaction was stirred at room temperature for 16 hours. After the reaction was complete, half of the solvent was removed, and the mixture was diluted with water (15 mL) and stirred for 20 minutes. The solid was filtered, washed with water (10 mL), and dried under vacuum to give N-(3-bromo-2-methylphenyl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide as a white solid.

[0592] Step d: A dichloromethane complex of Pd(dppf)Cl2 (120 mg, 0.127 mmol) was added to a mixture of 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-dioxoboron-2-yl)-[1,1'-biphenyl]-4-carboxaldehyde (550 mg, 1.27 mmol), and K2CO3 (500 mg, 3.17 mmol) in a p-dioxane / water (9:1 mL) solution. The reaction mixture was degassed (N2) for 2 min and stirred at 95 °C under N2 for 5 h. The reaction mixture was diluted with EtOAc, filtered through diatomaceous earth, washed with brine, and dried over MgSO4. Solvent was removed under reduced pressure, and the residue was purified using a silica gel rapid chromatography column (20%-100% ethyl acetate / n-hexane) to give N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide. MS: (ES) m / z C 28 H 26 FN4O5[M+H] + Calculated value: 517.2; Actual measured value: 517.2.

[0593] Step e: To a stirred solution of N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-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-aminopyrrolidone-2-one hydrochloride (23 mg, 0.155 mmol) in MeOH:DCE (1:1 mL), 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 hours. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC (0%–40%–100% MeCN / water) to give (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((5-oxopyrrolidone-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide, a white solid. 1H NMR (400MHz, CD3OD) δ11.08(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=8.2Hz,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,1H),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)m / zC 32 H 34 FN6O5[M+H] + Calculated value: 601.3, measured value: 601.2.

[0594] Example 130: (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((5-oxopyrrolidone-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide

[0595]

[0596] The compound was prepared using a process similar to step e of Example 129, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide and (S)-4-aminopyrrolidine-2-one-hydrochloride-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((5-oxopyrrolidone-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide, as a white solid. 1H NMR (400MHz, CD3OD) δ11.07(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,1 H),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)m / z C 32 H 34 FN6O5[M+H] + Calculated value: 601.3, measured value: 601.2.

[0597] Example 131: (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide

[0598]

[0599] The compound was prepared using a process similar to step e of Example 129, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide and (S)-5-(aminomethyl)pyrrolidine-2-one-hydrochloride. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide, as a white solid. 1H NMR(400MHz,CD3OD)δ11.08(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)m / z C 32 H 36 FN6O5[M+H] + Calculated value: 615.3, measured value: 615.2.

[0600] Example 132: (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide

[0601]

[0602] The compound was prepared using a process similar to step e of Example 129, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide and (R)-5-(aminomethyl)pyrrolidine-2-one-hydrochloride. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide, as a white solid. 1H NMR(400MHz,CD3OD)δ11.08(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)m / z C 32 H 36 FN6O5[M+H] + Calculated value: 615.3, measured value: 615.2.

[0603] Example 133: (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((methyl((5-oxopyrrolidone-2-yl)-methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide

[0604]

[0605] The compound was prepared using a process similar to step e of Example 129, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-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. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((methyl((5-oxopyrrolidone-2-yl)-methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide, as a white solid. 1H NMR (400MHz, CD3OD) δ11.08 (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)m / z C 34 H 38 FN6O5[M+H] + The calculated value is 629.3, and the measured value is 629.2.

[0606] Example 134: (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((6-oxopiridin-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide

[0607]

[0608] The compound was prepared using a process similar to step e of Example 129, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-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. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((6-oxopiridin-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide, as a white solid. 1H NMR(400MHz,CD3OD)δ11.09(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(d d,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)m / zC 33 H 36 FN6O5[M+H] + Calculated value: 615.3, measured value: 615.2.

[0609] Example 135: (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((6-oxopiridin-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide

[0610]

[0611] The compound was prepared using a process similar to step e of Example 129, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-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. The product was purified by HPLC (MeCN / water and 0.1% TFA) 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”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide, as a white solid. 1H NMR(400MHz,CD3OD)δ11.09(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)m / z C 33 H 36 FN6O5[M+H] + Calculated value: 615.3, measured value: 615.2.

[0612] Example 136: (1S,2R)-2-(((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-yl)methyl)amino)cyclopentan-1-ol

[0613]

[0614] A mixture of 3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-triphenyl]-4-carboxaldehyde (23 mg, 0.041 mmol), (1S,2R)-2-aminocyclopentane-1-ol hydrochloride (30 mg, 0.22 mmol), Et3N (15 mg, 0.15 mmol), and HOAc (75 mg, 1.25 mmol) in ethanol (1.5 mL) 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 under vacuum. The residue was purified by HPLC (MeCN / water and 0.1% TFA) to give (1S,2R)-2-(((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-yl)methyl)amino)cyclopentan-1-ol (TFA salt). 1H NMR (400MHz, CD3OD) δ9.25(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)m / z C 34 H 35 FN5O2[M+H] + Calculated value: 564.3, measured value: 564.3.

[0615] Example 137: (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((2-(5-oxopyrrolidone-2-yl)ethyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide

[0616]

[0617] The compound was prepared using a process similar to step e of Example 129, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide and (S)-5-(2-aminoethyl)pyrrolidine-2-one hydrochloride. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((2-(5-oxopyrrolidone-2-yl)ethyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide, as a white solid. 1H NMR (400MHz, CD3OD) δ11.08(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)m / z C 34 H 38 FN6O5[M+H] + The calculated value is 629.3, and the measured value is 629.2.

[0618] Example 138: N-(4”-(((3-amino-3-oxopropyl)amino)methyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide

[0619]

[0620] This compound was prepared using a procedure similar to step e of Example 129, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide and 3-aminopropylamine. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product N-(4”-(((3-amino-3-oxopropyl)amino)methyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dimethyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide, as a white solid. 1H NMR(400MHz,CD3OD)δ11.09(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),6.86(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)m / z C 31 H 34 FN6O5[M+H] + Calculated value: 589.3; Measured value: 589.2.

[0621] Example 139: (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((3-oxoisoxazolidine-4-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide

[0622]

[0623] The compound was prepared using a process similar to step e of Example 129, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide and (S)-4-aminoisooxazolidin-3-one. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((3-oxoisoxazolidine-4-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide, as a white solid. 1H NMR(400MHz,CD3OD)δ11.08(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),6.85(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)m / zC 31 H 32 FN6O6[M+H] + Calculated value: 603.2, measured value: 603.2.

[0624] Example 140: (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((2-oxopiridin-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide

[0625]

[0626] The compound was prepared using a process similar to step e of Example 129, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-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. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((2-oxopiridin-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide, as a white solid. 1H NMR(400MHz,CD3OD)δ11.08(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)m / z C 33 H 36 FN6O5[M+H] + Calculated value: 615.3, measured value: 615.2.

[0627] Example 141: (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((2-oxopiridin-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide

[0628]

[0629] The compound was prepared using a process similar to step e of Example 129, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-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. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((2-oxopiridin-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide, as a white solid. 1H NMR (400MHz, CD3OD) δ11.08(s,1H),8.07(t,J=8.2Hz,1H),7.37–7.26(m,2H),7.15(d,J=7.2 Hz,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),3.35–3.0 5(m,2H),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)m / z C 33 H 36 FN6O5[M+H] + Calculated value: 615.3, measured value: 615.2.

[0630] Example 142: (S)-N-(4”-(((2,6-dioxopiperidin-3-yl)amino)methyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide

[0631]

[0632] The compound was prepared using a process similar to step e of Example 129, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-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. The product was purified by HPLC (MeCN / water and 0.1% TFA) 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”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide, as a white solid. 1H NMR(400MHz,CD3OD)δ11.08(s,1H),8.06(t,J=8.2Hz,1H),7.33–7.26(m,3H),7.1 5(d,J=7.0Hz,1H),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)m / z C 33 H 34 FN6O6[M+H] + The calculated value is 629.2, and the measured value is 629.1.

[0633] 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”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide

[0634]

[0635] The compound was prepared using a process similar to step e of Example 129, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-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)-diketone hydrochloride. The product was purified by HPLC (MeCN / water and 0.1% TFA) to obtain 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”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide, which was a white solid. 1H NMR (400MHz, CD3OD) δ11.08(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),4.0 0(s,2H),3.98(s,3H),3.77(s,3H),3.38(s,3H),2.11(s,3H),1.94(s,3H). MS: (ES)m / z C 33 H 33 FN7O6[M+H] + Calculated value: 642.2, measured value: 642.1.

[0636] Example 144: N-(4”-(((2,4-dioxohexahydropyrimidin-5-yl)amino)methyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide

[0637]

[0638] The compound was prepared using a process similar to step e of Example 129, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-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. The product was purified by HPLC (MeCN / water and 0.1% TFA) to obtain the desired product N-(4”-(((2,4-dioxohexahydropyrimidin-5-yl)amino)methyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide, which was a white solid. 1H NMR (400MHz, CD3OD) δ11.08(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)m / zC 32 H 33 FN7O6[M+H] + Calculated value: 630.2, measured value: 630.2.

[0639] Example 145: (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((5-oxopyrrolidone-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0640]

[0641] Add (S)-4-aminopyrrolidone-2-one (28 mg, 0.28 mmol) to a 1:1 MeOH:DCE (2 mL) solution of N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (46 mg, 0.089 mmol). After stirring at room temperature for 75 minutes, add sodium triacetoxyborohydride (82 mg, 0.39 mmol). The reaction mixture was concentrated under vacuum, and the crude product was purified by HPLC (MeCN / water and 0.1% TFA) to give (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((5-oxopyrrolidone-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (TFA salt). 1H NMR(400MHz,CD3OD)δ11.17(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(dd,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)m / zC 33 H 35 FN5O5[M+H] + Calculated value: 600.3, measured value: 600.3.

[0642] Example 146: (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((5-oxopyrrolidone-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0643]

[0644] This compound was prepared using a procedure similar to that in Example 145, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((5-oxopyrrolidone-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1H NMR(400MHz,CD3OD)δ11.16(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(dd,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)m / z C 33 H 35 FN5O5[M+H] + The calculated value is 600.3, and the measured value is 600.2.

[0645] Example 147: (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((methyl(5-oxopyrrolidone-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0646]

[0647] Add 37% formalin aqueous solution (210 mg, 2.6 mmol) to a 1:1 MeOH:DCE (2 mL) solution of (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((5-oxopyrrolidone-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (87 mg, 0.15 mmol). After stirring at room temperature for 30 minutes, add sodium triacetoxyborohydride (128 mg, 0.60 mmol). After stirring for another 18 hours, the solvent was removed under reduced pressure, and the residue was purified by HPLC (MeCN / water and 0.1% TFA) to give (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((methyl(5-oxopyrrolidone-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR(400MHz,CD3OD)δ11.16(s,1H),8.63(s,1H),8.06(d,J=7.7Hz,1H),7.39–7.2 3(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)m / zC 34 H 37 FN5O5[M+H] + The calculated value is 614.3, and the measured value is 614.2.

[0648] Example 148: (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((methyl(5-oxopyrrolidone-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0649]

[0650] This compound was prepared using a process similar to Example 147, with (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(((5-oxopyrrolidone-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The product was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((methyl(5-oxopyrrolidone-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide). 1H NMR(400MHz,CD3OD)δ11.16(s,1H),8.63(s,1H),8.06(d,J=7.7Hz,1H),7.39–7.2 3(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)m / z C 34 H 37 FN5O5[M+H] + The calculated value is 614.3, and the measured value is 614.2.

[0651] Example 149: (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0652]

[0653] To a 1:1 MeOH:DCE (2 mL) solution of N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (46 mg, 0.089 mmol), (S)-5-aminomethylpyrrolidone-2-one hydrochloride (57 mg, 0.38 mmol) and diisopropylethylamine (0.066 mL, 0.38 mmol) were added. The mixture was stirred at room temperature for 1 hour, while 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 / water and 0.1% TFA) to obtain the desired product (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, CD3OD) δ11.17(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),4.08–4.03(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)m / z C 34 H 37 FN5O5[M+H] + Calculated value: 614.3, measured value: 614.3.

[0654] Example 150: (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0655]

[0656] This compound was prepared using a process similar to Example 149, with N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The reaction mixture was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1H NMR (400MHz, CD3OD) δ11.17(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),4.08–4.03(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)m / z C 34 H 37 FN5O5[M+H] + The calculated value is 614.3, and the measured value is 614.2.

[0657] Example 151: (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((methyl((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0658]

[0659] To a 1:1 MeOH:DCE (2 mL) solution of N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (46 mg, 0.089 mmol), (5S)-5-[(methylamino)methyl]pyrrolidine-2-one hydrochloride (58 mg, 0.35 mmol) and diisopropylethylamine (0.061 mL, 0.35 mmol) were added. After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (78 mg, 0.37 mmol) was added, and the reaction mixture was stirred for another 2 days. The solvent was removed under reduced pressure, and the residue was purified by HPLC (MeCN / water and 0.1% TFA) to give (S)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((methyl((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, CD3OD) δ8.63 (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),4.4 9(bs,2H),4.27(bs,1H),4.01(s,3H),3.55(s,3H),3.44(bs,2H),3.38(s,3 H)2.95(s,3H),2.53–2.33(m,3H),2.10(s,3H),1.95(s,3H),1.94(bs,1H). MS: (ES)m / z C 35 H 39 FN5O5[M+H] + The calculated value is 628.3, and the measured value is 628.3.

[0660] Example 152: (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((methyl((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0661]

[0662] This compound was prepared using a process similar to Example 147, with (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The residue was purified by HPLC (MeCN / water and 0.1% TFA) to give (R)-N-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-((methyl((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, as a white solid. 1H NMR (400MHz, CD3OD) δ11.17(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,3 H),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)m / zC 35 H 39 FN5O5[M+H] + The calculated value is 628.3, and the measured value is 628.3.

[0663] Example 153: (S)-4-(((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-yl)methyl)amino)pyrrolidone-2-one

[0664]

[0665] Step a: In a 100 mL round-bottom flask, add 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). The mixture is stirred at 60 °C for 42 hours. After cooling to room temperature, pour the reaction mixture into water (100 mL) and extract with a solution of 20% THF in EtOAc (3 × 200 mL). The extracts are concentrated and combined, and the residue is purified by silica gel rapid chromatography (6-25% ethyl acetate / n-hexane) to give N-(3-bromo-2-methylphenyl)pyrido[3,4-b]pyrazine-5-amine.

[0666] Step b: A dichloromethane complex of Pd(dppf)Cl2 (300 mg, 0.37 mmol) was added to a mixture of 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-dioxoboron-2-yl)-[1,1'-biphenyl]-4-carboxaldehyde (1.0 g, 2.7 mmol), and 2M K2CO3 (2.5 mL, 5.0 mmol). The mixture was degassed under N2 and then stirred at 90 °C for 2 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate and water. The organic phase was concentrated and purified by silica gel rapid chromatography (16-100% ethyl acetate / n-hexane, then 10% MeOH / DCM), followed by a second purification by silica gel rapid chromatography (4-6% ethyl acetate / 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”-triphenyl]-4-carboxaldehyde.

[0667] Step c: In a 40 mL round-bottom flask, add 3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-carboxaldehyde (44 mg, 0.092 mmol), (S)-4-amino-2-pyrrolidone (54 mg, 0.54 mmol), and 1:1 MeOH:DCE (2 mL). Heat the mixture until completely dissolved, then stir at room temperature for 3 minutes. 0 minutes. Add sodium triacetoxyborohydride (82 mg, 0.39 mmol), and stir the mixture for another 1.5 hours. Remove the solvent under reduced pressure, and purify the residue by HPLC (MeCN / water and 0.1% TFA) to give (S)-4-(((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-yl)methyl)amino)pyrrolidone-2-one. 1H NMR (400MHz, CD3OD) δ9.23(d,J=2.0Hz,1H),9.04(d,J=2.0Hz,1H),7.80(d,J=7.1Hz,1H) ,7.65–7.58(m,1H),7.57–7.48(m,1H),7.42–7.20(m,5H),6.98–6.86(m,2H),4.37(s,2H) ,4.27–4.19(m,1H),3.99(s,3H),3.88(dd,J=11.6,7.6Hz,1H),3.58(dd,J=11.6,3.9Hz,1 H), 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)m / z C 33 H 32 FN6O2[M+H] + Calculated value: 563.3, measured value: 563.3.

[0668] Example 154: (S)-5-((((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-yl)methyl)amino)methyl)pyrrolidone-2-one

[0669]

[0670] This compound was prepared using a process similar to step c of Example 153, with 3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-carboxaldehyde and (S)-5-aminomethylpyrrolidone-2-one hydrochloride. The resulting product was purified by HPLC (MeCN / water and 0.1% TFA) to give (S)-5-((((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-yl)methyl)amino)methyl)pyrrolidone-2-one. 1H NMR (400MHz, CD3OD) δ9.24 (d, J=2.0Hz, 1H), 9.05 (d, J=2.0Hz, 1H), 7.79 (d, J= 7.1Hz,1H),7.64–7.49(m,2H),7.42–7.33(m,3H),7.26(ddd,J=19.6,7.6,1.5 Hz,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). MS:(ES)m / z C 34 H 34 FN6O2[M+H] + The calculated value is 577.3, and the measured value is 577.2.

[0671] Example 155: (S)-4-(((2”-chloro-3-fluoro-5-methoxy-2'-methyl-3”-pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-yl)methyl)amino)pyrrolidone-2-one

[0672]

[0673] 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 hours. After the reaction was complete, the mixture was cooled and diluted with ethyl acetate and water. The organic phase was separated and purified by silica gel rapid chromatography (4-34% DCM / n-hexane), followed by secondary purification by silica gel rapid chromatography (2-10% MeOH / DCM) to give N-(3-bromo-2-chlorophenyl)pyrido[3,4-b]pyrazine-5-amine.

[0674] Step b: A dichloromethane complex of Pd(dppf)Cl2 (220 mg, 0.27 mmol) was added to a mixture of 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-dioxoboron-2-yl)-[1,1'-biphenyl]-4-carboxaldehyde (400 mg, 1.1 mmol), and 2M K2CO3 (1.5 mL, 3.0 mmol) in dioxane (4 mL). The mixture was degassed under N2 and stirred at 90 °C for 75 min. After the reaction was complete, the mixture was diluted with ethyl acetate and water. The organic phase was separated, dried, and concentrated. The residue was purified by rapid silica gel chromatography (4-30% ethyl acetate / n-hexane, 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”-triphenyl]-4-carboxaldehyde.

[0675] Step c: Add (S)-4-aminopyrrolidone-2-one (40 mg, 0.40 mmol) to a 1:1 MeOH:DCE (2 mL) solution of 2”-chloro-3-fluoro-5-methoxy-2'-methyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-carboxaldehyde (40 mg, 0.084 mmol). Stir the mixture at room temperature for 1.5 hours, then add triacetyloxy Sodium borohydride (123 mg, 0.58 mmol). The mixture was stirred for another 20 minutes. The solvent was removed under reduced pressure, and the residue was purified by HPLC (MeCN / water and 0.1% TFA) 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”-triphenyl]-4-yl)methyl)amino)pyrrolidone-2-one. 1H NMR (400MHz, CD3OD) δ9.11(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=7.5,1.5 Hz,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, 3.9 Hz, 1H), 2.91 (dd, J = 17.8, 8.8 Hz, 1H), 2.55 (dd, J = 17.8, 4.6 Hz, 1H), 2.03 (s, 3H). MS: (ES)m / z C 32 H 29 FClN6O2[M+H] + Calculated value: 583.2; measured value: 583.1.

[0676] Example 156: 3-(((2”-chloro-3-fluoro-5-methoxy-2'-methyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-yl)methyl)amino)-2,2-dimethylpropionamide

[0677]

[0678] This compound was prepared using a process similar to step c of Example 155, with 2”-chloro-3-fluoro-5-methoxy-2'-methyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-carboxaldehyde and 3-amino-2,2-dimethylpropionamide. The reaction mixture was purified by HPLC (MeCN / water and 0.1% TFA) to give the desired product 3-(((2”-chloro-3-fluoro-5-methoxy-2'-methyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-(1,1':3',1”-triphenyl]-4-yl)methyl)amino)-2,2-dimethylpropylamine. 1H NMR (400MHz, CD3OD) δ9.11(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)m / z C 33 H 33 FClN6O2[M+H] + The calculated value is 599.2, and the measured value is 599.1.

[0679] Example 157: (S)-5-((((2”-chloro-3-fluoro-5-methoxy-2'-methyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-triphenyl]-4-yl)methyl)amino)methyl)pyrrolidone-2-one

[0680]

[0681] This compound was prepared using a process similar to step c of Example 155, with 2”-chloro-3-fluoro-5-methoxy-2'-methyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-1,1':3',1”-triphenyl]-4-carboxaldehyde and (S)-5-(aminomethyl)pyrrolidone-2-one hydrochloride. The reaction mixture was purified by HPLC (MeCN / water and 0.1% TFA) to give (S)-5-((((2”-chloro-3-fluoro-5-methoxy-2'-methyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-yl)methyl)amino)methyl)pyrrolidone-2-one. 1H NMR (400MHz, CD3OD) δ9.13(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),7.3 3–7.22(m,2H),7.21–7.14(m,1H),6.98–6.86(m,2H),4.40(s,2H),4.09–4.03(m,1H) ,4.00(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)m / z C 33 H 31 FClN6O2[M+H] + Calculated value: 597.2; Measured value: 597.2.

[0682] Example 158: (S)-N-(2-chloro-3”-fluoro-5”-methoxy-2'-methyl-4”-(((5-oxopyrrolidone-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0683]

[0684] Step a: A dichloromethane complex of Pd(dppf)Cl2 (120 mg, 0.15 mmol) was added to a mixture of 3-bromo-2-chloroaniline (240 mg, 1.2 mmol), 3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-[1,1'-biphenyl]-4-carboxaldehyde (370 mg, 1.0 mmol), and 2M K2CO3 (1.5 mL, 3.0 mmol) in dioxane (8 mL). The mixture was degassed with nitrogen and stirred at 90 °C for 2.5 h. After cooling to room temperature, the reactants were diluted with ethyl acetate and water, and the organic phase was purified by rapid silica gel chromatography to give 3”-amino-3-fluoro-5-methoxy-2',2”-dimethyl-[1,1':3',1”-triphenyl]-4-carboxaldehyde.

[0685] Step b: Add a solution of 3”-amino-3-fluoro-5-methoxy-2',2”-dimethyl-[1,1':3',1”-triphenyl]-4-carboxaldehyde (200 mg, 0.54 mmol) and pyridine (0.12 mmol, 1.5 mmol) to a THF (4 mL) solution of 1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. Sonicate the mixture, briefly heat it, and allow it to stand at room temperature for 4 days. Remove the solvent to obtain N-(2-chloro-3”-fluoro-4”-formyl-5”-methoxy-2'-methyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide.

[0686] Step c: Briefly heat a mixture of crude aldehyde N-(2-chloro-3”-fluoro-4”-formyl-5”-methoxy-2'-methyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (approx. 0.11 mmol) and (S)-4-aminopyrrolidone-2-one (36 mg, 0.36 mmol) in a 1:1 MeoH:DCE (1.4 mL) solution, sonicate, and then stir at room temperature for 15 minutes. Add sodium triacetoxyborohydride (81 mg, 0.38 mmol), and stir the mixture again at room temperature for 15 minutes. The solvent was removed under reduced pressure, and the residue was purified by HPLC (MeCN / water and 0.1% TFA) to give (S)-N-(2-chloro-3”-fluoro-5”-methoxy-2'-methyl-4”-(((5-oxopyrrolidone-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD3OD) δ11.68(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)m / z C 32 H 32FClN5O5[M+H] + The calculated value is 620.2, and the measured value is 620.1.

[0687] 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”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0688]

[0689] This compound was prepared using a process similar to step c of Example 158, with N-(2-chloro-3”-fluoro-4”-formyl-5”-methoxy-2'-methyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and 3-amino-2,2-dimethylpropionic acid. The crude residue was purified by HPLC (MeCN / water and 0.1% TFA) 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”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD3OD) δ11.63(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)m / z C 33 H 36 FClN5O5[M+H] + The calculated value is 636.2, and the measured value is 636.3.

[0690] Example 160: (S)-N-(2-chloro-3”-fluoro-5”-methoxy-2'-methyl-4”-((((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0691]

[0692] This compound was prepared using a process similar to step c of Example 158, with N-(2-chloro-3”-fluoro-4”-formyl-5”-methoxy-2’-methyl-[1,1’:3’,1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (S)-5-(aminomethyl)pyrrolidine-2-one. The crude residue was purified by HPLC (MeCN / water and 0.1% TFA) to give (S)-N-(2-chloro-3”-fluoro-5”-methoxy-2’-methyl-4”-((((5-oxopyrrolidine-2-yl)methyl)amino)methyl)-[1,1’:3’,1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD3OD) δ11.61(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,3 H),3.25–3.16(m,2H),2.39–2.27(m,3H),1.92(s,3H),1.89–1.81(m,1H). MS: (ES)m / z C 33 H 34 ClFN5O5[M+H] + The calculated value is 634.2, and the measured value is 634.1.

[0693] Example 161: (S)-N-(2-chloro-3”-fluoro-5”-methoxy-2'-methyl-4”-(((6-oxopiridin-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0694]

[0695] This compound was prepared using a process similar to step c of Example 158, with N-(2-chloro-3”-fluoro-4”-formyl-5”-methoxy-2’-methyl-[1,1’:3’,1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (S)-5-aminopiperidin-2-one. The crude residue was purified by HPLC (MeCN / water and 0.1% TFA) to give (S)-N-(2-chloro-3”-fluoro-5”-methoxy-2’-methyl-4”-(((6-oxopiridine-3-yl)amino)methyl)-[1,1’:3’,1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR(400MHz,CD3OD)δ11.61(s,1H),8.59(s,1H),8.44(d,J=8.3Hz,1H),7.37– 7.18(m,3H),7.16–7.09(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),3.3 1(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)m / z C 33 H 34 ClFN5O5[M+H] + Calculated value: 634.2; Measured value: 634.2.

[0696] 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”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0697]

[0698] Step a: A mixture of dioxane (9 mL) and water (1.3 mL) of a dichloromethane complex of 2-fluoro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)benzaldehyde (511 mg, 1.82 mmol), 1,3-dibromo-2-chlorobenzene (750 mg, 2.77 mmol), K₂CO₃ (756 mg, 5.48 mmol), and Pd(dppf)Cl₂ (200 mg, 0.24 mmol) was stirred at N₂ and 95 °C for 8 hours. The mixture was cooled to room temperature and purified by silica gel rapid chromatography (0-100% ethyl acetate / n-hexane) to give 3'-bromo-2'-chloro-3-fluoro-5-methoxy-[1,1'-biphenyl]-4-carboxaldehyde. MS: (ES) m / z C 14 H9BrClFO2Na[M+Na] + Calculated value: 365.0, measured value: 365.0.

[0699] Step b: A mixture of 3'-bromo-2'-chloro-3-fluoro-5-methoxy-[1,1'-biphenyl]-4-carboxaldehyde (330 mg, 0.96 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxoborane) (270 mg, 1.06 mmol), KOAc (236 mg, 2.40 mmol), and a dioxane complex of Pd(dppf)Cl2 (120 mg, 0.15 mmol) in dioxane (5 mL) was stirred at 95°C under N2 for 5 hours. The mixture was cooled to room temperature and purified by silica gel rapid chromatography (0-100% ethyl acetate / n-hexane) to give 2'-chloro-3-fluoro-5-methoxy-3'-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)-[1,1'-biphenyl]-4-carboxaldehyde. MS: (ES) m / z C 20 H 22 BClFO4[M+H] + Calculated value: 391.1, measured value: 391.0.

[0700] Step c: A mixture of 2'-chloro-3-fluoro-5-methoxy-3'-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-[1,1'-biphenyl]-4-carboxaldehyde (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), K2CO3 (100 mg, 0.72 mmol), and a dioxane complex of Pd(dppf)Cl2 (45 mg, 0.055 mmol) in dioxane (3 mL) and water (0.45 mL) was stirred at N2 and 95°C for 2.5 hours. The mixture was cooled to room temperature and purified by silica gel rapid chromatography (0-100% ethyl acetate / n-hexane) to give N-(2'-chloro-3”-fluoro-4”-formyl-5”-methoxy-2-methyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. MS: (ES) m / z C 28 H 23 ClFN3O5[M+H] + Calculated value: 536.1, measured value: 536.1.

[0701] Step d: A mixture of N-(2'-chloro-3”-fluoro-4”-formyl-5”-methoxy-2-methyl-[1,1':3',1”-triphenyl]-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), Et3N (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 NaBH3CN (45 mg, 0.71 mmol) was added. After stirring at 0 °C for 3 min, the mixture was concentrated under vacuum. The residue was purified by HPLC (MeCN / water and 0.1% TFA) 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”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (TFA salt). 1H NMR (400MHz, CD3OD)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)m / z C 33 H 35 ClFN4O6[M+H] + Calculated value: 637.2; Measured value: 637.2.

[0702] Example 163: (S)-N-(2'-chloro-3”-fluoro-5”-methoxy-2-methyl-4”-(((6-oxopiridine-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0703]

[0704] A mixture of N-(2'-chloro-3”-fluoro-4”-formyl-5”-methoxy-2-methyl-[1,1':3',1”-triphenyl]-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), Et3N (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 NaBH3CN (45 mg, 0.71 mmol) was added. After stirring at 0 °C for 3 min, the mixture was concentrated under vacuum. The residue was purified by HPLC (MeCN / water and 0.1% TFA) to give (S)-N-(2'-chloro-3”-fluoro-5”-methoxy-2-methyl-4”-(((6-oxopiridin-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (TFA salt). 1 H NMR (400MHz, CD3OD)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,1H),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),3.50–3.4 2(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)m / z C 33 H 34 ClFN5O5[M+H] + Calculated value: 634.2; Measured value: 634.2.

[0705] 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”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0706]

[0707] A mixture of N-(2'-chloro-3”-fluoro-4”-formyl-5”-methoxy-2-methyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (25 mg, 0.046 mmol), 3-amino-2,2-dimethylpropionamide (25 mg, 0.021 mmol), and HOAc (120 mg, 2.0 mmol) in ethanol (1.5 mL) was heated at 70 °C for 0.5 h. The mixture was cooled to 0 °C, and NaBH3CN (40 mg, 0.63 mmol) was added. After stirring at 0 °C for 3 min, the mixture was concentrated under vacuum. The residue was purified by HPLC (MeCN / water and 0.1% TFA) 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”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (TFA salt). 1 HNMR(400MHz, CD3OD)8.56(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,1 H), 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)m / zC 33 H 36 ClFN5O5[M+H] + Calculated value: 636.2; Measured value: 636.2.

[0708] Example 165: (S)-N-(2'-chloro-3”-fluoro-5”-methoxy-2-methyl-4”-(((5-oxopyrrolidone-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0709]

[0710] A mixture of N-(2'-chloro-3”-fluoro-4”-formyl-5”-methoxy-2-methyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (19 mg, 0.035 mmol), (S)-4-aminopyrrolidone-2-one (10 mg, 0.010 mmol), and HOAc (60 mg, 1.0 mmol) in ethanol (1.5 mL) was heated at 70 °C for 0.5 h. The mixture was cooled to 0 °C, and NaBH3CN (40 mg, 0.63 mmol) was added. After stirring at 0 °C for 3 min, the mixture was concentrated under vacuum. The residue was purified by HPLC (MeCN / water and 0.1% TFA) to give (S)-N-(2'-chloro-3”-fluoro-5”-methoxy-2-methyl-4”-(((5-oxopyrrolidone-3-yl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (TFA salt). 1 H NMR (400MHz, CD3OD)11.10(s,1H),8.56(s,1H),8.05(dd,J=7.2,7.2Hz,1H),7.46–7. 35(m,2H),7.28(d,J=7.2Hz,1H),7.23(t,J=7.8Hz,1H),6.99(s,1H),6.96–6.90(m,2 H),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)m / z C 32 H 32 ClFN5O5[M+H] + The calculated value is 620.2, and the measured value is 620.1.

[0711] Example 166: (S)-N-(2'-chloro-3”-fluoro-5”-methoxy-2-methyl-4”-((((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0712]

[0713] A mixture of N-(2'-chloro-3”-fluoro-4”-formyl-5”-methoxy-2-methyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (22 mg, 0.040 mmol), (S)-5-(aminomethyl)pyrrolidine-2-one hydrochloride (15 mg, 0.10 mmol), Et3N (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 NaBH3CN (45 mg, 0.71 mmol) was added. After stirring at 0 °C for 3 min, the mixture was concentrated under vacuum. The residue was purified by HPLC (MeCN / water and 0.1% TFA) to give (S)-N-(2'-chloro-3”-fluoro-5”-methoxy-2-methyl-4”-((((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (TFA salt). 1 H NMR(400MHz,CD3OD)11.08(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,2H),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)m / z C 33 H 34 ClFN5O5[M+H] + Calculated value: 634.2; Measured value: 634.2.

[0714] Example 167: (S)-5-((((2'-chloro-3-fluoro-5-methoxy-2”-methyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-yl)methyl)amino)methyl)pyrrolidone-2-one

[0715]

[0716] Step a: A mixture of 2'-chloro-3-fluoro-5-methoxy-3'-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-[1,1'-biphenyl]-4-carboxaldehyde (86 mg, 0.22 mmol), N-(3-bromo-2-methylphenyl)pyrido[3,4-b]pyrazin-5-amine (70 mg, 0.22 mmol), K2CO3 (92 mg, 0.67 mmol), and a dichloromethane complex of Pd(dppf)Cl2 (45 mg, 0.049 mmol) in dioxane (3 mL) and water (0.45 mL) was stirred at N2 and 95°C for 2 hours. The mixture was cooled to room temperature and purified by silica gel rapid chromatography (0-100% ethyl acetate / n-hexane) to give 2'-chloro-3-fluoro-5-methoxy-2”-methyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-carboxaldehyde. MS: (ES) m / z C 28 H 21 ClFN4O2[M+H] + Calculated value: 499.1; Actual measured value: 499.0.

[0717] Step b: A mixture of 2'-chloro-3-fluoro-5-methoxy-2”-methyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-carboxaldehyde (20 mg, 0.040 mmol), (S)-5-(aminomethyl)pyrrolidine-2-one hydrochloride (11 mg, 0.073 mmol), Et3N (15 mg, 0.15 mmol), and HOAc (90 mg, 1.5 mmol) in ethanol (1.5 mL) was heated at 70 °C for 0.5 minutes. 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 minutes, the mixture was concentrated under vacuum. The resulting residue was purified by HPLC (MeCN / water and 0.1% TFA) to give (S)-5-((((2'-chloro-3-fluoro-5-methoxy-2”-methyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-yl)methyl)amino)methyl)pyrrolidone-2-one (TFA salt). 1H NMR(400MHz, CD3OD)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=6.8Hz,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)m / z C 33 H 31 ClFN6O2[M+H] + Calculated value: 597.2; Measured value: 597.2.

[0718] Example 168: (S)-4-(((2'-chloro-3-fluoro-5-methoxy-2”-methyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1''-triphenyl]-4-yl)methyl)amino)pyrrolidone-2-one

[0719]

[0720] A mixture of 2'-chloro-3-fluoro-5-methoxy-2”-methyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-carboxaldehyde (26 mg, 0.052 mmol), (S)-4-aminopyrrolidone-2-one (15 mg, 0.15 mmol), and HOAc (75 mg, 1.25 mmol) in ethanol (1.5 mL) was heated at 70 °C for 0.5 h. The mixture was cooled to 0 °C, and then... Add NaBH(OAc)3 (45 mg, 0.21 mmol). After stirring at 0 °C for 5 minutes, the mixture was concentrated under vacuum. The resulting residue was purified by HPLC (MeCN / water and 0.1% TFA) to give (S)-4-(((2'-chloro-3-fluoro-5-methoxy-2”-methyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-yl)methyl)amino)pyrrolidone-2-one (TFA salt). 1H NMR (400MHz, CD3OD) δ9.24(d,J=2.0Hz,1H),9.05(d,J=2.0Hz,1H),7.79(d,J=7.2Hz,1H),7.63( dd,J=7.9,1.4Hz,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)m / z C 32 H 29 ClFN6O2[M+H] + Calculated value: 583.2; Actual measured value: 583.2.

[0721] 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”-triphenyl]-4-yl)methyl)amino)tetrahydro-2H-pyran-3-ol

[0722]

[0723] A mixture of 2'-chloro-3-fluoro-5-methoxy-2”-methyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-carboxaldehyde (20 mg, 0.04 mmol), (3R,4R)-4-aminotetrahydro-2H-pyran-3-ol (13 mg, 0.085 mmol), Et3N (15 mg, 0.15 mmol), and HOAc (90 mg, 1.5 mmol) in EtOH (1.5 mL) solution 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 minutes, the mixture was concentrated under vacuum. The resulting residue was purified by HPLC (MeCN / water and 0.1% TFA) 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”-triphenyl]-4-yl)methyl)amino)tetrahydro-2H-pyran-3-ol (TFA salt). 1H NMR (400MHz, CD3OD) δ9.24(d,J=2.0Hz,1H),9.05(d,J=2.0Hz,1H),7.78(d,J=7.2Hz,1H),7. 63(d,J=7.2,1.4Hz,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,3 H),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)m / zC 33 H 31 ClFN5O2[M-OH,+H] + Calculated value: 583.2; measured value: 583.1.

[0724] Example 170: (S)-N-(2,2'-dichloro-3”-fluoro-5”-methoxy-4”-((((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0725]

[0726] Step a: A mixture of a solution of 2'-chloro-3-fluoro-5-methoxy-3'-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-[1,1'-biphenyl]-4-carboxaldehyde (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), K2CO3 (116 mg, 0.84 mmol), and a dichloromethane complex of Pd(dppf)Cl2 (45 mg, 0.055 mmol) in dioxane (3 mL) and water (0.45 mL) was stirred at N2 and 95°C for 3 hours. The mixture was cooled to room temperature and purified by silica gel rapid chromatography (0-100% ethyl acetate / n-hexane) to give N-(2,2'-dichloro-3”-fluoro-4”-formyl-5”-methoxy-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. MS: (ES) m / z C27 H 21 Cl2FN3O5[M+H] + Calculated value: 556.1, measured value: 556.0.

[0727] Step b: A mixture of N-(2,2'-dichloro-3”-fluoro-4”-formyl-5”-methoxy-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (20 mg, 0.036 mmol), (S)-5-(aminomethyl)pyrrolidine-2-one hydrochloride (12 mg, 0.080 mmol), Et3N (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 NaBH3CN (45 mg, 0.71 mmol) was added. After stirring at 0 °C for 3 min, the mixture was concentrated under vacuum. The residue was purified by HPLC (MeCN / water and 0.1% TFA) to give (S)-N-(2,2'-dichloro-3”-fluoro-5”-methoxy-4”-((((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (TFA salt). 1 H NMR (400MHz, CD3OD) δ11.57(s,1H),8.54(s,1H),8.42(d,J=8.4Hz,1H),7.42–7.35(m,2H),7.32–7.24(m,2H),7.00–6.93(m,2H),6.88(d,J= 9.6Hz,1H),4.29(s,2H),3.98–3.90(m,1H),3.90(s,3H),3.44(s,3H), 3.27(s,3H),3.20–3.12(m,2H),2.36–2.20(m,3H),2.07–1.95(m,1H). MS: (ES)m / z C 32 H 31 Cl2FN5O2[M+H] + Calculated value: 654.0, measured value: 654.0.

[0728] Example 171: (3R,4R)-4-(((3-fluoro-5-methoxy-2',2”-dimethyl-3''-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-yl)methyl)amino)tetrahydro-2H-pyran-3-ol

[0729]

[0730] A mixture of 3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-carboxaldehyde (20 mg, 0.041 mmol), (3R,4R)-4-aminotetrahydro-2H-pyran-3-ol (10 mg, 0.065 mmol), Et3N (15 mg, 0.15 mmol), and HOAc (75 mg, 1.25 mmol) in EtOH (1.5 mL) solution was heated at 70 °C for 0.5 h. The compound was cooled to °C, and NaBH(OAc)3 (45 mg, 0.21 mmol) was added. After stirring at 0 °C for 5 minutes, the mixture was concentrated under vacuum. The resulting residue was purified by HPLC (MeCN / water and 0.1% TFA) to give (3R,4R)-4-(((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1':3',1”-triphenyl]-4-yl)methyl)amino)tetrahydro-2H-pyran-3-ol (TFA salt). 1 H NMR (400MHz, CD3OD) δ9.23(d,J=1.6Hz,1H),9.04(s,1H),7.80(d,J=7.2Hz,1H),7.60(d,J=7.2Hz,1H), 7.52(t,J=7.6,2.0Hz,1H),7.40–7.33(m,3H),7.28(d,J=7.2Hz,1H),7.23(d,J=7.2Hz,1H),6.92(s,1H ),6.86(d,J=10Hz,1H),4.41(d,J=13.2Hz,1H),4.31(d,J=12.8Hz,1H),4.07(s,1H),3.98(s,5H),3.57 (d,J=12.4Hz,1H),3.60–3.42(m,2H),2.20–2.04(m,1H),2.12(s,3H),2.02(s,3H),1.86–1.80(m,1H). MS: (ES)m / z C 34 H 35 FN5O3[M+H] + The calculated value is 580.3, and the measured value is 580.2.

[0731] Example 172: (3R,4R)-4-(((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrido[3,4-b]pyrazin-8-ylamino)-[1,1':3',1”-triphenyl]-4-yl)methyl)amino)tetrahydro-2H-pyran-3-ol

[0732]

[0733] Step a: A mixture of 8-bromopyrido[3,4-b]pyrazine (450 mg, 2.14 mmol), 3-bromo-2-methylaniline (437 mg, 2.35 mmol), NaOtBu (514 mg, 5.35 mmol), Pd2(dba)3 (195 mg, 0.21 mmol), and racemic BINAP (266 mg, 0.43 mmol) in toluene (8 mL) was stirred at 100 °C under N2 for 4 hours. The mixture was cooled to room temperature and purified by silica gel rapid chromatography (0-100% ethyl acetate / n-hexane) to give N-(3-bromo-2-methylphenyl)pyrido[3,4-b]pyrazine-8-amine. MS: (ES) m / z C 14 H 12 BrN4[M+H] + Calculated value: 315.0, measured value: 315.0.

[0734] Step b: A mixture of N-(3-bromo-2-methylphenyl)pyrido[3,4-b]pyrazin-8-amine (480 mg, 1.52 mmol), 3-fluoro-5-methoxy-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-[1,1'-biphenyl]-4-carboxaldehyde (540 mg, 1.45 mmol), K2CO3 (600 mg, 4.35 mmol), and a dichloromethane complex of Pd(dppf)Cl2 (142 mg, 0.17 mmol) in dioxane (7 mL) and water (1.0 mL) was stirred at N2 and 95°C for 1.5 hours. The mixture was cooled to room temperature and purified by silica gel rapid chromatography (0-100% ethyl acetate / n-hexane) to give 3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrido[3,4-b]pyrazin-8-ylamino)-[1,1':3',1”-triphenyl]-4-carboxaldehyde.

[0735] Step c: A mixture of 1.5 mL of ethanol solution of 3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrido[3,4-b]pyrazin-8-ylamino)-[1,1':3',1”-triphenyl]-4-carboxaldehyde (25 mg, 0.051 mmol), (3R,4R)-4-aminotetrahydro-2H-pyran-3-ol (12 mg, 0.078 mmol), Et3N (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 N was added. aBH(OAc)3 (45 mg, 0.21 mmol). After stirring at 0 °C for 5 minutes, the mixture was concentrated under vacuum. The resulting residue was purified by HPLC (MeCN / water and 0.1% TFA) and then by silica gel rapid chromatography (0-100% MeOH / DCM) to give (3R,4R)-4-(((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyridino[3,4-b]pyrazin-8-ylamino)-[1,1':3',1”-triphenyl]-4-yl)methyl)amino)tetrahydro-2H-pyran-3-ol (TFA salt). 1 H NMR (400MHz, CD3OD) δ9.04 (s, 2H), 8.74 (s, 1H), 7.94 (s, 1H), 7.46 (d, J = 8.4Hz, 1H), 7.4 0–7.28(m,2H),7.23(d,J=7.2Hz,1H),7.17(d,J=7.6Hz,1H),7.08(d,J=7.6Hz,1H),6.81 (s,1H),6.74(d,J=10.4Hz,1H),3.91(s,3H),4.06–3.82(m,5H),3.54–3.38(m,2H),2.96 (d,J=10.4Hz,1H),2.03(s,3H),1.98(s,3H),1.94–1.82(m,1H),1.72(d,J=12.4Hz,1H). MS: (ES)m / z C 34 H 35 FN5O3[M+H] + The calculated value is 580.3, and the measured value is 580.2.

[0736] Example 173: (S)-5-(((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrido[3,4-b]pyrazin-8-ylamino)-[1,1':3',1”-triphenyl]-4-yl)methyl)amino)piperidin-2-one

[0737]

[0738] A mixture of 3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrido[3,4-b]pyrazin-8-ylamino)-[1,1':3',1”-triphenyl]-4-carboxaldehyde (25 mg, 0.052 mmol), (S)-5-aminopiperidin-2-one (15 mg, 0.10 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(OAc)3 (45 mL) was added. (mg, 0.21 mmol). After stirring at 0 °C for 5 minutes, the mixture was concentrated under vacuum. The resulting residue was purified by HPLC (MeCN / water and 0.1% TFA) and then by silica gel rapid chromatography (0-100% MeOH / DCM) to give (S)-5-(((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyridino[3,4-b]pyrazin-8-ylamino)-[1,1':3',1”-triphenyl]-4-yl)methyl)amino)piperidin-2-one (TFA salt). 1 H NMR (400MHz, CD3OD) δ9.03 (s, 2H), 8.74 (s, 1H), 7.94 (s, 1H), 7.45 (d, J = 8.0Hz, 1H), 7.40-7.28 (m, 2 H),7.23(d,J=6.8Hz,1H),7.16(d,J=7.6Hz,1H),7.08(d,J=8.0Hz,1H),6.80(s,1H),6.73(d,J=10.0 Hz,1H),3.96(s,2H),3.91(s,3H),3.51(dd,J=12.4,3.6Hz,1H),3.20–3.10(m,1H),3.04(bs,1H),2. 50–2.40(m,1H),2.38–2.27(m,1H),2.13–2.03(m,1H),2.03(s,3H),1.98(s,3H),1.86–1.74(m,1H). MS: (ES)m / z C 34 H 34 FN6O2[M+H] + The calculated value is 577.3, and the measured value is 577.2.

[0739] Example 174: (S)-4-(((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrido[3,4-b]pyrazin-8-ylamino)-[1,1':3',1”-triphenyl]-4-yl)methyl)amino)pyrrolidine-2-one

[0740]

[0741] A mixture of 3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrido[3,4-b]pyrazin-8-ylamino)-[1,1':3',1”-triphenyl]-4-carboxaldehyde (25 mg, 0.052 mmol), (S)-5-aminopiperidin-2-one (15 mg, 0.10 mmol), and HOAc (45 mg, 0.75 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 mL) was added. (mg, 0.21 mmol). After stirring at 0 °C for 5 minutes, the mixture was concentrated under vacuum. The resulting residue was purified by HPLC (MeCN / water and 0.1% TFA) and then by silica gel rapid chromatography (0-100% MeOH / DCM) to give (S)-4-(((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrido[3,4-b]pyrazin-8-ylamino)-[1,1':3',1”-triphenyl]-4-yl)methyl)amino)pyrrolidone-2-one (TFA salt). 1 H NMR (400MHz, CD3OD) δ9.03 (s, 2H), 8.73 (s, 1H), 7.94 (s, 1H), 7.45 (d, J = 8.0Hz, 1H), 7. 40–7.28(m,2H),7.23(d,J=7.2Hz,1H),7.16(d,J=7.6Hz,1H),7.08(d,J=7.6Hz,1H),6. 80(s,1H),6.73(d,J=9.6Hz,1H),3.92(s,2H),3.90(s,3H),3.70–3.58(m,2H),3.30-3 .23(m,1H),2.65–2.56(m,1H),2.24(dd,J=17.2,4.8Hz,1H),2.03(s,3H),1.98(s,3H). MS: (ES)m / z C 33 H 32 FN6O2[M+H] + Calculated value: 563.3, measured value: 563.3.

[0742] Example 175: (S)-5-((((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrido[3,4-b]pyrazin-8-ylamino)-[1,1':3',1”-triphenyl]-4-yl)methyl)amino)methyl)pyrrolidone-2-one

[0743]

[0744] A mixture of 3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyrido[3,4-b]pyrazin-8-ylamino)-[1,1':3',1”-triphenyl]-4-carboxaldehyde (30 mg, 0.065 mmol), (S)-5-(aminomethyl)pyrrolidine-2-one hydrochloride (15 mg, 0.15 mmol), Et3N (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 N was added. aBH(OAc)3 (45 mg, 0.21 mmol). After stirring at 0 °C for 5 minutes, the mixture was concentrated under vacuum. The resulting residue was purified by HPLC (MeCN / water and 0.1% TFA) and then by silica gel rapid chromatography (0-100% MeOH / DCM) to give (S)-5-(((((3-fluoro-5-methoxy-2',2”-dimethyl-3”-(pyridino[3,4-b]pyrazin-8-ylamino)-[1,1':3',1”-triphenyl]-4-yl)methyl)amino)methyl)pyrrolidone-2-one (TFA salt). 1 H NMR(400MHz,CD3OD)δ9.04(s,1H),8.74(s,1H),7.94(s,1H),7.46(d,J=8.4Hz,1H),7.4 0–7.29(m,2H),7.23(d,J=7.2Hz,1H),7.18(d,J=6.8Hz,1H),7.08(d,J=7.6Hz,1H),6.8 4(s,1H),6.77(d,J=9.6Hz,1H),5.48(s,1H),4.08(s,2H),3.93(s,3H),3.94–3.89(m,1 H),2.94–2.82(m,2H),2.40–2.25(m,3H),2.03(s,3H),1.99(s,3H),1.94–1.88(m,1H). MS: (ES)m / z C 34 H 34 FN6O2[M+H] + The calculated value is 577.3, and the measured value is 577.2.

[0745] Example 176: N-(3”-fluoro-4”-((((3R,4S)-4-hydroxytetrahydrofuran-3-yl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0746]

[0747] A mixture of N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (25 mg, 0.048 mmol), (3S,4R)-4-aminotetrahydrofuran-3-ol (20 mg, 0.020 mmol), and HOAc (75 mg, 1.25 mmol) in ethanol (1.5 mL) was heated at 70 °C for 0.5 h. The mixture was cooled to 0 °C, and NaBH3CN (40 mg, 0.63 mmol) was added. After stirring at 0 °C for 3 min, the mixture was concentrated under vacuum. The residue was purified by HPLC (MeCN / water and 0.1% TFA) to give N-(3”-fluoro-4”-((((3R,4S)-4-hydroxytetrahydrofuran-3-yl)amino)methyl)-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (TFA salt). 1 H NMR (400MHz, CD3OD) δ11.14(s,1H),8.61(s,1H),8.07(dd,J=7.2,7.2Hz,1H),7.36– 7.22(m,3H),7.15(d,J=6.8Hz,1H),6.98–6.92(m,2H),6.87(d,J=9.6Hz,1H),4.53(b s,1H),4.48–4.34(m,2H),4.20–4.08(m,2H),4.20–3.98(m,1H),3.99(s,3H),3.71(s ,1H),3.60(dd,J=9.6,4Hz,1H),3.54(s,3H),3.37(s,3H),2.09(s,3H),1.93(s,3H). MS: (ES)m / z C 33 H 36 FN4O6[M+H] + The calculated value is 603.3, and the measured value is 603.2.

[0748] Example 177: N-(4”-(((4-amino-4-oxobutyl)amino)methyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide

[0749]

[0750] A mixture of N-(3”-fluoro-4”-formyl-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide (22 mg, 0.042 mmol), 4-aminobutyramine hydrochloride (15 mg, 0.11 mmol), Et3N (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 NaBH3CN (40 mg, 0.63 mmol) was added. After stirring at 0 °C for 5 min, the mixture was concentrated under vacuum. The residue was purified by HPLC (MeCN / water and 0.1% TFA) to give N-(4”-(((4-amino-4-oxobutyl)amino)methyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide (TFA salt). 1 H NMR(400MHz,CD3OD)δ8.08(d,J=8.0Hz,1H),7.36–7.28(m,2H),7.25(d,J=8.0 Hz,1H),7.16(d,J=7.6Hz,1H),7.02(d,J=7.2Hz,1H),6.92(s,1H),6.86(d,J= 9.6Hz,1H),4.31(s,2H),3.98(s,3H),3.77(s,3H),3.38(s,3H),3.15(t,J=7. 0Hz, 2H), 2.43 (t, J = 6.6Hz, 2H), 2.11 (s, 3H), 2.03–1.94 (m, 2H), 1.94 (s, 3H). MS: (ES)m / zC 32 H 36 FN6O5[M+H] + The calculated value is 603.3, and the measured value is 603.2.

[0751] Example 178: N-(4”-(((3-amino-2,2-dimethyl-3-oxopropyl)amino)methyl)-3”-fluoro-5”-methoxy-2,2'-dimethyl-[1,1':3',1”-tripheny...

Claims

1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof: wherein: R 1a , R 1b , R 1c , and R 1d are each independently selected from the group consisting of H, halogen, and C 1-3 alkoxy; X 1 is a Ci-6alkylene; R 2a and R 2b are each independently selected from the group consisting of H, C 1-8 alkyl, -Y, -X 2 -C(O)2R a , -X 2 -OR a , -X 2 -NR a R b , -X 2 -CONR a R b , -X 2 -SO2R a and -X 2 -Y, wherein each X 2 is C 1-6 alkylene, optionally further substituted with one or two substituents independently selected from the group consisting of OH and CO2H, and each Y is selected from the group consisting of C 3-6 cycloalkyl, and C 4-8 heterocyclyl, each of which is optionally further substituted with one to four substituents independently selected from the group consisting of oxo, OH, C 1-4 alkyl, C 1-4 alkoxy, and CONH2; or R 2a and R 2b combined form a 4- to 10-membered monocyclic or 8-10 membered spiro ring, optionally having one or two additional ring vertices selected from O or N; wherein R 2a and R 2b combine to form a 4- to 10-membered monocyclic or 8- to 10-membered spirocyclic ring substituted with 0-4 substituents independently selected from the group consisting of oxo, C 1-8 alkyl, -X 3 -C(O)2R a , -X 3 -OR a and -X 3 -NR a R b ; wherein X 3 is a bond; R 3 and R 4 are each independently selected from the group consisting of F, Cl, and CH3; the subscript n is 0; R 6 , R 7 , and R 8 are each independently selected from H; A is -C(=0)NH-; Z is selected from the group consisting of monocyclic non-aromatic heterocycle; and has a structure selected from the group consisting of: Each R a Selected independently from the following groups: H and C 1-6 alkyl; Each R b Selected independently from the following groups: H and C 1-6 Alkyl groups; wherein each of them is optionally further substituted by one or two independent substituents selected from the group consisting of OH, CONH2 and CO2H.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, each Y is selected from the group consisting of C 3-6 cycloalkyl, and 5- to 6-membered heteroaryl.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein has a structure of Formula (lb):

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein has a structure of Formula (Ic):

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein has a structure of Formula (Id):

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Group R 1a For OCH3, R 1b It is F.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is a non-aromatic heterocycle having a structure selected from the group consisting of:

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R 2a and R 2b is H.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b form, together with the ring carbon to which they are attached, a 4-9 membered monocyclic or 8-10 membered spirocyclic ring, optionally having 1 or 2 additional ring vertices selected from O or N; wherein said 4-9 membered monocyclic or 8-10 membered spirocyclic ring is substituted with 0-4 substituents independently selected from the group consisting of oxo, C 1-8 alkyl, -X 3 -C(O)2R a , -X 3 -OR a , and -X 3 -NR a R b ; wherein X 3 is a bond.

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein -N(R 2a )(R 2b ) is selected from the group consisting of:

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein -N(R 2a )(R 2b ) is selected from the group consisting of:

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein -N(R 2a )(R 2b ) is selected from the group consisting of:

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2a is H or C 1-8 alkyl; R 2b is -Y or -X 2 -Y.

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is optically pure or enriched isomer.

15. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein Y is selected from the group consisting of C 3-6 cycloalkyl and C 4-8 heterocyclyl, wherein each is also optionally substituted with 1 substituent selected from the group consisting of oxo, OH, C 1-4 alkyl, C 1-4 alkoxy and CONH2.

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

17. The pharmaceutical composition of claim 16, wherein further comprising one or more additional therapeutic agents.

18. The pharmaceutical composition of claim 17, wherein, the one or more additional therapeutic agents are selected from the group consisting of antimicrobial agents, cytotoxic agents, gene expression modulators, anti-angiogenic agents, immunotherapeutic agents, anti-hormonal agents, anti-fibrotic agents, anti-neoplastic agents, and anti-proliferative agents.

19. The pharmaceutical composition of claim 17, wherein, the one or more additional therapeutic agents are selected from the group consisting of antiviral agents, anticancer agents, and radiotherapeutic agents.

20. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof or a composition of claim 16. for the preparation of a medicament for modulating an immune response mediated by the PD-1 signaling pathway in a subject.

21. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof or a composition of claim 16. for the preparation of a medicament for enhancing or increasing an immune response in a subject in need thereof.

22. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof or a composition of claim 16. for the preparation of a medicament for stimulating an immune response in a subject in need thereof.

23. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof or a composition of claim 16. for the preparation of a medicament for modulating an immune response in a subject in need thereof.

24. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof or a composition of claim 16. for the preparation of a medicament for inhibiting cancer cell growth, proliferation, or metastasis in a subject in need thereof.

25. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof or a composition of claim 16. for the preparation of a medicament for treating a subject suffering from or susceptible to a disease or disorder mediated by the PD-1 signaling pathway.

26. The use of claim 25, wherein, the subject is suffering from a disease or disorder selected from the group consisting of infectious diseases, immune diseases, and cancer.

27. The use of claim 25, wherein, the subject is suffering from a hematological malignancy.

28. The use of claim 25, wherein, the subject is suffering from an inflammatory disease.

29. The use of claim 25, wherein, the disease or disorder is selected from the group consisting of esophageal tumors, lymphoma, prostate cancer, meningioma, sarcoma, sepsis, biliary tract tumors, thymic tumors, uterine cancer, liver infection, neural tumors, leukemia, multiple myeloma, ovarian tumors, myelodysplastic syndrome, lung cancer, mesothelioma, breast cancer, colorectal cancer, gastric cancer, pancreatic tumors, head and neck cancer, HIV, herpes virus, papilloma virus, influenza, skin cancer, anal cancer, testicular cancer, small intestine cancer, endocrine system cancer, urethral cancer, penile cancer, bladder cancer, kidney cancer, ureter cancer, epidermoid cancer, asbestosis, adenoma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma, and fibroma.

30. The use of claim 25, wherein, the disease or disorder is selected from the group consisting of castration-resistant prostate cancer, small cell lung cancer, gastrointestinal cancer, central nervous system tumor, Hodgkin's disease, bone cancer, synovioma, colon cancer, rectal cancer, melanoma, Wilms' tumor, seminoma, thyroid cancer, parathyroid cancer, adrenal cancer, esophageal cancer, and ovarian cancer.

31. The use of claim 25, wherein, the disease or disorder is selected from the group consisting of spinal axis tumor, glioblastoma, brain stem glioma, squamous non-small cell lung cancer, and non-squamous non-small cell lung cancer.

32. The use of claim 25, wherein, the disease or disorder is selected from the group consisting of cancer, hepatitis A, hepatitis B, hepatitis C, and hepatitis D.

33. The use of claim 25, wherein, the subject is administered a therapeutically effective amount of one or more additional therapeutic agents.

34. The use of claim 33, wherein, The one or more additional therapeutic agents are selected from the group consisting of antimicrobial agents, cytotoxic agents, gene expression modulators, anti-angiogenic agents, immunotherapeutic agents, anti-hormonal agents, anti-fibrotic agents, anti-neoplastic agents, and anti-proliferative agents.

35. The use as described in claim 33, characterized in that, The one or more additional therapeutic agents are selected from the group consisting of antiviral agents, anticancer agents, and radiotherapeutic agents.

36. A compound selected from the group consisting of:

37. A compound selected from the group consisting of:

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